Giuseppe Buonocore, Rodolfo Bracci, Michael Weindling - Neonatology-Springer International Publishing (2018)
Uploaded by
Katy AGiuseppe Buonocore, Rodolfo Bracci, Michael Weindling - Neonatology-Springer International Publishing (2018)
Uploaded by
Katy AGiuseppe Buonocore
Rodolfo Bracci
Michael Weindling
Editors
Neonatology
A Practical Approach to
Neonatal Diseases
Second Edition
Neonatology
Giuseppe Buonocore • Rodolfo Bracci
Michael Weindling
Editors
Neonatology
A Practical Approach to Neonatal
Diseases
Second Edition
With 568 Figures and 386 Tables
Editors
Giuseppe Buonocore Rodolfo Bracci
Department of Pediatrics Department of Pediatrics
Obstetrics and Reproductive Medicine Obstetrics and Reproductive Medicine
University of Siena University of Siena
Siena, Italy Siena, Italy
Michael Weindling
Liverpool Women’s Hospital Neonatal Unit
Liverpool, UK
ISBN 978-3-319-29487-2 ISBN 978-3-319-29489-6 (eBook)
ISBN 978-3-319-29488-9 (print and electronic bundle)
https://doi.org/10.1007/978-3-319-29489-6
Library of Congress Control Number: 2018940273
1st edition: # Springer-Verlag Italia 2012
# Springer International Publishing AG, part of Springer Nature 2018
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or
part of the material is concerned, specifically the rights of translation, reprinting, reuse of
illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way,
and transmission or information storage and retrieval, electronic adaptation, computer software, or
by similar or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this
publication does not imply, even in the absence of a specific statement, that such names are exempt
from the relevant protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this
book are believed to be true and accurate at the date of publication. Neither the publisher nor the
authors or the editors give a warranty, express or implied, with respect to the material contained
herein or for any errors or omissions that may have been made. The publisher remains neutral with
regard to jurisdictional claims in published maps and institutional affiliations.
Printed on acid-free paper
This Springer imprint is published by the registered company Springer International Publishing
AG part of Springer Nature.
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
Introduction
Neonatology is a science in rapid evolution. The speed of this evolution may
cause some to doubt what a traditional textbook is able to achieve in bringing
the most up-to-date developments to a reader’s attention. Although the inter-
ested reader will use other electronic means to access current information, this
is not always possible. We firmly believe that, through their own experience,
experts are able to bring their own perspective and interest to a subject and act
as a guide to the interested and committed reader. We therefore believe that this
textbook should act as a conduit of reliable information from the expert to the
clinician. We have tried to make this textbook into a genuine guide to the best
and most up-to-date answers for neonatologists who are striving to give the
best and highest quality care to sick babies.
All practicing clinicians work within their own culture and resources. Each
has to make judgments about the best and most appropriate application of
available resources to the care of their small sick patients. We hope that this
textbook will support the dedicated clinician by providing the best evidence
available in the various sub-specialisms of neonatology, particularly when the
issue of best treatment continues to be debated. The reader who needs rapid
and comprehensive information about a topic requires that the information
provided should be synthetized intelligently, exhaustively, and clearly. Sub-
jects should be updated as much as possible. We have endeavored to meet
these requirements. We think that the aim of a modern textbook should be to
describe the present state of the science, suggesting ways in which this might
be improved, and to provide a sound understanding of pathophysiology and
diagnostic and therapeutic procedures. Our overall aim is to support and
optimize the care of the newborn. In this way, our approach is “practical”
and aims to assist neonatologists in their daily work.
In this second edition, the text has been largely revised by experts who
contributed to the previous volume. They have added new information, some
of it through short- and long-term follow-up, to support the evidence that
underpins good clinical practice. Some chapters are completely new.
We are grateful to all the authors for their time and contributions. We would
also like to thank Andrew Spencer, Tina Shelton, Vasowati Shome, and the
publication team of Springer for their great efforts in publishing this book.
We sincerely hope that this volume has built on the success of its prede-
cessor and continues to support clinicians in a readily accessible and
useful way.
v
Contents
Volume 1
Part I Epidemiology and Fetal Neonatal Medicine . . . . . . . . . . . 1
1 Development and General Characteristics of Preterm and
Term Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Domenico Arduini, Gaia Pasquali, Stefano Parmigiani,
Daniela Gianotti, and Giulio Bevilacqua
2 Risk Factors for Gestational Diseases . . . . . . . . . . . . . . . . . . 27
Silvia Vannuccini, Michela Torricelli, Filiberto Maria Severi,
and Felice Petraglia
3 Epigenetic Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Felicia M. Low and Peter D. Gluckman
4 Congenital Malformations and Syndromes: Early
Diagnosis and Prognosis in Neonatal Medicine . . . . . . . . . . . 49
Giovanni Corsello and Mario Giuffrè
5 Prenatal and Postnatal Inflammatory Mechanisms ....... 73
Kirsten Glaser and Christian P. Speer
6 The Fetus at Risk: Chorioamnionitis . . . . . . . . . . . . . . . . . . . 95
Mikko Hallman and Tuula Kaukola
7 Diagnosis of Fetal Distress . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Silvia Vannuccini, Caterina Bocchi, Filiberto Maria Severi,
and Felice Petraglia
8 In Vitro Fertilization and Multiple Pregnancies . . . . . . . . . . 129
Maria Angela Rustico, Mariano Lanna, and Enrico Ferrazzi
9 Intrauterine Growth Restriction: Obstetric and Neonatal
Aspects. Intervention Strategies . . . . . . . . . . . . . . . . . . . . . . . 147
Enrico Bertino, Giovanna Oggè, Paola Di Nicola,
Francesca Giuliani, Alessandra Coscia, and Tullia Todros
vii
viii Contents
10 Late Preterm Infants at Risk for Short-Term and
Long-Term Morbidity and Mortality . . . . . . . . . . . . . . . . . . . 171
Avroy A. Fanaroff
11 Ethical Problems in Neonatal Medicine . . . . . . . . . . . . . . . . . 183
Otwin Linderkamp
12 Care of Extremely Low-Birth-Weight Infants and
Timing of Discharge. Information and Psychosocial
Intervention in Neonatology . . . . . . . . . . . . . . . . . . . . . . . . . . 203
Fabio A. Mosca, Monica Fumagalli, Maria Elena Bolis, and
Massimo Agosti
13 The Process of Decision-Making in Neonatology . . . . . . . . . . 219
Endla K. Anday and Michael Spear
14 Follow-Up Outcomes of High-Risk Infants . . . . . . . . . . . . . . 229
Neil Marlow
15 Early Markers of Poor Outcome in Neonatal Medicine . . . . 237
Fabrizio Ferrari, Licia Lugli, Elisabetta Garetti, Isotta Guidotti,
Marisa Pugliese, and Laura Lucaccioni
16 Quality of Neonatal Intensive Care and Outcome
for High-Risk Newborn Infants . . . . . . . . . . . . . . . . . . . . . . . 251
Liz McKechnie and Kathryn Johnson
17 Cerebral Plasticity and Functional Reorganization in
Children with Congenital Brain Lesions . . . . . . . . . . . . . . . . 265
Viviana Marchi, Andrea Guzzetta, and Giovanni Cioni
Part II Perinatal and Neonatal Care . . . . . . . . . . . . . . . . . . . . . . . . . 277
18 Organization of Perinatal Care: Training of Doctors and
Nurses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
Neil Marlow
19 Neonatal Transport Services . . . . . . . . . . . . . . . . . . . . . . . . . . 291
Rocco Agostino, Roberto Aufieri, and Maurizio Gente
20 Risk Management of Newborns . . . . . . . . . . . . . . . . . . . . . . . 305
Isabelle Ligi and Sophie Tardieu
21 Guidelines and Protocols for Newborns . . . . . . . . . . . . . . . . . 315
Rinaldo Zanini and Roberto Bellù
22 Physical Environment for Newborns: The Thermal
Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
Daniele Trevisanuto and Gunnar Sedin
23 Neonatology and the Law . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
Vittorio Fineschi, Francesca Maglietta, and
Emanuela Turillazzi
Contents ix
24 Environment and Early Developmental Care for
Newborns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
Dominique Haumont
25 Neonatal Pain: Neurophysiology, Recognition, Prevention,
and Management with Nonpharmacological
Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
Carlo Bellieni, Celeste Johnston, Marsha Campbell-Yeo,
Britney Benoit, and Timothy Disher
26 Neonatal Anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
Nicola Disma, Leila Mameli, Rachele Bonfiglio,
Clelia Zanaboni, and Pietro Tuo
27 Neonatal Care in the Delivery Room: Initial Management
and Approach to Low Risk Newborns . . . . . . . . . . . . . . . . . . 395
Tara M. Randis and Jennifer M. Duchon
28 Early Detection of Neonatal Depression and Asphyxia . . . . . 409
Paolo Biban and Davide Silvagni
29 Resuscitation of the Newborn . . . . . . . . . . . . . . . . . . . . . . . . . 423
Ola D. Saugstad
30 Oxygen Toxicity in Newborns . . . . . . . . . . . . . . . . . . . . . . . . . 439
Rodolfo Bracci, Serafina Perrone, Maximo Vento, and
Giuseppe Buonocore
31 Physical Examination of the Newborn . . . . . . . . . . . . . . . . . . 457
Alessandra Coscia, Paola Di Nicola, Enrico Bertino, and
Claudio Fabris
32 Primary Investigations in the Term and Preterm
Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471
Diego Gazzolo, Francesco Risso, and Andrea Sannia
33 Oxygen Saturation Monitoring in Neonatal Period . . . . . . . . 481
Augusto Sola and Sergio Golombek
Part III Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
34 Physiology of the Gastrointestinal Tract in Newborns . . . . . 503
Arieh Riskin, Carlo Agostoni, and Raanan Shamir
35 Hormones and Gastrointestinal Function of Newborns . . . . 535
Flavia Prodam, Simonetta Bellone, Roberta Ricotti,
Alice Monzani, Giulia Genoni, Enza Giglione, and Gianni Bona
36 Human Milk and Formulas for Neonatal Nutrition . . . . . . . 557
Riccardo Davanzo, Jenny Bua, and Laura Travan
37 Nutritional Recommendations for the
Very-Low-Birth-Weight Newborn . . . . . . . . . . . . . . . . . . . . . 587
Ekhard E. Ziegler
x Contents
38 Enteral Feeding of the Very-Low-Birth-Weight Infant . . . . . 595
Johannes B. (Hans) van Goudoever
39 Parenteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605
Jacques Rigo and Thibault Senterre
40 Postdischarge Nutrition in Preterm Infants . . . . . . . . . . . . . . 619
Richard J. Cooke
41 Calcium and Phosphorus Homeostasis: Pathophysiology . . . 639
Jacques Rigo, Catherine Pieltain, Renaud Viellevoye, and
Franco Bagnoli
42 Micronutrients and Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . 669
Olivier Claris and Guy Putet
Part IV Pharmacology and Infants of Smoking, Addicted, and
Diabetic Mother . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675
43 Safety of Medications During Pregnancy and Breastfeeding:
Infants of Drug-Addicted Mothers . . . . . . . . . . . . . . . . . . . . . 677
Karel Allegaert, Timvan Mieghem, and John N. van den Anker
44 Developmental Pharmacology and Therapeutics in Neonatal
Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693
Karel Allegaert, Janko Samardzic, Milica Bajcetic, and
John N. van den Anker
45 Infants of Smoking Mothers . . . . . . . . . . . . . . . . . . . . . . . . . . 709
Roberto Paludetto, Letizia Capasso, and Francesco Raimondi
46 Infants of Diabetic Mothers . . . . . . . . . . . . . . . . . . . . . . . . . . 717
Erin A. Osterholm, Jane E. Barthell, and Michael K. Georgieff
Volume 2
Part V Respiratory System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731
47 Neonatal Lung Development and Pulmonary
Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 733
Corrado Moretti and Paola Papoff
48 Neonatal Pulmonary Physiology of Term and Preterm
Newborns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759
Corrado Moretti and Paola Papoff
49 Control of Breathing in Newborns . . . . . . . . . . . . . . . . . . . . . 775
Ruben E. Alvaro and Henrique Rigatto
50 Meconium Aspiration Syndrome . . . . . . . . . . . . . . . . . . . . . . 791
Simone Pratesi and Carlo Dani
Contents xi
51 Molecular Structure of Surfactant: Biochemical Aspects
in Newborns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 801
Tore Curstedt
52 Surfactant Metabolism in Neonatal Lung Diseases . . . . . . . . 809
Virgilio P. Carnielli and Paola E. Cogo
53 Respiratory Distress Syndrome: Predisposing Factors,
Pathophysiology, and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . 823
Mikko Hallman, Timo Saarela, and Luc J. I. Zimmermann
54 Treatment of Respiratory Failure in Newborn: Mechanical
Ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 843
Colin Morley and Gianluca Lista
55 Pulmonary Hemorrhage, Transient Tachypnea, and
Neonatal Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 865
Mary Elaine Patrinos and Richard J. Martin
56 Pulmonary Air Leakage in Newborns . . . . . . . . . . . . . . . . . . 873
Paola Papoff and Corrado Moretti
57 Bronchopulmonary Dysplasia/Chronic Lung Disease of
the Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 887
Vineet Bhandari
58 Lung Ultrasound in Neonatal Diagnostic . . . . . . . . . . . . . . . . 913
Francesco Raimondi, Fiorella Migliaro, and Letizia Capasso
59 Rare Lung Diseases of Newborns . . . . . . . . . . . . . . . . . . . . . . 917
Paolo Tagliabue and Elena Ciarmoli
60 Persistent Pulmonary Hypertension of the Newborn . . . . . . 933
Jason Gien, John P. Kinsella, and Steven H. Abman
61 Pulmonary Hypertension in Congenital Diaphragmatic
Hernia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 963
Jason Gien, John P. Kinsella, and Steven H. Abman
62 Continuous Positive Airways Pressure and Other
Noninvasive Respiratory Techniques in Newborns . . . . . . . . 971
Fabrizio Sandri, Gina Ancora, Gianluca Lista, and
Luc J. I. Zimmermann
63 Lung Diseases: Surfactant Replacement Therapy in
Newborns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 995
Henry L. Halliday
64 Extracorporeal Membrane Oxygenation
for Neonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1007
Anne Greenough, Niovi Papalexopoulou, Munir Ahmed, and
Adam P. R. Smith
xii Contents
65 Lung Diseases: Problems of Steroid Treatment of Fetus
and Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015
Henry L. Halliday
66 Apnea of Prematurity and Sudden Infant Death
Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1021
Christian F. Poets
Part VI Cardiovascular System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1035
67 Cardiovascular Physiology, Pathology, and Clinical
Investigation in Neonatal Medicine . . . . . . . . . . . . . . . . . . . . 1037
Luciane Piazza, Angelo Micheletti, Javier Fernandez Sarabia,
Diana Negura, Carmelo Arcidiacono, Antonio Saracino,
Mario Carminati, and Francesca R. Pluchinotta
68 Early Diagnosis of Congenital Heart Disease: When and
How to Treat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1065
Francesca R. Pluchinotta, Luciane Piazza, Angelo Micheletti,
Javier Fernandez Sarabia, Diana Negura, Carmelo Arcidiacono,
Antonio Saracino, and Mario Carminati
69 Patent Ductus Arteriosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1079
Bart Van Overmeire
70 Cardiac Emergencies in the Newborn . . . . . . . . . . . . . . . . . . 1093
Liam Mahoney, Hector Rojas-Anaya, and Heike Rabe
71 Blood Pressure Disorders in the Neonate: Hypotension and
Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1111
Jonathan M. Fanaroff and Avroy A. Fanaroff
72 Polycythemia and Hyperviscosity in Neonates . . . . . . . . . . . . 1125
Otwin Linderkamp
Part VII Hyperbilirubinemia and Liver Diseases . . . . . . . . . . . . . 1141
73 Bilirubin Metabolism, Unconjugated Hyperbilirubinemia,
and Physiologic Neonatal Jaundice . . . . . . . . . . . . . . . . . . . . 1143
Giovanna Bertini and Carlo Dani
74 Pathologic Unconjugated
Hyperbilirubinemia–Isoimmunization, Abnormalities of
Red Blood Cells, and Infections . . . . . . . . . . . . . . . . . . . . . . . 1151
Michael Kaplan, Ronald J. Wong, and David K. Stevenson
75 Kernicterus, Bilirubin-Induced Neurological Dysfunction,
and New Treatments for Unconjugated Hyperbilirubinemia
in Neonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1169
Christian V. Hulzebos, Claudio Tiribelli, Frans J. C. Cuperus,
and Petr H. Dijk
Contents xiii
76 Treatment of Hyperbilirubinemia in Newborns . . . . . . . . . . 1185
Jon F. Watchko and M. Jeffrey Maisels
77 Pathology and Treatment of Liver Diseases in Newborns . . . 1207
Giuseppe Maggiore, Silvia Riva, and Marco Sciveres
78 Neonatal Cholestasis: Conjugated Hyperbilirubinemia . . . . 1223
Nandini Kataria and Glenn R. Gourley
79 Surgical Treatment of Biliary Tract Malformations in
Newborns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1243
Pierluigi Pedersini
Part VIII Orofacial and Gastrointestinal Malformations and
Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1253
80 Orofacial Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1255
Giorgio Iannetti, Maria Teresa Fadda, Marco Della Monaca,
and Giulio Bosco
81 Esophageal Atresia of Newborns . . . . . . . . . . . . . . . . . . . . . . 1281
Mario Messina, Francesco Molinaro, Alfredo Garzi, and
Rossella Angotti
82 Gastrointestinal Malformations of Newborns . . . . . . . . . . . . 1295
Marcello Dòmini
83 Rare Surgical Emergencies of Newborns . . . . . . . . . . . . . . . . 1331
Mario Messina, Francesco Molinaro, and Rossella Angotti
84 Meconium Plug Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 1339
Mario Messina, Rossella Angotti, and Francesco Molinaro
85 Hirschsprung’s Disease in Newborns . . . . . . . . . . . . . . . . . . . 1345
Girolamo Mattioli, Maria Grazia Faticato, Alessio Pini Prato,
and Vincenzo Jasonni
86 Gastroenteritis and Intractable Diarrhea in Newborns . . . . 1355
Andrea De Luca and Giacomo Zanelli
87 Rehydration After Diarrhea in Newborns . . . . . . . . . . . . . . . 1365
Carlo V. Bellieni
88 Necrotizing Enterocolitis of Newborns . . . . . . . . . . . . . . . . . . 1373
Sarah Bajorek and Josef Neu
89 Surgical Treatment in Newborns of Necrotizing
Enterocolitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1395
Nigel J. Hall and Agostino Pierro
Part IX Hematology, Immunology, and Malignancies . . . . . . . . 1403
90 Hematology and Immunology of Newborns: Overview . . . . 1405
Robert D. Christensen
xiv Contents
91 Pathophysiology of Coagulation and Deficiencies of
Coagulation Factors in Newborn . . . . . . . . . . . . . . . . . . . . . . 1431
Paola Saracco and Rodney P. A. Rivers
92 The Thrombotic Risk of the Newborn . . . . . . . . . . . . . . . . . . 1455
Molinari Angelo Claudio and Paola Saracco
93 Coagulation Disorders: Clinical Aspects of Platelet
Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1471
Antonio Del Vecchio
94 Anemia in the Neonatal Period . . . . . . . . . . . . . . . . . . . . . . . . 1489
Robert D. Christensen and Robin K. Ohls
95 Fetal and Neonatal Hydrops . . . . . . . . . . . . . . . . . . . . . . . . . . 1515
Gennaro Vetrano and Mario De Curtis
96 Physiology and Abnormalities of Leukocytes in
Newborns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1523
Kurt R. Schibler
97 Neonatal Hereditary Neutropenia . . . . . . . . . . . . . . . . . . . . . 1549
Gaetano Chirico and Carmelita D’Ippolito
98 Recombinant G-CSF Treatment of Severe Chronic
Neutropenia in Neonates and Infants . . . . . . . . . . . . . . . . . . . 1561
Robert D. Christensen
99 Fundamentals of Feto-Neonatal Immunology . . . . . . . . . . . . 1575
Akhil Maheshwari and Edmund F. La Gamma
100 Congenital Immunodeficiencies in Newborns . . . . . . . . . . . . 1607
Alessandro Plebani, Gaetano Chirico, and Vassilios Lougaris
101 Inflammatory Mediators in Neonatal Asphyxia and
Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1619
Kaoru Okazaki, Akira Nishida, and Hirokazu Kimura
102 Neonatal Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1641
Serena Catania, Stefano Chiaravalli, Franca Fossati-Bellani,
and Maura Massimino
Volume 3
Part X Fetal and Neonatal Infections . . . . . . . . . . . . . . . . . . . . . . . 1661
103 Fetal Infections: Cytomegalovirus, Herpes Simplex, and
Varicella . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1663
Giovanni Nigro
104 Fetal Infections: Rubella, HIV, HCV, HBV, and Human
Parvovirus B19 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1681
Pier Angelo Tovo, Stefania Bezzio, and Clara Gabiano
Contents xv
105 Fetal Infections: Congenital Syphilis and
Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1703
Pier Angelo Tovo, Carlo Scolfaro, Silvia Garazzino, and
Federica Mignone
106 Toxoplasmosis in the Fetus and Newborn . . . . . . . . . . . . . . . 1711
Wilma Buffolano
107 Neonatal Bacterial and Fungal Infections . . . . . . . . . . . . . . . 1727
Mauro Stronati and Alessandro Borghesi
108 Neonatal Septic Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1773
Rajesh K. Aneja, Ruby V. Aneja, Misty Good, and
Joseph A. Carcillo
109 Neonatal Viral Infections: Enteroviruses and Respiratory
Syncytial Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1785
Paolo Manzoni, Davide Montin, Elena Tavella, and
Pier Angelo Tovo
110 Vaccinations and Neonatal Immunity . . . . . . . . . . . . . . . . . . . 1793
Alberto G. Ugazio and Alberto E. Tozzi
Part XI Endocrine, Metabolic, and Renal Diseases . . . . . . . . . . . 1803
111 Inborn Errors of Metabolism and Newborns . . . . . . . . . . . . . 1805
Nicola Brunetti-Pierri, Giancarlo Parenti, and Generoso Andria
112 Endocrine Diseases and Disorders of Thyroid Function in
Newborns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1833
Paolo Ghirri, Antonio Balsamo, Massimiliano Ciantelli,
Paolo Cavarzere, Alessandro Cicognani, Antonio Boldrini, and
Alessandra Cassio
113 Disorders of Sexual Development in Newborns . . . . . . . . . . . 1893
Antonio Balsamo, Paolo Ghirri, Silvano Bertelloni,
Rosa T. Scaramuzzo, Franco D’Alberton, Alessandro
Cicognani, and Antonio Boldrini
114 Pathophysiology of Fetal and Neonatal Kidneys . . . . . . . . . . 1919
Farid Boubred and Umberto Simeoni
115 Acute and Chronic Renal Failure in the Newborn Infant . . . 1935
Jean-Pierre Guignard and Uma Sankari Ali
116 Diagnosis and Treatment of Renal and Urinary Tract
Malformations in Newborns . . . . . . . . . . . . . . . . . . . . . . . . . . 1955
Vassilios Fanos, Marco Zaffanello, and Michele Mussap
xvi Contents
Part XII Neurology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1997
117 Brain Development and Perinatal Vulnerability to Cerebral
Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1999
Luca A. Ramenghi, Monica Fumagalli, and
Veena Supramaniam
118 Inflammation and Perinatal Brain Injury . . . . . . . . . . . . . . . 2019
Henrik Hagberg, Carina Mallard, and Karin Sävman
119 Normal and Abnormal Neurodevelopmental and Behavioral
Outcomes of Very Low-Birth Weight (VLBW) Infants . . . . . 2031
Betty R. Vohr
120 Neurological Examination of the Newborn Infant . . . . . . . . . 2055
Fabrizio Ferrari, Licia Lugli, Luca Ori, Elisa della Casa,
Isotta Guidotti, Natascia Bertoncelli, and Laura Lucaccioni
121 Neonatal Electroencephalography . . . . . . . . . . . . . . . . . . . . . 2081
Lena K. Hellström-Westas
122 Neuroimaging Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2091
Luca A. Ramenghi and Petra S. Hüppi
123 Malformations of Cortical Development in Newborns:
Genetic Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2113
Renzo Guerrini and Elena Parrini
124 Congenital Malformations of the Brain: Spectrum
and Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2125
Elie Saliba
125 Biochemical Basis of Hypoxic-Ischemic Encephalopathy . . . 2143
Maria Delivoria-Papadopoulos, Panagiotis Kratimenos, and
Endla K. Anday
126 Clinical Aspects and Treatment of the Hypoxic-Ischemic
Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2165
Floris Groenendaal and Frank van Bel
127 Neuroprotective Strategies for Newborns . . . . . . . . . . . . . . . 2185
Bobbi Fleiss, Claire Thornton, and Pierre Gressens
128 Cerebral Hemorrhage in Newborns . . . . . . . . . . . . . . . . . . . . 2201
Linda S. de Vries and Axel Heep
129 Neonatal Stroke: Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . 2225
Paul P. Govaert and Jeroen Dudink
130 Neonatal Stroke: Clinical Presentation, Imaging, Treatment,
and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2251
Paul P. Govaert and Jeroen Dudink
Contents xvii
131 Neonatal Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2287
Lena K. Hellström-Westas and Malcolm Levene
132 The Timing of Neonatal Brain Damage . . . . . . . . . . . . . . . . . 2295
Serafina Perrone and Giuseppe Buonocore
133 Epidemiology of Adverse Cerebral Outcome of
Newborns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2315
Neil Marlow
134 Neuromuscular Disorders in Newborns . . . . . . . . . . . . . . . . . 2323
Salvatore Grosso and Silvia Ferranti
Part XIII Ophthalmology, Orthopedics, and Skin Diseases . . . 2337
135 Ocular Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2339
Elena Piozzi and Alessandra Del Longo
136 Retinopathy of Prematurity . . . . . . . . . . . . . . . . . . . . . . . . . . 2349
José Carlos Rivera, Elsa Duchemin-Kermorvant,
Allison Dorfman, Tianwei Ellen Zhou, Luis H. Ospina, and
Sylvain Chemtob
137 Neonatal Orthopedic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . 2387
Peter D. Pizzutillo and Martin J. Herman
138 Neonatal Skin Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2391
Michele Fimiani, Roberta Bilenchi, Filomena Mandato,
Stefania Mei, Niccolò Nami, Rosa Maria Strangi, and
Arianna Lamberti
Part XIV Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2427
139 Laboratory Medicine: Reference Values and Evidence-Based
Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2429
Mariangela Longini, Fabrizio Proietti, Francesco Bazzini, and
Elisa Belvisi
140 Laboratory Medicine: Reference Intervals for Laboratory
Tests and Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2433
Mariangela Longini, Fabrizio Proietti, Francesco Bazzini, and
Elisa Belvisi
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2459
About the Editors
Giuseppe Buonocore is an Italian pediatrician, who is internationally recog-
nized for his research on neonatal diseases, oxidative stress, and early
identification of the newborn at high risk of brain damage. He is a full
Professor of Pediatrics, Department of Molecular and Developmental
Medicine, University of Siena, Italy, and Director of the Division of
Pediatric-Neonatology, Azienda Ospedaliera-Universitaria of Siena, Italy.
He is Chairman of Pediatrics at the School of Specialization in Pediatrics
and Neonatology, University of Siena, Italy.
He is the President and Coordinator of European scientific network
EURope Against Infant Brain Injury (EURAIBI). He has been a Visiting
Professor at the University of Pennsylvania, the University of Florida, the
University Hospitals of New York, as well as at the University of Oulu,
Finland, at Taipei Medical University, and at Chang Gung Memorial Hospital
at Linkou, Taiwan.
He is also the past President of ESPR and UENPS and currently President
of the National College of University Full Professors of Pediatrics. He is
involved in the coordination of numerous pan-European clinical trials as
well as American and Australian. He has received many scientific awards:
including the Seventh annual Dr. Donald V Eitzman lectures “Iron homeosta-
sis metabolism and toxicity,” University of Florida (2000), and the “Goccia
d’oro 2010” for the efforts and results in the scientific research in the field of
xix
xx About the Editors
Prenatal, Perinatal, and Neonatal Brain Damage. He also holds the patent of a
scientific invention: the “Machine for automatic assessment of pain in
neonates.”
Dr. Buonocore has supervised more than 200 M.D./Ph.D. students (1994/
2018) in Medicine and Surgery, Pediatrics, and Diagnostic Biochemistry. His
current research interests are in the mechanisms of cell damage in the neonatal
brain, with special reference to hypoxia, and the role of oxidant radicals in
neonatal diseases and in babies with birth asphyxia. Additional research
interest fields are ethics in perinatology and fetal and neonatal pain prevention.
His research team is funded by several agencies including the Italian Ministry
of University and Scientific Research as well as the European Community.
Prof. Buonocore is author of more than 900 publications: 3 books and 27 book
chapters, 300 peer-reviewed articles, and more than 617 presentations at
international conferences and national meetings. He is currently Editor-in-
Chief of Current Pediatric Reviews, Associate Editor of Journal of Pineal
Research, and on the editorial board of several international scientific journals.
He has organized more than 20 European conferences and has been the
scientific coordinator or participant in several national and international clin-
ical trials.
Rodolfo Bracci was born in Siena (Italy) in 1931. After graduating in
Medicine and Surgery from the University of Siena Medical School in 1955,
he became Assistant Professor of Pediatrics in the University of Siena. He was
Post doctoral Trainee at the Albert Einstein College of Medicine, New York
(1964–1965). At that time, working under the direction of Professor Ruth
Gross, he made the first experiences on the antioxidant properties of the red
cells of newborn. After his return to Italy, he became Assistant Professor of
Pediatrics at the University of Florence and later at the University of Siena. He
continued to be involved in the field of oxygen toxicity of the erythrocyte of
newborn, and in 1967, he demonstrated that the red cells of newborn may have
not only a low protection against reacting oxygen species but also an increased
production of them.
Professor of Neonatology of the University of Siena and Director of the
Neonatal Intensive Care Unit of the Siena Hospital, he was leading a staff of
researchers involved in the physiopathology of the neonate, particularly in the
calcium homeostasis, in the opioids metabolism, and especially in the
About the Editors xxi
problems of oxygen toxicity in the red cells as well as in various organs. More
than a hundred papers were published in important international journals by
the doctors working under the guidance of Rodolfo Bracci. He was invited
speaker in many international congresses and seminars in various cities in
Europe and in America.
He has been member of the European Society of Pediatric Hematology and
Immunology, the European Society for Pediatric Research, the European
Society for Perinatal Medicine, the Neonatal Intensive Care Collegium, the
Italian Society of Pediatrics, and the Italian Society of Neonatology.
Retired from University of Siena in 2001, he continued to publish papers,
mainly together with Professor G. Buonocore.
Michael Weindling is Emeritus Professor of Perinatal Medicine at the Uni-
versity of Liverpool and Honorary Consultant Neonatologist at Liverpool
Women’s Hospital, where he was responsible for the care of newborn babies
in a tertiary neonatal intensive care unit until he retired from clinical work in
2013. He is an Associate Editor of Acta Paediatrica. He continues with his
research interest into the maintenance of appropriate brain oxygenation, cere-
bral hemodynamics, and the prevention of acquired damage of the developing
brain.
He studied medicine at Guy’s Hospital in London and qualified in 1973. His
training in London included a period at the Great Ormond Street Hospital for
Sick Children and then as research fellow at the University of Oxford, where
he studied the cerebral hemodynamics of the developing brain. Michael
Weindling was appointed a Senior Lecturer and consultant in Liverpool in
1985. During his early years as a consultant, he undertook a master’s degree in
medical ethics at the University of Keele with a dissertation into the changing
moral status of the developing human from conceptus to neonate. He was
promoted to Professor in 1996 with a personal chair entitled Professor of
Perinatal Medicine, a title chosen to reflect his interest into the rapidly chang-
ing requirements of the developing brain. He has a considerable interest in
medical education and for several years was Head of the School of Paediatrics
in Merseyside.
Contributors
Steven H. Abman University of Colorado Denver – Anschutz Medical
Campus, Denver, CO, USA
Massimo Agosti Neonatology and NICU – Maternal and Child Department,
Ospedale ”F del Ponte”, Varese, Italy
Rocco Agostino Ethics Committee, Pediatric Hospital Bambino Gesù,
Rome, Italy
Carlo Agostoni Pediatric Clinic, Department of Clinical Sciences and Com-
munity Health, University of Milan Fondazione, IRCCS Ca Granda, Ospedale
Maggiore Policlinico, Milano, Italy
Munir Ahmed Division of Asthma, Allergy and Lung Biology, MRC Centre
for Allergic Mechanisms of Asthma, King’s College London, London, UK
Uma Sankari Ali Nephrology Division and PICU, BJ Wadia Hospital for
Children, Mumbai, India
Karel Allegaert Neonatal Intensive Care Unit, University Hospitals Leuven,
Leuven, Belgium
Department of Development and Regeneration, KU Leuven, Leuven, Belgium
Intensive Care and Department of Pediatric Surgery, Erasmus MC – Sophia
Children’s Hospital, Rotterdam, The Netherlands
Ruben E. Alvaro Department of Pediatrics, WR004 Women’s Hospital,
University of Manitoba, Winnipeg, MB, Canada
Gina Ancora Neonatology and Neonatal Intensive Care Unit, Ospedale
Infermi, Rimini, Italy
Endla K. Anday Department of Pediatrics, Drexel University College of
Medicine, St. Christopher’s Hospital for Children, Neonatal-Perinatal Medi-
cine, Philadelphia, PA, USA
Generoso Andria Department of Translational Medicine, Section of Pediat-
rics, Federico II University of Naples, Naples, Italy
xxiii
xxiv Contributors
Rajesh K. Aneja Departments of Critical Care Medicine and Pediatrics,
University of Pittsburgh School of Medicine, Children’s Hospital of Pitts-
burgh, Pittsburgh, PA, USA
Ruby V. Aneja Division of Neonatology, Temple University, West Penn
Hospital, Pittsburgh, PA, USA
Molinari Angelo Claudio Thrombosis and Hemostasis Unit, Giannina
Gaslini Children’s Hospital, Genova, Italy
Rossella Angotti Department of Pediatrics, Obstetrics and Reproductive
Medicine, Section of Pediatric Surgery, University of Siena, Siena, Italy
Carmelo Arcidiacono Department of Pediatric Cardiology, IRCCS
Policlinico San Donato, San Siro, Milan, Italy
Domenico Arduini Department of Obstetrics and Gynecology, University of
Rome Tor Vergata, Rome, Italy
Roberto Aufieri Division of Neonatology and Neonatal Intensive Care,
Casilino General Hospital, Rome, Italy
Franco Bagnoli Department of Pediatrics, Obstetrics and Reproductive
Medicine, University of Siena, Siena, Italy
Milica Bajcetic Institute of Pharmacology, Clinical Pharmacology and Tox-
icology, Medical Faculty, University of Belgrade, Belgrade, Serbia
Clinical Pharmacology Unit, University Children’s Hospital, Belgrade, Serbia
Sarah Bajorek Department of Pediatrics, Division of Neonatology, Univer-
sity of Florida, College of Medicine, Gainesville, FL, USA
Antonio Balsamo Department of Medical and Surgical Sciences, Pediatric
Unit, Center for Rare Endocrine Diseases (CARENDO BO), S.Orsola Malpi-
ghi University Hospital, Bologna, Italy
Jane E. Barthell Children’s Hospitals and Clinics of Minnesota, Minneapolis,
MN, USA
Francesco Bazzini Department of Molecular and Developmental Medicine,
University of Siena, Siena, Italy
Roberto Bellù NICU, Ospedale Manzoni, Lecco, Italy
Franca Fossati-Bellani Pediatric Oncology Department, Fondazione IRCCS
Istituto Nazionale dei Tumori, Milan, Italy
Carlo V. Bellieni Neonatal Intensive Care Unit, Siena University Hospital,
Siena, Italy
Simonetta Bellone Department of Health Sciences, Division of Pediatrics,
University of Piemonte Orientale, Novara, Italy
Elisa Belvisi Department of Molecular and Developmental Medicine,
University of Siena, Siena, Italy
Contributors xxv
Britney Benoit School of Nursing, Centre for Pediatric Pain Research,
Maternal-Newborn Program, Dalhousie University, IWK Health Centre,
Halifax, Canada
Silvano Bertelloni Adolescent Medicine Unit, Division of Pediatrics,
S. Chiara Hospital, University of Pisa, Pisa, Italy
Giovanna Bertini Neonatal Intensive Care Unit, Careggi University Hospital,
Florence, Italy
Enrico Bertino Neonatal Unit, University of Turin, Turin, Italy
Natascia Bertoncelli Neonatal Intensive Care Unit, Department of Medical
and Surgical Sciences of the Mother, Children and Adults, University Hospital
of Modena, Modena, Italy
Giulio Bevilacqua Department of Pediatrics and Neonatology, Eastern
Liguria Hospital, La Spezia, Italy
Stefania Bezzio Department of Pediatrics, University of Turin, Turin, Italy
Vineet Bhandari Neonatology/Pediatrics, St. Christopher’s Hospital for
Children/Drexel University College of Medicine, Philadelphia, PA, USA
Drexel University, Philadelphia, PA, USA
Paolo Biban Azienda Ospedaliera Universitaria Integrata Verona, Verona,
Italy
Roberta Bilenchi Department of Medical, Surgical and Neurological
Sciences, Dermatology Section, University of Siena, Siena, Italy
Caterina Bocchi Obstetrics and Gynecology, Department of Molecular and
Developmental Medicine, University of Siena, Siena, Italy
Antonio Boldrini Department of Clinical and Experimental Medicine, Divi-
sion of Neonatology and Neonatal Intensive Care Unit, Santa Chiara Univer-
sity Hospital, Pisa, Italy
Maria Elena Bolis Neonatology and NICU – Maternal and Child Depart-
ment, Ospedale ”F del Ponte”, Varese, Italy
Gianni Bona Department of Health Sciences, Division of Pediatrics, Univer-
sity of Piemonte Orientale, Novara, Italy
Rachele Bonfiglio Department of Anesthesia, Pediatric and Neonatal Inten-
sive Care, Istituto Giannina Gaslini, Genoa, Italy
Alessandro Borghesi Neonatal Intensive Care Unit, Fondazione IRCCS
Policlinico ‘San Matteo’, Pavia, Italy
Giulio Bosco Sapienza Università di Roma, Policlinico Umberto I di Roma,
Rome, Italy
Farid Boubred Division of Neonatology, La Conception Hospital, Marseille,
France
Rodolfo Bracci University of Siena, Siena, Italy
xxvi Contributors
Nicola Brunetti-Pierri Department of Translational Medicine, Section of
Pediatrics, Federico II University of Naples, Naples, Italy
Jenny Bua Division of Neonatology, Institute for Maternal and Child Health
IRCCS ‘Burlo Garofolo’, Trieste, Italy
Wilma Buffolano Heading Coordinating Centre for Perinatal Infection-
Campania Region, Translational Medicine Department, Federico II Medical
School, Naples, Italy
Giuseppe Buonocore University of Siena, Siena, Italy
Marsha Campbell-Yeo Departments of Pediatrics, Psychology and Neuro-
science, Dalhousie University School of Nursing, Halifax, Canada
Letizia Capasso Division of Neonatology, Department of Translational
Medical Sciences, Università “Federico II” di Napoli, Naples, Italy
Joseph A. Carcillo Departments of Critical Care Medicine and Pediatrics,
University of Pittsburgh School of Medicine, Children’s Hospital of Pitts-
burgh, Pittsburgh, PA, USA
Mario Carminati Department of Pediatric Cardiology, IRCCS Policlinico
San Donato, San Siro, Milan, Italy
Virgilio P. Carnielli Division of Neonatology, Salesi Hospital, Polytechnic
University of Marche, Ancona, Italy
Elisa della Casa Neonatal Intensive Care Unit, Department of Medical and
Surgical Sciences of the Mother, Children and Adults, University Hospital of
Modena, Modena, Italy
Alessandra Cassio Department of Medical and Surgical Sciences, Pediatric
Endocrinology Unit, S. Orsola-Malpighi University Hospital, Bologna, Italy
Serena Catania Pediatric Oncology Department, Fondazione IRCCS Istituto
Nazionale dei Tumori, Milan, Italy
Paolo Cavarzere Pediatric Unit, Department of Mother and Child, Univer-
sity Hospital of Verona, Verona, Italy
Sylvain Chemtob Departments of Pediatrics, Ophthalmology and Pharma-
cology, Centre Hospitalier, Universitaire Sainte-Justine, Research Center,
Montréal, QC, Canada
Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research
Center, Montréal, QC, Canada
Stefano Chiaravalli Pediatric Oncology Department, Fondazione IRCCS
Istituto Nazionale dei Tumori, Milan, Italy
Gaetano Chirico Neonatology and Intensive Neonatal Therapy Unit,
Spedali Civili of Brescia, Brescia, Italy
Contributors xxvii
Robert D. Christensen Divisions of Neonatology and Hematology, Depart-
ment of Pediatrics, University of Utah School of Medicine, Intermountain
Healthcare, Salt Lake City, UT, USA
Massimiliano Ciantelli Department of Clinical and Experimental Medicine,
Division of Neonatology and Neonatal Intensive Care Unit, S. Chiara Univer-
sity Hospital, Pisa, Italy
Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
Elena Ciarmoli Neonatologia e Terapia Intensiva Neonatale, Fondazione
MBBM, ASST-Ospedale San Gerardo-Monza, Monza, Italy
Alessandro Cicognani Department of Medical and Surgical Sciences, Pedi-
atric Unit, Center for Rare Endocrine Diseases (CARENDO BO), S.Orsola
Malpighi University Hospital, Bologna, Italy
Giovanni Cioni IRCCS Stella Maris, Department of Developmental Neuro-
science, Pisa, Italy
University of Pisa, Department of Clinical and Experimental Neuroscience,
Pisa, Italy
Olivier Claris Department of Neonatology, Hôpital Femme Mère Enfant,
Bron, France
Hospices Civils de Lyon and Université Claude Bernard, Lyon, France
Paola E. Cogo Division of Pediatrics, Department of Medicine, S. Maria
della Misericordia University Hospital, University of Udine, Udine, Italy
Richard J. Cooke Department of Pediatrics, University of Tennessee Health
Science Center, Memphis, TN, USA
Giovanni Corsello Department of Sciences for Health Promotion and
Mother and Child Care, University of Palermo, Palermo, Italy
Alessandra Coscia Neonatal Unit, University of Turin, Turin, Italy
Frans J. C. Cuperus Department of Gastroenterology and Hepatology,
University Medical Center Groningen, Groningen, The Netherlands
Tore Curstedt Department of Molecular Medicine and Surgery, Karolinska
Institutet, Karolinska University Hospital, Stockholm, Sweden
Mario De Curtis Dipartimento Materno-Infantile, Università “La Sapienza”,
Rome, Italy
Carlo Dani Neonatal Intensive Care Unit, Careggi University Hospital,
Florence, Italy
Università degli Studi di Firenze, Florence, Italy
Riccardo Davanzo Department of Mother and Child Health, Madonna delle
Grazie Hospital, Matera, Italy
xxviii Contributors
Franco D’Alberton Department of Medical and Surgical Sciences, Pediatric
Unit, Center for Rare Endocrine Diseases (CARENDO BO), S.Orsola Malpi-
ghi University Hospital, Bologna, Italy
Andrea De Luca Department of Medical Biotechnologies, University of
Siena, Siena, Italy
UOC Malattie Infettive Universitarie, Azienda Ospedaliera Universitaria
Senese, Siena, Italy
Linda S. de Vries Department of Neonatology, Wilhelmina Children’s Hos-
pital, University Medical Center, Utrecht, The Netherlands
Antonio Del Vecchio Department of Women’s and Children’s Health, Neo-
natal Intensive Care Unit, Di Venere Hospital, ASL Bari, Bari, Italy
Maria Delivoria-Papadopoulos Department of Pediatrics, Drexel Univer-
sity College of Medicine, St. Christopher’s Hospital for Children, Neonatal-
Perinatal Medicine, Philadelphia, PA, USA
Marco Della Monaca Sapienza Università di Roma, Policlinico Umberto I di
Roma, Rome, Italy
Paola Di Nicola Neonatal Unit, University of Turin, Turin, Italy
Petr H. Dijk Beatrix Children’s Hospital, University Medical Center Gro-
ningen, Groningen, The Netherlands
Carmelita D’Ippolito Pediatric Oncohematology and Bone Marrow Trans-
plant, Spedali Civili Hospital, Brescia, Italy
Timothy Disher Centre for Pediatric Pain Research, Dalhousie University
School of Nursing and IWK Health Centre, Halifax, Canada
Nicola Disma Department of Anesthesia, Pediatric and Neonatal Intensive
Care, Istituto Giannina Gaslini, Genoa, Italy
Marcello Dòmini U.O. di Chirurgia pediatrica – Ospedale S.Orsola,
Università degli Studi – Alma Mater Studiorum, di Bologna, Italy
Allison Dorfman Department of Ophthalmology/Neurology, McGill Uni-
versity-Montreal Children’s Hospital Research Institute, Montreal, QC,
Canada
Elsa Duchemin-Kermorvant INSERM UMRS1138, Centre de Recherche
des Cordeliers, Paris, France
Jennifer M. Duchon Division of Neonatology, St. Joseph’s Regional Med-
ical Center, Paterson, NJ, USA
Jeroen Dudink Neonatology, Sophia Children’s Hospital, Erasmus MC Rot-
terdam, Rotterdam, Zuid-Holland, The Netherlands
Claudio Fabris Neonatal Unit, University of Turin, Turin, Italy
Maria Teresa Fadda Sapienza Università di Roma, Policlinico Umberto I di
Roma, Rome, Italy
Contributors xxix
Avroy A. Fanaroff Case Western Reserve University School of Medicine
Rainbow Babies and Children’s Hospital, Cleveland, OH, USA
Jonathan M. Fanaroff Case Western Reserve University School of Medi-
cine Rainbow Babies and Children’s Hospital, Cleveland, OH, USA
Vassilios Fanos Department of Surgery, Neonatal Intensive Care Unit, Neo-
natal Pathology and Neonatal Section, AOU and University of Cagliari,
Cagliari, Italy
Maria Grazia Faticato Department of Pediatric Surgery, University of
Genoa, Genoa, Italy
Giannina Gaslini Institute, Genoa, Italy
Silvia Ferranti Department of Molecular Medicine and Development, Uni-
versity of Siena, Siena, Italy,
Fabrizio Ferrari Neonatal Intensive Care Unit, Department of Medical and
Surgical Sciences of the Mother, Children and Adults, University of Modena
and Reggio Emilia, Modena, Italy
Enrico Ferrazzi Prenatal Diagnosis and Fetal Surgery Unit, Dept. of
Woman, Mother and Neonate, Buzzi Children’s Hospital Department of Clin-
ical Sciences, University of Milan, Milan, Italy
Michele Fimiani Dipartimento di Medicina Clinica e Scienze
Immunologiche – Sezione di Dermatologia, Università degli Studi di Siena,
Policlinico “Santa Maria alle Scotte”, Siena, Italy
Department of Medical, Surgical and Neurological Sciences, Dermatology
Section, University of Siena, Siena, Italy
Vittorio Fineschi Department of Anatomical, Histological, Forensic Medi-
cine and Orthopaedic Sciences, “Sapienza” University of Rome, Rome, Italy
Bobbi Fleiss UMR1141, Insem-Paris Diderot University, Hôpital Robert
Debré, Paris, France
Centre for the Developing Brain, Department of Perinatal Imaging and Health,
Division of Imaging Sciences and Biomedical Engineering, King’s College
London, King’s Health Partners, St. Thomas’ Hospital, London, UK
Monica Fumagalli NICU, Department of Clinical Sciences and Community
Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico
Milano, Università degli Studi di Milano, Milan, Italy
Clara Gabiano Department of Pediatrics, University of Turin, Turin, Italy
Silvia Garazzino Department of Pediatrics, University of Turin, Regina
Margherita Childrens Hospital, AOU Città della Salute e della Scienza di
Torino, Turin, Italy
Elisabetta Garetti Neonatal Intensive Care Unit, Department of Medical and
Surgical Sciences of the Mother, Children and Adults, University of Modena
and Reggio Emilia, Modena, Italy
xxx Contributors
Alfredo Garzi Department of Pediatrics, Obstetrics and Reproductive Med-
icine, Section of Pediatric Surgery, University of Siena, Siena, Italy
Università degli Studi di Salerno, Fisciano, Italy
Diego Gazzolo Neonatal Intensive Care Unit, Department of Maternal, Fetal
and Neonatal Medicine, S. Arrigo Children’s Hospital, Alessandria, Italy
Giulia Genoni Department of Health Sciences, Division of Pediatrics, Uni-
versity of Piemonte Orientale, Novara, Italy
Maurizio Gente Department of Pediatrics and Infant Neuropsychiatry, Neo-
natal Emergency Transport Service, Sapienza University of Rome, Rome,
Italy
Michael K. Georgieff Division of Neonatology, Department of Pediatrics
Center for Neurobehavioral Development, University of Minnesota, Minne-
apolis, MN, USA
Paolo Ghirri Department of Clinical and Experimental Medicine, Division
of Neonatology and Neonatal Intensive Care Unit, Santa Chiara University
Hospital, Pisa, Italy
Daniela Gianotti Department of Pediatrics and Neonatology, Eastern Liguria
Hospital, La Spezia, Italy
Jason Gien University of Colorado Denver, Denver, CO, USA
Enza Giglione Department of Health Sciences, Division of Pediatrics, Uni-
versity of Piemonte Orientale, Novara, Italy
Mario Giuffrè Department of Sciences for Health Promotion and Mother
and Child Care, University of Palermo, Palermo, Italy
Francesca Giuliani Neonatal Unit, University of Turin, Turin, Italy
Kirsten Glaser University Children’s Hospital, University of Würzburg,
Würzburg, Germany
Peter D. Gluckman Liggins Institute, University of Auckland, Auckland,
New Zealand
Sergio Golombek New York Medical College, New York, USA
Misty Good Division of Neonatology, University of Pittsburgh School of
Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA
Glenn R. Gourley Department of Pediatrics, University of Minnesota, Min-
neapolis, USA
Paul P. Govaert Neonatology, Sophia Children’s Hospital, Erasmus MC
Rotterdam, Rotterdam, Zuid-Holland, The Netherlands
Contributors xxxi
Anne Greenough Division of Asthma, Allergy and Lung Biology, MRC
Centre for Allergic Mechanisms of Asthma, King’s College London, London,
UK
NIHR Biomedical Centre at Guy’s and St Thomas NHS Foundation Trust and
King’s College London, London, UK
NICU, King’s College Hospital, London, UK
Pierre Gressens UMR1141, Insem-Paris Diderot University, Hôpital Robert
Debré, Paris, France
Centre for the Developing Brain, Department of Perinatal Imaging and Health,
Division of Imaging Sciences and Biomedical Engineering, King’s College
London, King’s Health Partners, St. Thomas’ Hospital, London, UK
Floris Groenendaal Department of Neonatology, Wilhelmina Children’s
Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
Salvatore Grosso Department of Molecular Medicine and Development,
University of Siena, Siena, Italy,
Renzo Guerrini Pediatric Neurology and Neurogenetics Unit and Laborato-
ries, Neuroscience Department, A. Meyer Children’s Hospital – University of
Florence, Florence, Italy
Isotta Guidotti Neonatal Intensive Care Unit, Department of Medical and
Surgical Sciences of the Mother, Children and Adults, University Hospital of
Modena, Modena, Italy
Jean-Pierre Guignard Lausanne University Medical School, Lausanne,
Switzerland
Andrea Guzzetta IRCCS Stella Maris, Department of Developmental Neu-
roscience, Pisa, Italy
University of Pisa, Department of Clinical and Experimental Neuroscience,
Pisa, Italy
Henrik Hagberg Perinatal Center, Department of Obstetrics and Gynecol-
ogy, Sahlgrenska Academy, University of Gothenburg, Goteborg, Sweden
Centre for the Developing Brain, Division of Imaging Sciences and Biomed-
ical Engineering, King’s College London, King’s Health Partners, St. Thomas’
Hospital, London, UK
Nigel J. Hall University Surgery Unit, Faculty of Medicine, University of
Southampton, Southampton, UK
Henry L. Halliday Formerly Regional Neonatal Unit, Royal Maternity
Hospital, Belfast, UK
Formerly Department of Child Health, Queen’s University Belfast,
Belfast, UK
xxxii Contributors
Mikko Hallman Department of Children and Adolescents, Oulu University
Hospital, and PEDEGO Research Unit, Medical Research Center Oulu, Uni-
versity of Oulu, Oulu, Finland
Dominique Haumont Department of Neonatology, Saint – Pierre University
Hospital, Brussels, Belgium
Axel Heep Department of Neonatology, Southmead Hospital, North Bristol
NHS Trust, Bristol, UK
Lena K. Hellström-Westas Department of Women’s and Children’s Health,
Uppsala University and University Hospital, Uppsala, Sweden
Martin J. Herman Department of Orthopaedic Surgery, Drexel University
College of Medicine, St. Christopher’s Hospital for Children, Philadelphia,
PA, USA
Christian V. Hulzebos Beatrix Children’s Hospital, University Medical Cen-
ter Groningen, Groningen, The Netherlands
Petra S. Hüppi Division of Neonatology, Giannina Gaslini Children’s Hos-
pital, Genoa, Italy
Giorgio Iannetti Università degli Studi di Siena, Policlinico S. Maria alle
Scotte, Siena, Italy
Sapienza Università di Roma, Policlinico Umberto I di Roma, Rome, Italy
Vincenzo Jasonni Department of Pediatric Surgery, University of Genoa,
Genoa, Italy
Giannina Gaslini Institute, Genoa, Italy
Kathryn Johnson Centre for Newborn Care, Leeds Teaching Hospitals
Trust, Leeds, UK
Celeste Johnston School of Nursing, McGill University, Montreal, Canada
Michael Kaplan Department of Neonatology, Shaare Zedek Medical Center,
Jerusalem, Israel
The Faculty of Medicine, Hebrew University, Jerusalem, Israel,
Nandini Kataria Department of Pediatrics, University of Minnesota, Long
Beach, California, USA
Tuula Kaukola Department of Children and Adolescents, Oulu University
Hospital, and PEDEGO Research Center, MRC Oulu, University of Oulu,
Oulu, Finland
Hirokazu Kimura Infectious Diseases Surveillance Center, National Insti-
tute of Infectious Diseases, Tokyo, Japan
John P. Kinsella University of Denver, Denver, CO, USA
Panagiotis Kratimenos Neonatologist, Children’s National Medical Center,
Center for Research in Neuroscience, George Washington University School
of Medicine and Health Sciences, Washington, DC, USA
Contributors xxxiii
Edmund F. La Gamma Division of Newborn Medicine, Maria Fareri Chil-
dren’s Hospital, Westchester Medical Center – New York Medical College,
Valhalla, NY, USA
Arianna Lamberti Department of Medical, Surgical and Neurological Sci-
ences, Dermatology Section, University of Siena, Siena, Italy
Mariano Lanna Prenatal Diagnosis and Fetal Surgery Unit, Dept. of
Woman, Mother and Neonate, Buzzi Children’s Hospital Department of Clin-
ical Sciences, University of Milan, Milan, Italy
Malcolm Levene Academic Unit of Paediatrics and Child Health, University
of Leeds, Leeds, UK
Department of Neonatal Medicine, Leeds Teaching Hospitals Trust, Leeds, UK
Isabelle Ligi Division of Neonatology, La Conception Hospital, Marseille,
France
Otwin Linderkamp Division of Neonatology, Department of Pediatrics,
University of Heidelberg, Heidelberg, Germany
Gianluca Lista Neonatology and Neonatal Intensive Care Unit, Ospedale dei
Bambini V. Buzzi, Milan, Italy
Mariangela Longini Department of Molecular and Developmental Medi-
cine, University of Siena, Siena, Italy
Alessandra Del Longo Department of Pediatric Ophthalmology, Niguarda
Ca’ Granda Hospital, Milan, Italy
Vassilios Lougaris Pediatrics Clinic, Department of Clinical and Experimen-
tal Sciences, University of Brescia and Spedali Civili of Brescia, Brescia, Italy
Felicia M. Low Liggins Institute, University of Auckland, Auckland, New
Zealand
Laura Lucaccioni Neonatal Intensive Care Unit, Department of Medical and
Surgical Sciences of the Mother, Children and Adults, University Hospital of
Modena, Modena, Italy
Licia Lugli Neonatal Intensive Care Unit, Department of Medical and Sur-
gical Sciences of the Mother, Children and Adults, University Hospital of
Modena, Modena, Italy
Giuseppe Maggiore Department of Medical Sciences-Pediatrics, University
of Ferrara, University Hospital Arcispedale Sant Anna di Cona, CONA (Fer-
rara), Italy
Francesca Maglietta Department of Legal Medicine, University of Foggia,
Foggia, Italy
Akhil Maheshwari Division of Neonatology, University of South Florida,
Tampa, FL, USA
Liam Mahoney Academic Department of Paediatrics, Royal Alexandra
Children’s Hospital, Brighton, UK
xxxiv Contributors
M. Jeffrey Maisels Department of Pediatrics, Oakland University William
Beaumont School of Medicine, Beaumont Children’s Hospital, Royal Oak,
MI, USA
Carina Mallard Department of Physiology, Institute of Neuroscience and
Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg,
Sweden
Leila Mameli Department of Anesthesia, Pediatric and Neonatal Intensive
Care, Istituto Giannina Gaslini, Genoa, Italy
Filomena Mandato Department of Medical, Surgical and Neurological Sci-
ences, Dermatology Section, University of Siena, Siena, Italy
Paolo Manzoni Division of Neonatology, Department of Obstetrics and
Neonatology, AOU Città della Salute e della Scienza, Turin, Italy
Viviana Marchi IRCCS Stella Maris, Department of Developmental Neuro-
science, Pisa, Italy
University of Pisa, Department of Clinical and Experimental Neuroscience,
Pisa, Italy
Neil Marlow Institute for Women’s Health, University College London,
London, UK
Richard J. Martin Rainbow Babies and Children’s Hospital, Division of
Neonatology, Case Western Reserve University School of Medicine, Cleve-
land, OH, USA
Maura Massimino Pediatric Oncology Department, Fondazione IRCCS
Istituto Nazionale dei Tumori, Milan, Italy
Girolamo Mattioli Department of Pediatric Surgery, University of Genoa,
Genoa, Italy
Giannina Gaslini Institute, Genoa, Italy
Liz McKechnie Centre for Newborn Care, Leeds Teaching Hospitals Trust,
Leeds, UK
Stefania Mei Department of Medical, Surgical and Neurological Sciences,
Dermatology Section, University of Siena, Siena, Italy
Mario Messina Department of Pediatrics, Obstetrics and Reproductive Med-
icine, Section of Pediatric Surgery, Policlinico “Le Scotte”, University of
Siena, Siena, Italy
Department of Medical, Surgical and Neurological Sciences, Section of Pedi-
atric Surgery, University of Siena, Siena, Italy
Angelo Micheletti Department of Pediatric Cardiology, IRCCS Policlinico
San Donato, San Siro, Milan, Italy
Fiorella Migliaro Division of Neonatology, Department of Translational
Medical Sciences, Università “Federico II” di Napoli, Naples, Italy
Contributors xxxv
Federica Mignone Department of Pediatrics, University of Turin, Regina
Margherita Childrens Hospital, AOU Città della Salute e della Scienza di
Torino, Turin, Italy
Francesco Molinaro Department of Pediatrics, Obstetrics and Reproductive
Medicine, Section of Pediatric Surgery, Policlinico “Le Scotte”, University of
Siena, Siena, Italy
Department of Medical, Surgical and Neurological Sciences, Section of Pedi-
atric Surgery, University of Siena, Siena, Italy
Davide Montin Division of Neonatology, Department of Obstetrics and
Neonatology, AOU Città della Salute e della Scienza, Turin, Italy
Department of Pediatrics, University of Turin, Turin, Italy
Alice Monzani Department of Health Sciences, Division of Pediatrics, Uni-
versity of Piemonte Orientale, Novara, Italy
Corrado Moretti Università degli Studi di Roma “La Sapienza”, Rome, Italy
Colin Morley Dept Obstetrics and Gynecology, University of Cambridge at
Rosie Maternity Hospital, Cambridge, UK
Fabio A. Mosca NICU, Department of Clinical Sciences and Community
Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico
Milano, Università degli Studi di Milano, Milan, Italy
Michele Mussap Laboratory Medicine, Ospedale Policlinico San Martino,
Genoa, Italy
Niccolò Nami Department of Medical, Surgical and Neurological Sciences,
Dermatology Section, University of Siena, Siena, Italy
Diana Negura Department of Pediatric Cardiology, IRCCS Policlinico San
Donato, San Siro, Milan, Italy
Josef Neu Department of Pediatrics, Division of Neonatology, University of
Florida, College of Medicine, Gainesville, FL, USA
Giovanni Nigro Maternal-Infant Department, University of L’Aquila,
L’Aquila, Italy
Akira Nishida Department of Neonatology, Tokyo Metropolitan Children’s
Medical Center, Tokyo, Japan
Giovanna Oggè Maternal-Fetal Medicine Unit, University of Turin, Turin,
Italy
Robin K. Ohls Department of Pediatrics, Division of Neonatology, Univer-
sity of New Mexico, Albuquerque, NM, USA
Kaoru Okazaki Department of Neonatology, Tokyo Metropolitan Children’s
Medical Center, Tokyo, Japan
xxxvi Contributors
Luca Ori Neonatal Intensive Care Unit, Department of Medical and Surgical
Sciences of the Mother, Children and Adults, University Hospital of Modena,
Modena, Italy
Luis H. Ospina Departments of Pediatrics, Ophthalmology and Pharmacol-
ogy, Centre Hospitalier, Universitaire Sainte-Justine, Research Center, Mon-
tréal, QC, Canada
Erin A. Osterholm Division of Neonatology, Department of Pediatrics Cen-
ter for Neurobehavioral Development, University of Minnesota, Minneapolis,
MN, USA
Roberto Paludetto Translational Medical Sciences, Università “Federico II”
di Napoli, Naples, Italy
Niovi Papalexopoulou Division of Asthma, Allergy and Lung Biology,
MRC Centre for Allergic Mechanisms of Asthma, King’s College London,
London, UK
Paola Papoff Pediatric Intensive Care Unit, Sapienza University of Rome,
Rome, Italy
Giancarlo Parenti Department of Translational Medicine, Section of Pedi-
atrics, Federico II University of Naples, Naples, Italy
Stefano Parmigiani Department of Pediatrics and Neonatology, Eastern
Liguria Hospital, La Spezia, Italy
Elena Parrini Pediatric Neurology and Neurogenetics Unit and Laborato-
ries, Neuroscience Department, A. Meyer Children’s Hospital – University of
Florence, Florence, Italy
Gaia Pasquali Department of Obstetrics and Gynecology, University of
Rome Tor Vergata, Rome, Italy
Mary Elaine Patrinos Case Western Reserve University School of Medi-
cine, Cleveland, OH, USA
Pierluigi Pedersini National Center for Surgical Treatment of Pediatric
Hepatobiliary Malformations, Pediatric Surgery, University of Brescia, Bre-
scia, Italy
Serafina Perrone Department of Molecular and Developmental Medicine,
University Hospital of Siena, Siena, Italy
Felice Petraglia Obstetrics and Gynecology, Department of Molecular and
Developmental Medicine, University of Siena, Siena, Italy
Luciane Piazza Department of Pediatric Cardiology, IRCCS Policlinico San
Donato, San Siro, Milan, Italy
Catherine Pieltain Department of Neonatology, University of Liège, CHR
de la Citadelle, Liège, Belgium
Agostino Pierro Division of General and Thoracic Surgery, The Hospital for
Sick Children, Toronto, Canada
Contributors xxxvii
Alessio Pini Prato Giannina Gaslini Institute, Genoa, Italy
Elena Piozzi Department of Pediatric Ophthalmology, Niguarda Ca’ Granda
Hospital, Milan, Italy
Peter D. Pizzutillo Section of Orthopaedic Surgery, St. Christopher’s Hos-
pital for Children, Philadelphia, PA, USA
Tenet Healthcare, Dallas, TX, USA
Alessandro Plebani Pediatrics Clinic, Department of Clinical and Experi-
mental Sciences, University of Brescia and Spedali Civili of Brescia, Brescia,
Italy
Francesca R. Pluchinotta Department of Pediatric Cardiology, IRCCS
Policlinico San Donato, San Siro, Milan, Italy
Christian F. Poets Department of Neonatology, Tübingen University Hos-
pital, Tübingen, Germany
Simone Pratesi Neonatal Intensive Care Unit, Careggi University Hospital,
Florence, Italy
Flavia Prodam Department of Health Sciences, Division of Pediatrics, Uni-
versity of Piemonte Orientale, Novara, Italy
Fabrizio Proietti Department of Molecular and Developmental Medicine,
University of Siena, Siena, Italy
Marisa Pugliese Neonatal Intensive Care Unit, Department of Medical and
Surgical Sciences of the Mother, Children and Adults, University of Modena
and Reggio Emilia, Modena, Italy
Guy Putet Department of Neonatology, Hopital de la Croix-Rousse, Hos-
pices Civils de Lyon and Universite Claude Bernard, Lyon, France
Heike Rabe Academic Department of Paediatrics, Royal Alexandra Chil-
dren’s Hospital, Brighton, UK
Francesco Raimondi Division of Neonatology, Department of Translational
Medical Sciences, Università “Federico II” di Napoli, Naples, Italy
Luca A. Ramenghi Division of Neonatology, Giannina Gaslini Children’s
Hospital, Genoa, Italy
Tara M. Randis Department of Pediatrics, New York University School of
Medicine, New York, NY, USA
Roberta Ricotti Department of Health Sciences, Division of Pediatrics,
University of Piemonte Orientale, Novara, Italy
Henrique Rigatto Department of Pediatrics, WR004 Women’s Hospital,
University of Manitoba, Winnipeg, MB, Canada
Jacques Rigo Department of Neonatology, University of Liège, CHR de la
Citadelle, Liège, Belgium
xxxviii Contributors
Arieh Riskin Department of Neonatology, Bnai Zion Medical Center,
Rappaport Faculty of Medicine, Technion, Israel Institute of Technology,
Haifa, Israel
Francesco Risso Neonatal Intensive Care Unit, Department of Emergency
Medicine, G. Gaslini Children’s Hospital, Genoa, Italy
Silvia Riva Pediatric Hepatology and Liver Transplant Unit, IRCCS-
ISMETT - University of Pittsburgh Medical Center (UPMC), Palermo, Italy
José Carlos Rivera Departments of Pediatrics, Ophthalmology and Pharma-
cology, Centre Hospitalier, Universitaire Sainte-Justine, Research Center,
Montréal, QC, Canada
Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research
Center, Montréal, QC, Canada
Rodney P. A. Rivers Section of Paediatrics, Department of Medicine, Impe-
rial College, London, UK
Hector Rojas-Anaya Academic Department of Paediatrics, Royal
Alexandra Children’s Hospital, Brighton, UK
Maria Angela Rustico Prenatal Diagnosis and Fetal Surgery Unit, Dept. of
Woman, Mother and Neonate, Buzzi Children’s Hospital Department of Clin-
ical Sciences, University of Milan, Milan, Italy
Karin Sävman Department of Pediatrics, Sahlgrenska Academy, University
of Gothenburg, Gothenburg, Sweden
Timo Saarela Department of Children and Adolescents, Oulu University
Hospital, Oulu, Finland
Elie Saliba Department of Neonatology and Pediatric Intensive Care,
Université François Rabelais and CHRU de Tours, Tours, France
Inserm U930, France, Université François Rabelais and CHRU de Tours,
Tours, France
Janko Samardzic Department of Paediatric Pharmacology, University Chil-
dren’s Hospital Basel, Basel, Switzerland
Institute of Pharmacology, Clinical Pharmacology and Toxicology, Medical
Faculty, University of Belgrade, Belgrade, Serbia
Fabrizio Sandri Neonatology and Neonatal Intensive Care Unit, Ospedale
Maggiore, Bologna, Italy
Andrea Sannia Neonatal Intensive Care Unit, Department of Emergency
Medicine, G. Gaslini Children’s Hospital, Genoa, Italy
Javier Fernandez Sarabia Department of Pediatric Cardiology, IRCCS
Policlinico San Donato, San Siro, Milan, Italy
Paola Saracco Pediatric Hematology, Department of Pediatrics, University
Hospital Città della Salute e della Scienza, Torino, Italy
Contributors xxxix
Antonio Saracino Department of Pediatric Cardiology, IRCCS Policlinico
San Donato, San Siro, Milan, Italy
Ola D. Saugstad Department of Pediatric Research, Rikshospitalet, Oslo
University Hospital, University of Oslo, Oslo, Norway
Rosa T. Scaramuzzo Neonatology and Neonatal Intensive Care Unit, Santa
Chiara University Hospital, Pisa, Italy
Kurt R. Schibler Perinatal Institute, Cincinnati Children’s Hospital Medical
Center, Cincinnati, OH, USA
Marco Sciveres Pediatric Hepatology and Liver Transplant Unit, IRCCS-
ISMETT - University of Pittsburgh Medical Center (UPMC), Palermo, Italy
Carlo Scolfaro Department of Pediatrics, University of Turin, Regina
Margherita Childrens Hospital, AOU Città della Salute e della Scienza di
Torino, Turin, Italy
Gunnar Sedin Department of Women’s and Children’s Health, University
Children’s Hospital, Uppsala, Sweden
Thibault Senterre Department of Neonatology, University of Liège, CHR de
la Citadelle, Liège, Belgium
Filiberto Maria Severi Obstetrics and Gynecology, Department of Molecu-
lar and Developmental Medicine, University of Siena, Siena, Italy
Raanan Shamir Institute of Gastroenterology Nutrition and Liver Diseases,
Schneider Children’s Medical Center, Sackler Faculty of Medicine, Tel-Aviv
University, Petach-Tikva, Israel
Davide Silvagni Azienda Ospedaliera Universitaria Integrata Verona,
Verona, Italy
Umberto Simeoni Division of Pediatrics, CHUV and UNIL, Lausanne,
Vaud, Switzerland
Adam P. R. Smith Division of Asthma, Allergy and Lung Biology, MRC
Centre for Allergic Mechanisms of Asthma, King’s College London, London,
UK
Augusto Sola Ibero American Society of Neonatology (SIBEN), Wellington,
FL, USA
Michael Spear Department of Pediatrics, Drexel University College of Med-
icine, St. Christopher’s Hospital for Children, Philadelphia, PA, USA
Christian P. Speer University Children’s Hospital, University of Würzburg,
Würzburg, Germany
David K. Stevenson Department of Pediatrics, Stanford University School of
Medicine, Medical School Office Building, Stanford, CA, USA
Rosa Maria Strangi Department of Medical, Surgical and Neurological
Sciences, Dermatology Section, University of Siena, Siena, Italy
xl Contributors
Mauro Stronati Neonatal Intensive Care Unit, Fondazione IRCCS
Policlinico ‘San Matteo’, Pavia, Italy
Veena Supramaniam Perinatal Imaging Group, Robert Steiner MR Unit,
MRC Clinical Sciences Centre and Wigglesworth Perinatal Pathology Ser-
vices, Hammersmith Hospital, Imperial College, London, UK
Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale, Fondazione
MBBM, ASST-Ospedale San Gerardo-Monza, Monza, Italy
Sophie Tardieu Medical Evaluation Department, Public Health Department,
La Conception Hospital, Marseille, France
Elena Tavella Division of Neonatology, Department of Obstetrics and Neo-
natology, AOU Città della Salute e della Scienza, Turin, Italy
Claire Thornton Centre for the Developing Brain, Department of Perinatal
Imaging and Health, Division of Imaging Sciences and Biomedical Engineer-
ing, King’s College London, King’s Health Partners, St. Thomas’ Hospital,
London, UK
Claudio Tiribelli Liver Research Centre, University of Trieste, Trieste, Italy
Tullia Todros Maternal-Fetal Medicine Unit, University of Turin, Turin,
Italy
Michela Torricelli Obstetrics and Gynecology, Department of Molecular and
Developmental Medicine, University of Siena, Siena, Italy
Pier Angelo Tovo Department of Pediatrics, University of Turin, Regina
Margherita Childrens Hospital, AOU Città della Salute e della Scienza di
Torino, Turin, Italy
Alberto E. Tozzi Multifactorial and Complex Diseases Research Area, Bam-
bino Gesù Children’s Hospital, Rome, Italy
Laura Travan Division of Neonatology, Institute for Maternal and Child
Health IRCCS ‘Burlo Garofolo’, Trieste, Italy
Daniele Trevisanuto Department of Women’s and Children’s Health,
Azienda Ospedaliere di Padova, University of Padua, Padua, Italy
Pietro Tuo Department of Anesthesia, Pediatric and Neonatal Intensive Care,
Istituto Giannina Gaslini, Genoa, Italy
Emanuela Turillazzi Department of Legal Medicine, University of Foggia,
Foggia, Italy
Alberto G. Ugazio Institute of Child and Adolescent Health, Bambino Gesù
Children’s Hospital, Rome, Italy
Frank van Bel Department of Neonatology, Wilhelmina Children’s Hospital,
University Medical Center Utrecht, Utrecht, The Netherlands
Contributors xli
John N. van den Anker Division of Pediatric Clinical Pharmacology, Chil-
dren’s National Health System, Washington, DC, USA
Departments of Pediatrics, Integrative Systems Biology, Pharmacology and
Physiology, George Washington University, School of Medicine and Health
Sciences, Washington, DC, USA
Intensive Care and Department of Pediatric Surgery, Erasmus MC – Sophia
Children’s Hospital, Rotterdam, The Netherlands
Johannes B. (Hans) van Goudoever Department of Pediatrics, Emma Chil-
dren’s Hospital – AMC and VU University Medical Center, Amsterdam, The
Netherlands
Tim van Mieghem Department of Development and Regeneration, KU
Leuven, Leuven, Belgium
Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium
Bart Van Overmeire Neonatology Service, Erasmus Hospital Université
Libre de Bruxelles, Brussels, Belgium
Silvia Vannuccini Obstetrics and Gynecology, Department of Molecular and
Developmental Medicine, University of Siena, Siena, Italy
Maximo Vento Neonatal Research Unit, Health Research Institute Hospital
La Fe, University and Polytechnic Hospital La Fe, Valencia, Spain
Gennaro Vetrano U.O.C. Pediatria/Neonatologia/UTIN, Osp. “Sacro Cuore
di Gesù”, Benevento, Italy
Renaud Viellevoye Department of Neonatology, University of Liège, CHR
de la Citadelle, Liège, Belgium
Betty R. Vohr Department of Pediatrics, The Warren Alpert Medical School
of Brown University, Providence, RI, USA
Women and Infants Hospital, Providence, RI, USA
Jon F. Watchko Division of Newborn Medicine, Department of Pediatrics,
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Ronald J. Wong Department of Pediatrics, Stanford University School of
Medicine, Stanford, CA, USA
Marco Zaffanello Department of Surgical Sciences, Dentistry, Gynecology
and Pediatrics, University of Verona, Verona, Italy
Department of Life and Reproduction Sciences Pediatric Section, University
of Verona, Verona, Italy
Department of Surgery, University of Cagliari, Cagliari, Italy
Clelia Zanaboni Department of Anesthesia, Pediatric and Neonatal Intensive
Care, Istituto Giannina Gaslini, Genoa, Italy
xlii Contributors
Giacomo Zanelli Department of Medical Biotechnologies, University of
Siena, Siena, Italy
Rinaldo Zanini NICU, Ospedale Manzoni, Lecco, Italy
Tianwei Ellen Zhou Departments of Pediatrics, Ophthalmology and Phar-
macology, Centre Hospitalier, Universitaire Sainte-Justine, Research Center,
Montréal, QC, Canada
Ekhard E. Ziegler Department of Pediatrics, University of Iowa, Iowa City,
IA, USA
Luc J. I. Zimmermann Department of Pediatrics and Neonatology, School
for Oncology and Developmental Biology (GROW), Maastricht University
Medical Center, Maastricht, The Netherlands
Part I
Epidemiology and Fetal Neonatal
Medicine
Development and General
Characteristics of Preterm and 1
Term Newborn
Domenico Arduini, Gaia Pasquali, Stefano Parmigiani,
Daniela Gianotti, and Giulio Bevilacqua
Contents
1.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.2 Part 1 The Development from Fetus to Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.2.1 Developmental Phases of the Fetus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.2.2 Fetal Constitutional Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.2.3 Diagnosis of Fetal Well-being . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
1.2.4 Fetal Injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
1.2.5 Fetal Response to Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
1.3 Part 2 General Characteristics of Preterm and Term Newborn . . . . . . . . . . . . 19
1.3.1 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Abstract and threaten survival or intact survival. The
The embryonic phase is a critical stage of objective of modern obstetrics is the accurate
development. Fetal growth is mostly detection of suboptimal fetal growth. Cur-
influenced by maternal, uteroplacental fac- rently, sonography plays a critical role in
tors, as well as genetic and environmental providing a reliable estimate of fetal biome-
factors. During pregnancy, noninvasive try, thus confirming the clinical suspicion of
screening tests are used to evaluate a baby’s growth restriction and substantially influenc-
health. Severe acute or chronic intrauterine ing pregnancy management. Preterm birth,
hypoxic stress in utero are responsible for defined as birth at less than 37 weeks of
compromised circulation, organ dysfunction, gestation, is the main determinant of adverse
infant outcome in terms of both survival and
quality of life: the more preterm these infants
D. Arduini (*) · G. Pasquali are, the more serious are the complications.
Department of Obstetrics and Gynecology, University of Because of advances in the care of these very
Rome Tor Vergata, Rome, Italy vulnerable infants, survival at the earliest
e-mail: [email protected]; [email protected]
gestation is continuosly improving.
S. Parmigiani · D. Gianotti · G. Bevilacqua
Department of Pediatrics and Neonatology, Eastern Liguria
Hospital, La Spezia, Italy
e-mail: [email protected]; [email protected];
[email protected]
# Springer International Publishing AG, part of Springer Nature 2018 3
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_150
4 D. Arduini et al.
1.1 Salient Points The third week after conception marks the
beginning of the embryonic period. It ends at the
• Fetal hemoglobin has a higher affinity for oxy- end of the tenth week, when the embryo comprises
gen than adult hemoglobin, which facilitates three layers from which all organs will develop.
diffusion of oxygen from the maternal circula- The second fetal phase begins after the tenth week
tion to the fetus. and continues until the end of pregnancy. During this
• A continuous placental supply of glucose pro- phase, organs (liver, kidneys) begin to function.
vides the substrate for energy metabolism to From the 16th to 20th weeks, the fetus
the fetus, and this converts after birth to inter- undergoes a rapid growth spurt. Fat develops
mittent feeding. under a thin skin. Cardiac output increases. Meco-
• Individual characteristics based on the race, nium accumulates in the bowel. The fetus hiccups
obstetric history, and the constitution of the and spends time awake and asleep.
parents, especially of the mother, should be Fetal development slows down between the
taken into account to improve diagnostic accu- 21st and 24th weeks. By the 24th week, the fetus
racy and the construction of customized fetal weighs approximately 1.3 pounds (600 g).
growth charts and for the antenatal detection of Between the 25th and 28th weeks, lung devel-
the true small fetus, whose risk of adverse opment continues and surfactant secretion begins.
perinatal outcomes is substantially increased. By the 28th week, 90% of fetuses will survive ex
• Hypoxemia produces various circulatory adap- utero with appropriate support.
tations in the fetus that enhance fetal survival, From the 29th to the 40th weeks, the amount of
including the development of tachycardia, body fat rapidly increases. Thalamic brain con-
hypertension, redistribution of blood flow nections, which mediate sensory input, form.
toward the brain, myocardium and adrenals, Bones are fully developed. Most of the major
and depression of fetal breathing and skeletal systems and organs are complete. The immune
muscle activity. system develops.
• The goal in the management of the preterm By weeks 35–40, the fetus is sufficiently
fetus is to deliver the most mature fetus possi- developed for life outside the uterus without
ble, at least at 32–34 weeks, in the best possible any more support than that which would be
condition by improving fetal and maternal required by any newborn baby delivered at
monitoring. term. At 37 weeks, the fetus will continue to
• The history of family, pregnancy, and delivery add approximately one ounce (28 g) per day to
together with the first examination at birth has its body weight and it will be 48–53 cm (19–21
a pivotal role on assessing neonatal well-being. inches) in length at birth.
• A baby’s well-being is determined by peri-
conceptional events.
• Signs of immaturity should be recognized and 1.2.2 Fetal Constitutional
a favorable environment should be created. Characteristics
1.2.2.1 The Central Nervous System
1.2 Part 1 The Development from (CNS)
Fetus to Newborn The CNS is formed by four subdivisions of the
neural tube that develop into distinct regions of
1.2.1 Developmental Phases of the the central nervous system.
Fetus The neural tube is initially open both cranially
and caudally. These openings close during the
The embryonic phase is a critical stage of devel- fourth week. Failure of closure of these
opment, when systems undergo important basic neuropores can result in neural tube defects such
development. as anencephaly or spina bifida.
1 Development and General Characteristics of Preterm and Term Newborn 5
The dorsal part of the neural tube comprises the An important concept of the fetal circulation is
alar plate, which is primarily associated with sen- that fetal hemoglobin has a higher affinity for
sation. The ventral part of the neural tube com- oxygen than adult hemoglobin, which facilitates
prises the basal plate, which is primarily diffusion of oxygen from the maternal circulation
associated with motor control. to the fetus. The circulatory system of the mother
The spinal cord is a long, thin, tubular bundle is not directly connected to that of the fetus, so gas
of nervous tissue and supports cells that extend exchange takes place at the placenta. Oxygen
from the brain. The brain and spinal cord together diffuses from the placenta to the chorionic villus,
make up the central nervous system. The spinal an alveolus-like structure, from which it is then
cord functions primarily for the transmission of carried to the umbilical vein. Fetal hemoglobin
neural signals between the brain and the rest of the enhances the fetal ability to draw oxygen from
body but also contains neural circuits that inde- the placenta because the oxygen dissociation
pendently control numerous reflexes and central curve is shifted to the left, which has the effect
pattern generators. of oxygen being taken up at a lower concentration
than by adult hemoglobin. This enables fetal
1.2.2.2 The Fetal Circulation hemoglobin to take up oxygen from adult hemo-
The essential difference between the circulatory globin in the placenta, which has a lower partial
system of a fetus and that of the baby after birth is pressure of oxygen than at the lungs after birth.
that the lungs are not in use: the fetus obtains A developing fetus is highly susceptible to
oxygen and nutrients from the mother through anomalies of growth and metabolism, increasing
the placenta and the umbilical cord. Blood from the risk of birth defects.
the placenta is carried to the fetus by the umbilical
vein. A large proportion enters the fetal ductus 1.2.2.3 Fetal Metabolism
venosus and passes to the inferior vena cava, A continuous placental supply of glucose pro-
while the remainder enters the liver from vessels vides the substrate for energy metabolism to the
on its inferior border. The branch of the umbilical fetus, and this converts after birth to intermittent
vein that supplies the right lobe of the liver joins feeding. While the fetus is dependent on maternal
the portal vein and blood then passes to the right glucose as the main source of energy, it can also
atrium. In the fetus, there is an opening between use lactate, free-fatty acids, and ketone bodies
the right and left atria (the foramen ovale), and under some conditions (e.g., starvation or hyp-
most of the blood flows from the right into the left oxia). Fetal glucose utilization is augmented by
atrium, thus bypassing pulmonary circulation. insulin produced by the developing fetal pancreas
The majority of blood flow is then into the left in increasing amounts as gestation proceeds; this
ventricle from where it is pumped through the enhances glucose utilization in insulin-sensitive
aorta to supply the various organs. Blood then tissues (skeletal muscle, liver, heart, adipose tis-
flows from the aorta through the internal iliac sue), which increase in mass and thus glucose
arteries to the umbilical arteries and reenters the requirement during late gestation. Glucose-stimu-
placenta, where carbon dioxide and other waste lated insulin secretion increases with gestation.
products from the fetus are taken up and enter the Glycogen stores are maximal at term, but even
maternal circulation. A small proportion (about the term fetus only has sufficient glycogen avail-
4%) of the blood from the right atrium does not able to meet energy needs for 8–10 h, and this
enter the left atrium but enters the right ventricle store can be depleted even more quickly if
and is pumped into the pulmonary artery. In the demand is high. At 27 weeks’ gestation, only
fetus, a connection between the pulmonary artery 1% of a fetus’s body weight is fat; this increases
and the aorta, called the ductus arteriosus, directs to 16% at 40 weeks. Inadequate glucose substrate
most of the blood away from the lungs (which are can lead to hypoglycemia and fetal growth restric-
not being used for respiration at this point, as the tion. In cases of intrauterine growth restriction,
fetus is suspended in amniotic fluid). fetal weight-specific tissue-glucose uptake rates
6 D. Arduini et al.
and glucose transporters are maintained or an important role in supplying nutrients to the
increased, while synthesis of amino acids into fetus. Increased caloric intake is necessary during
protein and corresponding insulin-like growth the second and third trimesters to allow for fetal
factor (IGF) signal transduction proteins are and placental growth (Christian et al. 2003). A
decreased. These observations demonstrate the Cochrane systematic review of six randomized
mixed phenotype of the intrauterine growth controlled trials found that balanced protein-energy
restriction (IUGR) fetus that has an enhanced supplementation reduced the risk of small for ges-
capacity for glucose utilization, but a diminished tational age (SGA) neonates by approximately
capacity for protein synthesis and growth. Excess 30% (Kramer and Kakuma 2003). Glucose is an
substrate can also lead to problems, as with infants important nutrient in the control of fetal growth.
of diabetic mothers (IDM). Thus, the normal fetus Studies of diabetic women have shown that low
has a considerable capacity to adapt to changes in blood glucose levels during pregnancy as a result
glucose supply (Way 2006). of excessively tight glycemic control lead to a
greater incidence of SGA neonates, whereas high
1.2.2.4 Regulation of Fetal Growth blood glucose levels increase the likelihood of
Fetal growth depends on many different aspects, macrosomia (Leguizamon and von Stecher 2003).
mostly influenced by maternal and uteroplacental
factors. Maternal Uterine Artery Blood Flow
Increased uterine blood flow is essential to meet
Role of the Mother in Fetal Growth the metabolic demands of the growing uterus as
Regulation well those of the placenta and fetus (Kliman
Fetal growth and development are influenced by 2000). Uterine artery blood flow increases by
genetic as well as environmental factors. Maternal more than threefold during pregnancy, partly
genes have an important specific influence on fetal influenced by an increased artery diameter and
growth; for example, maternal height is a major reduced resistance to flow. In addition to increased
determinant of fetal size, representing uterine uterine blood flow during normal pregnancy, new
capacity and the potential for growth. blood vessels develop in the uterus, promoted by
In fact, the individual characteristic based on the placental hormones human chorionic gonado-
the race, obstetric history, and constitutional char- tropin (hCG) (Zygmunt et al. 2002) and IGF-II
acteristics of the parents, especially of the mother, (Zygmunt et al. 2003). Using Doppler assessment
could be taken into account to improve diagnostic of uterine arterial flow at 23 weeks’ gestation,
accuracy construction of customized fetal growth Albaiges et al. (2000) found that increased uterine
and for antenatal detection of the true small artery blood flow resistance was associated with
fetuses, whose risk of adverse perinatal outcomes an increased risk of an SGA baby. In the clinical
is substantially increased (Ghi et al. 2016). practice, women with an abnormal uterine artery
Although the birth weights of siblings are sim- Doppler at 20–24 weeks (defined as a pulsatility
ilar and correlate, environmental influences are index >95th centile) and women who have one
also important in determining growth. Maternal major risk factor for SGA (maternal age > 40 years;
constraint refers to the limited capacity of the chronic hypertension; diabetes with vascular dis-
uterus to support fetal growth and is important in ease; renal impairment; antiphospholipid syn-
limiting fetal overgrowth and subsequent dysto- drome; smoker >11cigarettes per day; cocaine;
cia, to ensure the mother’s capacity for future maternal or paternal SGA; previous SGA baby;
successful pregnancies (Picciano 2003). previous still-birth; intensive exercise; previous
pre-eclampsia; pregnancy interval <6 months;
Maternal Nutrient Intake pregnancy interval >60 months; heavy bleeding
The mother is the supplier of oxygen and essential similar to menses; PAPP-A < 0,4 MoM on first
nutrients to the fetus via the placenta. Maternal trimester screening) should be referred for serial
diet, caloric intake, and metabolic function have ultrasound measurement of fetal size and
1 Development and General Characteristics of Preterm and Term Newborn 7
assessment of well-being with umbilical artery pregnancy may contribute to reduced fetal
Doppler commencing at 26–28 weeks of preg- growth. Maternal health influences the maternal
nancy (RCOG 2014). state during pregnancy with implications for fetal
growth. In addition to inflammatory diseases,
Maternal Smoking and Drug Use many other maternal factors, including pre-
Maternal cigarette smoking is associated with eclampsia (Allen 2001), anemia (Fowden and
reduced birth weight. Early reports suggested a Forhead 2004), infections, and alcohol consump-
doubling of the rate of low birth weight in babies tion, influence fetal growth via changes in placen-
of smokers compared with those of nonsmokers tal function.
and a dose-dependent effect with increasing num-
ber of cigarettes smoked. More recent studies Role of the Placenta in Fetal Growth
demonstrated a 3.5-fold increased risk of SGA Regulation
infants in women who smoked during pregnancy The placenta receives and transmits endocrine
(Bamberg and Kalache 2004; Rich-Edwards et al. signals between the mother and fetus and is the
2003), with a greater effect on low birth weight site of nutrient and waste exchange.
with increasing maternal age (Krampl et al. 2000). During human pregnancy, the placenta is an
Growth restriction is usually symmetrical with important endocrine organ. It produces hormones,
reduced weight, head circumference, and abdom- including estrogens and progesterone, hCG,
inal circumference. The use of drugs, such as human growth hormone (GH) variant, and
cocaine and marijuana, also has significant nega- human placental lactogen. Some of these play a
tive effects on fetal growth. Cocaine use contrib- role in the regulation of fetal growth. Fetal insulin
utes to an increased rate of low birth weight and a promotes growth of the fetus, acting as a signal of
reduction in mean birth weight of at least 100 g. nutrient availability (Ferrazzi et al. 2000). Insulin
deficiency results in reduced fetal growth, as the
Maternal Hypoxia fetal tissues decrease their uptake and utilization
Maternal hypoxia influences fetal growth. Its of nutrients. There is also a relationship between
effect is independent of socioeconomic status, increased insulin production and increased fetal
prematurity, maternal smoking, pregnancy- growth. It has been proposed that the fetus
induced hypertension, and parity. The combina- increases its own production of insulin in response
tion of hypoxia and pregnancy appears to be to maternal hyperglycemia and that this increase
important in altering maternal physiology, includ- in fetal insulin is responsible for the increased
ing changes in immune pathways (Clapp 2003). growth and macrosomia observed in diabetic
Maternal hypoxia affects placental and uterine pregnancies.
blood flow, which contribute to reduced nutrient Adequate placental growth is essential for ade-
transport to the fetus (Skomsvoll et al. 2002). quate fetal growth. Several aspects of placental
function are critical for human fetal growth and
Maternal Inflammatory Diseases development, including adequate trophoblast
The presence of maternal inflammatory disease invasion, an increase in uteroplacental blood
may contribute to reduced fetal growth. Several flow during gestation, transport of nutrients such
inflammatory diseases are associated with as glucose and amino acids from mother to fetus,
reduced fetal growth, including rheumatoid arthri- and the production and transfer of growth-regu-
tis (McGaw 2002), inflammatory bowel disease, lating hormones. Increased blood flow during
systemic lupus erythematosus, and periodontal pregnancy increases the flow of nutrients from
disease (Bowden et al. 2001). Women with active mother to fetus, and uteroplacental blood flow
inflammatory arthritis during pregnancy have has been shown to be reduced by up to 50% in
smaller babies compared with healthy women or women with preeclampsia (ACOG 2012). Dopp-
women whose disease is in remission (Xiao et al. ler velocimetry is used to detect increased vascu-
2003), suggesting that active inflammation during lar resistance in the uterine arteries, which occurs
8 D. Arduini et al.
as a result of abnormal trophoblast invasion of the
spiral arteries. In addition, examination of the fetal
circulation, particularly umbilical artery wave-
forms, may reflect placental insufficiency
(ACOG 2012). Umbilical vein blood flow, mea-
sured by Doppler ultrasound, is decreased in
IUGR fetuses, representing reduced perfusion of
the fetal tissues.
1.2.3 Diagnosis of Fetal Well-being
During pregnancy, women are generally offered
noninvasive screening tests, such as blood tests,
ultrasound, and cardiotocography (CTG) to eval-
uate the baby’s health. Alternatively, more inva-
sive tests, such as chorionic villous sampling
(CVS) or amniocentesis, may be performed.
Fig. 1 Reconstructed 3-D imaging of fetal face (Image
1.2.3.1 Ultrasound courtesy of G. Rizzo)
Obstetric ultrasound is usually used to:
additional imaging of fetal structures. Today 3-D
• Diagnose pregnancy
ultrasound is most commonly performed for the
• Assess possible risks to the mother (miscar-
visualization of the baby’s face (Fig. 1). However,
riage or molar pregnancy)
it has the potential to become part of routine care
• Check for fetal malformation
and many hospitals use the 3-D ultrasound to
• Determine intrauterine growth restriction
detect fetal anomalies, especially of the heart and
• Note the development of fetal body parts
of the CNS (Figs. 2 and 3).
• Check the amniotic fluid and the umbilical
cord
1.2.3.2 Screening Tests for Aneuploidy
Women should be offered prenatal assessment for
Generally an ultrasound examination is aneuploidy by screening or diagnostic testing
ordered whenever an abnormality is suspected or regardless of maternal age or other risk factors
following a schedule similar to that outlined (Practice Bulletin No. 162 2016).
below: Prenatal genetic diagnostic testing is intended
to determine, with as much certainty as possible,
7 weeks: Confirm pregnancy whether a specific genetic disorder or condition
11–13 weeks: Determine expected date of delivery is present in the fetus. In contrast, prenatal
and screening for aneuploidy genetic screening is designed to assess whether
20–22 weeks: Perform a scan to assess anatomic a patient is at increased risk of having a
integrity fetus affected by a genetic disorder (Spencer
32 weeks: Evaluate fetal growth, verify the posi- et al. 1999).
tion of the placenta, and perform the Doppler Two methods are currently available in the
study to establish fetal well-being screening for aneuploidy:
Three-dimensional (3-D) and four-dimensional 1. At 11–13 weeks’ gestation, combination of
(4-D) ultrasound techniques are used to provide maternal age, fetal nuchal translucency
1 Development and General Characteristics of Preterm and Term Newborn 9
Fig. 2 Reconstructed 3-D
imaging of the eyes, palate,
and mandible from the fetal
profile
Fig. 3 Reconstructed 3-D imaging of the corpus callosum
(Image courtesy of G. Rizzo)
Fig. 4 Fetal profile at 12 weeks of gestation showing
nuchal translucency (Image courtesy of G. Rizzo)
thickness measured by ultrasound (Fig. 4) and
maternal serum concentration of free β-human Nuchal translucency (NT) is the sonographic
chorionic gonadotropin and pregnancy-associ- appearance of a collection of fluid under the skin
ated plasma protein-A could assess the risk for behind the fetal neck in the first-trimester of preg-
trisomy 21, trisomy 18, and trisomy 13 nancy. NT normally increases with gestation.
(Nicolaides 2004; Palomaki et al. 2011). Increased NT thickness over the normal range for
gestational age is related to chromosomal defects,
The incidence of fetal trisomies is directly especially trisomy 21, but is also associated with
related to maternal age. The risk of having a major abnormalities of the heart and great arteries
child with Down syndrome increases in a gradual, and a wide range of genetic syndromes.
linear trend until about age 30 and increases expo- The level of free b-hCG in maternal blood
nentially thereafter. normally decreases with gestation. In trisomy 21
10 D. Arduini et al.
pregnancies, free b-hCG is increased. The level of processing time (5–7 days versus 7–14 days), so
PAPP-A in maternal blood normally increases the results are available earlier in pregnancy.
with gestation, and in trisomy 21 pregnancies the The most recent meta-analysis of studies cal-
level is decreased. culated a procedure-related loss rate of 0.22%
Some studies demonstrated that the detection (Alfirevic et al. 2003).
rate of this test can increase to about 95% by also The incidence of culture failure, amniotic fluid
examining the nasal bone (absent or hypoplastic leakage, or infection after CVS is less than 0.5%
in a high proportion of fetuses with trisomy 21 and (Winsor et al. 1999).
other chromosomal abnormalities), ductus
venosus flow (a-wave absent or reversed in fetal Amniocentesis
aneuploidies or in fetal cardiac defects), and tri- Amniocentesis for the purpose of genetic diagno-
cuspid flow (tricuspid regurgitation is a common sis usually is performed between 15 weeks and
finding in fetuses with trisomy 21, 18, and 13 and 20 weeks of gestation, but it can be performed at
in those with major cardiac defects). any later gestational age. An amniotic fluid sam-
2. From the 10th week of gestation, analysis of ple of 20–30 ml is obtained from a pocket free of
cell-free DNA in maternal blood. Circulating fetal parts and umbilical cord.
cell-free DNA in the plasma of pregnant The most recent meta-analysis of studies cal-
women is a mixture of genomic DNA frag- culated a procedure-related loss rate of 0.11%
ments of maternal and fetal (placental) origin (Alfirevic et al. 2003).
that could be extracted and analyzed (Sparks The incidence of culture failure is approxi-
et al. 2012; Zimmermann et al. 2012; Canick mately 0.1% of samples (Winsor et al. 1999).
et al. 2013; Botto et al. 1996). Screening for
fetal aneuploidy in pregnant women using cell- 1.2.3.4 Cardiotocography
free DNA has demonstrated high sensitivity Cardiotocography is a technique of surveillance
and specificity to screen for common aneu- of fetal well-being useful first of all during labor to
ploidies in high-risk populations. Recently, identify the fetus compromise. When the risk of
this method started to include microdeletion antepartum fetal demise is increased (e.g., pre-
screening and whole genome screening. gestational and gestational diabetes mellitus;
hypertension; gestational hypertension; pre-
1.2.3.3 Invasive Tests eclampsia; systemic lupus erythematosus; chronic
After an abnormal first-trimester ultrasound renal disease; antiphospholipid syndrome; hyper-
examination or screening test, it is necessary to thyroidism; hemoglobinopathies; heart disease;
confirm the diagnosis with an invasive procedure, decreased fetal movement; oligohydramnios;
chorionic villous sampling, or amniocentesis. The fetal growth restriction; late-term or postterm
earlier CVS results allow for more management pregnancy; isoimmunization; previous fetal
options, although amniocentesis also is an option demise; monochorionic multiple gestation), it
for diagnosis (Spencer et al. 1999). may be necessary to monitor fetal activity during
pregnancy with a nonstress test (NST) to identify
Chorionic Villous Sampling some degree of uteroplacental compromise
Chorionic villus sampling for prenatal genetic (Liston et al. 2007). The NST is based on the
diagnosis generally is performed between 10 and premise that the heart rate of a fetus that is not
13 weeks of gestation. In fact, before 10 weeks acidotic or neurologically depressed will tempo-
there is a risk of limb-reduction defects (Akolekar rarily accelerate with fetal movement. Heart rate
et al. 2015). reactivity is thought to be a good indicator of
The primary advantage of CVS over amnio- normal fetal autonomic function. Loss of reactiv-
centesis is that the procedure can be performed ity may result from any cause of central nervous
earlier in pregnancy and the viable cells obtained system depression, including fetal acidemia.
by CVS for analysis allow for shorter specimen Attention is required for the preterm fetuses; in
1 Development and General Characteristics of Preterm and Term Newborn 11
fact, the NST of the normal preterm fetus is fre- pathophysiological processes that lead to a hyp-
quently nonreactive: from 24 weeks to 28 weeks oxic-ischemic encephalopathy.
of gestation, up to 50% of NSTs may not be The first compensatory adjustment to a hyp-
reactive (Bishop 1981), and from 28 weeks to oxic-ischemic (asphyxic) event is an increase in
32 weeks of gestation, 15% of NSTs are not reac- CBF due to hypoxia and hypercapnia. This is
tive (Macones et al. 2008). For this reason, associated with a redistribution of cardiac output
starting fetal monitoring after 32 weeks of gesta- so that the brain receives an increased proportion
tion is appropriate for most at-risk patients. How- of the cardiac output. This is followed by a slight
ever, in pregnancies with very high-risk increase in systemic blood pressure (BP) due to
conditions, testing might begin at a gestational increased release of epinephrine. In the fetus suf-
age when delivery would be considered for peri- fering from acute asphyxia (hypoxic ischemia), if
natal benefit (ACOG 2014). early compensatory adjustments fail, cerebral
blood flow (CBF) may become pressure passive,
and brain perfusion becomes dependent on sys-
1.2.4 Fetal Injuries temic BP. As BP falls, CBF falls below critical
levels, and a diminished blood supply in the brain
It is important during fetal development to main- leads to insufficient oxygen to meet its needs and
tain good fetal oxygen delivery to avoid irre- intracellular energy failure.
versible fetal compromise. Fetal hypoxia from Neuronal injury in hypoxic ischemia is an
any cause leads to conversion from aerobic to evolving process. During the early phases of
anaerobic metabolism, which produces less brain injury, brain temperature drops, and there
energy and more acid. If the oxygen supply is is local release of neurotransmitters, such as g-
not restored, the fetus dies. Hypoxia may be aminobutyric acid transaminase (GABA). The
classified as follows: magnitude of the final neuronal damage depends
on both the severity of the initial insult and dam-
• Hypoxemic hypoxia: reduced placental perfu- age due to energy failure, injury during reperfu-
sion with maternal blood and consequent sion, and apoptosis. The extent, nature, severity,
decrease in fetal arterial blood oxygen content and duration of the primary injury are all impor-
due to low pO2 tant in determining the magnitude of the residual
• Anemic hypoxia: reduced arterial blood oxygen neurological damage.
content due to low fetal hemoglobin Intracranial hemorrhage in the full-term infant
concentration can be intraventricular, subarachnoid, subdural, or
• Ischemic hypoxia: reduced blood flow to the intracerebellar. There is often ventilatory distur-
fetal tissues bance and hypoxia because of varying neurological
depression. Intraventricular hemorrhage (IVH),
Making this diagnose can be difficult, and some which is unusual in term infants, may be associated
episodes of hypoxia before and during birth may with evidence of intrapartum asphyxia but may also
pass unnoticed at the time but may affect the be clinically silent and underdiagnosed, causing
central nervous system and not become evident later deficits or hydrocephalus (Rohan and
until much later in life. Golombek 2009).
Approximately 20% of neonatal HIE is primar-
1.2.4.1 Causes of Hypoxia ily related to antepartum events that lead to hyp-
Two major categories of neurological injury can oxic ischemia. Maternal conditions such as
be observed in the full-term infant: (1) hypoxic- hypotension, placental vasculopathy, and insu-
ischemic encephalopathy (HIE) and (2) intracra- lin-dependent diabetes mellitus may predispose
nial hemorrhage (ICH). Brain hypoxia and ische- the fetus to intrapartum hypoxic ischemia because
mia due to systemic hypoxemia, reduced cerebral there is little reserve to compensate for the stresses
blood flow (CBF), or both are the primary of labor (Volpe 2008). Intrapartum events such as
12 D. Arduini et al.
prolapsed cord, abruptio placentae, and traumatic The fetal heart also has a greater capacity for
delivery have been linked to 35% of cases of HIE. anaerobic metabolism than the adult heart
Because of the limitations in determining the (Philipps 2004).
actual timing of the insult, it may be difficult to Renal impairment is commonly reported fol-
identify the antepartum contribution separately lowing a generalized hypoxic-ischemic insult at
from the intrapartum. Other events besides birth. The degree of insult varies in effect from
intrapartum hypoxia may be responsible for HIE oliguria with minor electrolyte abnormality and
or CP, as less than 25% of these infants have minimally elevated creatinine to complete renal
symptoms of hypoxic ischemia at birth (Task failure requiring dialysis.
Force on Neonatal Encephalopathy and Cerebral An elevated blood concentration of liver
Palsy Staff American College of Obstetricians and enzymes, as a marker of hepatocellular injury
Gynecologists with American Academy of Pedi- due to perinatal hypoxia, is also common after
atrics Staff 2014). acute hypoxia, but irreversible liver damage is
The true incidence of intracranial hemorrhage rare.
(ICH) in utero has not been determined. Signifi- Fetal cardiovascular and endocrine responses
cant subarachnoid hemorrhage can occur with may be altered, both in acute and in chronic
intrapartum hypoxia or may result from trauma hypoxia. Recurrence of mild hypoxia may
at delivery. It can be isolated or associated with occur in pregnancies where the blood flow
subdural bleeding and cerebral contusion. The to placenta, uterus, and fetus is repeatedly
presentation is variable but generally includes compromised by physiological and environmen-
CNS depression, irritability, and seizures. When tal influences. In chronic hypoxia, fetal growth
subarachnoid hemorrhage is associated with other restriction is not uncommon, and depression of
signs of physical injury and is caused by a difficult growth factors during hypoxia has an important
delivery, outcome is frequently poor. protective effect in conserving fetal substrate for
energy as opposed to growth needs (Noori et al.
2004; Seri and Evens 2001). The full-term
1.2.5 Fetal Response to Injury infant, while more likely to survive a severe
hypoxic-ischemic insult at birth than a preterm
During normal development, cardiovascular infant (approximately 70% vs. 30%), is also
and circulatory functions progress from fetal more likely to have significant long-term mor-
life, which is characterized by low PaO2 bidity (Cressens and Huppi 2006). In umbilical
(20–24 mmHg; 2.66–3.19 kPa) through transition venous blood, mild hypoxemia may be manifest
at birth, to normoxemia after birth (PaO2 through an absence of hypercapnia or acidemia.
70–80 mmHg; 9.31–10.64 kPa); the fetus and new- In severe uteroplacental insufficiency, the fetus
born are clearly able to thrive despite their “hyp- cannot compensate hemodynamically, and
oxic” environment. Adaptive responses by the hypercapnia and acidemia increase exponen-
cardiovascular, metabolic, and endocrine systems tially (Bastek et al. 2008). Hypoxemic growth-
allow fairly severe intrauterine hypoxic stress to be restricted fetuses also demonstrate a range of
tolerated, with the fetus having relatively normal hematological and metabolic abnormalities,
growth and development. However, severe acute or including erythroblastosis, thrombocytopenia,
chronic intrauterine hypoxic stress in utero can hypoglycemia, deficiency in essential amino
cause compromised circulation, organ dysfunction, acids, hypertriglyceridemia, hypoinsulinemia,
and threaten survival or intact survival. At the time and hypothyroidism. Low birth weight increases
of transition to extrauterine life, signs of a the risk for perinatal mortality (death shortly
depressed circulatory system because of intrauter- after birth), asphyxia, hypothermia, polycythe-
ine hypoxia may become apparent because of the mia, hypocalcemia, immune dysfunction, neu-
increased metabolic demands at birth and loss of rologic abnormalities, and other long-term
placental gas exchange (Anderson et al. 2004). health problems (Petrini et al. 2009).
1 Development and General Characteristics of Preterm and Term Newborn 13
1.2.5.1 Fetal Hemodynamic Aspects maximum negative velocity in diastolic flow
Acute hypoxemia produces various circulatory reversal, and Vmax mean is the maximum veloc-
adaptations in the fetus that enhance fetal survival, ity averaged over one cardiac cycle. Cerebral
including the development of tachycardia, hyper- vasodilatation produces a decrease in left ventric-
tension, redistribution of blood flow toward the ular afterload, while increased placental and sys-
brain, myocardium and adrenals, and depression temic resistance result in an increased right
of fetal breathing and skeletal muscle activity. ventricular afterload.
This results in an increased blood supply to the In severe hypoxemia, there is also redistribu-
brain, myocardium, and adrenal glands and tion of umbilical venous blood towards the ductus
reduced perfusion of the kidneys, gastrointestinal venosus. Consequently, blood flow in the umbil-
tract, and the lower extremities. There is preferen- ical vein, which contributes to the fetal cardiac
tial delivery of nutrients and oxygen to vital output, is increased. In contrast, a reduced afterl-
organs, compensating for a diminished placental oad is associated with an increase in peak diastolic
supply (Sheridan 2005). forward flow, indicating that fetal systemic vascu-
This compensation is manifest as cerebral lar resistance has a major influence on venous
vasodilatation and there is a decrease in the return and filling patterns of the right heart.
pulsatility index (PI) in cerebral vessels (Figs. 5 Increased placental resistance and peripheral
and 6). The PI index is an arterial blood-flow vasoconstriction cause an increase in right ven-
velocity waveform index designed to quantify tricular afterload, and thus ventricular end-dia-
the pulsatility or oscillations of the waveform. It stolic pressure increases. This may result in
is calculated by the formula PI = (Vmax highly pulsatile venous blood flow waveforms
Vmin)/Vmax mean, where Vmax is the peak sys- and umbilical venous pulsations due to the trans-
tolic velocity, Vmin is the minimum forward dia- mission of atrial pressure waves through the
stolic velocity in unidirectional flow or the ductus venosus.
Fig. 5 Flow velocity waveforms from the middle cerebral artery in a normal fetus (Image courtesy of G. Rizzo)
Fig. 6 Flow velocity waveforms from the middle cerebral artery in a growth-restricted fetus (Image courtesy of G. Rizzo)
14 D. Arduini et al.
Investigations of the venous vascular system antenatal detection of the true small fetuses,
have become increasingly important in the whose risk of adverse perinatal outcomes is sub-
assessment of fetal myocardial function, and dif- stantially increased (Ghi et al. 2016).
ferent indices are used to evaluate the blood flow The term small for gestational age (SGA)
velocity during the different phases of the cardiac describes a condition in which the fetus is smaller
cycle in the ductus venosus. Reference values for than expected for the number of weeks of preg-
ductus venosus flow velocities are represented by nancy (below the tenth percentile) and is unable to
ventricular systole (S wave) and diastole (D achieve its genetically determined potential size;
wave), the lowest forward velocity during atrial when a SGA fetus shows also signs of placental
contraction (A wave) (Fig. 7). Different indices insufficiency, it is defined an intrauterine growth
are calculated, e.g., the S/A ratio. The most restriction (IUGR) fetus. IUGR is not synony-
important parameter which represents the final mous with SGA. Some, but not all, growth-
stage of disease is the abnormal reversal of restricted fetuses/infants are SGA, while
blood flow velocities in the ductus venosus, 50–70% of SGA fetuses are constitutionally
inducing an increase in the S/A ratio, mainly small, with fetal growth appropriate for maternal
due to a reduced A component of the velocity size and ethnicity.
waveforms (Fig. 8). Reference values should be This functional definition is useful to identify
used for ductus venosus flow velocities during a population of fetuses at risk of poor outcome.
ventricular systole (S wave) and diastole (D The clinician’s challenge is to distinguish
wave), the lowest forward velocity during atrial between these two conditions and identify
contraction (A wave) and different calculated IUGR fetuses whose health is endangered in
indices as the S/A. utero because of a hostile intrauterine environ-
In the inferior vena cava, there is an increase of ment and consequently to monitor and intervene
reverse flow during atrial contraction with progres- appropriately.
sive fetal deterioration, suggesting a higher pres- In fact, data support the notion that long-term
sure gradient in the right atrium. (Figs. 9 and 10). consequences of IUGR last well into adulthood.
A high venous pressure induces a reduced veloc- These individuals are predisposed to the develop-
ity at end-diastole in the umbilical vein, causing ment of a metabolic syndrome later in life,
typical end-diastolic pulsations. The development manifesting as obesity, hypertension, hypercholes-
of these pulsations is close to the onset of abnor- terolemia, cardiovascular disease, and type 2 diabe-
mal fetal heart rate patterns and is frequently asso- tes. Several hypotheses suggest that intrauterine
ciated with acidemia and fetal endocrine changes. malnutrition results in insulin resistance, loss of
At this stage, there may be an increased coronary pancreatic beta-cell mass, and an adult predisposi-
blood flow velocity compared with that seen in tion to type 2 diabetes. Although the causative
normally grown third-trimester fetuses and, if the pathophysiology is uncertain, the risk of a meta-
affected fetus is not delivered, intrauterine death bolic syndrome in adulthood is increased among
may occur within a few days. individuals who were IUGR at birth (Engle et al.
2007). In addition to an increased risk for physical
1.2.5.2 Fetal Growing Aspects sequelae, mental health problems have been found
Accurate detection of suboptimal fetal growth is more commonly in children with growth restriction.
among the objectives of modern obstetrics. To
achieve this result, sonography plays a critical 1.2.5.3 Diagnosis
role in providing a reliable estimate of fetal biom- Fetal arterial Doppler studies are useful in the
etry, thus confirming the clinical suspicion of differential diagnosis of SGA and IUGR fetuses.
growth restriction and substantially influencing In normal pregnancies, umbilical artery (UA)
pregnancy management. An approach based on resistance shows a continuous decline as the preg-
customized charts has proved to be more accurate nancy progresses (Fig. 11), but this does not occur
than traditional population-based charts for in fetuses with uteroplacental insufficiency.
1 Development and General Characteristics of Preterm and Term Newborn 15
Fig. 7 Color Doppler examination of the ductus venosus with normal flow velocity waveforms (Image courtesy of G.
Rizzo)
Fig. 8 Abnormal DV
waveform with reversal of
flow during atrial
contraction and markedly
increased pulsatility systole
(S), diastole (D), atrial
contraction (a)
Fig. 9 Doppler
examination of the inferior
vena cava with normal flow
velocity waveforms
Fig. 10 Abnormal
waveform with increase in
reversed flow during atrial
contraction in a growth-
restricted fetus
16 D. Arduini et al.
The most commonly used measure of gesta- increased and the fetal middle cerebral artery
tional age-specific UA resistance is the systolic- PI is decreased; consequently, the PI ratio of
to-diastolic ratio of flow, the Pulsatility Index (PI), the middle cerebral artery to umbilical artery
which increases with worsening disease. As the (MCA/UA), defined as cerebroplacental ratio,
insufficiency progresses, end-diastolic velocity is (CPR) is decreased.
lost and eventually reversed (Fig. 12). The status The CPR is emerging as an important predictor
of UA blood flow supports the diagnosis of IUGR of adverse outcome not only for IUGR fetuses but
and provides early evidence of circulatory abnor- also for SGA and appropriate for gestational age
malities in the fetus, helping clinicians to identify (AGA) fetuses close to term (DeVore 2015).
these high-risk fetuses. UA Doppler measure- Recent evidence suggests that a proportion
ments may help the clinician decide whether a of these SGA fetuses have milder forms of
small fetus is truly growth restricted and to iden- late-onset intrauterine growth restriction as
tify a small fetus at risk of chronic hypoxemia, but suggested by an increased risk of adverse peri-
IUGR diagnosis is challenging and cannot only be natal outcome (McCowan et al. 2000; Doctor et
based only on umbilical artery Doppler (Cruz- al. 2001; Figueras et al. 2008a), abnormal neo-
Martínez et al. 2011). natal neurobehavioral performance (Figueras et
In hypoxemic fetuses with impaired placental al. 2009), and suboptimal neurodevelopment in
perfusion, the PI in the umbilical artery is childhood (McCowan et al. 2002; Figueras et al.
2008b). These findings add to the body of evi-
dence suggesting that the diagnostic category of
SGA includes a proportion of cases with true
growth restriction and mild placental insuffi-
ciency, which is not reflected in the umbilical
artery Doppler. Recent studies suggest that the
risk of adverse outcome in these fetuses is best
established by means of brain Doppler exami-
nation. Thus, brain sparing as measured by the
middle cerebral artery Doppler is associated
with poorer perinatal outcome, higher risk
of cesarean delivery for nonreassuring fetal sta-
tus (Severi et al. 2002), and increased risk of
abnormal neurodevelopmental tests at birth
Fig. 11 Color Doppler of the umbilical artery with normal (Oros et al. 2010) and at 2 years of age (Eixarch
flow velocity waveforms (Image courtesy of G. Rizzo) et al. 2008).
Fig. 12 Color Doppler of the umbilical artery with reversed flow (Image courtesy of G. Rizzo)
1 Development and General Characteristics of Preterm and Term Newborn 17
1.2.5.4 Timing of Delivery and Babies born just a few weeks earlier than full-
Management term usually do not experience any problems
In the past, the period from 3 weeks before until related to their slight prematurity. However, the
2 weeks after the estimated date of delivery was more premature these infants are, the more serious
considered “term,” with the expectation that neo- are the complications.
natal outcomes from deliveries in this interval were Although there are recommendations that term
uniform and good. Increasingly, however, research IUGR fetuses should be monitored during deliv-
has shown that neonatal outcomes, especially ery as high-risk pregnancies (Royal College of
respiratory morbidity, vary depending on the Obstetricians and Gynaecologists 2002), there is
timing of delivery within this 5-week gestational no consensus about the best strategy for delivery.
age range. To address this lack of uniformity, The The Lancet published data on brain develop-
American College of Obstetricians and Gynecolo- ment in survivors of the multicenter Growth
gists and the Society for Maternal-Fetal Medicine Restriction Intervention Trial (GRIT) (Thornton
recommended that the label “term” be replaced et al. 2004). The aim of this study was to identify
with the designations below (ACOG 2013): compromised fetuses between 24 and 36 weeks’
gestation and answer the question of whether it
• Early term (37 0/7 weeks of gestation through was safer to deliver them immediately or to delay
38 6/7 weeks of gestation) until there was no clinical doubt that delivery was
• Full term (39 0/7 weeks of gestation through 40 necessary. In the GRIT study, the 24 week gesta-
6/7 weeks of gestation) tion babies were very different from those at
• Late term (41 0/7 weeks of gestation through 36 weeks. In the absence of severe congenital
41 6/7 weeks of gestation) abnormalities, the current infant mortality after
• Postterm (42 0/7 weeks of gestation and 32 weeks’ gestation is low: the causes of this
beyond) rare event include asphyxia, necrotising enteroco-
litis, and infection; respiratory distress syndrome is
Preterm birth, defined as birth at less than rare in this group. By contrast, before 32 weeks,
37 þ 0 weeks of gestation, is the most important and particularly in the extreme preterm fetus, there
single determinant of adverse infant outcome in is a much higher mortality, and the levels of mor-
terms of both survival and quality of life (Saigal bidity were also emphasized by the EPICure Study,
and Doyle 2008). in which 49% of surviving infants born at less than
An useful pragmatic definition for a “prema- 26 weeks’ gestation had some disability at
ture” infant is one who has not yet reached the 30 months of age and 19% were severely disabled
level of fetal development that generally allows (Wood et al. 2000). The EPICure study reached
life outside the womb. In the normal human fetus, some important conclusions. It demonstrated that
several organ systems mature between 34 and 44% of infants born at 25 weeks’ gestation sur-
37 weeks, and the fetus reaches adequate maturity vived to discharge, whereas delivery at 22 weeks
by the end of this period. One of the main organs almost invariably resulted in neonatal death.
greatly affected by premature birth is the lung. Neonatologists, obstetricians, and parents must
In Europe and many developed countries, the increasingly recognize that infants born less than
preterm birth rate is generally 5–9%, and in the 25 weeks’ gestation who survive are at risk of
USA, it has risen to 12–13% in the last decades. disability at school age. In the EPICure study,
There are three categories of preterm birth: only 20% were totally free of disability at school
(1) spontaneous preterm births are the 40–45% age and so the prognosis must be guarded. Dis-
preterm births that follow preterm labor of spon- ability was classified as follows:
taneous (i.e., idiopathic) onset; (2) 25–30% pre-
term births occur after premature rupture of the 1. Severe: The child was likely to be highly depen-
membranes; (3) the remaining 30–35% are pre- dent on care-givers, e.g., non-ambulant cerebral
term births that are induced for obstetric reasons. palsy, profound hearing loss, or blindness.
18 D. Arduini et al.
2. Moderate: Children who were likely to be rea- In recent years, placental and fetal arterial
sonably independent, e.g., ambulant cerebral Doppler flow-velocity waveforms have guided
palsy, some hearing loss, or some visual the timing of delivery. Doppler has been particu-
impairment. larly effective in assessing the growth-restricted
3. Mild: Children with neurological signs with pregnancy and has been a useful adjunct for the
minimal functional consequences. assessment of the very preterm fetus, when
cardiotocographical monitoring is unhelpful. How-
In the EPICure study, over half of the survivors ever, in the growth-restricted hypoxemic fetus,
had moderate disability or no disability at school redistribution of well-oxygenated blood to vital
age. In addition, some of the 24% with moderate organs, such as the brain, heart, and adrenals, rep-
disability were improved with spectacles and resents a compensatory mechanism to prevent fetal
hearing aids. damage, and when the reserve capacities of the
There is uncertainty about whether iatrogenic circulatory redistribution reach their limits, fetal
delivery of the very preterm (before 33 weeks of deterioration may occur rapidly. In clinical prac-
gestation) growth-restricted fetus should be tice, serial Doppler investigations estimate the
undertaken before the development of signs duration and degree of fetal blood flow redistribu-
of severe hypoxemia, with a consequent risk tion. The onset of an abnormal venous Doppler
of prematurity-related neonatal complications, recording indicates deterioration in the fetal condi-
or whether delivery should be delayed, incur- tion and iatrogenic delivery should be considered.
ring risks of prolonged exposure to hypoxia Delivery of IUGR fetuses remain a challenging
and malnutrition imposed by the hostile intra- problem for clinicians not only for preterm but
uterine environment (Walter et al. 2009). With also for fetuses near term. In practice, term preg-
every week that passes, there is a decreasing nancies are often delivered, and the delivery of the
risk of complications including intraventricular late preterm (34 þ 0–36 þ 6 weeks) or early term
hemorrhage, retinopathy of prematurity, and (37 weeks) growth-restricted fetus is also
sepsis. However, delay may expose the recommended if there are additional risk factors
growth-restricted fetus to ischemic injury of for adverse outcome, such as maternal medical/
the brain, resulting in asphyxia, periventricular obstetrical disorders, arrest of growth over a 3–4
leukomalacia, and intraventricular hemorrhage, week interval, and/ or absence or reversal Doppler
as well as a significant risk of intrauterine death. flow in the umbilical artery (Spong et al. 2011).
It is important to weigh the risks and benefits of A recent multicenter clinical trial, the Dispro-
early interventions. This is a dynamic process, portionate Intrauterine Growth Intervention Trial
in which advancements in both fetal and neona- At Term (DIGITAT), failed to demonstrate differ-
tal medicine are of crucial importance for the ences in perinatal outcome between expectant
appropriate counseling of parents and the man- management compared with induction of labor
agement of these pregnancies. in fetuses beyond 36 weeks’ gestation (Boers
The GRIT study showed a small increase in et al. 2010; Tajik et al. 2014).
fetal death if the obstetrician delayed delivery, and The study confirms that the relatively favorable
a small increase in neonatal death if early delivery neonatal outcomes in both study groups could
was chosen. Thus the monitoring of fetal health is reflect the fact that participants and clinicians
particularly important if there is growth restric- were more alert to possible complications and
tion. Such fetuses have few metabolic reserves, monitoring was intensified.
and sudden death during pregnancy may occur. In conclusion, the goal in the management of
Labor is an intermittently hypoxic event, and the preterm fetus is to deliver the most mature
anaerobic metabolism may not be an option fetus possible, at least at 32–34 weeks, in the
when there are inadequate stores of fat and best condition possible increasing fetal and mater-
glycogen. nal monitoring (Table 1).
1 Development and General Characteristics of Preterm and Term Newborn 19
Table 1 Suggested management of the preterm fetus syndrome, gluten intolerance, achondroplasia).
What to do Perform parental counseling Anemia in the parents can be a marker of a hema-
Share any type of decisions with the tological defect (e.g., thalassemia), as well as the
neonatologist, the anesthesiologist, and place of origin and ethnicity of the parents (e.g.,
the couple, personalizing the specific G6PD deficiency).
situation
Fill the informed consent as much
detailed as it is possible 1.3.1.1 History of the Pregnancy and
Considering Short-term consequences: RDS, NEC, Delivery
IVH, PVL, pulmonary dysplasia, sepsis A baby’s well-being is determined by peri-
Long-term consequences: cerebral palsy, conceptional events. The mother’s medical his-
mental impairment, attention disorders tory is important, including the possibility of
Pregnancy age and prognosis age maternal diabetes mellitus and other illnesses
Etiology of the preterm labor (maternal
and her immune status (HBV, HCV, HIV, CMV,
causes, fetal causes)
Maternal mortality related to the type of
toxoplasmosis, rubella, HSV-HZV, and syphilis).
delivery The possibility of seroconversion during preg-
Fetal presentation nancy should be considered. Enquiry should be
Obstetric anamnesis of the patient made about the course of the pregnancy. Account
Combination of the multiple factors should be taken of the time of booking for ante-
When Better after 26 weeks natal care (late booking may be a sign of a disor-
Using corticosteroids between 48 h and ganized life style and associated problems).
7 days before delivery The results of antenatal checks should be
Where Any hospital with NICU
noted: fetal growth and ultrasound results, amni-
How Trying to reduce the effects of the
otic fluid volume, maternal anemia, urine results
hypoxia
Balance maternal and fetal morbidity
and maternal diabetes mellitus, and pregnancy-
Preterm delivery is not itself an induced hypertension or pre-eclampsia. The
indication of cesarean section unless results of vaginal and anal bacterial swabs within
associated with maternal or fetal the month before delivery should be noted (group
consequences B streptococci or Listeria monocytogenes) and
whether the mother was given appropriate intra-
partum antibiotic prophylaxis.
1.3 Part 2 General Characteristics A history of the pregnancy should include note
of Preterm and Term Newborn of drugs taken during the pregnancy and their
indications. Consider evidence of infectious ill-
1.3.1 History nesses or fever close to the time of delivery and
take note of the timing of membrane rupturing and
A full family history is essential. This should the quantity and color (blood or meconium
include a full medical and social history. Note staining) of the amniotic fluid.
should be taken of alcohol ingestion and of any Details of the delivery should be noted, i.e.,
drugs (prescribed or recreational). It should whether vaginal, operative (forceps of vacuum
enquire about the possibility of consanguinity – extraction), cesarean section (planned or emergency,
the question, “Are your families related?” to both before or during the labor), and evidence of fetal
parents is one way of approaching this often del- distress.
icate subject. Enquiry should be made about the The baby’s presentation should be noted
presence of possible transmissible and inheritable because abnormal limb position may be due to a
diseases in the families of both parents. Tall or breech presentation. The possibility of birth
short stature can generate a search for specific trauma (e.g., cephalohematoma, fracture of the
undiagnosed diseases in the parents (e.g., Marfan clavicle) should be considered.
20 D. Arduini et al.
Adaptation to postnatal life should be consid- Another new approach is to start the resuscita-
ered, bearing in mind that during the first hours tion of term babies with room air, adding oxygen
after birth the baby is in a transitional period, after 30–60 s preferably under pulsoximeter guid-
passing from intra- to extrauterine life. ance. In fact, it has been shown that asphyxiated
A baby’s condition during the minutes just infants resuscitated with room air started regular
after birth is described by the Apgar score, usually breathing significantly before than those resusci-
recorded at 1 and 5 min (see Table 2). Although tated with 100% oxygen (Rabi et al. 2011).
the Apgar score may be criticized (it is subjective Another important topic related to assistance at
on the part of the observer, often recorded some birth is if delayed cord clamping can improve car-
time after delivery), in its favor, it is almost uni- dio-circulatory adaptation after birth. Some data
versally recorded. The score was described in seem in favor of retarded cord clamping after
1953 by Dr. Virginia Apgar, a North American 1 min or after first breath in term infants; however,
pediatric anesthetist. She intended it to indicate this is still controversial and not yet well under-
whether or not resuscitation was needed. stood under the physiopathologic aspect
Although imperfect, there is no doubt that a low (Parmigiani and Corona 2016; Hooper et al. 2016).
score (0 or 1, signifying an absent or slowly beat- Most healthy babies are inclined to breastfeed
ing heart) indicates a baby who is barely alive at during the first hour of life, and babies recognize
the time of birth, and a score of 8 or more indicates their mother’s smell. This is the best moment to
an individual whose general condition is good. favor mother-infant bonding and breastfeeding.
However, the Apgar score is an imperfect indica- A baby’s size is an indicator of intrauterine
tor of subsequent progress or outcome. A baby development and nutrition. Intrauterine growth
who has a high initial score may develop difficul- restriction can be a consequence of poor placen-
ties with gas exchange in the minutes that follow, tal function (e.g., due to diseases such as preg-
even if these problems are transient. nancy-induced hypertension, systemic lupus
More recent researches have shown that the erythematosus, cocaine ingestion, or infection)
great majority of normal term infants reach trans- and congenital disease, chromosomopathy, or
cutaneous pre-ductal values of oxygen satura- fetal alcohol syndrome.
tion 90% after 10 min from birth and that Observation of a baby’s movements, when
premature infants <32 weeks’ gestation can undressed and preferably in the presence of one
require a longer time to reach the same target or both parents, allows for observation of the
(Wychoff et al. 2015; Parmigiani and Corona quality of movements (whether symmetrical,
2016). coordinate, and smooth).
Eyes may be difficult to examine at birth
Table 2 Apgar score because there is often some eyelid edema, but
they must be checked later to note the presence
Sign 0 1 2
of a red reflex. In the case of babies who are
Appearance Blue or Pink body Completely
(color) pale with blue pink discharged early from hospital, this may need to
extremities be done at home by the family doctor or commu-
Pulse (heart Absent 60– <100 >100 beats/ nity midwifery team.
rate) or <60 beats/min min Lips, gums, and palate must be examined to
beats/min exclude the presence of a cleft or other
Grimace No Grimace Cough or
malformation.
(reflex response sneeze
irritability) The hips should be examined to exclude con-
Activity Limp Some flexion Active genital dislocation. During the immediate neona-
(muscle movements tal period, the ability to achieve full abduction is a
tone) useful sign. It may only be possible to elicit a
Respiration Absent Slow, Good, positive Ortolani sign, an index of hip luxation/
irregular crying
subluxation, later during the first week.
1 Development and General Characteristics of Preterm and Term Newborn 21
Arms, legs, fingers, and toes should be exam- Hyperalertness, characterized by wide-open
ined to identify any abnormality (e.g., webbing, eyes with a panicked, worried look; an appearance
of extreme vigilance
number, length). Examination of the chest should Uncoordinated eye movements: roving or float-
note any asymmetry during respiration, subcostal ing eyes
or intercostal retraction, and ancillary nipples. Immature tone, posture, and general
The skin may show areas of hypo- or hyper- coordination
pigmentation, scars, blisters, pustules, petechiae,
or evidence of birth trauma (cuts, bruises). The
diaper area should be examined to look for anom- The five senses can be altered by prematurity:
alies of the external genitalia, an imperforate or
anterior anus, and hairy tufts or dimples over the 1. The earliest response to auditory stimulation
sacrum. has been recorded at 19 weeks’ gestation but
consistent responsiveness is established by
25 weeks. Deafness is a complication of intra-
1.3.1.2 Clinical Aspects of CNS
ventricular hemorrhage or periventricular
Development
leukomalacia affecting 5–10% of preterm
Motor and sensory functions mature during preg-
infants. It may also be the result of a cytomeg-
nancy and are already in great part developed by the
alovirus infection, which may have caused
middle of the second trimester of pregnancy and the
preterm delivery. The ambient noise of a
process continues after birth. Ultrasound, particu-
NICU is rarely less than 40 dB (as in the
larly so-called 4D ultrasound, allows for the identi-
womb), and more often around 70–100 dB
fication and classification of fetal movements, and
(American Academy of Pediatrics. Committee
natural fetal behavior has been studied. Sporadic,
on Environmental Health 1997).
irregular (“vermiform”) movements are seen
2. Functional maturation of the visual system
between 6 and 7 weeks’ gestation, involving the
starts at around 5 months and it is still imma-
whole body. Generalized, brief movements from
ture at term (Graven 2004). Retinopathy of
the legs to the neck and head (such as “startle”)
prematurity (ROP), formerly known as
are observed at 8 weeks’ gestation. At 9 weeks,
retrolental fibroplasia and affecting premature
flexor movements of the cranial and caudal poles
babies exposed to excessive oxygen, is nowa-
towards the centre appear, interspersed with jerks
days largely preventable: oxygen delivery is
that allow small movements within the amniotic
monitored carefully and all infants below
liquid and partial rotation of the head. At the tenth
32 weeks’ gestation have regular examination
week, hand-to-head movements, mouth opening
of the retina following a generally accepted
with tongue protrusion, swallowing, rotation along
international protocol. Advanced stages of
the longitudinal axis, and independent movements
ROP are treated by cryo- or laser therapy.
of limb flexion and extension can be observed
However, decreased visual acuity or strabis-
(Ianniruberto and Tajani 1981; Kurjak et al. 2008).
mus may follow. Nowadays, total blindness is
The maturation of the central nervous system
infrequent.
(CNS) determines an infant’s response and toler-
3. Taste develops under the influence of amniotic
ance to various sensory inputs. A premature infant
fluid flavonoids and odorants transmitted from
may demonstrate signs of immaturity (Holditch-
the maternal diet from as early as 14 weeks’
Davis et al. 2003) such as:
gestation. Taste after birth can be disturbed by
Diffuse and indeterminate sleep or waking states drugs, by the late introduction of oral feeding,
with frequent whimpering, facial twitches, or appar- or by the impaired development of taste
ent smiling centers.
Abrupt transitions between states
4. The sensory system starts to develop at
Periods of fussiness or crying
Low-level alertness, characterized by a dull, 8 weeks and is functional by 12 weeks’ gesta-
glassy-eyed look tion. Being touched may be uncomfortable
22 D. Arduini et al.
even for full-term infants who have not devel- Table 3 Neonatal states classification scale
oped all the receptors and pathways, and per- State Characteristics
ception may also be disturbed by drugs, e.g., Quiet sleep Regular breathing, eyes closed.
maternal cocaine use. In the preterm infant, Spontaneous activity confined to startle
touch may be a powerful stressor. Touch should and jerky movements at regular intervals.
be gentle and combined with the stimulation of Responses to external stimuli are partially
inhibited, and any response is likely to be
other senses, for example, speaking to the baby. delayed. No eye movements, and state
Touching for no good reason should similarly changes are less likely after stimuli or
be avoided. Parents should be taught to touch startles than in other states.
gently and about “kangaroo care”. Active Irregular breathing patterns, sucking
sleep movements, eyes closed but rapid eye
5. The olfactory tract is part of the primitive
movements can be detected underneath
encephalon and a baby at term is able to rec- the closed lids. Infants also have some
ognize its mother’s odor. The olfactory system low-level and irregular motor activity.
is fully functional by 14 weeks’ gestation. Startles occur in response to external
stimuli and can produce a change in state.
Strong odors can be stressful for preterm
Drowsiness While the newborn is semi-dosing, eyes
babies who are unable to communicate this to may be open or closed; eyelids often
their carer. flutter; activity level variable and
interspersed with mild startles. Drowsy
These signs of immaturity should be recog- newborns are responsive to sensory
stimuli but with some delay, and state
nized and a favorable environment should be cre- change frequently follows stimulation.
ated, avoiding overstimulation. Woolf (1959, Alert A bright alert look, with attention focused
1966), Brazelton (1984), and Prechtl (1974) inactivity on sources of auditory or visual stimuli;
described different states of behavior. The motor activity is inhibited while attending
Brazelton scale assesses neonatal behavior in six to stimuli.
Active Eyes open, considerable motor activity,
states: quiet sleep, active sleep, drowsiness, alert
awake thrusting movements of extremities, and
inactivity, active awake, and crying (Table 3). The occasional startles set off by activity;
baby should be observed in a state of quiet reactive to external stimulation with an
wakefulness. increase in startles or motor activity.
Discrete responses are difficult to
distinguish due to general high activity
1.3.1.3 The Preterm Infant level.
Maturity is determined by the length of gestation, Crying Intense irritability in the form of sustained
and the severity of problems related to prematurity crying and jerky limb movement. This
is directly related to gestation. state is difficult to break through with
stimulation.
Weeks of gestation are generally considered as
completed weeks. The World Health Organization Data from (Brazelton 1984)
has defined preterm infants as those with gesta-
tional age less than 37 weeks. Recently, the term • Low birth weight (LBW), 1501–2500 g
“late preterm infants” (instead of “near-term”) has • Very low birth weight (VLBW), 1001–1500 g
been used for those infants that are born at a • Extremely low birth weight (ELBW), 1000 g
gestational age between 34 weeks and 36 weeks
and 6 days. These infants have a rather higher Because of the survival of very light and pre-
morbidity and mortality than term infants (gesta- mature babies, the term “incredibly low birth
tional age 37 weeks), even though they are of weight” has been used to refer to babies weighing
similar size (Woolf 1959, 1966; Brazelton 1984; less than 750 g.
Prechtl 1974). Some North American authors A fundamental problem for all preterm infants is
have also used the terms “premies” and “micro- their poor ability to maintain body temperature
premies” to describe very immature babies. because of reduced glycogen stores (depending on
Classification by birth weight is as follows: gestational age) and thinner skin, with the most
1 Development and General Characteristics of Preterm and Term Newborn 23
immature lacking the ability to shiver. Thus a pri- considered elsewhere (see ▶ Chap. 17, “Cerebral
mary aim is to avoid heat loss (and insensible water Plasticity and Functional Reorganization in Chil-
losses) by drying, heating, and covering the baby. dren with Congenital Brain Lesions”).
This also decreases glucose consumption, reducing Not only babies at extremely low gestation but
the risk of hypoglycemia. Plastic wrapping of body also those born late preterm are at risk.
and head (apart the face) immediately after birth is Various evidence points to the environment
advisable for babies <32 weeks’gestation to main- being of major importance for appropriate devel-
tain temperature between 36.5 C and 37.5 C opment. Although neonatologists strive to recre-
(Wychoff et al. 2015). ate an extrauterine environment that is similar to
The preterm baby often experiences delayed that of the womb, there are many differences.
respiratory adaptation. Depending on the degree Light, painful interventions, development in air
of immaturity, the lungs are morphologically instead of surrounded by amniotic fluid, noise,
immature and lack surfactant. Such babies may stress, sleep-wake cycles interrupted by nursing pro-
require the endotracheal administration of exoge- cedures, continuous intravenous nutrition (without
nous surfactant and mechanical ventilation. the intermittent glycemic peaks of normal feeding
Bronchopulmonary dysplasia (chronic lung dis- and maternal ingestion), fluctuations in oxygen
ease with O2 dependency) is a complication of delivery, carbon dioxide, pH levels, and blood pres-
severe prematurity, which may continue to cause sure may all interfere with normal brain develop-
problems during subsequent years. ment. A high tech/soft touch approach may be
Premature infants have reduced immune beneficial and a mother’s touch and breastfeeding
defenses. Furthermore, infection may be the pri- should be encouraged even for very tiny babies.
mary cause of preterm delivery, sometimes affect- In some units, parents are supported by a psy-
ing the baby before birth. Such infections, in chologist to help with attachment. In spite of the
combination with lung and brain immaturity, best endeavors of staff, having a baby in a neona-
increase the risk of later disability (see tal unit, often for several months, is undoubtedly
▶ Chap. 14, “Follow-Up Outcomes of High- stressful, giving rise to feelings of inadequacy on
Risk Infants”). the part of the mother, who may feel a biological
The gastrointestinal tract is not yet adapted to failure, and anxiety on the part of the father, who
enteral feeds, posing considerable challenges to is no longer in control of the situation.
those responsible for their care. Early nonnutritive
feeding should be considered. Milk, preferably
from the mother or a human milk bank, may be
References
started early but cautiously, particularly for the
most immature infant. Careful note should be ACOG (2012) Committee Opinion 545 Noninvasive Pre-
taken of early signs of gastrointestinal intolerance, natal Testing for Fetal Aneuploidy
e.g., increased volume or bile-staining of gastric ACOG (2013) Committee Opinion No 579: definition of
aspirates or abdominal swelling. The most imma- term pregnancy. Obstet Gynecol 122(5):1139–1140
ACOG (2014) Antepartum fetal surveillance. Obstet
ture infants require parenteral nutrition (partial or Gynecol 124:1
total) to provide adequate nutrients and calories Akolekar R et al (2015) Procedure-related risk of miscar-
for growth, and this may need to be continued for riage following amniocentesis and chorionic villus
several weeks. This practice requires a central, sampling: a systematic review and meta-analysis.
Ultrasound Obstet Gynecol 45:16–26
indwelling catheter, increasing the risk of Albaiges G, Missfelder-Lobos H, Lees C et al (2000) One-
infection. stage screening for pregnancy complications by color
Because of advances in the care of these very Doppler assessment of the uterine arteries at 23 weeks’
vulnerable infants, survival at the earliest gesta- gestation. Obstet Gynecol 96:559–564
Alfirevic Z, Mujezinovic F, Sundberg K (2003) Amnio-
tion is improving. centesis and chorionic villus sampling for prenatal
Survival at early gestation and the associated diagnosis. Cochrane Database Syst Rev Issue 3. Art.
risks of neurodevelopmental impairment are No.: CD003252.
24 D. Arduini et al.
Allen LH (2001) Biological mechanisms that might under- term fetuses with cerebral blood flow redistribution.
lie iron’s effects on fetal growth and preterm birth. Ultrasound Obstet Gynecol 32:894–899
J Nutr 131:S581–S589 Engle A, Tomashek KM, Wallman C, Committee on Fetus
American Academy of Pediatrics. Committee on Environ- and Newborn (2007) ‘Late preterm’ infants: a popula-
mental Health (1997) Noise: a hazard for the fetus and tion at risk. Pediatrics 120:1390–1401
the newborn. Pediatrics 100:724–727 Ferrazzi E, Rigano S, Bozzo M et al (2000) Umbilical vein
Anderson P, Kleiman C, Lister G, Telner N (2004) Cardio- blood flow in growth-restricted fetuses. Ultrasound
vascular function during development and response to Obstet Gynecol 16:432–438
hypoxia. In: Polin R, Fox W, Abman S (eds) Fetal Figueras F, Eixarch E, Gratacos E, Gardosi J (2008a)
and neonatal physiology. Saunders, Philadelphia, Predictiveness of antenatal umbilical artery Doppler
pp 645–669 for adverse pregnancy outcome in small-for-gesta-
Bamberg C, Kalache KD (2004) Prenatal diagnosis of fetal tional-age babies according to customised birthweight
growth restriction. Semin Fetal Neonatal Med centiles: population-based study. BJOG 115:590–594
9:387–394 Figueras F et al (2008b) Small-for-gestational-age fetuses
Bastek LA, Sammel MD, Paré E et al (2008) Adverse with normal umbilical artery Doppler have suboptimal
neonatal outcomes: examining the risk between pre- perinatal and neurodevelopmental outcome. Eur J
term, late preterm, and term infants. Am J Obstet Obstet Gynecol Reprod Biol 136:34–38
Gynecol 199:367.e1–367.e8 Figueras F et al (2009) Neurobehavior in term, small-
Bishop EH (1981) Fetal acceleration test. Am J Obstet forgestational age infants with normal placental func-
Gynecol 141:905–909 tion. Pediatrics 124:e934–e941
Boers KE et al (2010) Induction versus expectant monitoring Fowden AL, Forhead AJ (2004) Endocrine mechanisms of
for intrauterine growth restriction at term: randomised intrauterine programming. Reproduction 127:515–526
equivalence trial (DIGITAT). BMJ 341:c7087 Ghi T et al (2016) Customized fetal growth charts for
Botto LD, Olney RS et al (1996) Chorionic villus sampling parents’ characteristics, race, and parity by quantile
and transverse digital deficiencies: evidence for ana- regression analysis. J Ultrasound Med 35:e35–e44
tomic and gestational-age specificity of the digital defi- Graven SN (2004) Early neurosensory visual development
ciencies in two studies. Am J Med Genet 62:173–178 of the fetus and newborn. Clin Perinatol 31:199–216
Bowden AP, Barrett JH, Fallow W, Silman AJ (2001) Holditch-Davis D, Blackburn ST, Vandenberg K (2003)
Women with inflammatory polyarthritis have babies Newborn and infant neurobehavioural development.
of lower birth weight. J Rheumatol 28:355–359 In: Kenner C, Wright Lott J (eds) Comprehensive neo-
Brazelton TB (1984) Neonatal behavioral assesment scale, natal nursing: a physiological perspective, 3rd edn. WB
2nd edn. Heinemann, London Saunders, St Louis, pp 236–284
Canick JA et al (2013) The impact of maternal plasma Hooper SB, Binder-Heschl C, Polglase GR et al (2016)
DNA fetal fraction on next generation sequencing The timing of umbilical cord clamping at birth: phys-
tests for common fetal aneuploidies. Prenatal Diagnosis iological considerations. Maternal Health Neonatol
33:667–674 Perinatol 2:4
Christian P, Khatry SK, Katz J et al (2003) Effects of Ianniruberto A, Tajani E (1981) Ultrasonographic study of
alternative maternal micronutrient supplements on fetal movements. Semin perinatol 5:175–181
low birth weight in rural Nepal: double blind Kliman HJ (2000) Uteroplacental blood flow. The story of
randomised community trial. BMJ 326:571 decidualization, menstruation, and trophoblast inva-
Clapp JF (2003) The effects of maternal exercise on fetal sion. Am J Pathol 157:1759–1768
oxygenation and feto-placental growth. Eur J Obstet Kramer MS, Kakuma R (2003) Energy and protein intake
Gynecol Reprod Biol 110(Suppl 1):S80–S85 in pregnancy. Cochrane Database Syst Rev CD000032
Cressens P, Huppi PS (2006) The CNS: hypoxic ischemic Krampl E, Lees C, Bland JM et al (2000) Fetal biometry at
encephalopathy. In: Fanaroff AA, Martin R, Walsh 4300 m compared to sea level in Peru. Ultrasound
MC (eds) Neonatal-perinatal medicine. Mosby, St Obstet Gynecol 16:9–18
Louis Kurjak A, Tikvica A, Stanojevic M et al (2008) The assess-
Cruz-Martínez R et al. (2011) Fetal brain doppler to predict ment of fetal neurobehavior by three-dimensional and
cesarean delivery for nonreassuring fetal status in four-dimensional ultrasound. J Matern Fetal Neonatal
term small-for-gestational-age fetuses. Obstet Gynecol Med 21:675–684
117(3):618–26 Leguizamon G, von Stecher F (2003) Third trimester gly-
DeVore GR (2015) The importance of the cerebroplacental cemic profiles and fetal growth. Curr Diab Rep
ratio in the evaluation of fetal well-being in SGA and 3:323–326
AGA foetuses. Am J Obstet Gynecol 213(1):5–15 Liston R, Sawchuck D, Young D (2007) Fetal health sur-
Doctor BA et al (2001) Perinatal correlates and neonatal veillance: antepartum and intrapartum consensus
outcomes of small for gestational age infants born at guideline. J Obstet Gynaecol Can 29:909
term gestation. Am J Obstet Gynecol 185:652–659 Macones GA, Hankins GD, Spong CY, Hauth J, Moore T
Eixarch E et al (2008) Neurodevelopmental outcome in 2- (2008) The 2008 National Institute of Child Health and
year-old infants who were small-for-gestational age Human Development workshop report on electronic
1 Development and General Characteristics of Preterm and Term Newborn 25
fetal monitoring: update on definitions, interpretation, Royal College of Obstetricians and Gynaecologists (2002)
and research guidelines. Obstet Gynecol 112:661–666 The investigation and management of the small-for-
McCowan LM, Harding JE, Stewart AW (2000) Umbilical gestational-age fetus. Evidence-based clinical guide-
artery Doppler studies in small for gestational age line no. 31. RCOG, London, pp 1–16
babies reflect disease severity. BJOG 107:916–925 Saigal S, Doyle LW (2008) An overview of mortality and
McCowan LM, Pryor J, Harding JE (2002) Perinatal pre- sequelae of preterm birth from infancy to adulthood.
dictors of neurodevelopmental outcome in small-for- Lancet 371:261–269
gestational-age children at 18 months of age. Am J Seri I, Evens J (2001) Controversies in the diagnosis and
Obstet Gynecol 186:1069–1075 management of hypotension in the newborn infant.
McGaw T (2002) Periodontal disease and preterm delivery of Curr Opin Pediatr 13:116–123
low-birth-weight infants. J Can Dent Assoc 68:165–169 Severi FM et al (2002) Uterine and fetal cerebral Doppler
Nicolaides KH (2004) Nuchal translucency and other first- predict the outcome of third-trimester small-for-gesta-
trimester sonographic markers of chromosomal abnor- tional age fetuses with normal umbilical artery Doppler.
malities. Am J Obstet Gynecol 191:45–67 Ultrasound Obstet Gynecol 19:225–228
Noori S, Friedlich P, Seri I (2004) Pathophysiology of Sheridan C (2005) Intrauterine growth restriction. Aust
shock in the fetus and newborn. In: Polin R, Fox W, Fam Physic 34:717–723
Abman S (eds) Fetal and neonatal physiology. Skomsvoll JF, Baste V, Irgens LM, Ostensen M (2002) The
Saunders, Philadelphia, pp 772–781 recurrence risk of adverse outcome in the second preg-
Oros D et al (2010) Middle versus anterior cerebral artery nancy in women with rheumatic disease. Obstet
Doppler for the prediction of perinatal outcome and Gynecol 100:1196–1202
neonatal neurobehavior in term small-for-gestational- Sparks AB et al (2012) Noninvasive prenatal detection and
age fetuses with normal umbilical artery Doppler. selective analysis of cell-free DNA obtained from
Ultrasound Obstet Gynecol 35:456–461 maternal blood: evaluation for trisomy 21 and trisomy
Palomaki GE et al (2011) DNA sequencing of maternal 18. Am J Obstet Gynecol 206:319 e311–319 e319
plasma to detect down syndrome: an international clin- Spencer K, Souter V, Tul N, Snijders R, Nicolaides KH
ical validation study. Genet Med 13:913–920 (1999) A screening program for trisomy 21 at
Parmigiani S, Corona MF (2016) Capitolo 28. Promozione 10–14 weeks using fetal nuchal translucency, maternal
dell’allattamento al seno. In: Felis S, Parmigiani S (eds) serum free b-human chorionic gonadotropin and preg-
Il parto. Edi-Ermes Publisher, Milan, pp 359–372 nancy-associated plasma protein-A. Ultrasound Obstet
Petrini JR, Dias T, Mc Cormick MC et al (2009) Increased Gynecol 13:231–237
risk of adverse neurological development for late pre- Spong CY, Mercer BM, D’alton M, Kilpatrick S, Blackwell
term infants. J Pediatr 154:169–176 S, Saade G (2011) Timing of indicated late-preterm and
Philipps A (2004) Oxygen consumption and general car- early-term birth. Obstet Gynecol 118:323–333
bohydrate metabolism of the fetus. In: Polin R, Fox W, Tajik P et al (2014) Which intrauterine growth restricted
Abman S (eds) Fetal and neonatal physiology. fetuses at term benefit from early labour induction? A
Saunders, Philadelphia, pp 465–478 secondary analysis of the DIGITAT randomised trial.
Picciano MF (2003) Pregnancy and lactation: physiologi- Eur J Obstet Gynecol Reprod Biol 172:20–25
cal adjustments, nutritional requirements and the role of Task Force on Neonatal Encephalopathy and Cerebral
dietary supplements. J Nutr 133:1997S–2002S Palsy Staff American College of Obstetricians and
Practice Bulletin No. 162 (2016 May) Prenatal diagnostic Gynecologists with American Academy of Pediatrics
testing for genetic disorders. Obstet Gynecol 127(5): Staff (2014) Neonatal Encephalopathy and Neurologic
e108–e122 Outcome, Second Edition. Obstetrics & Gynecology
Prechtl HFR (1974) The behavioral states of the newborn 123(4): 896–901
infant: a review. Brain Res 76:1304–1311 Thornton JG, Hornbuckle J, Vail A et al (2004) Infant
Rabi Y, Singhal N, Nettel-Aguirre A (2011) Room-air wellbeing at 2 years of age in the Growth Restriction
versus oxygen administration for resuscitation of pre- Intervention Trial (GRIT): multicentred randomized
term infants: the ROAR study. Pediatrics 128: controlled trial. Lancet 364:513–520
e374–e381 Volpe JJ (2008) Hypoxic-ischemic encephalopathy: clini-
RCOG (2014) The investigation and management of the cal aspects. In: Volpe JJ (ed) Neurology of the newborn.
small-for-gestational-age fetus. Green top guideline 31- Elsevier Saunders, Philadelphia, pp 400–480
Jan 2014 Walter EC, Ehlenbach WJ, Hotchkin DL et al (2009) Low
Rich-Edwards JW, Buka SL, Brennan RT, Earls F (2003) birth weight and respiratory disease in adulthood. A
Diverging associations of maternal age with low population-based case-control study. Am J Respir Crit
birthweight for black and white mothers. Int J Care Med 180:176–180
Epidemiol 32:83–90 Way W (2006) Recent observations on the regulation of the
Rohan AJ, Golombek SG (2009) Hypoxia in the term fetal metabolism of glucose. J Physiol 572:17–24
newborn: part three – sepsis and hypotension, neuro- Winsor EJ et al (1999) Cytogenetic aspects of the Canadian
logic, metabolic and hematologic disorders. MCN Am early and mid-trimester amniotic fluid trial (CEMAT).
J Matern Child Nurs 34:224–233 Prenat Diagn 19:620–627
26 D. Arduini et al.
Wolff PH (1959) Observations on newborn infants. Xiao R, Sorensen TK, Williams MA, Luthy DA (2003)
Psychosom Med 21:110–118 Influence of pre-eclampsia on fetal growth. J Matern
Wolff PH (1966) The causes, controls and organi- Fetal Neonatal Med 13:157–162
zation of behaviour in the neonate. Psychol Issues Zimmermann B et al (2012) Noninvasive prenatal aneu-
5:1–105 ploidy testing of chromosomes 13, 18, 21, X, and Y,
Wood NS, Marlow N, Costeloe K et al (2000) Neuro- using targeted sequencing of polymorphic loci. Prenat
logic and developmental disability after extremely Diagn 32:1233–1241
preterm birth. N Engl J Med 343:378–384. comment Zygmunt M, Herr F, Keller-Schoenwetter S et al (2002)
343:429–430 Characterization of human chorionic gonadotropin as a
Wychoff MH, Aziz K, Escobedo M et al (2015) Part 13: novel angiogenic factor. J Clin Endocrinol Metab
neonatal resuscitation. 2015 American Heart Associa- 87:5290–5296
tion guidelines update for cardiopulmonary resuscita- Zygmunt M, Herr F, Munstedt K et al (2003) Angiogenesis
tion and emergency cardiovascular care. Circulation and vasculogenesis in pregnancy. Eur J Obstet Gynecol
132(Suppl 2):S543–S560 Reprod Biol 110(Suppl 1):S10–S18
Risk Factors for Gestational Diseases
2
Silvia Vannuccini, Michela Torricelli, Filiberto Maria Severi, and
Felice Petraglia
Contents
2.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2.3 Preterm Birth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2.3.1 Risk Factors of Preterm Birth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2.4 Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
2.4.1 Risk Factors for Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Abstract 2.1 Salient Points
Preterm birth (PTB) and preeclampsia (PE) are
severe pathologies that may affect and com- • Preterm birth (PTB) and preeclampsia (PE) are
promise the course of pregnancy, with a high severe pathologies that may affect and com-
perinatal morbidity and mortality. They repre- promise the course of pregnancy, with a high
sent the main “obstetric syndromes,” caused by perinatal morbidity and mortality.
multiple conditions and characterized by com- • Knowledge of the pathogenic mechanisms that
plex pathogenesis. The knowledge of the path- lead to preterm birth and preeclampsia is
ogenetic mechanisms leading to these needed for the recognition of women at risk,
conditions is very important in order to recog- their prevention, and reduction of associated
nize women at risk and to perform the strate- morbidity and mortality.
gies for preventing their onset and reducing • Preterm birth is a syndrome initiated by various
associated morbidity and mortality. conditions, such as inflammation/infection,
uteroplacental ischemia or hemorrhage, uterine
overdistension, cervical disease, stress and
endocrine disorders, and other immunologi-
cally mediated processes.
• Preeclampsia (PE) is defined as persistent
S. Vannuccini · M. Torricelli · F. M. Severi ·
F. Petraglia (*)
blood pressure elevation, edema, and protein-
Obstetrics and Gynecology, Department of Molecular and uria first diagnosed after 20 weeks of gestation.
Developmental Medicine, University of Siena, Siena, Italy Maternal risk factor profiles of early onset PE
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 27
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_151
28 S. Vannuccini et al.
(<32 weeks) and late onset PE differ, intellectual disabilities, and vision and hearing
suggesting that early and late PE may be dif- impairments (Mwaniki et al. 2012). Two-thirds
ferent diseases. of preterm births occur after the spontaneous
onset of labor, whereas the remainder is medically
indicated because of maternal or fetal complica-
2.2 Introduction tions, such as preeclampsia or intrauterine growth
restriction (Goldenberg et al. 2012). The condi-
Preterm birth (PTB) and preeclampsia (PE) are tion merely describes an event that occurs before
severe pathologies that may affect and compro- its due time and is not a diagnosis in itself. There
mise the course of pregnancy, with a high perina- are many pathways leading to preterm birth, and
tal morbidity and mortality (Plunkett et al. 2008). the prevention of each requires different types of
They represent the main “obstetric syndromes,” scientific inquiry and clinical strategies
caused by multiple conditions and characterized (Newnham et al. 2014). Despite the high global
by complex pathogenesis. Nonetheless, recent burden of PTB on childhood mortality, morbidity,
evidences attest that deregulation of the immune and healthcare expenditure, few strategies are
system and exaggeration of inflammatory pro- available to effectively detect women at risk and
cesses, taking place in the fetoplacental unit, rep- prevent preterm delivery (Rubens et al. 2014).
resent common central mechanisms occurring in The risk factors associated with spontaneous
both diseases (Torricelli et al. 2012). preterm births (sPTB) seem to vary by gestational
The knowledge of the pathogenetic mecha- age, social, and environment factors. However,
nisms leading to these conditions is very impor- more than 50% them have no causal factor identi-
tant in order to recognize women at risk and to fied (Menon 2008; Lockwood 2002). Preterm and
perform the strategies for reducing perinatal mor- term labor shared the same clinical events of
bidity and mortality. Interventions can be classi- increased uterine contractility, cervical dilatation,
fied as primary (detected in all women before or and rupture of the chorioamniotic membranes. The
during pregnancy to prevent and reduce risk), common pathway is activated physiologically in
secondary (aimed at eliminating or reducing risk the case of labor at term, whereas in preterm labor
in women with known risk factors), or tertiary several disease processes activate one or more of
(initiated after disease has developed, with a goal the components. In fact, PTB is considered a syn-
of preventing delivery or improving outcomes for drome initiated by various conditions, such as
infants). Most obstetric interventions are intended inflammation/infection, uteroplacental ischemia or
to reduce the burden of prematurity-related ill- hemorrhage, uterine overdistension, cervical dis-
ness, but the primary prevention is a desirable ease, stress and endocrine disorders, and other
goal (Iams et al. 2008). immunologically mediated processes (Petraglia
et al. 2012; Romero et al. 2014a).
2.3 Preterm Birth
2.3.1 Risk Factors of Preterm Birth
PTB, defined as birth before 37 weeks’ gestational
age, occurs with an incidence of 5–18% (Beck Multiple risk factors increase a woman’s risk of
et al. 2010), and it is the leading cause of neonatal PTB (Rubens et al. 2014; Institute of Medicine
death and the second cause of childhood death (US) Committee on Understanding Premature
below the age of 5 years (Liu et al. 2010). Neo- Birth and Assuring Healthy Outcomes et al. 2007),
nates born preterm are at an increased risk of and they may be identified before pregnancy, at
short-term complications attributed to immaturity conception, or during pregnancy (Iams 2014).
of multiple organ systems as well as neurodeve- These include maternal genetics and demography
lopmental disorders, such as cerebral palsy, (e.g., age, ethnicity, poor socioeconomic status),
2 Risk Factors for Gestational Diseases 29
poor nutritional status, pregnancy history, external 2.3.1.1 Preconceptional Factors
factors (e.g., smoking, alcohol ingestion, drugs of • Genetics: Genetic factors are thought to be
abuse), characteristics of the present pregnancy, and important causal components (Plunkett and
associated conditions (infection, uterine contrac- Muglia 2008), as both maternal and fetal
tions, and cervical length shortening) (Table 1). genomes have been shown to influence the
However, the biological basis for many of these risk of sPTB (Haataja et al. 2011). Epidemio-
risk factors and the underlying mechanisms remain logical analyses of large, population-based
poorly understood. Although some of these risk cohorts have revealed increased risk of PTB if
factors are not modifiable, others represent potential the mother herself was born preterm or has
targets for treatment and risk reduction (Goldenberg sisters that have had preterm children (Boyd
et al. 2005, 2008). et al. 2009). More formal genetic studies in
offspring of twins and segregation analysis of
Table 1 Risk factors for preterm birth traits in families consistently demonstrated that
30–40% of the variation in birth timing is due
Preconceptional
to genetic factors (Bezold et al. 2013). How-
Genetics
ever, recent evidence showed that a maternal
Ethnicity
Age
effect accounts for 15.2% of the variance of
Nutritional status gestational age at birth, while the remaining
Socioeconomic status 60.3% is contributed by individual environ-
Obstetric history mental effects (Wu et al. 2015).
Interval between pregnancies • Ethnicity: Women classified as black,
Previous preterm birth African-American, and Afro-Caribbean are
Maternal disorders three times more likely to have a very early
Systemic diseases PTB than women from other ethnic groups.
Hypertension The racial disparity persists after adjustment
Diabetes for social, educational, economic, and medi-
Asthma cal risk factors (Healy et al. 2006; Smith
Thyroid diseases et al. 2007a).
Local or systemic infections • Age: Low and high maternal age are associated
Reproductive disorders with PTB. Age 40 is associated with signif-
PCOS
icantly higher rates of preterm birth (8% vs
Endometriosis/adenomyosis
16%). Similarly, prematurity is more likely in
Uterine fibroids
adolescents (Auger et al. 2013).
Previous cervical surgery
• Nutritional status: A low pregnancy body mass
External factors
Stress
index (BMI) is associated with high risk of
Smoking spontaneous PTB. Women with low serum
Drugs and substances of abuse concentrations of iron, folate, or zinc have
Pregnancy-associated risk factors more PTB than those with measurements
ART conception within the normal range (Bloomfield 2011).
Multiple pregnancy The risk of PTB is increased in obese and
Intrauterine infection and bacterial vaginosis overweight women as well (Cnattingius
Vaginal bleeding et al. 2013; Lynch et al. 2014; McDonald
Short cervix and cervical insufficiency et al. 2010).
Biochemical markers • Socioeconomic status: Low socioeconomic
fFN, phIGFBP1 status is an important risk factor for preterm
Biophysical markers birth. Socioeconomic disadvantage is associ-
TVS cervical length ated with unhealthy or risky behaviors,
30 S. Vannuccini et al.
exposure to stress, and psychological reactions 2.3.1.2 Maternal Disorders
that influence gestation negatively. Indeed, – Systemic diseases: Thyroid diseases, asthma,
behavioral risk factors, such as cigarette diabetes, and hypertension are associated with
smoking, alcohol and drug use, sexually trans- increased rates of PTB (Czeizel and Bánhidy
mitted infections, poor food intake, and obe- 2011; Bramham et al. 2014; American College
sity, are all associated with preterm birth of Obstetricians and Gynecologists 2015;
(Kramer et al. 2001). Gage et al. 2015).
• Obstetric history: – Local or systemic infections: Infections, such
– Interval between pregnancies: An as pyelonephritis and asymptomatic bacteri-
interpregnancy interval of less than uria, pneumonia, and appendicitis, are associ-
6 months confers a greater than twofold ated with PTB (Wing et al. 2014). Periodontal
increased risk of PTB (Smith et al. 2003). disease appears to cause an inflammatory con-
Indeed, Caesarean delivery in the first preg- dition, predisposing to increased risk of PTB
nancy and short interpregnancy interval (Horton and Boggess 2012).
<18 months are significant risk factors for – Reproductive disorders: Women with uterine
term-preterm sequence (Wong et al. 2015). fibroids, endometriosis, adenomyosis, and
Furthermore, women whose first birth was polycystic ovary syndrome (PCOS) have an
preterm are far more likely to have a short increased risk of poor obstetric outcome,
interval than women who had a term first including preterm birth (Conti et al. 2013,
birth, thus compounding the risk. 2015; Naver et al. 2014; Palomba et al. 2015;
– Previous PTB: The recurrence risk in Juang et al. 2007). Inflammatory, endocrine,
women with a previous PTB ranges from and metabolic aberrations associated with
15% to 50%, depending on the number and these disorders are implicated in the pathogen-
gestational age of previous deliveries esis of obstetric complications (Vannuccini
(Kazemier et al. 2014). The number, et al. 2016). Infertility and subfertility itself
sequence, and weeks of gestation of previ- are also risk factors for preterm birth
ous births all affect the risk of recurrence, (DoPierala et al. 2015; Stern et al. 2015).
which ranges from less than 15% among – Previous cervical surgery: Cervical surgery is
women with one preterm birth after associated with spontaneous preterm birth;
32 weeks of gestation followed by a term however, it is unclear whether this increased
delivery to nearly 60% among women with risk is due to the surgery itself or to the cervical
a history of two or more preterm births intraepithelial neoplasia underlying the surgery
(Goldenberg et al. 2006). Based on the clin- (Bruinsma and Quinn 2011). Women who
ical presentation of a prior spontaneous pre- attend colposcopy for precancerous changes
term birth, patients with a history of in cervix are at a higher risk of a subsequent
advanced cervical dilatation are at an preterm birth (regardless of whether or not they
increased risk of having recurrent preterm are treated) (Castanon et al. 2012, 2015). The
birth and cervical shortening in a subse- risk is greater still among those who receive an
quent pregnancy compared with women excisional treatment (biopsy sample or loop
with prior preterm birth associated electrocautery excision), and it is particularly
PPROM or preterm labor (Drassinower high when the depth of the tissue excised is
et al. 2015). Spontaneous preterm births 15 mm (Castanon et al. 2014).
are also more common among women
with a history of giving birth between 2.3.1.3 External Factors
16 and 20 weeks of gestation or with a – Stress: Mothers experiencing psychological
history of stillbirth before 24 weeks of ges- stress are at increased risk of PTB (Dole
tation (McManemy et al. 2007; Edlow et al. 2003). Although the mechanism underly-
et al. 2007). ing the link between psychological or social
2 Risk Factors for Gestational Diseases 31
stress and increased risk of PTB is unknown, a and cervix into the choriodecidual space,
role has been proposed for corticotrophin- affecting the myometrium, fetal membranes,
releasing hormone (Voltolini and Petraglia and amniotic fluid. Ascending bacterial infec-
2014; Ruiz et al. 2015). Moreover, exposure tion is implicated in about 40–50% of preterm
to two or more adverse childhood experiences births. Infection may infrequently enter the
was associated with a twofold risk of preterm uterus by the hematogenous route, through
birth in adulthood, demonstrating that stressors retrograde seeding via the fallopian tube
throughout life can have a significant effect on (Witkin 2015). Intrauterine infection is an
pregnancy outcomes (Christiaens et al. 2015). important mechanism leading to PTB through
– Smoking: Tobacco use increases the risk of the activation of the innate immune system.
PTB. Both nicotine and carbon monoxide are Microbial endotoxins and proinflammatory
powerful vasoconstrictors and are associated cytokines stimulate the production of prosta-
with placental damage and decreased glandins and matrix-degrading enzymes. Pros-
uteroplacental blood flow, leading to fetal taglandins stimulate uterine contractility,
growth restriction and PTB (Shah and Bracken whereas degradation of the extracellular matrix
2000; Ko et al. 2014; Ion et al. 2015). in the fetal membranes leads to PPROM (Kemp
– Drugs and substances of abuse: Several mater- 2014). Recent studies have examined the role of
nal drugs affect the developing fetus, and the the vaginal, gastrointestinal, and oral
baby after birth may manifest signs attributable microbiome and possible associations with
to withdrawal. Maternal cocaine, opiate, and PTB. Advances in DNA sequencing technology
diazepam use are particularly relevant, as a have dramatically improved our understanding
history of excessive alcohol ingestion, espe- of the maternal microbiome and its impact on
cially binge drinking (Bonello et al. 2014). pregnancy and PTB, far beyond what traditional
culture-based technology has done to date (Fox
2.3.1.4 Pregnancy-Associated Risk and Eichelberger 2015). Metagenomic studies
Factors have begun to characterize the healthy vaginal
– Assisted reproductive technologies (ART): and gut microbiomes in the nongravid and
Pregnancies from assisted conception are at gravid state, as well as the rich diverse placental
increased risk of both spontaneous and indicated microbiome. It has been proposed that the
preterm births than those with natural concep- increased stability of the vaginal microbiome
tion. In vitro techniques, ovarian stimulation, during pregnancy may play a protective role in
culture media, and possibly additional freezing the prevention of ascending vaginal infection by
or vitrification procedures, together with infer- means of the dominance of lactobacilli (Romero
tility itself, seem to play a role in the pathogen- et al. 2014b). Disturbances in lactobacilli in the
esis of adverse obstetric outcome in ART vaginal microbiome often lead to dysbiosis and
pregnancies (Pinborg et al. 2013; Messerlian bacterial vaginosis (BV), a known risk factor for
et al. 2013; Dunietz et al. 2015). preterm delivery. Common bacterial species
– Multiple pregnancy: Multiple gestations carry identified in PTB-associated infections include
a risk of PTB and result in 15–20% of all PTB. Ureaplasma urealyticum, Mycoplasma hominis,
Uterine overdistension, resulting in contrac- Bacteroides spp., Gardnerella vaginalis, and
tions and PPROM, is believed to be the caus- Fusobacterium nucleatum. These organisms
ative mechanism for the rate of increased typically display low virulence unless they
spontaneous PTB (Voltolini et al. 2013). reach the intrauterine environment (Mysorekar
– Bacterial vaginosis (BV) and intrauterine and Cao 2014; Petricevic et al. 2014).
infection: Inflammation, whether or not related – Vaginal bleeding: Uterine contractions and
to infection, is one of the best-studied path- PTB can be instigated by bleeding between
ways in humans and animal models of PTB. the chorion and decidua at the placental bed,
Infection commonly ascends from the vagina causing overt or subclinical separation of the
32 S. Vannuccini et al.
placenta from the implantation site at the uter- 2.3.1.5 Biochemical Markers
ine wall, clinically known as abruption (Nor- Biological fluids (amniotic fluid, urine, cervical
man et al. 2010). The plasma protease mucus, vaginal secretions, serum or plasma, and
thrombin plays a central role in the signaling saliva) have been used to assess the value of bio-
cascade that is initiated by blood in the markers for the prediction of PTB. These body
subchorionic space. Vaginal bleeding caused fluids provide rich sources of proteins and metab-
by placental abruption is associated with a olites that vary in concentration in response to
very high risk of PTB. Similarly, placental pregnancy and adverse pregnancy states. With the
implantation abnormalities such as placenta development of genomic and proteomic technolo-
previa, placenta accreta, and vasa previa are gies over the past two decades, the simultaneous
associated with increased risk of preterm birth screening of thousands of genes and gene products
(Vahanian et al. 2015). However, bleeding in from small samples of tissue or body fluid has
the first and second trimesters, that is not asso- become possible. Hormones and inflammatory
ciated with either placental abruption or pla- and angiogenic mediators are implicated in PTB
cental abnormalities, is also associated with pathogenesis. However, it has becoming evident
subsequent PTB (Krupa et al. 2006). that single biomarker approaches for the early
– Short cervix and cervical insufficiency: At the detection of preterm birth may never achieve the
beginning of pregnancy, the etiology of a short desired diagnostic efficiency (Klein et al. 2014; De
cervix differs from what occurs in the middle and Bonis et al. 2012).
at the end of pregnancy. A cervix that starts to There are two commonly used clinical bio-
diminish at the beginning of pregnancy may be a marker tests for the prediction of preterm labor,
sign of previous damage to the cervix, such as namely, fetal fibronectin (fFN) and phosphorylated
through surgery (conization or excision using a insulin-like growth factor binding protein-1
LEEP loop) or due to uterine malformations (phIGFBP1). The most useful biochemical PTB
(Vaisbuch et al. 2010; Poon et al. 2012; Miller predictor is fetal fibronectin, a glycoprotein that
et al. 2015). In the second trimester of pregnancy, when present in cervicovaginal fluid is a marker of
isthmocervical incompetence is the most impor- choriodecidual disruption (Goldenberg et al. 1996).
tant cause of cervical shortening, thereby caus- Although fetal fibronectin is normally absent from
ing late abortions and spontaneous preterm cervicovaginal secretions from 24 weeks until term,
delivery. This may be congenital (primary) or 3–4% of women undergoing routine screening at
be acquired (secondary) through trauma to the 24–26 weeks are positive and at increased risk of
isthmocervical region, such as untimely cervical PTB. Owing to its high negative predictive value, a
dilatation, application of a high forceps, or negative fFN result has been shown to reduce
amputation. However, distinguishing cervical unnecessary interventions, change patient manage-
insufficiency from cervical shortening attribut- ment, and reduce healthcare costs, by allowing early
able to other causes has proven difficult, and the reassurance and return to normal care pathways,
exact contribution to preterm birth is unknown. while care can be concentrated on those at risk.
Short cervical length (i.e., values below the tenth Indeed, the fFN test appears to be more informative
percentile for gestational age), as measured with in predicting spontaneous preterm birth within the
the use of transvaginal ultrasonography at 18–24 7–14 days in women presenting with threatened
weeks of gestation, is a consistent predictor of an preterm labor, due to its generally poor positive
increased risk of preterm delivery, regardless of predictive value (Foster and Shennan 2014).
other factors. The risk increases as cervical length phIGFBP1 is secreted by decidual cells and
decreases in the second trimester; the risk asso- leaks into cervical secretions when fetal mem-
ciated with a cervical length below the tenth branes detach from decidua. It has been used to
percentile (25 mm) is 25–30%, and the risk asso- clinically assess cervical maturation. Clinical
ciated with a cervical length at or below the third diagnostic trials indicate that, like fFN,
percentile (15 mm) is 50% (Hughes et al. 2015). phIGFBP1 is a good negative predictor of preterm
2 Risk Factors for Gestational Diseases 33
birth (92% specificity) but lacks suitable sensitiv- prematurity, although uteroplacental insufficiency
ity and positive predictive value in asymptomatic may also be associated with the disease. The only
women (Conde-Agudelo and Romero 2015). known cure is cessation of pregnancy, although
temporizing measures are often undertaken (Sibai
2.3.1.6 Biophysical Markers 2005; Steegers et al. 2010). In general, the mater-
Ultrasound measurement of uterine cervical nal risk factor profiles vary between early-onset
length can be useful in evaluating the likelihood PE (<32 weeks) and late-onset PE. This has led to
of early labor in those women known to be at the view that early and late PE may be different
increased risk for prematurity (Hughes diseases. An alternative view is that PE is a spec-
et al. 2015). A statistically significant inverse rela- trum disorder, the degree of which is reflected in
tionship between cervical length seen on gestational age at the time of delivery (Poon and
transvaginal ultrasonography in the second tri- Nicolaides 2014).
mester and the risk of preterm delivery has been The exact cause of preeclampsia is currently
demonstrated in both low-risk asymptomatic sin- unknown, but there is a consensus that the pla-
gle pregnancies and high-risk patients, including centa plays a cardinal role in the pathogenesis of
those with previous preterm delivery. The risk of preeclampsia because delivery of the placenta
preterm delivery varies as a function of the gesta- resolves the clinical symptoms. Changes in the
tional age at the time of diagnosing the cervical oxygenation levels of the placenta due to failure
shortening. Almost two-thirds of the women diag- of spiral artery transformation are thought to be
nosed with a short cervix before the 20th week of responsible for the underlying pathology of pre-
pregnancy will deliver at the threshold of viability eclampsia. This syndrome is thought to occur in
(<24 weeks of gestation), and less than one quar- two stages with abnormal placentation leading to
ter of them will still be pregnant when the 28th a maternal inflammatory response. In preeclamp-
week of gestation is completed. Between 22 and sia, cytotrophoblast invasion of the interstitial
30 weeks, the tenth percentile for cervical length uterine compartment is frequently shallow, and
is 25 mm, and a length less than this measurement in many locations spiral artery invasion is incom-
is significantly associated with preterm birth. plete. There are many fewer endovascular
Women with a history of preterm birth and a cytotrophoblasts, and some vessels retain portions
cervical length less than 25 mm are 3.3–4.5 of their endothelial lining with relatively intact
times more likely to experience preterm birth muscular coats, showing deficits in the differenti-
than the general population (Iams et al. 1996; ation program that enables cytotrophoblast inva-
Hibbard et al. 2000). sion of the uterine wall (Fisher 2015).
Recent discoveries of an imbalance in
antiangiogenic factors and loss of cytoprotective
2.4 Preeclampsia mechanisms in preeclamptic placentas have pro-
vided new insights into the pathophysiology of
PE is defined as persistent blood pressure eleva- PE. Systemic maternal vascular dysfunction
tion, edema, and proteinuria first diagnosed after seems to be a major phenotype of pregnancies
20 weeks of gestation. The minimal criteria for the with preeclampsia, contributing to increased
diagnosis of PE are proteinuria, defined as 300 mg peripheral vascular resistance, maternal hyper-
or more of urinary protein excretion per 24 h, and tension, and proteinuria. The mechanisms of sys-
hypertension, defined as blood pressure of temic vascular dysfunction in preeclamptic
140/90 mmHg or higher (Sibai et al. 2005). PE pregnancies involve an imbalance in the produc-
affects 5–7% of all pregnancies and is responsible tion of constrictors and dilators in vascular cells,
for 7–15% of maternal mortality. Severe and/or hyperresponsiveness to constrictor stimuli,
early-onset PE is an important cause of fetal and reduced endothelium-dependent dilation, and
maternal morbidity and mortality. Neonatal out- oxidative stress (Goulopoulou and Davidge
comes are directly related to iatrogenic 2015).
34 S. Vannuccini et al.
2.4.1 Risk Factors for Preeclampsia – Previous preeclampsia: Mothers who had PE
in their first pregnancy are at higher risk for the
Early identification of women at risk for pre- development of PE in a subsequent pregnancy,
eclampsia (before 13 weeks) is a core tenet of especially when PE is severe, occurs early
management. Several studies identified risk fac- during the pregnancy, or is associated with a
tors for early detection of high risk women low birth weight (Duckitt and Harrington
(Table 2) (Dekker and Sibai 2001; Duckitt 2005).
and Harrington 2005). – Time between pregnancies: The association
between risk of preeclampsia and interval is
2.4.1.1 Preconceptional Factors more significant than the association between
– Age: The risk of preeclampsia increases by risk and change of partner. The risk in a second
30% for every additional year of age past 34. or third pregnancy was directly related to the
Women aged 40 had approximately twice the time elapsed since the previous delivery. When
risk of developing preeclampsia (Lamminpää the interval was 10 years or more, the risk of
et al. 2012). preeclampsia was about the same as that in
– Nulliparity: Nulliparous women have almost nulliparous women (Skjaerven et al. 2002).
three times the risk for preeclampsia, as conse-
quence of an abnormal response to paternal anti- 2.4.1.2 Maternal Disorders
gens in fetoplacental unit (Bdolah et al. 2014). – Chronic hypertension and renal disease: The
– A family history of preeclampsia: Severe PE risk of developing superimposed PE is partic-
and eclampsia have a familial occurrence. A ularly increased in women with severe hyper-
family history of PE is associated with a three- tension and in those with cardiovascular or
fold increased risk of PE and a fourfold renal disease. The incidence of superimposed
increased risk of severe PE (North et al. 2011). PE increases in patients with chronic renal
disease, especially if there is coexisting hyper-
tension (Bramham et al. 2014).
– Obesity, insulin resistance, PCOS, and diabe-
Table 2 Risk factors for preeclampsia
tes: Obesity, insulin resistance, and glucose
Preconceptional intolerance are strongly associated with
Age nonpregnant hypertension and PCOS. Essen-
Nulliparity
tial hypertension is an insulin-resistant state
Previous preeclampsia
itself. Obesity is probably the most common
Family history
cause of insulin resistance and represents a risk
Maternal disorders
factor for developing pregnancy-induced
Chronic hypertension and renal diseases
Obesity
hypertension as well as PE (Bhattacharya
Insulin resistance and diabetes et al. 2007; Spradley et al. 2015). In women
PCOS with PCOS, the prevalence of gestational
Thrombophilic disorders hypertension and preeclampsia is estimated at
External factors 10–30% and 8–15%, respectively. This preva-
Stress lence may be even higher when PCOS women
Pregnancy-associated risk factors are obese and hyperinsulinemic (Petraglia
Oocyte donation et al. 2015). There is a certain degree of insulin
Multiple pregnancy resistance and hyperinsulinemia in preeclamptic
Congenital and chromosomal anomalies women during pregnancy. The insulin resistance
Biophysical markers appears to be based on a higher mean body mass
Uterine artery Doppler study index in women with PE. Overt type 1 diabetes
Biochemical markers mellitus is associated with an increased inci-
hCG, activin A, inhibin A, PIGF, VEGF, sFlt-1, PAPP-A dence of PE (Colatrella et al. 2010).
2 Risk Factors for Gestational Diseases 35
– Thrombophilic disorders: Patients with severe associated with noncritical heart defects in off-
early-onset PE often have hemostatic or meta- spring, while PE before 34 weeks was associ-
bolic abnormalities, which are associated with a ated with critical heart defects (Auger
tendency to vascular thrombosis. There is an et al. 2015).
increased incidence of activated protein C
(aPC) resistance or factor V Leiden mutation 2.4.1.5 Biophysical Markers
in women with a history of PE and/or adverse Reduced uteroplacental blood flow and placental
perinatal outcome. Thus, women with familial ischemia leads to the release of placental factors
thrombophilia are at increased risk not only of with detrimental effects on the maternal vascular
PE but also of fetal loss. Protein S deficiency endothelium, leading to a rise in blood pressure
and aPC resistance both result in an impaired and changes in the uterine artery flow velocities.
aPC pathway. This impairment appears to be In the early days, the most important predictors of
associated with a more aggressive course of PE were those related to the early recognition of
the pathologic changes (thrombosis, acute raised blood pressure in the mother (Wright
atherosis) in the spiral arteries. Classic et al. 2015); more recently, there has been detec-
homocystinuria is the homozygous form of the tion of impaired uterine artery blood velocities
autosomal recessively inherited cystathionine and particularly their wave forms by uterine artery
β-synthase deficiency. The incidence of Doppler sonography (notch). Assessed during
hyperhomocysteinemia increases the risk for midtrimester, such abnormal Doppler findings
preeclampsia, mainly for severe early-onset PE indicate a substantially increased risk for the
(Berks et al. 2015). development of PE. Uterine artery Doppler
sonography more accurately predicted PE than
2.4.1.3 External Factors intrauterine growth retardation, and the most pow-
– Stress: Working women have 2.3 times the risk erful Doppler index for predicting PE was an
of developing PE compared with nonworking increased pulsatility with notching in the second
women (Klonoff-Cohen et al. 1996), even if trimester (Akolekar et al. 2013).
more recent studies reported controversial
results (Vollebregt et al. 2008). 2.4.1.6 Biochemical Markers
Trophoblastic abnormalities play a central role in
2.4.1.4 Pregnancy-Associated Risk the development of PE and precede the appear-
Factors ance of clinical signs and symptoms; some pla-
– Oocyte donation: The risk of preeclampsia is cental hormones change in the maternal
higher in oocyte donation pregnancies com- circulation, indicating altered placental function.
pared to other methods of assisted reproductive The levels of several placental hormones are ele-
technology or natural conception (Masoudian vated in maternal serum before the diagnosis of
et al. 2016). PE, and these may be considered preclinical man-
– Multiple pregnancy: The incidence and sever- ifestations of the earlier stages of the disease. Such
ity of PE, the incidence of eclampsia, and the hormones have therefore been proposed as early
incidence of early-onset PE are significantly predictive markers of PE (Anderson et al. 2012).
increased in patients with twin pregnancies, Women with PE in the third trimester have
who have a fourfold increased risk of PE increased maternal serum human chorionic gonad-
(Fox et al. 2014). otropin (hCG) levels. Maternal hCG levels are
– Congenital and chromosomal anomalies: already increased in the second trimester in preg-
Malformations of the male genital apparatus nancies that subsequently develop PE (Kalinderis
should be considered as risk factors for PE et al. 2011; Bahado-Singh et al. 1998). Maternal
(Vesce et al. 1997). There is also an increased serum activin A and inhibin A levels are increased
incidence of preeclampsia in cases of fetal in the presence of hypertensive disorders. Because
hydrops. Preeclampsia was significantly activin A is involved in the control of trophoblast
36 S. Vannuccini et al.
cell differentiation in the first trimester, altered index, mean arterial pressure, and placental
expression of this protein may affect placental growth factor predicted 75% of PE (O’Gorman
invasiveness, resembling the pathogenesis of et al. 2016).
PE. Inhibin A is elevated several weeks before
the onset of clinical signs of PE. However, when
both proteins are measured at 15–19 weeks, inhibin References
A appears to be more sensitive than activin A in
predicting early-onset PE culminating with deliv- Akolekar R, Syngelaki A, Poon L et al (2013) Competing
ery before 34 weeks (Florio et al. 2001, 2002; risks model in early screening for preeclampsia by
biophysical and biochemical markers. Fetal Diagn
Muttukrishna et al. 2000). Ther 33:8–15
Phosphatidylinositol-glycan biosynthesis class American College of Obstetricians and Gynecologists
F (PlGF) and vascular endothelial growth factor (2015) Practice bulletin no. 148: thyroid disease in
(VEGF) are potent angiogenic factors, inhibited pregnancy. Obstet Gynecol 125:996–1005
Anderson UD, Olsson MG, Kristensen KH et al (2012)
by the soluble form of the vascular endothelial Review: biochemical markers to predict preeclampsia.
growth factor receptor-1 (sVEGFR-1), also Placenta 33(Suppl):S42–S47
known as soluble fms-like tyrosine kinase-1 Andraweera PH, Dekker GA, Laurence JA et al (2012)
(sFlt-1), which may be considered the most Placental expression of VEGF family mRNA in
adverse pregnancy outcomes. Placenta 33:467–472
important candidate for preventing of PE and Auger N, Hansen AV, Mortensen L (2013) Contribution of
also targets placental growth factor. PlGF and maternal age to preterm birth rates in Denmark and
VEGF-A are expressed by trophoblasts and Quebec, 1981–2008. Am J Public Health 103:e33–e38
show altered expression patterns in PE, and par- Auger N, Fraser WD, Healy-Profitós J et al (2015) Asso-
ciation between preeclampsia and congenital heart
ticularly lower PlGF. sFLT-1 serum concentra- defects. JAMA 314:1588–1598
tions are also increased in PE and correlate with Bahado-Singh RO, Oz U, Isozaki T et al (1998)
the severity of the disease (Cooper et al. 1996; Midtrimester urine human chorionic gonadotropin
Andraweera et al. 2012; Smith et al. 2007b). Preg- beta-subunit core fragment levels and the subsequent
development of pre-eclampsia. Am J Obstet Gynecol
nancy-associated plasma protein A (PAPP-A) is a 179:738–741
large glycoprotein complex, which is predomi- Bdolah Y, Elchalal U, Natanson-Yaron S, Yechiam H
nantly produced by the placenta. PAPP-A cleaves et al (2014) Relationship between nulliparity and pre-
insulin-like growth factor binding protein eclampsia may be explained by altered circulating sol-
uble fms-like tyrosine kinase 1. Hypertens Pregnancy
(IGFBP)-4 and -5 and, thereby, modulates the 33:250–259
activity of insulin-like growth factor (IGF)-1 and Beck S, Wojdyla D, Say L et al (2010) The worldwide
-2. Moreover, PAPP-A has been suggested to play incidence of preterm birth: a systematic review of
a role in human implantation. Its circulating levels maternal mortality and morbidity. Bull World Health
Organ 88:31–38
were found to be elevated after the onset of PE and Berks D, Duvekot JJ, Basalan H et al (2015) Associations
lower in women who subsequently developed PE between phenotypes of preeclampsia and
(Spencer et al. 2006, 2008). thrombophilia. Eur J Obstet Gynecol Reprod Biol
In pregnancies that experienced preeclampsia, 194:199–205
Bezold KY, Karjalainen MK, Hallman M et al (2013) The
the values of uterine artery pulsatility index and genomics of preterm birth: from animal models to
mean arterial pressure were increased, and the human studies. Genome Med 5:34
values of serum pregnancy-associated plasma Bhattacharya S, Campbell DM, Liston WA et al (2007)
protein-A and placental growth factor were Effect of Body Mass Index on pregnancy outcomes in
nulliparous women delivering singleton babies. BMC
decreased. For all biomarkers, the deviation Public Health 7:168
from normal was greater for early than late pre- Bloomfield FH (2011) How is maternal nutrition related to
eclampsia; therefore, the performance of screen- preterm birth? Annu Rev Nutr 31:235–261
ing was related inversely to the gestational age Bonello MR, Xu F, Li Z et al (2014) Mental and behavioral
disorders due to substance abuse and perinatal out-
at which delivery became necessary for mater- comes: a study based on linked population data in
nal and/or fetal indications. Combined screen- New South Wales, Australia. Int J Environ Res Public
ing by maternal factors, uterine artery pulsatility Health 11:4991–5005
2 Risk Factors for Gestational Diseases 37
Boyd HA, Poulsen G, Wohlfahrt J et al (2009) Maternal Dole N, Savitz DA, Hertz-Picciotto I et al (2003) Maternal
contributions to preterm delivery. Am J Epidemiol stress and preterm birth. Am J Epidemiol 157:14–24
170:1358–1364 DoPierala AL, Bhatta S, Raja EA et al (2015) Obstetric
Bramham K, Parnell B, Nelson-Piercy C, Seed PT consequences of subfertility: a retrospective cohort
et al (2014) Chronic hypertension and pregnancy out- study. BJOG 123:1320–8
comes: systematic review and meta-analysis. BMJ 348: Drassinower D, Običan SG, Siddiq Z et al (2015) Does the
g2301 clinical presentation of a prior preterm birth predict risk
Bruinsma FJ, Quinn MA (2011) The risk of preterm birth in a subsequent pregnancy? Am J Obstet Gynecol
following treatment for precancerous changes in the 213:686.e1–686.e7
cervix: a systematic review and meta-analysis. BJOG Duckitt K, Harrington D (2005) Risk factors for
118:1031–1041 pre-eclampsia at antenatal booking: systematic review
Castanon A, Brocklehurst P, Evans H et al (2012) Risk of of controlled studies. BMJ 330:565
preterm birth after treatment for cervical intraepithelial Dunietz GL, Holzman C, McKane P et al (2015) Assisted
neoplasia among women attending colposcopy in reproductive technology and the risk of preterm birth
England: retrospective-prospective cohort study. BMJ among primiparas. Fertil Steril 103:974–979
345:e5174 Edlow AG, Srinivas SK, Elovitz MA (2007) Second trimes-
Castanon A, Landy R, Brocklehurst P et al (2014) Risk of ter loss and subsequent pregnancy outcomes: what is the
preterm delivery with increasing depth of excision for real risk? Am J Obstet Gynecol 197:581.e1–581.e6
cervical intraepithelial neoplasia in England: nested Fisher SJ (2015) Why is placentation abnormal in pre-
case–control study. BMJ 349:g6223 eclampsia? Am J Obstet Gynecol 213(4 Suppl):
Castañon A, Landy R, Brocklehurst P, PaCT Study Group S115–S122
et al (2015) Is the increased risk of preterm birth fol- Florio P, Cobellis L, Luisi S et al (2001) Changes in
lowing excision for cervical intraepithelial neoplasia inhibins and activin secretion in healthy and patholog-
restricted to the first birth post treatment? BJOG ical pregnancies. Mol Cell Endocrinol 180:123–130
122:1191–1199 Florio P, Ciarmela P, Luisi S et al (2002) Pre-eclampsia
Christiaens I, Hegadoren K, Olson DM (2015) Adverse with fetal growth restriction: placental and serum
childhood experiences are associated with spontaneous activin A and inhibin A levels. Gynecol Endocrinol
preterm birth: a case-control study. BMC Med 13:124 16:365–372
Cnattingius S, Villamor E, Johansson S et al (2013) Mater- Foster C, Shennan AH (2014) Fetal fibronectin as a bio-
nal obesity and risk of preterm delivery. JAMA marker of preterm labor: a review of the literature and
309:2362–2370 advances in its clinical use. Biomark Med 8:471–484
Colatrella A, Loguercio V, Mattei L et al (2010) Hyperten- Fox C, Eichelberger K (2015) Maternal microbiome and
sion in diabetic pregnancy: impact and long-term out- pregnancy outcomes. Fertil Steril 104:1358–1363
look. Best Pract Res Clin Endocrinol Metab Fox NS, Roman AS, Saltzman DH et al (2014) Risk factors
24:635–651 for preeclampsia in twin pregnancies. Am J Perinatol
Conde-Agudelo A, Romero R (2015) Cervical phos- 31:163–166
phorylated insulin-like growth factor binding Gage S, Kan P, Lee HC et al (2015) Maternal asthma,
protein-1 test for the prediction of preterm birth: a preterm birth, and risk of bronchopulmonary dysplasia.
systematic review and metaanalysis. Am J Obstet J Pediatr 167:875–880
Gynecol 214:57–73 Goldenberg RL, Mercer BM, Meis PJ et al (1996) The
Conti N, Tosti C, Pinzauti S et al (2013) Uterine fibroids preterm prediction study: fetal fibronectin testing and
affect pregnancy outcome in women over 30 years old: spontaneous preterm birth. Obstet Gynecol
role of other risk factors. J Matern Fetal Neonatal Med 87:643–648
26:584–587 Goldenberg RL, Goepfert AR, Ramsey PS (2005) Bio-
Conti N, Cevenini G, Vannuccini S et al (2015) Women chemical markers for the prediction of preterm birth.
with endometriosis at first pregnancy have an increased Am J Obstet Gynecol 192:36–46
risk of adverse obstetric outcome. J Matern Fetal Neo- Goldenberg RL, Andrews WW, Faye O et al (2006) The
natal Med 28:1795–1798 Alabama preterm birth project: placental histology in
Cooper JC, Sharkey AM, Charnock-Jones DS et al (1996) recurrent spontaneous and indicated preterm birth. Am
VEGF mRNA levels in placentae from pregnancies J Obstet Gynecol 195:792–796
complicated by pre-eclampsia. Br J Obstet Gynaecol Goldenberg RL, Culhane JF, Iams JD, Romero R (2008)
103:1191–1196 Epidemiology and causes of preterm birth. Lancet
Czeizel AE, Bánhidy F (2011) Chronic hypertension in 371:75–84
pregnancy. Curr Opin Obstet Gynecol 23:76–81 Goldenberg RL, Gravett MG, Iams J et al (2012) The preterm
De Bonis M, Vellucci FL, Di Tommaso M et al (2012) birth syndrome: issues to consider in creating a classifi-
Clinical use of placental hormones in pregnancy man- cation system. Am J Obstet Gynecol 206:113–118
agement. J Endocrinol Invest 8:776–781 Goulopoulou S, Davidge ST (2015) Molecular mecha-
Dekker G, Sibai B (2001) Primary, secondary, and tertiary nisms of maternal vascular dysfunction in preeclamp-
prevention of pre-eclampsia. Lancet 357:209–215 sia. Trends Mol Med 21:88–97
38 S. Vannuccini et al.
Haataja R, Karjalainen MK, Luukkonen A et al (2011) Krupa FG, Faltin D, Cecatti JG et al (2006) Predictors of
Mapping a new spontaneous preterm birth susceptibil- preterm birth. Int J Gynaecol Obstet 94:5–11
ity gene, IGF1R, using linkage, haplotype sharing, and Lamminpää R, Vehviläinen-Julkunen K, Gissler M
association analysis. PLoS Genet 7:e1001293 et al (2012) Preeclampsia complicated by advanced
Healy AJ, Malone FD, Sullivan LM et al (2006) Early maternal age: a registry-based study on primiparous
access to prenatal care: implications for racial disparity women in Finland 1997–2008. BMC Pregnancy Child-
in perinatal mortality. Obstet Gynecol 107:625–631 birth 12:47
Hibbard JU, Tart M, Moawad AH (2000) Cervical length at Liu L, Johnson HL, Cousens S, Child Health Epidemiol-
16–22 weeks’ gestation and risk for preterm delivery. ogy Reference Group of WHO and UNICEF
Obstet Gynecol 96:972–978 et al (2010) Global, regional, and national causes of
Horton AL, Boggess KA (2012) Periodontal disease and child mortality: an updated systematic analysis for
preterm birth. Obstet Gynecol Clin N Am 39:17–23 2010 with time trends since 2000. Lancet 380:1308
Hughes K, Kane SC, Araujo Júnior E et al (2015) Cervical Lockwood CJ (2002) Predicting premature delivery-no
length as a predictor of spontaneous preterm birth in easy task. N Engl J Med 346:282–284
high-risk singleton pregnancy – current knowledge. Lynch AM, Hart JE, Agwu OC et al (2014) Association of
Ultrasound Obstet Gynecol 48:7–15 extremes of prepregnancy BMI with the clinical pre-
Iams JD (2014) Prevention of preterm parturition. N Engl J sentations of preterm birth. Am J Obstet Gynecol 210:
Med 370:1861 e19, 428
Iams JD, Goldenberg RL, Meis PJ et al (1996) The length Masoudian P, Nasr A, De Nanassy J et al (2016) Oocyte
of the cervix and the risk of spontaneous premature donation pregnancies and the risk of preeclampsia or
delivery. N Engl J Med 334:567–572 gestational hypertension: a systematic review and
Iams JD, Romero R, Culhane JF, Goldenberg RL (2008) meta-analysis. Am J Obstet Gynecol 214:328–39
Primary, secondary, and tertiary interventions to reduce McDonald SD, Han Z, Mulla S, Knowledge Synthesis
the morbidity and mortality of preterm birth. Lancet Group et al (2010) Overweight and obesity in mothers
371:164–175 and risk of preterm birth and low birth weight infants:
Institute of Medicine (US) Committee on Understanding systematic review and meta-analyses. BMJ 341:c3428
Premature Birth and Assuring Healthy Outcomes, McManemy J, Cooke E, Amon E et al (2007) Recurrence
Behrman RE, Butler AS (eds) (2007) Preterm birth: risk for preterm delivery. Am J Obstet Gynecol
causes, consequences, and prevention. National Acad- 196:576.e1–576.e6
emies Press, Washington, DC Menon R (2008) Spontaneous preterm birth, a clinical
Ion RC, Wills AK, Bernal AL (2015) Environmental dilemma: aetiological, pathophysiological and genetic
tobacco smoke exposure in pregnancy is associated heterogeneities and racial disparity. Acta Obstet
with earlier delivery and reduced birth weight. Reprod Gynecol Scand 87:590–600
Sci 22:1603–1611 Messerlian C, Maclagan L, Basso O (2013) Infertility
Juang CM, Chou P, Yen MS et al (2007) Adenomyosis and and the risk of adverse pregnancy outcomes: a sys-
risk of preterm delivery. BJOG 114:165–169 tematic review and meta-analysis. Hum Reprod
Kalinderis M, Papanikolaou A, Kalinderi K et al (2011) 28:125–137
Elevated serum levels of interleukin-6, interleukin-1β Miller ES, Sakowicz A, Grobman WA (2015) The
and human chorionic gonadotropin in pre-eclampsia. association between cervical dysplasia, a short cervix,
Am J Reprod Immunol 66:468–475 and preterm birth. Am J Obstet Gynecol 213:543.
Kazemier BM, Buijs PE, Mignini L et al (2014) Impact of e1–543.e4
obstetric history on the risk of spontaneous preterm Muttukrishna S, North RA, Morris J et al (2000) Serum
birth in singleton and multiple pregnancies: a system- inhibin A and activin A are elevated prior to the onset of
atic review. BJOG 121:1197–1208 pre-eclampsia. Hum Reprod 15:1640–1645
Kemp MW (2014) Preterm birth, intrauterine infection, Mwaniki MK, Atieno M, Lawn JE et al (2012) Long-term
and fetal inflammation. Front Immunol 5:574 neurodevelopmental outcomes after intrauterine and neo-
Klein J, Buffin-Meyer B, Mullen W et al (2014) Clinical natal insults: a systematic review. Lancet 379:445–452
proteomics in obstetrics and neonatology. Expert Rev Mysorekar I, Cao B (2014) Microbiome in parturition and
Proteomics 11:75–89 preterm birth. Semin Reprod Med 32:50–55
Klonoff-Cohen HS, Cross JL, Pieper CF (1996) Job stress Naver KV, Grinsted J, Larsen SO et al (2014) Increased
and preeclampsia. Epidemiology 7:245–249 risk of preterm delivery and pre-eclampsia in women
Ko TJ, Tsai LY, Chu LC et al (2014) Parental smoking during with polycystic ovary syndrome and hyperandro-
pregnancy and its association with low birth weight, genaemia. BJOG 121:575–581
small for gestational age, and preterm birth offspring: a Newnham JP, Dickinson JE, Hart RJ et al (2014) Strategies
birth cohort study. Pediatr Neonatol 55:20–27 to prevent preterm birth. Front Immunol 5:584
Kramer MS, Goulet L, Lydon J et al (2001) Socio- Norman SM, Odibo AO, Macones GA et al (2010) Ultra-
economic disparities in preterm birth: causal pathways sound detected subchorionic hemorrhage and the
and mechanisms. Paed Perinat Epidemiol 15:104–123 obstetric implications. Obstet Gynecol 116:311–315
2 Risk Factors for Gestational Diseases 39
North RA, McCowan LM, Dekker GA et al (2011) Clinical Sibai M, Dekker G, Kupferminc M (2005) Pre-eclampsia.
risk prediction for pre-eclampsia in nulliparous women: Lancet 365:785–799
development of model in international prospective Skjaerven R, Wilcox AJ, Lie RT (2002) The interval
cohort. BMJ 342:d1875 between pregnancies and the risk of preeclampsia. N
O’Gorman N, Wright D, Syngelaki A et al (2016) Com- Engl J Med 346:33–38
peting risks model in screening for preeclampsia by Smith GC, Pell JP, Dobbie R (2003) Interpregnancy inter-
maternal factors and biomarkers at 11–13 weeks gesta- val and risk of preterm birth and neonatal death: retro-
tion. Am J Obstet Gynecol 214:103.e1–103.e12 spective cohort study. BMJ 327:313
Palomba S, de Wilde MA, Falbo A et al (2015) Pregnancy Smith LK, Draper ES, Manktelow BN et al (2007a) Socio-
complications in women with polycystic ovary syn- economic inequalities in very preterm birth rates. Arch
drome. Hum Reprod Update 21:575–592 Dis Child Fetal Neonatal Ed 92:F11–F14
Petraglia F, Arcuri F, de Ziegler D et al (2012) Inflamma- Smith GC, Crossley JA, Aitken DA et al (2007b) Circulat-
tion: a link between endometriosis and preterm birth. ing angiogenic factors in early pregnancy and the risk
Fertil Steril 98:36–40 of preeclampsia, intrauterine growth restriction, spon-
Petraglia F, Orlandini C, Vannuccini S et al (2015) PCOS taneous preterm birth, and stillbirth. Obstet Gynecol
and pregnancy: impact of endocrine and metabolic 109:1316–1324
factors. In: Ferrazzi E, Sears B (eds) Metabolic syn- Spencer K, Yu CK, Savvidou M et al (2006) Prediction of
drome and complications of pregnancy. Springer Inter- pre-eclampsia by uterine artery Doppler ultrasonogra-
national Publishing, Cham, pp 91–102 phy and maternal serum pregnancy-associated plasma
Petricevic L, Domig K, Nierscher F et al (2014) Charac- protein-A, free beta-human chorionic gonadotropin,
terisation of the vaginal Lactobacillus microbiota asso- activin A and inhibin A at 22 þ 0 to 24 þ 6 weeks’
ciated with preterm delivery. Sci Rep 4:5136 gestation. Ultrasound Obstet Gynecol 27:658–663
Pinborg A, Wennerholm UB, Romundstad LB et al (2013) Spencer K, Cowans NJ, Nicolaides KH (2008) Low levels
Why do singletons conceived after assisted reproduc- of maternal serum PAPP-A in the first trimester and the
tion technology have adverse perinatal outcome? Sys- risk of pre-eclampsia. Prenat Diagn 28:7–10
tematic review and meta-analysis. Hum Reprod Update Spradley FT, Palei AC, Granger JP (2015) Immune mech-
19:87–104 anisms linking obesity and preeclampsia. Biomolecules
Plunkett J, Muglia LJ (2008) Genetic contributions to 5:3142–3176
preterm birth: implications from epidemiological and Steegers EA, von Dadelszen P, Duvekot JJ et al (2010)
genetic association studies. Ann Med 40:167–195 Pre-eclampsia. Lancet 376:631–644
Plunkett J, Borecki I, Morgan T et al (2008) Population- Stern JE, Luke B, Tobias M et al (2015) Adverse preg-
based estimate of sibling risk for preterm birth, preterm nancy and birth outcomes associated with underlying
premature rupture of membranes, placental abruption diagnosis with and without assisted reproductive tech-
and pre-eclampsia. BMC Genet 9:44 nology treatment. Fertil Steril 103:1438–1445
Poon LC, Nicolaides KH (2014) Early prediction of pre- Torricelli M, Voltolini C, De Bonis M et al (2012) The
eclampsia. Obstet Gynecol Int 2014:297397 identification of high risk pregnancy: a new challenge
Poon LC, Savvas M, Zamblera D et al (2012) Large loop in obstetrics. J Matern Fetal Neonatal Med 25(Suppl
excision of transformation zone and cervical length in 1):2–5
the prediction of spontaneous preterm delivery. BJOG Vahanian SA, Lavery JA, Ananth CV et al (2015) Placental
119:692–698 implantation abnormalities and risk of preterm deliv-
Romero R, Dey SK, Fisher SJ (2014a) Preterm labor: one ery: a systematic review and metaanalysis. Am J Obstet
syndrome, many causes. Science 345:760–765 Gynecol 213(4 Suppl):S78–S90
Romero R, Hassan S, Gajer P et al (2014b) The vaginal Vaisbuch E, Romero R, Erez O et al (2010) Clinical sig-
microbiota of pregnant women who subsequently have nificance of early (<20 weeks) vs. late (20–24 weeks)
spontaneous preterm labor and delivery and those with detection of sonographic short cervix in asymptomatic
a normal delivery at term. Microbiome 2:18 women in the mid-trimester. Ultrasound Obstet
Rubens CE, Sadovsky Y, Muglia L et al (2014) Prevention Gynecol 36:471–481
of preterm birth: harnessing science to address the Vannuccini S, Clifton VL, Fraser IS et al (2016) Infertility
global epidemic. Sci Transl Med 6:262sr5 and reproductive disorders: impact of hormonal and
Ruiz RJ, Dwivedi AK, Mallawaarachichi I et al (2015) Psy- inflammatory mechanisms on pregnancy outcome.
chological, cultural and neuroendocrine profiles of risk Hum Reprod Update 22:104–115
for preterm birth. BMC Pregnancy Childbirth 15:204 Vesce F, Farina A, Giorgetti M et al (1997) Increased inci-
Shah NR, Bracken MB (2000) A systematic review and dence of pre-eclampsia in pregnancies complicated by
meta-analysis of prospective studies on the association fetal malformations. Gynecol Obstet Invest 44:107–111
between maternal cigarette smoking and preterm deliv- Vollebregt KC, van der Wal MF, Wolf H et al (2008) Is
ery. Am J Obstet Gynecol 182:465–472 psychosocial stress in first ongoing pregnancies associ-
Sibai BM (2005) Diagnosis, prevention, and management ated with pre-eclampsia and gestational hypertension?
of eclampsia. Obstet Gynecol 105:402–410 BJOG 115:607–615
40 S. Vannuccini et al.
Voltolini C, Petraglia F (2014) Neuroendocrinology of preg- Wong LF, Wilkes J, Korgenski K et al (2015) Risk factors
nancy and parturition. Handb Clin Neurol 124:17–36 associated with preterm birth after a prior term delivery.
Voltolini C, Torricelli M, Conti N et al (2013) Understand- BJOG 2015:28
ing spontaneous preterm birth: from underlying mech- Wright A, Wright D, Ispas CA et al (2015) Mean arterial
anisms to predictive and preventive interventions. pressure in the three trimesters of pregnancy: effects of
Reprod Sci 20:1274–1292 maternal characteristics and medical history. Ultra-
Wing DA, Fassett MJ, Getahun D (2014) Acute pyelone- sound Obstet Gynecol 45:698–706
phritis in pregnancy: an 18-year retrospective analysis. Wu W, Witherspoon DJ, Fraser A et al (2015) The herita-
Am J Obstet Gynecol 210:219.e1–219.e6 bility of gestational age in a two-million member
Witkin SS (2015) The vaginal microbiome, vaginal anti- cohort: implications for spontaneous preterm birth.
microbial defence mechanisms and the clinical chal- Hum Genet 134:803–808
lenge of reducing infection-related preterm birth.
BJOG 122:213–218
Epigenetic Mechanisms
3
Felicia M. Low and Peter D. Gluckman
Contents
3.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3.3 Epigenetic Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3.3.1 Histone Modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3.3.2 DNA Methylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
3.3.3 Noncoding RNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
3.4 Genomic Imprinting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
3.5 Developmental Plasticity, Epigenetics, and Disease Risk . . . . . . . . . . . . . . . . . . . . 46
3.6 Reversibility of Developmentally Induced
Epigenetic Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Abstract part by epigenetic mechanisms. However, a
Epidemiological and experimental studies mismatch between the induced phenotype
have provided considerable evidence that and mature environment contributes to an
early environmental cues may influence an increased propensity toward developing
individual’s susceptibility to disease in later chronic noncommunicable disease. In this
life. Organisms have evolved with the capacity chapter we describe several epigenetic mecha-
for developmental plasticity in order to match nisms and some diseases that arise from
their developmental trajectory to the environ- non-environmentally induced epigenetic
ment, and this adaptive response is driven in errors. We also provide an overview of the
evidence that early-life environmental varia-
tions alter predisposition to chronic metabolic
The authors would like to thank Emilia Tng for assistance and cardiovascular disease at maturity and that
with research. this is mediated by epigenetic processes. The
F. M. Low · P. D. Gluckman (*) potential for reversibility of developmentally
Liggins Institute, University of Auckland, Auckland, induced epigenetic changes is discussed.
New Zealand
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 41
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_152
42 F. M. Low and P. D. Gluckman
3.1 Salient Points from maladaptive fetal responses, and in imprint-
ing disorders, which result from defects in the
• Early environmental cues may modulate dis- establishment or erasure of specific epigenetic
ease risk in later life. marks, is discussed.
• Epigenetic mechanisms have been implicated
in the development of cardiometabolic dis-
eases and imprinting disorders. 3.3 Epigenetic Mechanisms
• Epigenetic mechanisms include modification
of histone proteins, DNA methylation, and Epigenetics, as used in the context of this chapter,
noncoding RNA activity. refers to the molecular mechanisms that give rise to
• Emerging evidence suggests that developmen- stable, mitotically heritable changes in gene function
tally induced epigenetic changes may be without a corresponding change in the DNA
reversed. sequence. They include chromatin remodeling
through histone modifications, DNA methylation,
and posttranscriptional control by noncoding
RNAs. The mammalian epigenome in early life
3.2 Introduction appears susceptible to a range of physiological and
pathophysiological cues that can have persistent
While phenotypic variation such as disease effects on structure and function (Low et al. 2014).
vulnerability has traditionally been viewed as
being determined by the interaction between
genes and the environment, it is now clear that 3.3.1 Histone Modifications
this is oversimplistic. Developmental plasticity
describes the phenomenon whereby development In eukaryotes, DNA is wound around an octameric
of the phenotype from a given genotype is complex of histone proteins – two subunits each of
influenced by developmental experiences, and phe- the histones H2A, H2B, H3, and H4 – forming the
notypic variation in turn influences how the indi- nucleosome (Fig. 1a). Chromatin is formed when
vidual interacts with its mature environment, thus nucleosomes are packaged closely, strung together
affecting disease risk. It is now recognized that by double-stranded DNA (Fig. 1b). Therefore, cer-
developmental plasticity is underpinned at least in tain covalent modifications such as acetylation,
part by epigenetic processes (Low et al. 2011). methylation, phosphorylation, sumoylation, ADP
These are the environmentally induced changes in ribosylation, and glycosylation at specific amino
patterns and regulation of gene expression brought acid residues on histone proteins can cause higher-
about by a set of modifications in DNA and order structural changes. This remodeling of chro-
DNA-associated molecules, without changes in matin can influence gene expression depending on
the base sequence. Epigenetic processes are phylo- whether the modifications result in chromatin con-
genetically old, and the mechanisms involved densation or unwinding and the subsequent acces-
modulate both gene dosage and the conditions sibility of DNA to transcription factors (specific
under which genes are expressed. Developmental proteins which facilitate DNA recognition by
plasticity is but one of several processes which are RNA polymerases) and other DNA-associated
mediated by epigenetic mechanisms; in mammals complexes (Beaujean 2014).
other processes include transposable element sup- Histone modifications occur on residues at the
pression, cell differentiation, X-chromosome inac- amino termini of histone tails via activity of
tivation in females, and genomic imprinting. enzymes such as histone acetyltransferases (HAT),
This chapter describes several of the most histone deacetylases (HDAC), methyltransferases,
extensively studied epigenetic mechanisms to kinases, and ubiquitilases. Some of the most com-
date. Their involvement in the development of mon modifications include acetylation, which
metabolic and cardiovascular diseases that stem involves addition of CH3OH in a reaction catalyzed
3 Epigenetic Mechanisms 43
Fig. 1 (a) DNA is wound
around an octameric
complex of histones to form
the nucleosome. The
amino-terminal histone tails
may be amenable to
posttranslational
modification.
(b) Chromatin consists of
multiple nucleosome units
strung together by double-
stranded DNA.
(c) Schematic
representation of known
modifications of the first
30 amino acids at the
amino-terminal tail of H3.
The lysine residues at
positions 4 and 9 are
indicated in red.
M methylation,
A acetylation
by HAT, and methylation, which involves addition CpG dinucleotides are called CpG islands,
of CH3 (Fig. 1c). The impact of each type of mod- which are usually found at the promoter regions
ification on chromatin configuration varies and of many genes and are normally unmethylated.
often in a context-dependent manner (Bowman DNA methylation exerts a regulatory effect
and Poirier 2015). Generally, increased acetylation in a combination of ways: modifying the bind-
leads to an increase in transcriptional activity ing affinity of transcription factors to their
(so-called active chromatin; see Fig. 3), whereas target sites on DNA and inhibiting RNA
deacetylation, catalyzed by HDAC, leads to tran- polymerase activity, recruiting methyl-CpG-
scriptional repression (inactive chromatin) (Galvani binding proteins such as MeCP1 and MeCP2
and Thiriet 2015). Some histone marks may have that in turn attract associated proteins that
opposing effects on gene expression depending on cause the nucleosome to condense, thereby
the residue modified; trimethylation of the ninth inhibiting transcription, and modulating the
lysine residue on histone H3 (H3K9me3) favors transcription of noncoding RNAs (Figs. 2
gene silencing while that on the fourth residue and 3). DNA methylation is commonly asso-
(H3K4me3) promotes gene expression. ciated with gene silencing, although there is
increasing evidence that this may be dependent
on other factors such as the site of modifica-
3.3.2 DNA Methylation tion and CpG density. An individual’s DNA
methylome is established during embryogene-
In mammals, DNA methylation involves the sis and generally persists through the life
addition of a methyl group on the C5 position course. However during early life, when levels
of cytosine residues in a process mediated by of developmental plasticity tend to be highest,
DNA methyltransferases (Schubeler 2015). environmental cues may lead to persistent
This usually occurs in the context of CpG dinu- alteration of specific epigenetic marks with
cleotides (cytosine linked to guanine by a phos- long-term phenotypic consequences (Low
phate group); non-CpG methylation has been et al. 2014). Acute challenges later in life,
observed in the mammalian brain and skeletal such as those involving dietary or exercise
muscle, but its functional significance remains challenges, may induce transient and revers-
unclear. Genomic regions with an enrichment of ible changes in methylation state.
44 F. M. Low and P. D. Gluckman
Fig. 2 Gene expression is
modulated by nearby DNA
sequences called promoters,
which often include CpG
islands. Methylated DNA
(top) recruits methyl-CpG-
binding proteins that in turn
attract associated proteins to
inhibit transcription. In
contrast, unmethylated CpG
islands (bottom) allow
binding of RNA
polymerase and
transcription factors for
initiation of transcription
Fig. 3 In transcriptionally active chromatin (top), acetyl deacetylation and promoter CpG methylation (Me) and
groups (Ac) on specific lysine residues of core histones in hence decreased binding of transcriptional factors.
the nucleosome decrease their binding to DNA. The miRNA molecules are among the ncRNAs that provide
resulting “open” chromatin structure, coupled with the posttranscriptional epigenetic control, in this case by bind-
unmethylated state of CpG sequences in promoter regions ing to complementary sequences at the 30 end of mRNA,
of actively transcribed genes, facilitates access of transcrip- thus reducing the rate of protein synthesis (Modified from
tion factors to DNA. Conversely, transcriptionally inactive Gluckman et al. 2008, with permission)
chromatin (bottom) is characterized by histone
3.3.3 Noncoding RNAs (ncRNAs) are highly involved in myriad aspects
of the regulation of cell differentiation and devel-
The regulatory role of RNA began to emerge upon opment through modulation of chromatin (Meller
the discovery of RNAs that are not translated into et al. 2015) and are further classified based on their
proteins. These so-called noncoding RNAs length and mechanism of action. For example,
3 Epigenetic Mechanisms 45
microRNAs (miRNAs), which are approximately nutrition as they are required for the formation
22 nucleotides long, form base pairs with their of a functional placenta. The first genes shown to
target messenger RNA (mRNA) and promote its be imprinted were the fetal growth factor IGF2
destabilization through the recruitment of effector and its receptor IGF2R. More than 100 imprinted
proteins (Iwakawa and Tomari 2015). Gene genes have been identified to date in mice and
expression can therefore be regulated at the post- humans, with a majority of them located in clus-
transcriptional level (Fig. 3). Small nucleolar ters throughout the genome. These clusters usu-
RNAs (snoRNAs), which range from about ally contain a few protein-coding genes and at
60–140 nucleotides in length, regulate ribosome least one ncRNA gene. Each gene cluster is reg-
biogenesis as well as the alternative splicing and ulated by a cis-acting element called an imprint-
posttranscriptional modification of mRNA. ing control region (ICR). Between them, the
SnoRNAs have been implicated in physiological ICRs of the chromosome pair acquire different
functions that regulate feeding and growth and in levels of methylation; this determines which
pathological conditions such as the Prader-Willi allele is silent or active, thereby enabling
and Angelman syndromes (see later) and cancer imprinting control of all the genes within the
(Stepanov et al. 2015). The long noncoding RNAs cluster. The regulation of the imprinted mouse
(lncRNAs; >200 nucleotides in length) participate gene Igf2r, which encodes a growth suppressor,
in numerous biological functions as diverse as is shown in Fig. 4.
genomic imprinting, protein assembly, and regula- A consequence of genomic imprinting is that
tion of enzyme activity (Quinn and Chang 2016). viable embryos must receive two haploid
genome complements from each parent. Parent-
specific imprinting marks are established during
3.4 Genomic Imprinting gametogenesis. Deletions, duplications, muta-
tions, or alterations of imprinting of the only
Some mammalian genes are expressed from only active allele, or loss of imprinting of the inactive
the maternal or paternal allele in a phenomenon allele, lead to an imbalance in the dosage of the
known as genomic imprinting (Adalsteinsson gene product. The loss or gain of function of
and Ferguson-Smith 2014). Many imprinted imprinted genes may then have phenotypic
genes play major roles in fetal growth and consequences.
Fig. 4 The Igf2r/Air imprinted region. Igf2r, Slc22a2, and Air promoter and is methylated on the maternal allele.
Slc22a3 are maternally expressed protein-coding genes. When the Air transcript is truncated, biallelic expression
Slc22a1 is a biallelically expressed gene (expressed from of Igf2r, Slc22a2, and Slc22a3 is acquired, indicating a role
both maternal and paternal alleles). Air is paternally for the Air ncRNA in the repression of the paternal alleles
expressed and encodes an ncRNA. The ICR contains the (Regha et al. 2006)
46 F. M. Low and P. D. Gluckman
3.5 Developmental Plasticity, maternal undernutrition had effects on the epige-
Epigenetics, and Disease Risk netic state of hypothalamic GR through alterations
in promoter methylation, histone acetylation, and
The influence of the fetal environment on later-life histone methylation (Begum et al. 2013). There is
susceptibility to chronic noncommunicable disease also increasing evidence for the role of epigenetic
has been demonstrated by a multitude of epidemi- mechanisms in modulating clinically relevant traits
ological and experimental studies. In humans, in in humans. For example, a 2011 study reported a
utero exposure to adverse conditions such as mater- graded association between neonatal methylation
nal undernutrition has been associated with hyper- levels at a specific CpG site in the RXRA gene
tension, ischemic heart disease, glucose promoter and childhood fat mass; the effect size
intolerance, insulin resistance, type 2 diabetes was large, with at least 25% of the variation in
mellitus, obesity, and reproductive disorders in adiposity being attributed to methylation levels
adulthood (Hanson and Gluckman 2014). In rodent (Godfrey et al. 2011).
studies used to simulate human pathology, manip- The epigenetic mechanisms underlying several
ulation of maternal nutrition (e.g., food intake or imprinting disorders are well established. Human
protein restriction), stress (e.g., via glucocorticoid chromosome 15q11-q13 contains an imprinted
administration), or physical condition (e.g., liga- cluster called the Prader-Willi/Angelman syn-
tion of uterine arteries to reduce uteroplacental drome (PWS/AS) region. Incorrect establishment
blood flow, thus inducing intrauterine growth of imprinting in this region results in two distinct
restriction) can induce slowed fetal growth and neurological disorders, Prader-Willi syndrome
permanent changes in cardiovascular and meta- (PWS) and Angelman syndrome (AS). PWS is
bolic function in the offspring. The fetus’ ability characterized by multiple symptoms including
to respond to challenging environmental cues and hypotonia, hyperphagia, obesity, and short stat-
adjust its developmental trajectory to match its ure. Psychomotor development is mildly affected
environment reflects the processes of developmen- and behavioral problems are evident. Patients
tal plasticity. Although these responses are adaptive with AS show a completely different phenotype
and aimed at promoting fitness later in life, a characterized by severe mental retardation, absent
mismatch between the eventual phenotypic out- speech, autistic-like behavior, severe epilepsy,
come and the later environment may manifest as and postnatal microcephaly. PWS is caused by
chronic noncommunicable disease, and this is the the loss of the normal paternal contribution of
basis for the “developmental origins of health and gene expression, whereas AS is caused by the
disease” paradigm (Gluckman et al. 2015). Indeed, loss of the normal maternal contribution (Kalsner
there is growing evidence that developmental plas- and Chamberlain 2015).
ticity can account, at least in part, for a broad array Other imprinting disorders include Silver-
of diseases. Russell syndrome and Beckwith-Wiedemann
The mechanistic basis of the effect of early syndrome, which arise from imprinting defects
environmental cues on subsequent susceptibility in human chromosome imprinted region
to metabolic disease has been extensively investi- 11p15.
gated in animals. For example, offspring of preg- Rett syndrome is a devastating X-linked neu-
nant rats fed a low-protein diet during pregnancy rological disease that affects mostly females. Girls
developed hypertension and endothelial dysfunc- with this condition initially exhibit normal growth
tion. Concomitant changes were detected at the but show signs of deteriorating motor and cogni-
epigenetic and gene expression levels, including tive function such as repetitive teeth-grinding,
gene promoter hypomethylation, and accordingly hand-wringing, and autistic-like behaviors some-
protein over-expression, of the hepatic glucocorti- time between the age of 6 and 18 months. This
coid receptor (GR) and peroxisome proliferator- eventually culminates in severe intellectual dis-
activated receptor-α (PPARα) (Lillycrop ability. Rett syndrome is associated with loss of
et al. 2005). In sheep, exposure to periconceptional function mutations in MECP2 (Liyanage and
3 Epigenetic Mechanisms 47
Rastegar 2014). Absence of MeCP2 interferes care over the first week of postnatal life are asso-
with transcriptional regulation of the maternally ciated with reduced fearfulness and a dampened
imprinted DLX5 through the loss of a silent hypothalamic-pituitary-adrenal axis response
chromatin-associated loop and the activation of when exposed to stress. Interestingly, pharmaco-
additional neighboring chromatin (Horike logical intervention in adulthood may alter these
et al. 2005). Mouse studies have also implicated behavioral responses by changing the epigenetic
aberrant lncRNA transcriptional patterns in the status of relevant genes, in particular the hippo-
pathology of Rett syndrome. This disease thus illus- campal GR. The administration of the HDAC
trates how different epigenetic mechanisms – in this inhibitor trichostatin A in stress-challenged off-
case loss of imprinting, chromatin remodeling, and spring that had received lower maternal care
ncRNA transcriptome dysregulation – can act in induces behavior more similar to that of offspring
concert to cause various perturbations in gene exposed to high levels of maternal care (Weaver
expression, ultimately leading to a disease et al. 2004). The methyl donor L-methionine
phenotype. induces the opposite effect, with adult offspring
exposed to high maternal care exhibiting a poten-
tiated behavioral response to stress. The effects of
3.6 Reversibility these interventions have been linked to methyla-
of Developmentally Induced tion and expression levels of hippocampal GR.
Epigenetic Changes At present, the prevention or reversibility of
developmentally induced epigenetic changes has
The “plastic” responses demonstrated by the only been investigated in animals. Nevertheless,
developing fetus to cope with an adverse prenatal the contribution of epigenetic mechanisms to the
environment may not be irreversible. Numerous elucidation of developmental pathways to human
animal studies have demonstrated that maternal or disease is now well recognized. Emerging evi-
postnatal dietary supplementation, and postnatal dence from the clinical and epidemiological
pharmacological interventions, may reverse the domains increasingly supports the notion that spe-
phenotypic fates induced in early development cific epigenetic marks can serve as biomarkers
(reviewed in Vickers and Sloboda 2012). of later-life disease risk (García-Giménez 2016).
For example, offspring of undernourished The clinical implications of such prognostics are
rats develop obesity, hyperinsulinemia, and clear – by identifying individuals with increased
hyperleptinemia in adulthood, especially in the susceptibility to chronic disease in later life,
presence of a high-fat diet. Intervention by way appropriate nutritional, pharmacological, or edu-
of neonatal leptin administration to primed rat cational interventions could be then employed as
pups normalized weight gain, insulin levels, and preventative measures. Adopting a life-course
leptin concentrations (Vickers et al. 2005). The approach with a particular focus on the prenatal
corrective effects on phenotype were accompa- and early postnatal periods appears to be prudent
nied by normalized promoter methylation and (Low et al. 2016).
expression of PPARα, reflecting an epigenetic
basis for the physiological mechanisms that lead
to either phenotype (Gluckman et al. 2007). Die- References
tary supplements as varied as methyl donors, anti-
Adalsteinsson BT, Ferguson-Smith AC (2014) Epigenetic
oxidants, taurine, and n-3 fatty acids have been control of the genome—lessons from genomic imprint-
reported to ameliorate the adverse effects of a ing. Genes 5:635–655
primed phenotype. Anacker C, O’Donnell KJ, Meaney MJ (2014) Early life
In the rat, variations in postnatal maternal care adversity and the epigenetic programming of
hypothalamic-pituitary-adrenal function. Dialogues
stably alter the development of behavioral and Clin Neurosci 16(3):321–333
endocrine responses to stress in the offspring Beaujean N (2014) Histone post-translational modifica-
(Anacker et al. 2014). High levels of maternal tions in preimplantation mouse embryos and their role
48 F. M. Low and P. D. Gluckman
in nuclear architecture. Mol Reprod Dev pregnant rats induces and folic acid supplementation
81(2):100–112 prevents epigenetic modification of hepatic gene
Begum G, Davies A, Stevens A, Oliver M, Jaquiery A, expression in the offspring. J Nutr 135:1382–1386
Challis J et al (2013) Maternal undernutrition Liyanage VRB, Rastegar M (2014) Rett syndrome and
programs tissue-specific epigenetic changes in the glu- MeCP2. Neuromol Med 16:231–264
cocorticoid receptor in adult offspring. Endocrinology Low FM, Gluckman PD, Hanson MA (2011) Developmen-
154(12):4560–4569 tal plasticity and epigenetic mechanisms underpinning
Bowman GD, Poirier MG (2015) Post-translational modi- metabolic and cardiovascular diseases. Epigenomics
fications of histones that influence nucleosome dynam- 3(3):279–294
ics. Chem Rev 115(6):2274–2295 Low FM, Gluckman PD, Hanson MA (2014) Epigenetic
Galvani A, Thiriet C (2015) Nucleosome dancing at the and developmental basis of risk of obesity and meta-
tempo of histone tail acetylation. Genes 6:607–621 bolic disease. In: Ulloa-Aguirre A, Conn PM (eds)
García-Giménez JL (ed) (2016) Epigenetic biomarkers and Cellular endocrinology in health and disease. Elsevier,
diagnostics. Academic, London London, pp 111–132
Gluckman PD, Lillycrop KA, Vickers MH, Pleasants AB, Low FM, Gluckman PD, Hanson MA (2016) A life course
Phillips ES, Beedle AS et al (2007) Metabolic plasticity approach to public health: why early life matters. In:
during mammalian development is directionally depen- van den Bosch M, Bird W (eds) Oxford textbook of
dent on early nutritional status. Proc Natl Acad Sci nature and public health. Oxford University Press,
USA 104(31):12796–12800 Oxford
Gluckman PD, Hanson MA, Cooper C, Thornburg KL Meller VH, Joshi SS, Deshpande N (2015) Modulation of
(2008) Effect of in utero and early-life conditions on chromatin by noncoding RNA. Annu Rev Genet
adult health and disease. N Engl J Med 359(1):61–73 49:673–695
Gluckman PD, Buklijas T, Hanson MA (2015) The devel- Quinn JJ, Chang HY (2016) Unique features of long
opmental origins of health and disease (DOHaD) con- non-coding RNA biogenesis and function. Nat Rev
cept: past, present, and future. In: Rosenfeld CS Genet 17(1):47–62
(ed) The epigenome and developmental origins of Regha K, Latos PA, Spahn L (2006) The imprinted mouse
health and disease. Academic, London, pp 1–13 Igf2r/Air cluster – a model maternal imprinting system.
Godfrey KM, Sheppard A, Gluckman PD, Lillycrop KA, Cytogenet Genome Res 113(1–4):165–177
Burdge GC, McLean C et al (2011) Epigenetic gene Schubeler D (2015) Function and information content of
promoter methylation at birth is associated with child’s DNA methylation. Nature 517(7534):321–326
later adiposity. Diabetes 60:1528–1534 Stepanov GA, Filippova JA, Komissarov AB, Kuligina
Hanson MA, Gluckman PD (2014) Early developmental EV, Richter VA, Semenov DV (2015) Regulatory role
conditioning of later health and disease: physiology or of small nucleolar RNAs in human diseases. BioMed
pathophysiology? Physiol Rev 94:1027–1076 Res Int 2015:10
Horike S-i, Cai S, Miyano M, Cheng J-F, Kohwi- Vickers MH, Sloboda DM (2012) Strategies for reversing
Shigematsu T (2005) Loss of silent-chromatin looping the effects of metabolic disorders induced as a conse-
and impaired imprinting of DLX5 in Rett syndrome. quence of developmental programming. Front Physiol
Nat Genet 37(1):31–40 3:242
Iwakawa H-o, Tomari Y (2015) The functions of Vickers MH, Gluckman PD, Coveny AH, Hofman PL,
MicroRNAs: mRNA decay and translational repres- Cutfield WS, Gertler A et al (2005) Neonatal leptin
sion. Trends Cell Biol 25(11):651–665 treatment reverses developmental programming. Endo-
Kalsner L, Chamberlain SJ (2015) Prader-Willi, crinology 146:4211–4216
Angelman, and 15q11-q13 duplication syndromes. Weaver ICG, Cervoni N, Champagne FA, D’Alessio AC,
Pediatr Clin North Am 62(3):587–606 Sharma S, Seckl JR et al (2004) Epigenetic
Lillycrop KA, Phillips ES, Jackson AA, Hanson MA, programming by maternal behavior. Nat Neurosci
Burdge GC (2005) Dietary protein restriction of 7(8):847–854
Congenital Malformations
and Syndromes: Early Diagnosis 4
and Prognosis in Neonatal Medicine
Giovanni Corsello and Mario Giuffrè
Contents
4.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
4.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
4.3 Classifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
4.4 Clinical Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
4.5 Genetic Counseling and Prenatal Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
4.6 Associations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
4.6.1 VACTERLS Association . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
4.6.2 Infants of Diabetic Mothers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
4.7 Sequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
4.7.1 Holoprosencephalic Sequence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
4.7.2 Pierre Robin Sequence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
4.7.3 Potter Sequence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
4.7.4 Prune Belly Sequence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
4.8 Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
4.8.1 Chromosomal Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
4.8.2 Monogenic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
4.9 Disruptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
4.9.1 Biologic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
4.9.2 Chemical Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
4.9.3 Vascular Disruptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
4.10 Dysostoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
4.10.1 Craniofacial Dysostoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
4.10.2 Thoraco-vertebral Dysostoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
4.10.3 Limb Dysostoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
G. Corsello (*) · M. Giuffrè
Department of Sciences for Health Promotion and Mother
and Child Care, University of Palermo, Palermo, Italy
e-mail: [email protected]; [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 49
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_153
50 G. Corsello and M. Giuffrè
4.11 Osteochondrodysplasias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
4.11.1 Achondroplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
4.11.2 Thanatophoric Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
4.11.3 Campomelic Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
4.11.4 Diastrophic Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
4.11.5 Pseudodiastrophic Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
4.11.6 Osteogenesis Imperfecta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
4.11.7 Osteodysplastic Primordial Dwarfism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Abstract 4.2 Introduction
Congenital malformations are defects of the
morphogenesis of organs or body regions iden- The genetic counseling has been recently defined
tified during intrauterine development or at as a unique combination of intense science, criti-
birth. They may be isolated and single or mul- cal thinking, and empathic process. This
tiple. Their global birth prevalence is about multidimensional definition contains all domains
2–3%. Congenital defects may be caused by for a correct approach to a newborn with congen-
genetic and/or environmental factors, acting ital malformations, but at the same time, it high-
singly or in combination. A deep knowledge lights several critical issues for the clinician who
of the family and pregnancy histories, of the needs to start an early approach soon after birth or
congenital anomalies and/or dysmorphic fea- even prenatally. Modern diagnostic tools and ther-
tures’ classification, as well as of the most apeutic resources have allowed better identifica-
appropriate cytogenetic and/or molecular tion of congenital malformations and have
genetic tests may facilitate the neonatologist reduced long-term morbidity and mortality in
to the newborn’s correct assessment and affected patients. Because of increased life expec-
management. tancy, congenital malformations today represent a
major issue in health care because of the resources
needed for multidisciplinary care.
4.1 Salient Points
• Congenital malformations are defects of the 4.3 Classifications
morphogenesis that can be classified based on
clinical, etiological, or pathogenetic criteria. Based on clinical criteria, major malformations
• The clinical and instrumental approach to con- are defined as defects causing functional impair-
genital malformations and syndromes is a com- ment and therefore needing medical or surgical
plex, long-lasting, and stressful process for treatment. Defects that do not produce functional
both patients and their families. impairment and do not require medical interven-
• Diagnosis, treatment, and follow-up of con- tion are termed minor malformations if their prev-
genital defects require the involvement of a alence at birth is less than 4% and phenotypic
multidisciplinary team of different specialists. variants when the birth prevalence is higher.
• Improvement in diagnostic and therapeutic Major and/or minor congenital malformations
resources has determined an increase in sur- are frequently associated; apparently isolated
vival and quality of life for many conditions defects may be associated with malformations
with congenital defects. that are not clinically evident at birth.
• Congenital malformations and syndromes are a On the basis of etiological criteria, it is possible
major issue for health services in terms of costs to distinguish primary malformations, secondary
and resources. malformations (disruptions), and deformations
4 Congenital Malformations and Syndromes: Early Diagnosis and Prognosis in Neonatal Medicine 51
Table 1 Etiologic classification of congenital occur when an environmental factor interferes
malformations with an otherwise normal developmental process,
Primary (genetic) Secondary (environmental) causing global impairment or specific damage
Chromosomal Biologic agents affecting a single developmental region. The
abnormalities causes of secondary malformations may be bio-
Numeric Viruses logical, chemical, metabolic, or physical. Defor-
Polyploidy Cytomegalovirus
mations arise from extrinsic mechanical
Polysomy Rubella
compression of one or more regions of the body
Monosomy Herpesviruses
during fetal development. The most common
Structural Bacteria
causes of deformations are amniotic bands, twin-
Deletions Treponema pallidum
Duplications Parasites
ning, uterine malformations, and masses.
Insertions Toxoplasma gondii Patients with multiple malformations can be
Translocations Chemical agents classified as having syndromes, sequences, asso-
Monogenic Drugs ciations, or dysplasias. Syndromes are conditions
Point mutations Antiblastics where all the structural defects arise from a single
Nonsense Anticonvulsants etiological factor, which may be genetic or envi-
Missense Antibiotics ronmental. Sequences are characterized by a cas-
Frameshift Abuse substances cade of dysmorphic processes, linked by a cause/
Dynamic Alcohol effect relationship with a single initiating event.
mutations Thus, a primary defect may induce several sec-
Triplet Smoke ondary defects, which are chronologically and
amplification
pathogenetically related. Associations are spo-
Epigenetic Cocaine
regulation radic events with different defects being present
Imprinting Opiates more frequently than would be expected if they
defects were random events, without evidence of any
Uniparental Metabolic conditions etiological or pathogenetic relationship. In recent
disomy years, some associations have been recognized
Polygenic Hyperglycemia, as disorders of blastogenesis, which are caused
hyperinsulinemia
by genetic or environmental factors that interfere
Oligohydramnios Hyperphenylalaninemia
Uterine Hyperandrogenism
with early development when the embryo is a
malformations Physical agents single developmental field, and producing
Ionizing radiation defects in apparently unrelated organs and body
Electromagnetic radiation regions. Blastogenesis is the first 4 weeks after
Vascular disruptions conception and is characterized by processes that
Subclavian artery vascular determine the midline and body axes, symmetry
disruption and lateralization, neurulation, and somite for-
Twin-twin disruption mation. Some associations are identified by an
sequence
acronym of the defects, such as VACTERLS
Mechanical causes
(vertebral defects, anorectal atresia, cardiac
(deformations)
Amniotic bands
anomalies, tracheoesophageal fistula, esopha-
Twinning geal atresia, renal anomalies, limb defects, single
Uterine tumors umbilical artery) and MURCS (Mullerian duct
aplasia, renal dysplasia, cervical somite anoma-
lies). Dysplasias are structural defects involving
specific tissues where a single gene mutation
(Table 1). Primary malformations are morpho- may determine the abolition or reduction of pro-
genic defects arising from an intrinsic error of tein synthesis as well as the production of defec-
development with a genetic origin. Disruptions tive proteins.
52 G. Corsello and M. Giuffrè
4.4 Clinical Considerations to-date knowledge of the natural history of the
disease, (c) an understanding of its prognostic
The birth of a baby with congenital malformations and therapeutic implications, (d) knowledge of
is the starting point of a clinical process that is its pattern of inheritance, and (e) an awareness of
aimed at making a precise diagnosis (Wiedemann the possibilities for early (prenatal) diagnosis. The
et al. 1992; Twining et al. 2000). This leads to main factors that determine a need for genetic
appropriate clinical planning and definition of counseling are the presence of an index case
prognosis and counseling of the parents. Different with a congenital malformation or of genetic dis-
causal pathways may lead to a similar phenotype ease in the family as well as the presence of
(Donnai and Winter 1995; Jones 1997), and the parental risk factors (consanguinity, advanced
diagnostic process may be long and difficult, maternal age, recurrent abortions, mutation car-
requiring follow-up to establish the natural history rier). If the disease is multifactorial (due to a
of the disorder. The diagnostic process includes an combination of genetic and environmental fac-
accurate history and description of the phenotype, tors), a recurrence risk may be given only on the
with appropriate imaging and laboratory tests. basis of an empirical approach that takes account
Improvements in informatics have led to the of the prevalence in a certain population or at a
development of computerized systems to improve certain maternal age, number of affected subjects,
diagnostic accuracy. The history should include and consanguinity within the family. In the case of
consideration of the whole family with the defini- monogenic diseases with Mendelian inheritance
tion of a genealogical tree and the identification of (autosomal dominant, autosomal recessive,
risk factors (consanguinity, multiple abortions, X-linked), the relative recurrence risk must be
stillbirths, advanced maternal and/or paternal explained to the family, who must also be
age), the preconceptional period and environmen- informed about available opportunities for early
tal factors (infections, maternal metabolic dis- diagnosis (preconceptional, prenatal, neonatal).
eases, diabetes mellitus, drugs, alcohol), and the The recent identification of complex genetic
pregnancy. Analysis of the phenotype is aimed at mechanisms (genomic imprinting, uniparental
the identification and description (with photo- disomy, triplet amplification) has increased the
graphic documentation) of structural defects (iso- number of diseases in which it is possible to give
lated and multiple, major and minor) and should helpful genetic counseling.
include a description of clinical associations with
genetic syndromes, such as developmental delay,
growth restriction, disorders of sexual differenti- 4.6 Associations
ation, or pubertal development.
Associations are usually sporadic conditions with
a low recurrence risk. Environmental factors
4.5 Genetic Counseling (alcohol, drugs, maternal diabetes) as well as
and Prenatal Diagnosis chromosomal and single gene disorders may
interfere with the blastogenic processes. A genetic
Genetic counseling has been recently defined as background may also increase an individual’s
unique combination of intense science, critical susceptibility to environmental factors.
thinking, and empathy counseling (Barry 2015).
It consists in a nondirective process of communi-
cating with and giving information to a family 4.6.1 VACTERLS Association
(usually the parents) to enable the making of deci-
sions relating to patients with genetic diseases that VACTERLS association is characterized by the
are considered, responsible, and rational. It is manifestation of some or all of the defects summa-
important that genetic counselors have (a) a con- rized by the acronym: vertebral defects, anorectal
firmed diagnosis for the index patient, (b) an up- atresia, cardiac anomalies, tracheoesophageal
4 Congenital Malformations and Syndromes: Early Diagnosis and Prognosis in Neonatal Medicine 53
fistula, esophageal atresia, renal anomalies, limb these factors may interact and interfere with
defects, single umbilical artery. Tracheoesophageal blastogenesis, inducing abnormalities of the
and anorectal defects require early surgery during midline structures and symmetric organs. All
the neonatal period. The most frequent heart defects types of malformations (skeletal, cardiac, renal,
affect the ventricular septum. Limb defects include gastrointestinal, CNS) are more common in the
radial ray abnormalities (radial hypoplasia, thumb infants of diabetic mothers. Some are specific,
aplasia, or hypoplasia as well as its duplication), such as caudal dysgenesis, characterized by
polydactyly, and syndactyly. Other features may be defects of vertebral, urogenital, and intestinal
prenatal and postnatal growth restriction and ear structures arising from the caudal mesoderm,
and external genitalia abnormalities. VACTERLS with a wide spectrum of expression including
association is often sporadic with a low recurrence sirenomelia, in which there is also a complex
risk. It is more frequent in the offspring of diabetic vascular defect. The fetus may be macrosomic
mothers. In some patients with associated obstruc- because of fetal hyperinsulinemia, although a
tive hydrocephalus, gene mutations with autosomal placental microangiopathy may also cause intra-
recessive (AR) inheritance have been documented. uterine growth restriction.
Antenatal diagnosis can be challenging, as certain
features can be difficult to ascertain prior to birth.
Management typically centers around surgical cor- 4.7 Sequences
rection of the specific congenital anomalies (typi-
cally anal atresia, esophageal atresia, and certain Malformation sequences may be caused by
types of cardiac malformations) in the immediate genetic as well as environmental factors. Several
postnatal period, followed by long-term medical organs and systems may be involved in malfor-
management of sequelae of the congenital mation sequences (Table 2).
malformations. If optimal surgical correction is
achievable, the prognosis can be relatively good,
though some patients will continue to be affected by 4.7.1 Holoprosencephalic Sequence
their congenital malformations throughout life (Sol-
omon 2011; Shaw-Smith 2006). Most patients have Holoprosencephalic sequence presents at birth
normal cognition, although they may present as with a wide spectrum of defects of the encephalon
failure to thrive and with neuromotor disabilities. and the median craniofacial areas due to a devel-
opmental defect of the median subdivision of the
prosencephalic vesicle and surrounding
4.6.2 Infants of Diabetic Mothers mesoderm.
Three anatomical variants (alobar, semilobar,
Congenital malformations in the offspring of and lobar) and four clinical variants (cyclopia,
diabetic mothers are clinically heterogeneous. ethmocephaly, cebocephaly, and premaxillar agen-
Their frequency is two- to fourfold higher than esis) have been described. Clinical evaluation
in the general population. The relative risk for must include CNS imaging to define the full phe-
malformations is much higher in newborns of notype. The severity of CNS defects is the main
women with type 1 insulin-dependent diabetes reason for the high and early lethality of the con-
mellitus and is inversely correlated with the dition. If the phenotype is only partially expressed,
effectiveness of maternal glycemic control, par- longer survival is possible, frequently associated
ticularly during the periconceptional period. with relevant neurologic problems. The parents
Several factors are involved in the pathogenesis and relatives of patients must be investigated for
of such defects: hyperglycemia, hyperglyco- minor signs of the sequence (hypotelorism, single
sylation of proteins involved in differentiation, median incisor) in order to recognize a possible
chronic hypoxia, polycythemia/hyperviscosity, autosomal dominant (AD) inheritance (Dubourg
and lactic acidosis (Mitanchez et al. 2015). All et al. 2011; Lami et al. 2013).
54 G. Corsello and M. Giuffrè
Table 2 Main malformation sequences region. It is characterized by microretrognathia,
Developmental field and organs cleft palate, and functional disturbances
Name involved (swallowing deficit, respiratory distress). A defi-
Holoprosencephaly Precordial mesoderm, ciency of mesoderm induction may cause a pri-
prosencephalic vesicle, mary cleft palate (V-shape). Alternatively, the
rhinencephalon, orbits, nose,
premaxilla cleft palate may be secondary to jaw arch hypo-
Septo-optic dysplasia Optic chiasm, hypophysis plasia, which leads to the position of the tongue
Pierre Robin Jaw bone, oropharyngeal region being fixed between the palatine processes, caus-
Poland Pectoral muscle, superior limb ing a defect of fusion of the secondary palate in the
Klippel-Feil Spine midline (U-shape). Respiratory obstruction is
Potter Kidneys, urinary tract, lungs, caused by the tongue falling backwards and by a
limbs, facies primitive pharyngeal stenosis (secondary to a
Prune belly Urinary tract, abdominal wall migration deficit of neural crest cells). The
Bladder-cloacal Periumbilical mesoderm sequence may present with a wide phenotypical
exstrophy
spectrum, either in isolation or as part of a more
Rokitansky Muller ducts
complex syndrome (del 18q, Stickler syndrome,
Sirenomelia Caudal mesoderm
Caudal regression Caudal mesoderm
del 22q11, etc.). All these variables influence the
Premature rupture of Median axis, limb
prognosis (Thouvenin et al. 2013). Newborns
amnion deformations, facial clefts may require prolonged respiratory and/or nutri-
Fetal akinesia Multiple body regions tional support and long-term hospitalization and
Twin-twin disruption Multiple body regions follow-up. In the most severely affected cases,
sequence surgery to the jaw distraction may improve the
outcome.
The etiology is very heterogeneous: from chro-
mosomal abnormalities (such as trisomy 13), 4.7.3 Potter Sequence
known syndromes (such as Smith-Lemli-Opitz
syndrome, CHARGE syndrome) to environmen- The Potter sequence is caused by absent or
tal factors (maternal diabetes or hypocholes- severely reduced fetal urine output from the
terolemia during gestation). In nonchromosomal first trimester. It may be secondary to bilateral
non-syndromic holoprosencephalic sequence, at renal agenesis (a differentiation defect of the
least 14 genes have been implicated: four major metanephric blastema) or to other renal and uri-
genes SHH, ZIC2, SIX3, and TGIF and ten minor nary tract malformations. The cascade mecha-
genes. Molecular analyses of the four main genes nism starts with diminished urine production by
are routinely performed with a mutation detection the fetus; this leads to a reduced volume of amni-
rate of 25%. Array-CGH (comparative genomic otic fluid (anhydramnios or oligohydramnios),
hybridization) analysis shows 22% micro- which gives rise to pulmonary hypoplasia, lead-
rearrangements in HPE (Winter et al. 2015). How- ing to respiratory distress at birth, facial
ever, the underlying genetic complexity is to be dysmorphism (prominent nose and flat profile),
clarified yet; most cases are supposed to be mul- and diminished fetal movements with multiple
tifactorial and the recurrence risk for families with postural deformations particularly of the lower
a sporadic case is estimated at around 6%. limbs. When the phenotype is fully expressed,
the severe renal and pulmonary damage is respon-
sible for the high perinatal mortality (Shastry et al.
4.7.2 Pierre Robin Sequence 2012). Prenatal diagnosis by ultrasound reveals the
kidney defect, oligohydramnios, and other associ-
Pierre Robin sequence is a developmental defect ated malformations. The sequence is often sporadic,
of the mandible and surrounding oropharyngeal with etiological heterogeneity and a recurrence risk
4 Congenital Malformations and Syndromes: Early Diagnosis and Prognosis in Neonatal Medicine 55
of about 3%. It may occasionally be associated with a spontaneous abortion or fetal death because of
other defects in a more complex syndrome developmental impairment. About 50% of spon-
(Meckel-Gruber syndrome: occipital taneous abortions have an abnormal chromosomal
encephalocele, renal cystic disease, polydactyly, structure. Chromosomal aberrations may affect
and an autosomal recessive inheritance). autosomes and/or sex chromosomes and may
involve their number or structure. Numeric aber-
rations have a prezygotic origin (meiotic nondis-
4.7.4 Prune Belly Sequence junction, frequently related to advanced maternal
age). They may also arise from a postzygotic error
This sequence was named because of the charac- when they are present only in a variable propor-
teristic appearance of the abdomen (wrinkled tion of cells (mosaics). Structural aberrations
skin, also referred to as “flabby abdomen”) in the may occur de novo from a meiotic rearrangement
affected newborns. The sequence may be related or may be inherited from one parent, who carries a
to various defects of the genitourinary tract, balanced non-symptomatic chromosomal
involving the proximal urethra (urethral agenesis, translocation.
cloacal persistence, urethral stenosis, posterior
urethral valves in males) (Smolkin et al. 2008). 4.8.1.1 Down Syndrome (Trisomy 21)
Urethral obstruction is responsible for Down syndrome is the most frequent chromosomal
oligohydramnios (and possible secondary Potter aberration at birth (about 1:700). It is determined by
sequence) and accumulation of urine in the prox- a trisomy of chromosome 21. In most (95%) cases,
imal renal tract, leading to parenchymal damage trisomy 21 is secondary to a maternal meiotic non-
(bladder dilatation, bilateral ureteric dilatation, disjunction of homologous chromosomes 21; more
and hydronephrosis). Bladder hypertrophy and rarely there may be a Robertsonian translocation or
dilatation may interfere with development of the a postzygotic mitotic nondisjunction (mosaic with
abdominal wall muscles and diaphragm and tes- milder phenotype). The incidence is related to
ticular migration in the scrotum in males (crypt- maternal age at conception (1/1,500 at 20 years
orchidism). Abdominal wall muscle hypoplasia is and 1/28 at 45 years). The overall recurrence risk
responsible for the prune belly appearance is low (about 1%), although it significantly increases
because of visible intestinal loops through the when one of the parents carries a balanced translo-
thin abdominal wall. Diaphragmatic defects and cation. The phenotype at birth is characteristic: main
oligohydramnios cause lung hypoplasia and facial features are Brushfield spots (gray spots in the
severe respiratory distress at birth. Although median zone of the iris), upslanting palpebral fis-
early prenatal diagnosis by ultrasonography is sures, epicanthal folds, small nose, small mouth
possible, the differential diagnosis between iso- with prominent tongue, flat facial profile, brachy-
lated renal cystic conditions and obstructive cephaly with a flat occipital bone, small low-set
uropathies may be difficult. Prenatal bladder cath- ears, and short neck with redundant skin folds.
eterization allows urine to flow into the amniotic Newborn babies are hypotonic with lax joints. A
cavity and must be followed by surgical correc- single palmar crease and clinodactyly of the little
tion after birth. finger are frequent. Organ involvement includes
congenital heart defects (atrioventricular canal, ven-
tricular septal defects, tetralogy of Fallot), duodenal
4.8 Syndromes atresia or stenosis, Hirschsprung’s disease, hypothy-
roidism, and urinary tract malformations. Long-
4.8.1 Chromosomal Abnormalities term follow-up is required because of developmen-
tal delay, intellectual disability, growth retardation,
The overall incidence of chromosomal anomalies occurrence of autoimmune diseases, immunodefi-
is estimated at about 1:170 live births. Their prev- ciencies, and leukemia (Karmiloff-Smith et al.
alence at conception is much higher, giving rise to 2016). Survival rates and the quality of life have
56 G. Corsello and M. Giuffrè
improved significantly with educational and screen- iris coloboma, and large low-set external ears.
ing programs and the development of multidis- Heart, renal, and skeletal defects are frequent.
ciplinary follow-up. The degree of extension of the chromosomal dele-
tion influences the severity of phenotype and neo-
4.8.1.2 Edwards Syndrome (Trisomy 18) natal mortality rate. Surviving patients show
Edwards syndrome is determined by trisomy of severe postnatal growth retardation and psycho-
chromosome 18, sometimes as a mosaic or in motor developmental delay.
association with other chromosomal abnormali-
ties. Its birth prevalence is about 1:8,000 because 4.8.1.5 Cri du chat Syndrome (5p-)
most affected fetuses abort spontaneously. New- Cri du chat syndrome is due to a variable deletion
borns show severe prenatal growth restriction, of the short arm of chromosome 5, named because
dolichocephaly with prominent occiput and of the characteristic high-pitched catlike cry of
low-set dysplastic external ears, jaw hypoplasia, affected newborns caused by hypoplasia of laryn-
flexed hands with the index finger overlapping the geal cartilages, which disappears after the first
middle finger, single palmar crease, and talipes months of life (Rodríguez-Caballero et al. 2012).
with rocker-bottom feet. There are frequently Other phenotypical features are microcephaly,
associated malformations (heart, renal, intestinal, round face, hypertelorism, micrognathia,
CNS), which are responsible for the very grave epicanthal folds, and low-set ears. At birth there
prognosis and high neonatal mortality (Wu et al. is generalized hypotonia. Later there is limb
2013). hypertonia and severe developmental delay.
4.8.1.3 Patau Syndrome (Trisomy 13) 4.8.1.6 Mosaic 8 Chromosome Trisomy
Patau syndrome is determined by trisomy of chro- The full trisomy of chromosome 8 is extremely
mosome 13, sometimes with chromosomal trans- rare in humans. It is more common as a mosaic.
location or rarely as mosaic. Its birth prevalence is The phenotype of mosaic trisomy 8 includes
about 1/10,000. Newborns show prenatal growth scaphocephaly, ankylosed large joints, clubfoot,
restriction, a small trigonocephalic skull, areas of absent or hypoplastic patellae, arachnodactyly,
aplasia cutis on the scalp, cleft lip and palate, and brachydactyly. Deep grooves in the palms
microphthalmia, variable hypotelorism up to and soles (Fig. 1) are virtually diagnostic in
cyclopia (i.e., expression of an associated infancy but become less prominent with age
holoprosencephalic sequence), postaxial polydac- (Biesecker and Spinner 2013). The face is
tyly and/or syndactyly, forced flexion of the fin-
gers, single palmar crease, plantar convexity, and
cryptorchidism. Other organs are frequently
involved (heart, kidneys). Patients with fully
expressed phenotype usually die during the first
month of life; those with milder signs (mosaics)
may survive with severe developmental deficits
(Wu et al. 2013; Barry et al. 2015).
4.8.1.4 Wolf-Hirschhorn Syndrome (4p-)
This is a rare condition determined by deletion of
the distal part of the short arm of chromosome
4. Newborns present with prenatal growth restric-
tion, hypotonia, severe microcephaly with
brachycephaly, prominent nose, downturned cor-
ners of the mouth, arched palate, jaw hypoplasia, Fig. 1 Deep plantar grooves in a newborn with mosaic
hypertelorism, downslanting palpebral fissures, 8 chromosome trisomy
4 Congenital Malformations and Syndromes: Early Diagnosis and Prognosis in Neonatal Medicine 57
characterized by a prominent pouting lower lip 4.8.1.8 DiGeorge Syndrome
and small jaw. Intellectual disability may be pre- DiGeorge syndrome, also noted as 22q11.2 dele-
sent but is often mild and may remain undetected. tion syndrome, is a chromosomal disorder whose
common features include cardiac defects, palatal
4.8.1.7 Turner Syndrome anomalies, facial dysmorphism, developmental
Turner syndrome is the most frequent aneuploidy delay, and immune deficiency (McDonald-McGinn
of sex chromosomes with a birth prevalence of and Sullivan 2011; Botto et al. 2003). This condi-
1/2,500. It is determined by a monosomy of tion has been previously reported with the acronym
chromosome X, which may be complete (50%) CATCH 22 (Cardiac abnormality, Abnormal face,
or partial (20%); it frequently presents as a mosaic Thymic hypoplasia, Cleft palate, Hypoparathyroid-
with a milder phenotype (30%). During the neo- ism, chromosome 22 microdeletion).
natal period, the diagnosis is suspected because of Heart defects are conotruncal (aortic arch
lymphedema of the hands and feet (Fig. 2), nail interruption, common arterial trunk, tetralogy
dysplasia, neck pterygium, a large mouth with of Fallot). When the brachial structures are
downturned corners, dysplastic external ears, involved, there is dysfunction of the immune
and left heart output defects (aortic coarctation, system (T-cell deficiency) and parathyroidal
left heart hypoplasia). In addition, there may be a abnormalities with low serum calcium levels.
prenatal history of cystic hygroma. The clinical During the neonatal period, the full expression
phenotype changes with age when other features of the phenotype results in hypocalcemia and
become evident: short stature, short neck, low craniofacial dysmorphism (micrognathia, cleft
posterior hairline, restricted thorax, cubitus val- palate, anteverted nares, low-set external ears)
gus, shortness of the fourth metacarpal bone, pri- with a conotruncal heart defect and absent
mary amenorrhea, absence of secondary sexual thymic shadow at chest X-ray delineating the
signs, and an endocrine profile of gonadal dysgen- phenotype with full expressivity. In most
esis. Life expectancy is not reduced, but long-term cases, the syndrome is due to a 3 Mb deletion
follow-up is required and appropriate hormonal on the chromosomal region 22q11.2; there are
therapy (growth hormone in the first decade and also atypical deletions which are nested within
estrogen-progesterone after puberty must be given the DiGeorge critical region. Some of them
in order to improve height and induce the men- include the TBX1 gene that has been shown
strual cycle) (Blum et al. 2013). to be implicated in cardiac, parathyroid, thy-
mus, and facial structure development. The
variable expression of the 22q11.2 phenotype
is thought to be due to genetic modifiers on
either the other 22q11.2 allele or on other
chromosomes. Diagnosis is suspected upon
clinical examination and detection of anoma-
lies but needs to be confirmed by detection of
the 22q11.2 deletion, using fluorescence in situ
hybridization (FISH), MLPA, aCGH, or
genome-wide SNP (single nucleotide polymor-
phism) microarrays (Hacıhamdioğlu et al.
2015).
4.8.2 Monogenic Disorders
Monogenic disorders are single gene mutations
Fig. 2 Foot lymphedema in a baby with Turner syndrome with a Mendelian mode of inheritance. The
58 G. Corsello and M. Giuffrè
genotype-phenotype correlation remains
undefined for many conditions. Each syndrome
may be due to different mutations in the same
gene or in different genes (genetic heterogene-
ity). The same mutation may determine different
phenotypes (phenotypical variability) in the
same family and appears to depend on interfer-
ence by other genetic and/or environmental fac-
tors. In addition, epigenetic factors (e.g., DNA
methylation) may act during the differentiation
processes to modify gene expression and may
depend on the parental origin of the gene (geno-
mic imprinting).
4.8.2.1 Cornelia de Lange Syndrome Fig. 3 Typical facial appearance of a newborn baby with
(CdLS) Cornelia de Lange syndrome, showing synophrys, a
CdLS affects 1/10,000 newborns and is usually depressed nasal bridge, anteverted nares, long philtrum,
sporadic. Causative mutations in genes involved and carp mouth
in chromosomal cohesion (cohesin complex) have
been identified. The NIPBL gene (locus at 5p13.1) and broad thumbs and toes. Chromosome abnor-
is mutated in approximately 50% of patients and is malities are occasionally observed on routine
the major gene involved in the syndrome. Muta- cytogenetic testing. CREBBP and EP300 are the
tions in SMC3, RAD21, SMC1A, and HDAC8 only genes currently known to be associated with
have recently been described with an autosomal RSTS. FISH analysis of CREBBP detects
dominant or an X-linked dominant pathways of microdeletions in approximately 10% of individ-
inheritance. Newborns show a typical facial uals with RSTS. Sequence analysis detects
appearance (microbrachycephaly, low anterior CREBBP pathogenic variants in another 40–50%
and posterior hairline, synophrys, small nose of affected individuals. Pathogenic variants in
with a depressed nasal bridge, anteverted nares, EP300 are identified in approximately 3–8% of
long philtrum, “carp” mouth, maxillary progna- individuals with RSTS (Schorry et al. 2008;
thism, low-set ears, Fig. 3), with intrauterine and Pagon et al. 1993). Familial cases with autosomal
postnatal growth retardation, hypertrichosis, and dominant inheritance have been described.
upper limb anomalies (small limbs, reduction The diagnosis of RSTS is primarily based on
defects including phocomelia, limited elbow clinical features. The main craniofacial features
extension, single palmar crease, oligosyndactyly) (Fig. 4) are microcephaly, frontal bossing, large
(Bhuiyan et al. 2006; Ramos et al. 2015). anterior fontanelle, downslanting palpebral fis-
Urogenital, heart, and intestinal malformations sures, broad nasal bridge, beaked nose, epicanthal
may also be present. Most patients show develop- folds, strabismus, maxillary hypoplasia, high-
mental delay and growth retardation. Infections, arched palate, and external ear abnormalities.
feeding difficulties, and neurologic disturbances (sei- There is hand and foot involvement (broad distal
zures, motor and speech retardation) require long- phalanges of thumbs and halluces with medial
term multidisciplinary follow-up and family support. deviation, clinodactyly, or duplication). There
may also be hirsutism and abnormalities of the
4.8.2.2 Rubinstein-Taybi Syndrome skeleton (spinal, pelvic), heart (septal defects, pat-
(RSTS) ent ductus arteriosus), and urogenital tract (hypo-
RSTS is a rare malformation syndrome character- spadias, cryptorchidism). Growth retardation,
ized by intellectual disability, facial abnormalities, skeletal maturation delay, and severe intellectual
4 Congenital Malformations and Syndromes: Early Diagnosis and Prognosis in Neonatal Medicine 59
aortic dilatation, aortic dissection) and ocular
signs develop (ectopia lentis, early glaucoma)
(Loeys et al. 2010).
4.8.2.4 Noonan Syndrome (NS)
NS is a relatively frequent (1/2,000) condition
with some phenotypic features similar to those
of Turner syndrome (male Turner, pseudo-
Turner). In approximately 50% of cases, the dis-
ease is caused by missense mutations in the
PTPN11 gene (12q24.1), resulting in a gain of
function of the non-receptor protein tyrosine
phosphatase SHP-2 protein. Recently, mutations
in other genes from the RAS-MAPK pathway
(KRAS, SOS1, and RAF1) have been identified in
Fig. 4 Newborn with Rubinstein-Taybi syndrome show-
ing microcephaly, frontal bossing, downslanting palpebral a small portion of patients with NS. Mutation
fissures, broad nasal bridge, beaked nose, epicanthus, and analysis can be carried out on blood samples and
maxillary hypoplasia should be recommended for any subject with a
suspected diagnosis of NS. However, the diagno-
sis cannot be excluded on a molecular basis, as the
disability are more common with increasing age sensitivity of combined screening of all known
(Pagon et al. 1993). genes allows confirmation in less than 75% of
patients, with sporadic as well as familial cases
4.8.2.3 Marfan Syndrome (MS) (Roberts et al. 2013). The inheritance is autosomal
MS is characterized by several congenital defect dominant and parents must be always investigated
of the connective tissue involving the skeleton, for mild clinical signs.
eye, and cardiovascular system. It is determined Newborns show hypertelorism, upslanting pal-
by heterozygous mutations in the FBN1 gene pebral fissures, low-set posteriorly rotated ears,
(15q21.1) encoding for fibrillin-1 protein, which neck pterygium, a shield chest with deformation
is a component of collagen (Tiecke et al. 2001). of the sternum, and lymphedema (Fig. 5). Cardiac
Frontier forms have been identified, secondary to
mutations in the TGFBR2 gene located on chro-
mosome 3 which encodes for a TGF-beta recep-
tor. It is inherited as an autosomal dominant with
variable clinical expression; about 25% of cases
are sporadic, due to de novo mutations correlated
with advanced paternal age. Newborns show
arachnodactyly, long and thin limbs, increased
length joint laxity and hypermobility, muscular
hypotonia, hernias, and pectus carinatum or
excavatum. Cardiac abnormalities comprise
mitral valve prolapse and aortic defects (aortic
root dilatation and aortic aneurysm). Patients
with most severe neonatal phenotype (neonatal
Marfan syndrome) have high early mortality
rates. Skeletal and cardiac problems usually Fig. 5 A patient with Noonan syndrome with
evolve with growth (kyphoscoliosis, progressive hypertelorism, upslanting palpebral fissures, and shield chest
60 G. Corsello and M. Giuffrè
involvement is mainly of the pulmonary outflow
tract (pulmonary valve dysplasia and stenosis,
cuspid thickening, and hypomobility). Other pos-
sible features are cryptorchidism in males and a
bleeding tendency, due to thrombocytopenia and
partial deficiency of coagulation factors. Later in
infancy, other signs become evident: postnatal
growth retardation (with short stature and retarded
bone age), triangular face, mild psychomotor, and
intellectual delay (Ferrero et al. 2008). The differ-
ential diagnosis should include Turner syndrome,
cardiofaciocutaneous syndrome, Costello syn-
drome, neurofibromatosis type 1, and LEOPARD
syndrome. Life expectancy depends exclusively
on the severity of heart defects. Fig. 6 The neonatal phenotype of Prader-Willi syndrome:
hypomimic face, reduced bitemporal diameter, almond-
4.8.2.5 Prader-Willi Syndrome (PWS) shaped eyes, small mouth with downturned corners, and
thin upper lip
Prader-Willi syndrome is determined by the fail-
ure of expression of genes of paternal origin in
the 15q11-q13 region. These genes are normally
subjected to maternal imprinting (DNA methyl- retardation, and speech delay. Treatment with
ation) which avoids maternal copy transcription growth hormone (GH) is possible and good clin-
and determines a functional gene monosomy ical results have been reported (Wolfgram et al.
(only the paternal copy is expressed). This con- 2013).
dition may arise from microdeletions of paternal
chromosome 15 (70–75%), maternal uniparental 4.8.2.6 Beckwith-Wiedemann Syndrome
disomy (25–30%), or imprinting center defects (BWS)
(1%). Methylation testing identifies almost all Beckwith-Wiedemann syndrome is a sporadic
patients; FISH and microsatellite DNA analysis condition determined by an altered balance
may reveal microdeletions and maternal UPD. between cooperating genes in the region 11p15.
PWS newborns (Fig. 6) present with congenital The genetic mechanism is complex and involves
hypotonia, a prenatal history of reduced fetal imprinted genes encoding for several important
movements, poverty of facial expression, doli- growth factors and receptors. Various genotypic
chocephaly with reduced bitemporal diameter, abnormalities have been described in BWS
almond-shaped eyes with upslanting palpebral patients, e.g., microduplication of paternal region
fissures, a small mouth with downturned corners 11p15, microdeletion of the maternal region, and
and thin upper lip, small hands and feet, and mutations and paternal uniparental disomy of
genital hypoplasia with cryptorchidism in males chromosome 11. Molecular subgroups are associ-
(Gunay-Aygun et al. 2001). Hypotonia of the ated with different recurrence risks and different
respiratory, orofacial, and pharyngoesophageal clinical findings (e.g., tumor risks) (Weksberg
muscles causes variable degrees of respiratory et al. 2010).
and feeding difficulties (poor suction and The main neonatal clinical features (Fig. 7) are
swallowing), which are present from birth and exomphalos, macroglossia, and gigantism (EMG
tend to improve after the neonatal period. After syndrome). Other features are visceromegaly, adre-
the first year of life, the phenotype modifies and nocortical cytomegaly, dysplasia of the renal
is characterized by hyperphagia, obesity, sleep medulla, typical linear indentations of the helix and
disturbances, short stature, hypogonadotropic the auricular lobe of the ear, hypoglycemia during
hypogonadism, mild to moderate mental the first days of life, and limb hemihypertrophy.
4 Congenital Malformations and Syndromes: Early Diagnosis and Prognosis in Neonatal Medicine 61
a maternal microduplication of the region. Diag-
nosis is mainly clinical, as there is no specific
biological test, but it can be confirmed by the
detection of the underlying molecular anomaly
with methylation-specific PCR, microsatellite
typing, methylation-specific MLPA, and/or
array CGH (Abu-Amero et al. 2008; Eggermann
et al. 2011). The neonatal phenotype is charac-
terized by severe intrauterine growth restriction
with normal development of the skull
(pseudohydrocephalic appearance), poor post-
natal growth, craniofacial features (triangular-
shaped face and broad forehead), body asymme-
try, and a variety of minor malformations
(clinodactyly and syndactyly of the little finger).
The phenotypic expression changes during
childhood and adolescence, with the facial fea-
tures and asymmetry usually becoming more
subtle with age. GH therapy should be consid-
ered to improve final height.
4.8.2.8 Goldenhar Syndrome (GS)
GS is a spectrum of malformations involving the
eye, ear, and vertebrae with heterogeneous etiol-
ogy and a highly variable phenotype (Gorlin
Fig. 7 Exomphalos, macroglossia, and gigantism et al. 1990). Its prevalence at birth is about
1/5,000. Most cases are sporadic, although
some families with autosomal dominant inheri-
Prenatal diagnosis may be because of exomphalos tance have been described. GS originates from a
and generalized overgrowth seen on ultrasound vascular disruption of the first and second bran-
scanning. The neonatal diagnosis is based on clinical chial arches, with consequent malformations of
findings, although careful molecular cytogenetic related organs and tissues. Defects are more
analysis of the 11p15 region is recommended. Over- often unilateral and an increased incidence has
growth and macroglossia tend to become less evi- been reported in the offspring of diabetic
dent with age, but there is an increased risk of mothers, as have other disorders of
malignant tumors (Wilms’ tumor, adrenal carci- blastogenesis. GS newborns show multiple cra-
noma, hepatoblastoma). niofacial anomalies (Fig. 8): hemifacial
microsomia, ipsilateral deformity of the external
4.8.2.7 Silver-Russell Syndrome ear (preauricular tags, atresia of the external
Silver-Russell syndrome is a sporadic condition auditory canal, anomalies in size and shape of
with genetic heterogeneity. Most cases are spo- the external auricle), epibulbar dermoid, and
radic. Maternal uniparental disomy of chromo- coloboma of the upper eyelid. In addition,
some 7 is observed in 10% of patients. defects of the cervical vertebrae (hemivertebrae,
Approximately 30% of the cases show fusions, segmental agenesis), cleft palate,
hypomethylation of the H19 gene, located in choanal atresia, heart, kidney, and CNS defects
the 11p15 imprinted region. Hypomethylation may be found. Auditory function must be
results in most cases from an epigenetic mecha- assessed early to preserve speech and cognitive
nism or a genomic micro-rearrangement, such as development (Paludetti et al. 2012).
62 G. Corsello and M. Giuffrè
supplementation. Treatment trials are underway
investigating combined treatment with cholesterol
supplementation and a HMG-CoA reductase
inhibitor. Surgery is proposed in case of second-
ary problems due to malformations (Porter 2008).
4.9 Disruptions
Some congenital malformations can be related to
exogenous factors, which act during intrauterine
life, inducing abnormalities of developmental and
differentiation processes. The most susceptible
Fig. 8 Hemifacial microsomia and atresia of the external period is the first trimester of pregnancy in
auricle in a baby with Goldenhar syndrome which the identification of developmental fields,
organogenesis, and differentiation take place.
Biological, chemical, metabolic, physical and
4.8.2.9 Smith-Lemli-Opitz Syndrome mechanical agents (Table 1) may cause defects
(SLOS) of morphogenesis. The etiologic identification is
SLOS is a rare (1/30,000) autosomal recessive important for effective genetic counseling and
condition, caused by mutations in the DHCR7 reducing the risk of recurrence in an affected
gene (11q13.4) leading to deficiency of the family.
enzyme 3 beta-hydroxysterol-delta 7-reductase
that converts 7-dehydrocholesterol (7DHC) to
cholesterol (Wassif et al. 1998; Porter 2008). 4.9.1 Biologic Agents
The enzyme deficiency causes a severe deficit of
endogenous cholesterol production and its deriv- Most morphogenetic defects determined by bio-
ative compounds (sexual steroids, components of logical agents are pathogenetically and clini-
the myelin and cellular membranes), starting from cally characterized. A high IgM level soon
intrauterine life. SLOS newborns show intrauter- after birth is strongly suggestive of a prenatal
ine growth restriction, severe hypotonia, infection of the fetus, although only 30% of
microdolichocephaly, high forehead, palpebral these newborns show clinical consequences.
ptosis, anteverted nares, and micrognathia. There The earlier the timing of intrauterine infection
may be other features, such as agenesis of the (particularly during the first trimester of gesta-
corpus callosum, cleft palate, syndactyly of the tion), the more severe is the effect of morpho-
second and third toes, congenital heart defects, genetic defects due to viral and bacterial agents,
and liver dysfunction. Male patients usually have and there is usually associated intrauterine
hypospadias, micropenis, cryptorchidism, and growth restriction. The most common
sometimes various degrees of ambiguous genita- embryofetopathies due to biologic agents are
lia, because of the prenatal androgen deficiency. described in Table 3.
Diagnosis is based on the detection of low choles-
terol and elevated 7DHC levels in plasma or tis-
sues and confirmed due DHCR7 sequence 4.9.2 Chemical Agents
analysis, which allows confirmation of the prena-
tal diagnosis for at-risk couples. Failure to thrive Any substance introduced to the human organism
worsens with age and there is always severe psy- can be considered as a chemical agent. They may
chomotor delay. Management is symptomatic and be drugs or foods associated with flawed lifestyle
most patients are treated with dietary cholesterol choices (alcohol consumption, cigarette smoking,
4 Congenital Malformations and Syndromes: Early Diagnosis and Prognosis in Neonatal Medicine 63
Table 3 Main disruptions determined by biologic agents Table 4 Main disruptions determined by chemical agents
Biologic agent Phenotype Chemical agent Phenotype
Cytomegalovirus Microcephaly, intracranial Anticonvulsant drugs Cleft lip and palate, neural
calcifications, psychomotor delay, tube defects, congenital heart
sensorineural hearing loss, defects
chorioretinitis, Hydantoin (microcephaly,
hepatosplenomegaly, mental retardation, CNS
thrombocytopenia, virus presence abnormalities, small nose,
in secretions and biologic fluids facial bone hypoplasia,
(urine) epicanthus, hypertelorism,
Rubella virus Microcephaly, psychomotor delay, strabismus, cleft lip and
congenital cataract, sensorineural palate, micrognathia, short
hearing loss, heart defects, neck, heart defects)
hematologic alterations (anemia, Trimethadione
thrombocytopenia) (microcephaly, facial bone
Varicella-zoster Mental retardation, cortical atrophy, hypoplasia, palpebral
virus seizures, chorioretinitis, skin scars synophrys, epicanthus,
Treponema Palmoplantar pemphigus, external ear dysplasia,
pallidum exanthema with skin scars, anemia, urogenital defects, heart
thrombocytopenia, defects)
hepatosplenomegaly, myocarditis, Valproic acid
chorioretinitis, muco-hematic (trigonocephaly, reduced
rhinitis, skeletal alterations bitemporal diameter, facial
(lacunae, caput quadratum, bone hypoplasia, small nose,
metaphyseal ossification defects, cleft lip and palate,
osteochondritis, and secondary urogenital and limb defects)
pseudoparalysis) Alcohol IUGR, peculiar face
Toxoplasma Hydrops, hydrocephalus, (microcephaly, short palpebral
gondii intracranial calcifications, fissures, small nose with
chorioretinitis, cataract, seizures, anteverted nares, hypoplastic
hepatosplenomegaly, skin rush nasal philtrum,
microretrognathia), neurologic
abnormalities (hypotonia,
seizures, poor motor
ingestion of substances of abuse) or produced by coordination, mental
maternal metabolism in specific situations. Some retardation)
drugs and single molecules, which are well toler- Cocaine Prematurity, IUGR,
ated by an adult, may be seriously dangerous for microcephaly, urogenital and
the development of the embryo and fetus. Drug skeletal malformations
Heroin IUGR, low birth weight,
testing in human pregnancy is difficult and all
congenital malformations
drugs have therefore to be considered potentially Maternal diabetes Macrosomia, hypoglycemia,
harmful, requiring careful risk/benefit evaluation. hypocalcemia, ventricular
Substances may cross the placenta and reach the septal hypertrophy, caudal
fetus and placental function may reduce or dysgenesis, any kind of
congenital malformations
increase their effects. Individual metabolism may
(skeletal, cardiac, renal,
influence the clinical effects, dosage, and timing intestinal, CNS, etc.)
of administration. The most frequent disruptions Maternal Defects of cellular
by chemical agents are reported in Table 4. proliferation and migration
with myelinization delay
(IUGR, severe microcephaly,
hypotelorism)
4.9.3 Vascular Disruptions Hyperphenylalaninemia Prominent nose, low-set
dysplastic external ears, mental
Any vascular accident during early embryonic retardation, cleft lip and palate,
and fetal development may determine subsequent conotruncal heart defects
64 G. Corsello and M. Giuffrè
morphogenetic defects in the relevant body for all cases, and it can be influenced by other
region. genes (epistatic) as well as other interactive cyto-
Disruption of the subclavian artery includes a plasmic and environmental factors.
heterogeneous group of clinically and etiologi-
cally different conditions, characterized by alter-
ation of different mesodermal structures supplied 4.10.1 Craniofacial Dysostoses
by the subclavian artery. Thus, the Poland
sequence includes pectoral muscle agenesis and Full fusion of all cranial sutures is normally
ipsilateral superior limb reduction defects. Kidney achieved at about 25 years of age. Craniosy-
and urinary tract defects are frequently associated, nostoses depend on a precocious closure of one
expanding the phenotype toward an acro- or more cranial sutures and may cause a restriction
pectoral-renal developmental field. in the size of the cranium. The closure of a suture
Twin-twin disruption sequence (TTDS) may limits cranial growth at that site, and there is
involve various structures such as the brain, bra- increased cranial growth at the other sutures, pro-
chial arches, limbs, gut, and kidneys. It is caused ducing deformation of the skull (sometimes with
by the intrauterine developmental impairment and brain growth restriction, hydrocephalus, and intra-
subsequent death of a monozygotic twin. The cranial hypertension). Skull morphology depends
presence of vascular placental anastomoses on suture involvement (nature, timing, extension,
between the arterial supplies of twins and abnor- and symmetry). The overall incidence of
mal communicating flow allows the passage of craniosynostoses is estimated to affect about
thromboemboli to the surviving twin, with 1/3,000 newborns. It may present in isolation or
reduced or interrupted blood flow causing struc- as part of a more complex syndrome.
tural damage. The complex vascular interactions
between monozygotic twins may result in other 4.10.1.1 Non-syndromal
vascular disruptions (e.g., because of an acardiac Craniosynostoses
twin) or a twin-twin transfusion sequence, which Scaphocephaly depends on the premature fusion
are particular features of monozygotic twins of the sagittal suture with consequent restriction of
(Giuffrè et al. 2012). growth along the transverse axis and compensa-
tory increased growth along the anteroposterior
axis. Plagiocephaly depends on the premature
4.10 Dysostoses fusion of a single coronal suture with consequent
ipsilateral growth restriction and flattening of the
A heterogeneous group of birth defects with sin- frontal bone; the involvement of facial structures
gle or multiple involvement of skeletal segments varies from simple deviation of nasal septum to
(with no systemic cartilaginous tissue involve- severe asymmetry of the sphenoid and maxillary
ment), due to mutations of the genes involved in bones. Brachycephaly is due to premature fusion
bone development. Dysostoses classification is of both coronal sutures with consequent growth
based on phenotypic criteria and the body region restriction along the anteroposterior axis and com-
most involved. In some instances, a genetic clas- pensatory increase in skull height; hypoplasia of
sification is now possible. Most syndromal the frontal region is often present. Acrocephaly
craniosynostoses are determined by mutations in depends on the premature fusion of the coronal
fibroblast growth factor receptor (FGFR) genes, and sagittal sutures with consequent severe
with string evidence of genetic heterogeneity (the growth restriction along both anteroposterior and
same condition being determined by different transverse axes and compensatory increased
mutations in the same gene or in different FGFR development of the frontal region. Intracranial
genes) and genetic pleiotropism (the same muta- hypertension is frequently present and requires
tion being responsible for different phenotypes). early surgical correction to avoid severe CNS
Genotype/phenotype correlation is not possible complications. Trigonocephaly is due to the
4 Congenital Malformations and Syndromes: Early Diagnosis and Prognosis in Neonatal Medicine 65
premature fusion of the metopic suture, often evi- a complete syndactyly (spoon-shaped hand) with
dent because of a longitudinal bone crest in the bone and nail fusion. Synostosis may also be
median frontal region, giving the skull a triangular found in the carpal and tarsal bones and cervical
appearance with hypotelorism and flattening of vertebrae. Mental retardation may be present, as
the lateral frontal regions. Cloverleaf skull is due well as intracranial hypertension, particularly in
to the premature fusion of the coronal, sagittal, the absence of early neurosurgical correction. A
and lambdoidal sutures with excessive skull complex surgical program must be planned for
growth in height and to both sides, giving a the correction of multiple synostosis (skull
trilobar appearance. Intracranial hypertension is remodeling, hand surgery). Apert syndrome is
consistently severe and gives rise to CNS due to mutations in the exon 7 of the FGFR2
complications. gene (different mutations have been identified),
with autosomal dominant inheritance and a high
4.10.1.2 Syndromal Craniosynostoses rate of de novo mutations correlated with
Apert syndrome is a rare and serious phenotype advanced paternal age (Wilkie et al. 1995).
described in newborns with acrocephaly and Crouzon syndrome is the most frequently
syndactyly of the hands and feet (Fig. 9). The reported syndromal craniosynostosis, character-
premature fusion of both coronal sutures is ized by acrocephaly with no hand and foot
responsible for acrocephaly, frontal bossing, flat involvement. Premature fusion of the coronal
occipital bone, and facial dysmorphic features sutures causes the acrocephaly, frontal bossing,
(downslanting palpebral fissures, exophthalmus, and flat occipital bone. Looking at the face,
hypertelorism, small upturned nose, maxillary there is hypoplasia of the midline structures,
hypoplasia, low-set ears). Hands and feet present reduced orbital volume and ocular proptosis,
strabismus, a small upturned nose, and maxil-
lary hypoplasia. Fusions of cervical vertebrae
and mild mental retardation may occur.
Crouzon syndrome may be due to different
mutations of the FGFR2 gene with a wide
range of phenotypical expression. It may be
sporadic, due to a de novo mutation often
related to advanced paternal age or familiar
with autosomal dominant inheritance.
Muenke syndrome is a relatively frequent uni-
lateral coronal craniosynostosis with
brachydactyly. It is caused by a mutation
(Pro250Arg) of the FGFR3 gene, with autosomal
dominant inheritance and variable clinical expres-
sion (Doherty et al. 2007). Most cases are familial,
but unless there is an index case in the family, the
diagnosis may be missed in newborns with a mild
phenotype.
Pfeiffer syndrome is a rare acrocephalo-
syndactyly caused by several mutations in
FGFR1 and FGFR2 genes, with autosomal
dominant inheritance and variable clinical
expressivity. Premature fusion of the coronal
sutures causes acrocephaly, frontal bossing,
Fig. 9 Baby with Apert syndrome showing acrocephaly,
frontal bossing, exophthalmus, small upturned nose, max- and flat occipital bone. Concomitant synostosis
illary hypoplasia, and spoon-shaped hands of sagittal and lambdoidal sutures may cause a
66 G. Corsello and M. Giuffrè
cloverleaf appearance of the skull. The face is
characterized by downslanting palpebral fis-
sures, ocular proptosis, strabismus,
hypertelorism, maxillary hypoplasia, and
low-set ears. Hands and feet usually show
hypoplasia of the first ray (large first finger
and toe, trapezoidal toe) and various degrees
of postaxial syndactyly. There may be associ-
ated elbow ankylosis or synostosis and verte-
bral fusions. Most severely affected patients
require early surgical correction to prevent
CNS complications. The prognosis is related
to the degree of phenotypical expression.
4.10.1.3 Treacher Collins Syndrome
(Franceschetti Syndrome)
This syndrome is characterized by a develop-
mental defect of the jaw and facial bones.
There is wide variability. It is determined by
several different mutations in the TCOF1 gene
(5q32) encoding the nucleolar phosphoprotein
treacle, which has a key role in early craniofacial
development, or in the POLR1C (6p21.1) or
POLR1D (13q12.2) genes, encoding for RNA
polymerase I and III subunits (Dixon 1996; Fig. 10 Baby with Nager syndrome showing microceph-
aly, micrognathia, malar hypoplasia, and preaxial limb
Trainor et al. 2009). Neonatal features are
reduction defects
downslanting palpebral fissures, palpebral
coloboma, malar hypoplasia, macrostomia,
micrognathia, external ear hypoplasia with atre- patients, NAFD has been associated with hetero-
sia of the middle ear, and hearing loss. Cleft zygous mutations in the SF3B4 gene (1q21.2),
palate and choanal atresia may also be present. coding for a component of the splicing machin-
In the most severely affected patients, there may ery (Petit et al. 2014). Patients have a
be impaired nutrition and respiratory function. mandibulofacial dysostosis with associated pre-
Growth and psychomotor development are usu- axial limb abnormalities (Fig. 10). The
ally normal, but affected children need long-term mandibulofacial dysostosis is mainly character-
multidisciplinary follow-up. Hearing loss ized by microcephaly, severe micrognathia and
requires early treatment to preserve speech malar hypoplasia, low-set posteriorly rotated
development. Surgical treatment may correct ears, and external auditory canal atresia. The
bony defects and achieve useful functional and limb deformities consist of radial aplasia or
aesthetic advantages. hypoplasia, radioulnar synostosis with limitation
of elbow extension, and hypoplasia or absence
4.10.1.4 Nager Syndrome (Acrofacial of the thumbs.
Dysostosis Nager Type)
Nager syndrome is likely genetically heteroge-
nous with confirmed autosomal dominant inher- 4.10.2 Thoraco-vertebral Dysostoses
itance, but autosomal recessive inheritance is
suspected based on sibling recurrence in consan- Klippel-Feil malformation is a developmental
guineous families. In approximately 50% of defect of the spine, with possible changes at the
4 Congenital Malformations and Syndromes: Early Diagnosis and Prognosis in Neonatal Medicine 67
cervical, thoracic, and/or lumbar level (short neck, Oligodactyly is the absence or severe hypopla-
pterygium, kyphosis, scoliosis). X-ray investigation sia of one or more digital axes. It may be preaxial
of the spine is required to show vertebral changes or postaxial and is frequently associated with
(fusions, hemivertebrae, hemispondyls) and com- other defects.
plete the diagnostic work-up; there are three clinical
variants. It is more frequent in females. Its etiology
is heterogeneous, with genetic and environmental 4.11 Osteochondrodysplasias
(vascular disruptions) causes. It may also be part of a
more complex phenotype (cervico-oculoacoustic Osteochondrodysplasias are a wide and hetero-
syndrome, MURCS association). geneous group of genetically determined con-
ditions, involving the development and growth
of bony and cartilaginous tissues. The bone
4.10.3 Limb Dysostoses involvement is often prenatally diagnosed,
although some cases become evident after
Digital defects are caused by a differentiation birth. The overall prevalence at birth is about
defect of one or more contiguous bones. Digital 1/5,000. There has been a significant reduction
development is determined by a complex in recent years because of ultrasonographic
genetic system, which is phylogenetically com- prenatal diagnosis of the most severe condi-
mon to most vertebrates. Digital anomalies may tions. The classification of osteochondro-
be sporadic or familial with Mendelian inheri- dysplasias, based on phenotype, has recently
tance and may be associated with other digital been modified by advances in molecular genet-
defects (polysyndactyly) and other syndromic ics applied to genes involved in the synthesis
defects. of collagen and elastin, fibroblast growth factor
Polydactyly may be defined as the presence of receptors, cartilaginous proteins, vitamin D
one or more supernumerary fingers or toes. It is receptor complex, and lysosomal and peroxi-
termed as complete if it involves all phalanges, somal enzymes.
partial if it involves only distal phalanges (dupli- Lethal osteochondrodysplasias are character-
cation). In the preaxial forms, the extra digit is ized by death during the perinatal period because
related to the thumb; in the postaxial forms, it is of generalized involvement including long bones,
related to the little finger. spine, and cranial bones. Mortality is mainly
Syndactyly is the fusion of two or more digits: related to respiratory failure (due to skeletal
it may involve only the skin and muscle or include abnormalities and lung hypoplasia) and associ-
the bones. In the most severe cases, it may affect ated visceral and CNS malformations. Milder
all the fingers of the limb causing a “spoon” osteochondrodysplasias (with normal life expec-
appearance. Symphalangism is the fusion of one tancy, short stature, and abnormal bone develop-
or more phalanges in the same digit, with severe ment) may benefit from surgical bone elongation
ankylosis of the interphalangeal joint. and other corrective surgery and rehabilitation
Brachydactyly is the shortening of a digit due programs.
to developmental defect of one or more phalan-
ges. It is often associated with metacarpal or meta-
tarsal hypoplasia. 4.11.1 Achondroplasia
Ectrodactyly is a severe developmental anom-
aly of the median axis of the hand or foot causing a This is the most common cause of dispropor-
“lobster-claw” appearance. It is usually caused by tionate short stature with short limbs, deter-
a genetic etiology and may be associated with mined by a heterozygous mutation
other malformations (e.g., ectodermal defects (Gly380Arg) of the FGFR3 gene at 4p16.3
and cleft palate in the ectrodactyly-ectodermal which encodes a transmembrane receptor that
dysplasia-cleft syndrome [EEC syndrome]). is important in regulating linear bone growth,
68 G. Corsello and M. Giuffrè
“telephone receiver” femurs, narrow thorax,
severe platyspondyly (flattening of the vertebral
bodies), facial bone hypoplasia, and craniosynos-
tosis. TD includes two forms: TD, type 1 (TD1)
and TD, type 2 (TD2) that can be differentiated
from each other by femurs (bowed “telephone
receiver” femurs in TD1) and skull shape (clover-
leaf skull is main reported in TD2). All patients
are sporadic and due to de novo autosomal dom-
inant mutations in the FGFR3 gene (4p16.3)
which cause overactivity of the FGFR3 protein,
resulting in the disturbances in bone growth and
other tissues that are characteristic of TD.
4.11.3 Campomelic Dysplasia
Campomelic dysplasia is a severe autosomal
recessive bone dysplasia with high perinatal
lethality and female prevalence, due to mutations
Fig. 11 Neonatal achondroplasia with rhizomelic short
limb dwarfism, megalencephaly, frontal bossing, facial
in the SOX9 gene at 17q24. The phenotype
bone hypoplasia, and narrow thorax includes sex reversal (female external genitalia
with male chromosomes), macrocephaly, large
fontanelles, broad depressed nasal root,
among other functions. It is inherited as an micrognathia, short neck, pectus carinatum,
autosomal dominant trait with a high rate of short limb dwarfism, talipes, anterior bowing of
de novo mutations (80–90% of patients) and is tibiae, and poor ossification signs (Mansour et al.
related to advanced paternal age. The recur- 2002).
rence risk is low if parents are not affected.
The phenotype at birth (Fig. 11) is characteris-
tic: megalencephaly, frontal bossing, depressed 4.11.4 Diastrophic Dysplasia
nasal bridge, facial bone hypoplasia, progna-
thism, narrow thorax, rhizomelic short limb Diastrophic dysplasia is a rare autosomal reces-
dwarfism, brachydactyly, trident hands, and sive condition due to mutations of the SLC26A2
hypotonia. Psychomotor development is nor- gene at 5q31-q34 which encodes a sulfate trans-
mal. Patients frequently develop severe ortho- porter that is predominantly expressed in the
pedic complications (lumbar hyperlordosis). In cartilage. Mutations in the same gene have
some cases CNS complications, such as the been implicated in a moderate form of epiphy-
cord compressions and hydrocephalus, may seal dysplasia and in several lethal disorders
occur during childhood. such as achondrogenesis type 1b and
atelosteogenesis type 2. The distinct morpho-
logic abnormality of the growth plate consists
4.11.2 Thanatophoric Dysplasia of an irregular distribution of degenerating
chondrocytes in the resting cartilage with areas
Thanatophoric dysplasia (TD) is a severe and of intracartilaginous ossification. Patients have
generally lethal skeletal dysplasia. The phenotype rhizomelic short limb dwarfism, bilateral
is characterized by severe micromelic dwarfism clubbed foot, cystic lesions of the pinnae with
with bowing and deformations of long bones, calcification of the cartilage, premature calcification
4 Congenital Malformations and Syndromes: Early Diagnosis and Prognosis in Neonatal Medicine 69
of the costal cartilages, kyphoscoliosis, hip contrac- – Type 3: AD/AR, blue sclerae, hydrocephalus,
tures, and cleft palate. The “hitchhiker” thumb is cortical atrophy, joint hyperlaxity, shortness
particularly characteristic and is due to a deformity and bowing of limbs, and possible dental
of the first metacarpal. Intelligence is normal. Short abnormalities
stature with skeletal abnormalities becomes more – Type 4: AD, macrocephaly, frontal bossing,
marked with advancing age. hearing loss, joint hyperlaxity, osteoporosis,
mild long bone deformations, and possible
dental abnormalities
4.11.5 Pseudodiastrophic Dysplasia – Type 5: AR, mild to moderate short stature,
dislocation of the radial head, mineralized
Pseudodiastrophic dysplasia is an autosomal reces- interosseous membranes, hyperplastic callus,
sive condition described by Burgio in patients with white sclera, and no dental abnormalities
a phenotype similar to diastrophic dysplasia but
with proximal phalangeal joint dislocation, normal Other genetically different types have been
first metacarpal, platyspondyly, tonguelike lumbar observed (types 6–9) but they are not clinically
vertebral deformities, and marked lumbar lordosis different from types 2 to 4.
without cystic deformity of the helix (Fischetto
et al. 1997). The histologic appearance is different
from diastrophic dysplasia and no SLC26A2 muta- 4.11.7 Osteodysplastic Primordial
tions have been demonstrated. Most patients die Dwarfism
during the first months of life.
Osteodysplastic primordial dwarfism is a group of
brachymelic microcephalic dwarfisms with likely
4.11.6 Osteogenesis Imperfecta genetic heterogeneity and autosomal recessive
inheritance. Different clinical variants have been
Osteogenesis imperfecta is a genetically and pheno- described in patients with a prenatal onset of
typically heterogeneous group of conditions charac- severe dwarfism (Fig. 12), microcephaly, delayed
terized by increased bone fragility, low bone mass, closure of fontanelles, prominent eyes and
and susceptibility to bone fractures with variable
severity (Bodian et al. 2009). Most frequently
affected genes are those encoding for type 1 collagen
(COL1A1 on 17q21-q22 and COL1A2 on 7q22)
with autosomal dominant (AD) and autosomal
recessive (AR) inheritance. Five different clinical
variants have been differentiated, but only type
2 and type 3 are present at birth with a severe
phenotype and high perinatal lethality:
– Type 1: AD, triangular face, blue sclerae, oto-
sclerosis with secondary hearing loss, mitral
valve prolapse, macrocephaly, joint
hyperlaxity, and possible dental abnormalities
– Type 2: AD/AR, ossification deficiency,
craniotabes, pseudohydrocephalic skull,
micrognathia, small nose, blue sclerae, cardiac
valve degeneration, endocardic and aortic Fig. 12 Patient with osteodysplastic primordial dwarfism
microcalcifications, and multiple dental with microcephaly, severe shortness and deformations of
abnormalities long bones, and redundant skin folds at limbs
70 G. Corsello and M. Giuffrè
strabismus, microretrognathia, pointed nose, Eggermann T, Buiting K, Temple IK (2011) Clinical utility
high-arched palate, oligodontia, small low-set gene card for: Silver-Russell syndrome. Eur J Human
Genet 19(3):e1–e3
dysplastic ears, sparse scalp hair, pectus Ferrero GB, Baldassarre G, Delmonaco AG et al (2008)
carinatum, delayed bone age, severe osteoporosis, Clinical and molecular characterization of 40 patients
and multiple skeletal abnormalities (hip disloca- with Noonan syndrome. Eur J Med Genet 51:566–572
tion, coxa vara, joint contractures, short bowed Fischetto R, Causio F, Corso G et al (1997)
Pseudodiastrophic dysplasia type Burgio in a newborn.
long bones, small proximal femoral epiphyses, Am J Med Genet 71(2):222–225
thin diaphyses of long bones, brachydactyly, tali- Giuffrè M, Piro E, Corsello G (2012) Prematurity and
pes). Postnatal failure to thrive, mental retarda- twinning. J Matern-Fetal Neonatal Med 25(sup3):6–10
tion, sensory defects are consistently present Gorlin RJ, Cohen MM Jr, Levin LS (1990) Syndromes of
the head and neck. Oxford University Press, New York
during growth. Life expectancy is reduced. Gunay-Aygun M, Schwartz S, Heeger S et al (2001) The
changing purpose of Prader-Willi syndrome clinical
diagnostic criteria and proposed revised criteria. Pedi-
atrics 108, e92
References Hacıhamdioğlu B, Hacıhamdioğlu D, Delil K (2015)
22q11 deletion syndrome: current perspective. Appl
Abu-Amero S, Monk D, Frost J et al (2008) The genetic Clin Genet 8:123
aetiology of Silver-Russell syndrome. J Med Genet Jones KL (1997) Smith’s recognizable patterns of human
45:193–199 malformations. WB Saunders, Philadelphia
Barry T (2015) Genetics counseling in the genomic era. Karmiloff-Smith A, Al-Janabi T, D’Souza H, et al (2016)
https://www.jax.org. Accessed 6 Apr 2016 The importance of understanding individual differ-
Barry SC, Walsh CA, Burke AL et al (2015) Natural ences in Down syndrome. F1000Research, 5
history of fetal trisomy 13 after prenatal diagnosis. Lami F, Carli D, Ferrari P et al (2013) Holoprosencephaly:
Am J Med Genet A 167(1):147–150 report of four cases and genotype–phenotype correla-
Bhuiyan ZA, Klein M, Hammond P et al (2006) Genotype- tions. J Genet 92(1):97–101
phenotype correlations of 39 patients with Cornelia de Loeys BL, Dietz HC, Braverman AC et al (2010) The
Lange syndrome: the Dutch experience. J Med Genet revised Ghent nosology for the Marfan syndrome. J
43:568, 43:5 Med Genet 47(7):476–485
Biesecker LG, Spinner NB (2013) A genomic view of Mansour S, Offiah AC, McDowall S et al (2002) The
mosaicism and human disease. Nat Rev Genet 14 phenotype of survivors of campomelic dysplasia. J
(5):307–320 Med Genet 39:597–602
Blum WF, Ross JL, Zimmermann AG et al (2013) GH McDonald-McGinn DM, Sullivan KE (2011) Chromo-
treatment to final height produces similar height gains some 22q11.2 deletion syndrome (DiGeorge syn-
in patients with SHOX deficiency and Turner syn- drome/velocardiofacial syndrome). Medicine 90
drome: results of a multicenter trial. J Clin Endocrinol (1):1–18
Metab 98(8):E1383–E1392 Mitanchez D, Yzydorczyk C, Siddeek B et al (2015) The
Bodian DL, Chan T-F, Poon A et al (2009) Mutation and offspring of the diabetic mother – short- and long-term
polymorphism spectrum in osteogenesis imperfecta implications. Best Pract Res Clin Obstet Gynaecol 29
type II: implications for genotype-phenotype relation- (2):256–269
ships. Hum Mol Genet 18:463–471 Paludetti G, Conti G, Di Nardo W et al (2012) Infant
Botto LD, May K, Fernhoff PM et al (2003) A population- hearing loss: from diagnosis to therapy. Acta Otorhino-
based study of the 22q11.2 deletion: phenotype, inci- laryngol Ital 32:347–370
dence, and contribution to major birth defects in the Petit F, Escande F, Jourdain AS et al (2014) Nager syn-
population. Pediatrics 112:101–107 drome: confirmation of SF3B4 haploinsufficiency as
Dixon MJ (1996) Treacher Collins syndrome. Hum Mol the major cause. Clin Genet 86(3):246–251
Genet 1996:1391–1396 Porter FD (2008) Smith–Lemli–Opitz syndrome: patho-
Doherty ES, Lacbawan F, Hadley DW (2007) Muenke genesis, diagnosis and management. Eur J Hum Genet
syndrome (FGFR3-related craniosynostosis): expan- 16(5):535–541
sion of the phenotype and review of the literature. Am Ramos FJ, Puisac B, Baquero-Montoya C, et al (2015)
J Med Genet 143A:3204–3215 Clinical utility gene card for: Cornelia de Lange syn-
Donnai D, Winter RM (1995) Congenital malformation drome. Eur J Hum Genet 23(10):e1–e4
syndromes. Chapman & Hall Medical, London Roberts AE, Allanson JE, Tartaglia M et al (2013) Noonan
Dubourg C, David V, Gropman A et al (2011) Clinical syndrome. Lancet 381(9863):333–342
utility gene card for: holoprosencephaly. Eur J Hum Rodríguez-Caballero Á, Torres-Lagares D, Yáñez-Vico
Genet 19(1):118, preceeding RM et al (2012) Assessment of orofacial characteristics
4 Congenital Malformations and Syndromes: Early Diagnosis and Prognosis in Neonatal Medicine 71
and oral pathology associated with cri-du-chat syn- Trainor PA, Dixon J, Dixon MJ (2009) Treacher Collins
drome. Oral Dis 18(2):191–197 syndrome: etiology, pathogenesis and prevention. Eur J
Rubinstein-Taybi syndrome. In: Pagon RA, Adam MP, Hum Genet 17(3):275–283
Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Twining P, McHugo JM, Pilling DW (2000) Textbook of
Bird TD, Fong CT, Mefford HC, Smith RJH, Stephens fetal abnormalities. Churchill Livingstone, London
K (eds). University of Washington, Seattle, Wassif CA, Maslen C, Kachilele-Linjewile S (1998) Muta-
GeneReviews ®eneReviewsRJ Seattle. 1993–2016 tions in the human sterol delta-7-reductase gene at
Schorry EK, Keddache M, Lanphear N et al (2008) 11q12-13 cause Smith-Lemli-Opitz syndrome. Am J
Genotype-phenotype correlations in Rubinstein-Taybi Hum Genet 63:5555Ge
syndrome. Am J Med Genet 146A:2512–2519 Weksberg R, Shuman C, Beckwith JB (2010)
Shastry SM, Kolte SS, Sanagapati PR (2012) Potter’s Beckwith–Wiedemann syndrome. Eur J Hum Genet
sequence. J Clin Neonatol 1(3):157 18(1):8–14
Shaw-Smith C (2006) Oesophageal atresia, tracheo- Wiedemann HR, Kunze J, Dibbern H (1992) An atlas of
oesophageal fistula, and the VACTERL association: clinical syndromes. A visual aid to diagnosis, 2nd edn.
review of genetics and epidemiology. J Med Genet 43 Wolfe Publishing, London
(7):545–554 Wilkie AOM, Slaney SF, Oldridge M et al (1995) Apert
Smolkin T, Soudack M, Goldstein I et al (2008) Prune belly syndrome results from localized mutations of FGFR2
syndrome: expanding the phenotype. Clin Dysmorphol and is allelic with Crouzon syndrome. Nat Genet 9(165t
17:133–135 9):1
Solomon BD (2011) Vacterl/Vater association. Orphanet J Winter TC, Kennedy AM, Woodward PJ (2015)
Rare Dis 6(56):5 Holoprosencephaly: a survey of the entity, with embry-
Thouvenin B, Djadi‐Prat J, Chalouhi C et al (2013) Devel- ology and fetal imaging. Radiographics 35(1):275–290
opmental outcome in Pierre Robin sequence: a longi- Wolfgram PM, Carrel AL, Allen DB (2013) Long-term
tudinal and prospective study of a consecutive series of effects of recombinant human growth hormone therapy
severe phenotypes. Am J Med Genet A 161 in children with Prader-Willi syndrome. Curr Opin
(2):312–319 Pediatr 25:509–514
Tiecke F, Katzke S, Booms P et al (2001) Classic, atypi- Wu J, Springett A, Morris JK (2013) Survival of trisomy
cally severe and neonatal Marfan syndrome: twelve 18 (Edwards Syndrome) and trisomy 13 (Patau Syn-
mutations and genotype-phenotype correlations in drome) in England and Wales: 2004–2011. Am J Med
FBN1 exons 24–40. Eur J Hum Genet 9:13, 9:1 Genet A 161(10):2512–2518
Prenatal and Postnatal Inflammatory
Mechanisms 5
Kirsten Glaser and Christian P. Speer
Contents
5.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
5.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
5.3 Prenatal Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
5.3.1 Chorioamnionitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
5.3.2 Fetal Inflammatory Response Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
5.4 Postnatal Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
5.4.1 Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
5.4.2 Mechanical Ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
5.4.3 Hyperoxia and Hypoxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
5.5 Molecular Mechanisms of Adverse Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . 81
5.5.1 Cellular and Humoral Mediators of Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
5.5.2 Cellular and Endothelial Interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
5.5.3 Chemotactic and Chemokinetic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
5.5.4 Pro- and Anti-Inflammatory Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
5.5.5 Pattern Recognition Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
5.5.6 Oxygen Radicals and Proteolytic Mediators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
5.5.7 Microvascular and Tissue Integrity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
5.5.8 Modulators of Angiogenesis and Growth Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
5.5.9 Repair Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
5.5.10 Genetic Predisposition to Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
5.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Abstract significant risk factors in the development of
During the past 20 years, intrauterine infection fetal and neonatal morbidity and mortality, as
and inflammation have been identified as well as adverse long-term outcome in very
immature preterm infants. Besides severe
infections, immature preterm infants are at
high risk for syndromes of dysregulated
K. Glaser (*) · C. P. Speer (*)
University Children’s Hospital, University of Würzburg, inflammation including bronchopulmonary
Würzburg, Germany dysplasia (BPD), necrotizing enterocolitis
e-mail: [email protected]; [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 73
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_154
74 K. Glaser and C. P. Speer
(NEC), and preterm cerebral white matter RDS Respiratory distress syndrome
disease (WMD). Although pathogenesis is ROS Reactive oxygen species
multifactorial, inflammation has been SP Surfactant protein
acknowledged as principle mechanism, being TGF-β Transforming growth factor-β
caused, sustained, and aggravated by multiple TLR Toll-like receptor
perinatal factors interacting in a multiple-hit TNF-α Tumor necrosis factor-α
sequence. An inflammatory state is presumed VCAM Vascular cell adhesion molecules
to be either initiated prenatally by chorioam- VEGF Vascular endothelial growth factor
nionitis or induced and sustained by
pro-inflammatory postnatal conditions, such
as oxygen toxicity, mechanical ventilation, 5.1 Salient Points
and neonatal infection. Perturbation of pro-
and anti-inflammatory central signaling path- • Inflammation is the final common mechanism
ways and subsequently imbalanced inflamma- through which many factors can affect fetal
tory responses may lead to severe organ injury mortality and morbidity.
affecting parenchymal development during a • Inflammation-promoting factors may be pre-
window of vulnerability. Maturation- or post-natal.
dependent factors and genetic predisposition • Pre-natal factors may cause a “fetal systemic
may underlie a particular vulnerability. inflammatory response syndrome” – FIRS – in
susceptible fetuses.
Abbreviations • Post-natal factors may act like a second hit,
BALF Bronchoalveolar lavage fluid amplifying the damage.
BPD Bronchopulmonary dysplasia • Brain and lung injury are the main expression
CA Chorioamnionitis of inflammation-induced damage.
CP Cerebral palsy • Many substances, such as cytokines,
CPAP Continuous positive airway pressure chemokines, oxygen radicals, and growth fac-
CSF Cerebrospinal fluid tors, may lead to an imbalance between pro-
ELBW Extremely low birth weight and anti-inflammatory factors.
EOS Early-onset sepsis
FIRS Fetal inflammatory response
syndrome 5.2 Introduction
ICAM Intercellular adhesion molecules
IFN-γ Interferon-y Various microorganisms residing in the maternal
IL Interleukin recto-vaginal tract may invade the chorioamniotic
IL-1ra IL-1 receptor antagonist membranes and may induce an inflammatory
IRAK IL-1 receptor-associated kinase response in the amniotic cavity, the fetus and the
LOS Late-onset sepsis mother (Kim et al. 2015). Both ascending micro-
LPS Lipopolysaccharide (endotoxin) bial infection and maternal bacteremia may initi-
MCP Monocyte chemoattractant protein ate a similar sequence of inflammation in the
MIP Macrophage inflammatory protein placenta and the amniotic cavity, which is associ-
MMP Matrix metalloproteinase ated with an increased risk for the development of
MRI Magnetic resonance imaging fetal systemic inflammatory response syndrome
NF-KB Nuclear transcription factor KB (FIRS) and adverse neonatal outcome (Khwaja
PCR Polymerase chain reaction and Volpe 2008; Speer 2011; Dammann and
PMNs Polymorphonuclear cells Leviton 2014; Garcia-Munoz Rodrigo et al.
Pre- Pre-myelinating oligodendrocytes 2014; Korzeniewski et al. 2014; Thomas and
OLs Speer 2014). Activation of fetal inflammatory
PRR Pattern recognition receptor response may inversely correlate with gestational
5 Prenatal and Postnatal Inflammatory Mechanisms 75
age, leaving very immature preterm infants at normal vascular and organ development
highest risk of long-term complications (Garcia- (Thebaud and Abman 2007; Kaindl et al. 2009).
Munoz Rodrigo et al. 2014; Lee et al. 2015). The role of genetic predisposition has been sub-
However, clinical observations indicate that fetal ject of clinical studies and in vitro trials (Lal and
exposure to severe chorioamnionitis (CA) might Ambalavanan 2015). This chapter will try to sum-
not necessarily result in an inflammatory response marize the current concepts of prenatal and post-
of an individual fetus. In contrast, a rather smol- natal inflammatory mechanisms in the human
dering or nearly inapparent amniotic infection/ fetus and preterm infant with main emphasis on
inflammation might induce a severe fetal reaction the pathogenetic role of inflammatory events in
(Thomas and Speer 2011). Since the underlying preterm lung and brain injury. Both aspects have
pathogenetic mechanisms are poorly understood, been reasonably well studied and have been con-
we are currently unable to identify a fetus at risk tinuously discussed and updated (Khwaja and
for developing serious sequelae following expo- Volpe 2008; Dammann and Leviton 2014;
sure to prenatal inflammation. Thomas and Speer 2014; Viscardi 2012; Speer
Acute fetal inflammatory response may pro- 2009). BPD is the most common respiratory dis-
mote secondary and tertiary damage mechanisms ease following preterm birth characterized by
(Dammann and Leviton 2014; Korzeniewski inflammation, apoptosis, and extensive extracel-
et al. 2014; Thomas and Speer 2014; Viscardi lular matrix remodeling that significantly affects
2012) and may result in subsequent neonatal neonatal morbidity and mortality (Jobe 2011).
inflammation-induced disorders, such as Diffuse or focal preterm WMD, usually referred
bronchopulmonary dysplasia (BPD) (Speer to as periventricular leukomalacia (PVL), is the
2009), necrotizing enterocolitis (NEC) most common form of brain injury in preterm
(Nanthakumar et al. 2011), and preterm cerebral infants of gestational ages less than 32 weeks,
white matter disease (WMD) (Khwaja and Volpe associated with a high risk of neurodevelopmental
2008) (Figs. 2 and 3). Moreover, respiratory dis- impairment (Khwaja and Volpe 2008). Although
tress syndrome (RDS) may be aggravated by an pathogenesis of preterm lung and brain injury is
injurious inflammatory sequence inactivating the multifactorial, both infection-induced inflamma-
surfactant system and affecting the integrity of the tion and nonspecific inflammation have been
immature lung (Speer 2011). Various adverse assumed principle underlying mechanisms.
postnatal conditions such as oxygen toxicity,
mechanical ventilation, and neonatal infection
may act as a “second or third strike” amplifying 5.3 Prenatal Inflammation
or aggravating an injurious inflammatory
response (Korzeniewski et al. 2014; Thomas and 5.3.1 Chorioamnionitis
Speer 2014; Speer 2009; Reyburn et al. 2012;
Bose et al. 2013). Cytokines, chemokines, oxygen Intra-amniotic inflammation seems to be preva-
radicals, growth factors, and other substances may lent in about 30% of patients with preterm labor
orchestrate a complex interplay of sustained and with intact membranes and in 50–80% of patients
dysregulated inflammation constituting neonatal with preterm premature rupture of the membranes
inflammation-induced organ injury (Khwaja and and spontaneous preterm birth (Kim et al. 2015).
Volpe 2008; Dammann and Leviton 2014; CA has been defined using histological, microbi-
Viscardi 2012; Speer 2009; Reyburn et al. 2012; ological, clinical, and biochemical criteria (Fig. 1)
Bose et al. 2008). Immaturity and dysfunction of (Kim et al. 2015). Histologic CA is an inflamma-
innate immune cells and impairments in the ter- tory condition of the placenta involving amnion,
mination of inflammation may contribute to per- choriodecidua, and/or chorionic plate in response
petuated inflammation (Dammann and Leviton to microbial invasion or pathological processes
2014; Speer et al. 1988; Nguyen et al. 2010; Gla- (Kim et al. 2015). However, definition of CA
ser and Speer 2013), subsequently affecting may also refer to clinical data, such as fever,
76 K. Glaser and C. P. Speer
Fig. 1 Schematic illustration of different approaches to membranes, as well as clinical data, based on clinical
define chorioamnionitis (Modified from Thomas and Speer manifestations of local or systemic inflammation (Kim
(2011)). The term “chorioamnionitis” is inconsistently et al. 2015). While acute chorioamnionitis is evidence of
used among clinicians and across epidemiologic studies. a maternal host response, funisitis and chorionic vasculitis
Definition of CA may refer to histologic examination, represent fetal inflammatory response
based on microscopic evidence of inflammation of the
tachycardia, elevated maternal inflammation appear to be inversely related to gestational age
parameters, uterine tenderness, foul-smelling vag- with the highest risk in very immature preterm
inal discharge, and fetal tachycardia (Kim infants <28 weeks of gestation, contributing itself
et al. 2015). Severity of CA may vary significantly to prematurity-associated neonatal morbidities
and depend on the duration of in utero infection (Kim et al. 2015; Garcia-Munoz Rodrigo
(Lee et al. 2015; Goldenberg et al. 2008). Most et al. 2014; Lee et al. 2015; Goldenberg
pathogens associated with CA are of low viru- et al. 2008; Hartling et al. 2012; Ericson and
lence implying subclinical courses in many Laughon 2015). Attempts to assess a gestation-
cases. In general, anaerobic, aerobic, and independent effect of CA on BPD and neonatal
atypical bacteria contribute to the list, such as brain injury have presented inconclusive results
Ureaplasma species (spp.), Mycoplasma hominis, (Khwaja and Volpe 2008; Thomas and Speer
Fusobacterium spp., Streptococcus spp., 2011; Viscardi 2012; Hartling et al. 2012; Ericson
Bacteroides spp., and Prevotella spp. (Kim and Laughon 2015; Wu 2002). However, a rele-
et al. 2015). Ureaplasma-induced intrauterine vant number of studies confirmed the impact of
inflammation has been associated with increased CA on preterm lung and brain injury in concert
risk of FIRS as well as perinatal lung and brain with adverse pro-inflammatory conditions, such
injury (Viscardi 2012, 2014; Goldenberg as hyperoxia or hypoxia, mechanical ventilation,
et al. 2008; Normann et al. 2009). In preterm and postnatal infection (Reyburn et al. 2012;
infants who develop BPD, Ureaplasma spp. Bose et al. 2013; Kaindl et al. 2009; Inatomi
have been the most common microorganisms iso- et al. 2012). Correlation between CA and neonatal
lated from the amniotic fluid, cord blood, and morbidities may be challenging due to a number
respiratory tract (Viscardi 2012, 2014). In a of antenatal and postnatal confounding factors,
mouse model of Ureaplasma-induced CA, fetal such as imprecise diagnoses of CA, and diseases
CNS inflammation is followed by significant dis- of prematurity, variability of study populations,
turbance of brain development (Normann higher prevalence of antenatal steroids and
et al. 2009). Incidence and prevalence of CA surfactant replacement therapy nowadays,
5 Prenatal and Postnatal Inflammatory Mechanisms 77
polymicrobial immunomodulation and pathogen on the incidence of RDS. This maturational
synergy, the individual fetal response, and con- effect in turn seems to contribute to a heightened
tributing postnatal factors (Lee et al. 2015; susceptibility of the lung to postnatal injury
Thomas and Speer 2011; Viscardi 2012; Hartling (Thomas and Speer 2011; Speer 2009). Data for
et al. 2012). CA clearly increases the likelihood of histological CA are consistent with data of matu-
very premature preterm birth with the latter being rational effects in an animal model. However, in
the most important risk factor for the development the same animal model, pulmonary maturation is
of diseases of prematurity. Moreover, fetal expo- followed by significantly disturbed structural
sure to prenatal inflammation may induce an development of the lung (Kramer et al. 2009).
adverse sequence of fetal inflammation that may Attempts to correlate CA and BPD have presented
directly affect the vulnerable immature lung and inconclusive results (Thomas and Speer 2011,
brain and, moreover, may confer a heightened 2014). Various studies indicated an increased
susceptibility to postnatal adverse conditions. association of CA and BPD; others reported a
The latter – acting as “second or third strike” – decreased association or no effect of CA on neo-
may amplify inflammation-induced lung and natal respiratory outcome (Thomas and Speer
white matter injury (Figs. 2 and 3). 2011; Viscardi 2012).
5.3.1.1 Lung Injury 5.3.1.2 Brain Injury
Clinical CA has been identified as an independent Attempts to assess a gestation-independent effect
risk factor for RDS in preterm infants, whereas of CA on neonatal brain injury have not provided
histological CA seems to confer a beneficial effect definite results. Controlling for gestational age
Fig. 2 Illustration of potential pathogenetic mechanisms inflammatory state is presumed to be either initiated pre-
linking chorioamnionitis and fetal inflammatory response natally by chorioamnionitis or induced and sustained by
with adverse sequences of neonatal lung and brain injury pro-inflammatory postnatal conditions, such as oxygen
(Modified from Thomas and Speer (2011)). An toxicity, mechanical ventilation, and neonatal infection
78 K. Glaser and C. P. Speer
Fig. 3 Schematic
illustration of the complex
interplay of prenatal and
postnatal pro-inflammatory
conditions contributing to
perpetuated adverse lung
inflammation. BPD may
result from inflammation-
induced lung injury and
impaired lung development
during a window of
vulnerability. Individual
infants may be particularly
susceptible to sustained
lung inflammation due to
predisposing genetic factors
reduced or abolished an association between CA and Volpe 2008; Korzeniewski et al. 2014;
and PVL in some studies (Thomas and Speer Viscardi 2012; Viscardi et al. 2004). Increased
2011; Wu 2002), while others confirmed an asso- levels of pro-inflammatory cytokines in fetal cord
ciation of CA and WMD especially in very imma- blood were identified as independent risk factors
ture preterm infants (Khwaja and Volpe 2008; for BPD and adverse neurologic outcomes in pre-
Thomas and Speer 2011; Leviton et al. 2010). term infants (Viscardi 2012; Speer 2009; Viscardi
CA has been associated with increased risk for et al. 2004). Of note, fetal exposure to severe
arterial hypotension, which has been acknowl- maternal chorioamnionitis might not necessarily
edged as significant risk factor for WMD (Khwaja result in an inflammatory response of an individual
and Volpe 2008). fetus, while a rather smoldering or nearly inappar-
ent amniotic infection/inflammation might induce
a severe fetal reaction (Thomas and Speer 2011).
5.3.2 Fetal Inflammatory Response
Syndrome 5.3.2.1 Lung Injury
Pronounced infiltration of inflammatory cells, an
Intrauterine inflammation may induce a fetal increased expression of cytokines and markers of
inflammatory response, characterized histologi- endothelial activation, and a large number of
cally by funisitis with polymorphonuclear cell apoptotic airway cells were observed in lung
(PMN) infiltration and biochemically by tissues of human fetuses with funisitis (May
elevated umbilical cord concentrations of et al. 2004).
pro-inflammatory cytokines, chemokines, matrix
metalloproteinases (MMPs), and angiogenic fac- 5.3.2.2 Brain Injury
tors such as vascular endothelial growth factor Experimental, epidemiological, and immunohis-
(VEGF) (Fig. 1) (Thomas and Speer 2011). Induc- tochemical data also confirm an association of
tion of cytokines and augmentation of deleterious FIRS and neonatal brain injury, documenting
effects, including free radical and excitatory upregulation of cerebrospinal fluid (CSF) cyto-
amino acid release, have been implicated in the kines and augmentation of deleterious effects,
development of diseases of prematurity (Khwaja such as free radical and excitatory amino acid
5 Prenatal and Postnatal Inflammatory Mechanisms 79
release (Dammann and Leviton 2014; Viscardi factor. Animal experiments indicate that
2014; Viscardi et al. 2004). Downstream pathoge- LPS stimulation may initiate pulmonary inflam-
netic mechanisms affecting the developing brain mation reflected by increased expression of
may comprise microglial activation, inhibition of pro-inflammatory cytokines and chemokines,
oligodendrocyte differentiation, disturbances of recruitment of PMNs and monocytes, and
apoptosis, impaired neurogenesis, and myelin impaired alveolar and microvascular development
degeneration (Khwaja and Volpe 2008; Kaindl (Kramer et al. 2009).
et al. 2009).
5.4.1.2 Brain Injury
In animal models of bacterial meningitis, elevated
5.4 Postnatal Inflammation serum levels of pro-inflammatory mediators alter
blood-brain barrier (BBB) integrity, promote
5.4.1 Infection BBB breakdown, and induce an adverse cascade
of CNS inflammation involving perpetuated cyto-
Bacteremia and neonatal sepsis are associated kine and chemokine synthesis, leukocyte activa-
with considerable acute and long-term morbidity, tion, MMP and prostaglandin synthesis, and lipid
especially in preterm infants, including death, peroxidation (Strunk et al. 2014; Kim 2003).
chronic lung disease, and neurodevelopmental Moreover, peripheral intravenous LPS stimula-
impairment (Stoll et al. 2011; Bersani and Speer tion was shown to result in CSF cytokine response
2012; Boghossian et al. 2013; Strunk et al. 2014). and to exacerbate brain lesions similar to those
Early-onset sepsis (EOS), associated with acqui- found in human infants with cerebral palsy
sition of microorganisms by transplacental or (CP) (Dommergues et al. 2000). LPS injected
ascending infection, is most commonly caused directly into the fetal brain of rats resulted in
by group B Streptococci and Escherichia coli hypomyelination, loss of oligodendrocytes, cystic
with decreasing incidence due to the implementa- damage, and ventricular enlargement consistent
tion of a prenatal screening and treatment protocol with diffuse PVL and persistently impaired
for group B Streptococci (Stoll et al. 2011). Nos- myelination in the long term (Cai et al. 2003).
ocomial late-onset sepsis (LOS) is mainly caused Of note, bacterial infection leads to a heightened
by bacterial infection from coagulase-negative susceptibility of the preterm brain to
Staphylococci, S. aureus, or gram-negative bacte- non-inflammatory insults, such as hypoxia
ria (Dong and Speer 2015). Highest incidence (Strunk et al. 2014).
rates are documented in very immature preterm
infants due to increased susceptibility and more
frequent invasive procedures (Bersani and Speer 5.4.2 Mechanical Ventilation
2012; Boghossian et al. 2013). Both EOS and
LOS have been identified as individual risk fac- Assisted ventilation may be the most common
tors of BPD and neonatal brain injury (Speer prolonged stimulus for systemic inflammation in
2006a, 2009; Strunk et al. 2014). Conversely, preterm infants (Bose et al. 2013). Moreover, any
both histological and clinical CA have been asso- kind of mechanical ventilation may be injurious to
ciated with increased risk of EOS in very imma- the airways and lung tissue, provoking a stretch-
ture preterm infants (Ericson and Laughon 2015; induced injurious cascade (Reyburn et al. 2012;
Strunk et al. 2012), underlying the pathogenetic Bose et al. 2013; Hillman et al. 2011) that is
role of intrauterine inflammation in the develop- characterized by bronchial epithelial disruption
ment of BPD and WMD. and the release of pro-inflammatory mediators
with subsequent leukocyte influx (Bose
5.4.1.1 Lung Injury et al. 2013; Hillman et al. 2011). In animal
Priming of the fetal lung by endotoxin (lipopoly- models, the severity of inflammatory reaction
saccharide, LPS) may be a relevant orchestrating was related to ventilation strategies characterized
80 K. Glaser and C. P. Speer
by high peak and lack of positive end expiratory increased pro-inflammatory cytokine expression
pressure (Hillman et al. 2011). Current neonatal within the lungs and brains, contributing to
strategies attempt to minimize the need for endo- CA-induced brain injury (Barton et al. 2014).
tracheal intubation and intermittent positive pres-
sure ventilation and favor continuous positive
airway pressure (CPAP)-based strategies (Morley 5.4.3 Hyperoxia and Hypoxia
2010; Hallman et al. 2013). Lung volume recruit-
ment and avoidance of high tidal volumes are key Increased oxidative stress and imbalance of anti-
elements of current lung-protective ventilation oxidant enzymes may play a significant role in
strategies (Lozano and Newnam 2016). However, the pathogenesis of neonatal lung and brain
more and more extremely low birth weight injury. Reactive oxygen (ROS) and nitrogen spe-
(ELBW) infants exposed to no or minimal baro- cies (RNS) are produced by several inflamma-
trauma and to relatively low levels of supplemen- tory cells. Profound deficiency in antioxidant
tal oxygen may develop respiratory deterioration enzyme activity may leave very immature pre-
at a postnatal age of 1–2 weeks (Martin and term infants at high risk of suffering from
Fanaroff 2013). hyperoxia-induced detrimental effects (Khwaja
and Volpe 2008; Saugstad 2005). Transition
5.4.2.1 Lung Injury from the fetal normotoxic in utero environment
In a murine model of BPD, inflammation-induced to postnatal room air represents a sudden expo-
alterations and structural lung damage were sure to a relatively “hyperoxic” environment. On
strongly related to developmental stages with the the contrary, episodes of hypoxia or fluctuating
saccular stage of lung development being partic- oxygen saturations most often due to apnea of
ularly vulnerable (Backstrom et al. 2011). Con- prematurity adversely affect lung and brain
sistently, clinical studies documented that very development, both directly and by iatrogenic
immature preterm infants <28 weeks of gesta- oxygen supplementation (Bhandari 2010). Data
tion (saccular stage) are at highest risk for from animal models demonstrate hypoxia-
inflammation-induced BPD, whereas preterm induced aggravation of LPS-induced inflamma-
infants born >32 weeks of gestation (early alve- tion in neonatal lung and brain tissue (Strunk
olar stage) are at much lower risk (Jobe 2011). In et al. 2014; Vuichard et al. 2005; Girard
newborn rat lungs, even low tidal volume venti- et al. 2012).
lation was shown to induce acute phase cytokines
and CXC chemokines. This pro-inflammatory 5.4.3.1 Lung Injury
response was amplified by oxygen and oxygen In animal models, hyperoxia has been shown to
combined with LPS pretreatment (Kroon affect a complex orchestra of genes involved in
et al. 2010). In a rat model of lung injury, LPS inflammation, extracellular matrix turnover,
challenge resulted in significantly increased coagulation, and other events and to induce
levels of pro-inflammatory cytokines in influx of inflammatory cells in pulmonary tissue
bronchoalveolar lavage fluid (BALF) despite (Bhandari 2010; Wagenaar et al. 2004). More-
“less injurious” ventilation strategies (Ricard over, hyperoxia resulted in progressive lung dis-
et al. 2001). The latter data may underline the ease demonstrating many features of the BPD
relevant pathogenetic role of pro-inflammatory phenotype (Wagenaar et al. 2004). A consider-
priming on the downhill progression to BPD able number of studies confirmed injurious
(Fig. 3). effects of perinatal supplemental oxygen admin-
istration on pulmonary development (Bhandari
5.4.2.2 Brain Injury 2010). Subsequently, optimum target ranges of
Irrespective of the strategy used, mechanical ven- oxygen saturation in extremely premature pre-
tilation increased hemodynamic instability in neo- term infants have been reassessed (Hallman
natal lambs born with CA and, moreover, et al. 2013).
5 Prenatal and Postnatal Inflammatory Mechanisms 81
5.4.3.2 Brain Injury contribute to the inflammatory state (Dammann
Experimental and clinical data suggest that both and Leviton 2014; Speer et al. 1988; Nguyen
inflammation and elevated oxygen concentra- et al. 2010; Levy and Serhan 2014).
tions, by itself or in combination, may contribute
to brain injury in preterm infants (Schmitz
et al. 2011). In animal model, hyperoxia induced 5.5.1 Cellular and Humoral Mediators
maturation-dependent cell death in oligodendrog- of Inflammation
lia (Brehmer et al. 2012). Pro-inflammatory cyto-
kines, induction of MMPs, and generation of Priming and activation of PMNs and mononuclear
ROS and RNS were shown to be involved in - cells (peripheral blood mononuclear cells,
hyperoxia-induced apoptosis (Brehmer PBMCs) are essential stages of the early immune
et al. 2012). response to invading microorganisms or tissue
However, beside inflammation, hypoxia- damage (Speer 2009; Nguyen et al. 2010). Circu-
ischemia is the principle initiating mechanism in lating neutrophils and monocytes become rapidly
the pathogenesis of WMD, activating the adverse activated within 1–3 h (Turunen et al. 2006),
downstream mechanisms of excitotoxicity, refer- followed by adherence to the endothelium and
ring to excessive glutamatergic activation, and initiation of pro-inflammatory events. Apoptosis
free radical attack by ROS and RNS culminating of inflammatory neutrophils and their timely
in pre-OL injury (Khwaja and Volpe 2008). In removal by resident macrophages is critical to
animal model, systemic inflammation prior to an resolution of inflammation. However, a relevant
excitotoxic insult or oxidative stress significantly number of studies documented altered neonatal
exacerbated white matter lesions, demonstrating a phagocyte function, a reduced phagocytosis of
potentiating interaction between systemic inflam- apoptotic tissue cells, and prolonged survival of
mation and hypoxia-ischemia in the pathogenesis neonatal PMNs, potentially contributing to
of neonatal brain injury (Khwaja and Volpe 2008; prolonged and perpetuated inflammation (Speer
Kaindl et al. 2009). et al. 1988; Nguyen et al. 2010).
5.5.1.1 Lung Injury
5.5 Molecular Mechanisms In BPD, several studies revealed significantly
of Adverse Inflammation higher and persisting numbers of neutrophils and
macrophages in BALFs and lung tissues of pre-
Inflammatory responses comprise initiation and term infants affected compared to infants who did
resolution phases aiming at microbial clearance, not develop chronic lung disease (Groneck
remodeling, and tissue regeneration. Ideally, et al. 1994; Murch et al. 1996a). Ventilation-
acute inflammation is self-limited and leads to induced influx of neutrophils and mononuclear
complete resolution and restored homeostasis cells has been associated with pulmonary edema
(Levy and Serhan 2014). This resolution of formation reflecting injury to the alveolar-
inflammation is tightly regulated by anti- capillary unit (Groneck et al. 1994; Jaarsma
inflammatory and pro-resolving proteins and a et al. 2004). Neonatal neutrophils surviving spon-
number of polyunsaturated fatty acid-derived taneous apoptosis were shown to exhibit aug-
pro-resolving mediators, potently reducing mented inflammatory function reflected by
cytokine expression, terminating PMN invasion, enhanced secretion of interleukin (IL)-8 and mac-
and enhancing macrophage uptake (Dammann rophage inflammatory protein (MIP)-1β (Nguyen
and Leviton 2014; Levy and Serhan 2014). et al. 2010). Besides, alveolar and pulmonary
Unresolved and perpetuated inflammation may tissue macrophages have been shown to play a
lead to severe organ injury. In preterm infants, central role in lung inflammation by orchestrating
maturation-dependent impairments in the inflammatory response via cytokine release
inflammation-resolution mechanisms may (Viscardi 2012; Bose et al. 2008).
82 K. Glaser and C. P. Speer
5.5.1.2 Brain Injury has been found to be induced by
The neuropathologic hallmarks of preterm pro-inflammatory stimuli, such as TNF-α and
WMD are microglial activation and depletion IL-1β, reflecting the inflammatory phenotype of
of pre-myelinating oligodendroglia (Kaindl human BBB (O’Carroll et al. 2015).
et al. 2009). Microglial cells are the main
source of stimulus-induced cytokine synthesis
as well as generation of ROS, RNS, and gluta- 5.5.3 Chemotactic and Chemokinetic
mate, thus playing a central role in the detri- Factors
mental effects of a pro-inflammatory cytokine
cascade on the neonatal brain. Neutrophils con- Recruitment of inflammatory cells is mainly pro-
tribute to the release of cytotoxic factors, ROS, moted by chemokines (Baier et al. 2004).
RNS, and lipid peroxidation (Khwaja and Chemokines are classified into four families (C,
Volpe 2008). The maturation-dependent den- CC, CXC, and CX3C) with the CC family being
sity of microglia throughout the white matter activators of monocytes and macrophages, lym-
and a gestational age-dependent vulnerability phocytes, eosinophils, and basophils (Zlotnik and
of pre-OLs to toxic ROS and cytokine attack Yoshie 2012).
may underlie a particular vulnerability of the
immature brain (Khwaja and Volpe 2008; 5.5.3.1 Lung Injury
Kaindl et al. 2009). IL-8 (CXCL8) may be the most important chemo-
tactic factor for recruitment of monocytes and
neutrophils to the site of inflammation (Garcia-
5.5.2 Cellular and Endothelial Ramallo et al. 2002). Moreover, IL-8 plays a
Interaction pivotal role in neutrophil activation by
upregulation of neutrophil adhesion molecules,
A relevant number of adhesion molecules, such as promotion of transendothelial migration, and
intercellular adhesion molecules (ICAMs) and stimulation of oxidative burst and lysosomal
vascular cell adhesion molecules (VCAMs), pro- enzyme release (Garcia-Ramallo et al. 2002). A
mote attachment of inflammatory cells to the role for CC chemokines in the pathogenesis of
endothelium (Sarelius and Glading 2015). acute and chronic lung disease was suggested by
animal and clinical studies (Smith 1996). The
5.5.2.1 Lung Injury application of a selective chemokine receptor
In infants with BPD, increased concentrations of antagonist was shown to inhibit neutrophil influx
selectins and ICAMs were detected in airway into the rat lung, to suppress pulmonary inflam-
secretions and circulation, reflecting enhanced mation and to enhance lung growth
shedding in response to inflammation (D’Alquen (Yi et al. 2004). Increased concentrations of mem-
et al. 2005). Moreover, significant upregulation of bers of the CC family, monocyte chemoattractant
ICAM-1 on endothelial cord cells and increased protein (MCP)-1 and MIP-1α, were found in ven-
serum levels of soluble ICAM-1 were shown in tilated preterm infants suffering from acute lung
preterm infants exposed to CA (D’Alquen injury and correlated with BPD (Murch
et al. 2005). These data may point to an effective et al. 1996a). Moreover, increased tracheal aspi-
recruitment of circulating neutrophils and mono- rate concentrations of MCP-1, MCP-2, MCP-3,
cytes into the airways and pulmonary tissue of and MIP-1β were identified as independent risk
preterm infants. factors for RDS and BPD (Baier et al. 2004).
Additional chemoattractants, such as C5a, IL-8,
5.5.2.2 Brain Injury IL-16, lipoxygenase products, leukotriene B4,
In human brain microvascular endothelial cells, elastin fragments, metalloproteases, and fibronec-
surface expression of both ICAM-1 and VCAM-1 tin, were also increased in infants with BPD
5 Prenatal and Postnatal Inflammatory Mechanisms 83
compared to those who recovered from RDS paucity of some of these proteins and mediators
(Speer 2006a, 2009). (Dammann and Leviton 2014).
5.5.3.2 Brain Injury 5.5.4.1 Lung Injury
In infants diagnosed with inflammation-related Macrophage-derived TNF-α is considered to con-
WMD, levels of both pro-inflammatory cytokines tribute significantly to the pro-inflammatory reac-
and IL-8 are elevated in amniotic fluid, cord blood, tion being a known trigger of various
CSF, and cerebral tissue (Strunk et al. 2014). Thus, inflammatory mediators in alveolar cells (Speer
beside other humoral mediators, IL-8 may be a key 2009). IL-1β is a central pro-inflammatory cyto-
mediator in the pathogenesis of inflammation- kine found in the amniotic fluid in CA (Yoon
induced neonatal brain injury (Dammann and et al. 1997) that has been shown to significantly
Leviton 2014; Strunk et al. 2014). disturb lung morphogenesis in a fetal mouse
model (Hogmalm et al. 2014). Increased protein
levels and high mRNA expression of
5.5.4 Pro- and Anti-Inflammatory pro-inflammatory TNF-α and IL-1β have been
Cytokines detected in respiratory fluids, in bronchoalveolar
and pulmonary cells, and in the systemic circu-
Pro-inflammatory cytokines, such as TNF-α, lation of preterm infants with RDS and evolving
IL-1β and IL-6, play a crucial role in early inflam- BPD pointing toward imbalance of pro- and anti-
mation, mediating up- and/or downregulation of inflammatory factors (Speer 2006a, 2009; Bose
genes and transcription factors (Bose et al. 2008). et al. 2008). The influx of TNF-α-positive mac-
Pro-inflammatory cytokines are synthesized by rophages in pulmonary tissues of preterm infants
various inflammatory cells, including PMNs; who had died of severe RDS was found to be
monocytes and macrophages; microglial and pul- associated with severe destruction of pulmonary
monary cells, upon stimulation by LPS; other interstitium (Murch et al. 1996b). In a
bacterial cell wall constituents; a wide range of bi-transgenic mouse model, perinatal
endogenous ligands, hyperoxia, and hypoxia; and overexpression of IL-1β in pulmonary epithelial
biophysical factors such as volutrauma and baro- cells was shown to induce increased TNF-α and
trauma (Khwaja and Volpe 2008; Speer 2006a). IL-6 expression and profound tissue injury sim-
Innate and adaptive immune responses in term ilar to BPD (Hogmalm et al. 2014; Kolb
and especially preterm neonates exhibit quanti- et al. 2001). Both production of IL-1β and acti-
tative and qualitative developmental particulari- vation of nuclear transcription factor kappa
ties (Dammann and Leviton 2014; Speer (NF-kB) in lung macrophages were found to sig-
et al. 1988; Nguyen et al. 2010; Glaser and nificantly contribute to arrested lung develop-
Speer 2013). A propensity toward the ment (Blackwell et al. 2011). IL-10 was
pro-inflammatory state has been postulated undetectable in most airway samples of preterm
(Kollmann et al. 2009; Levy and Wynn 2014). infants with BPD, but regularly found in term
Experimental and clinical data indicate that the infants with respiratory failure (Jones
profound fetal pro-inflammatory response may, in et al. 1996). Especially in preterm infants
part, be attributed to inadequate anti-inflammatory exposed to CA or affected by FIRS, insufficient
cytokine responses, involving IL-4, IL-10, IL-11, inhibition of exaggerated fetal pro-inflammatory
IL-12, IL-13, IL-18, or IL-1 receptor antagonist cytokine responses may increase the risk of BPD
(IL-1ra) as well as pro-resolving proteins and a (Paananen et al. 2009). In surfactant-depleted
number of polyunsaturated fatty acid-derived rabbits, prophylactic treatment with aerosolized
pro-resolving mediators (Dammann and Leviton anti-inflammatory IL-1ra decreased inflamma-
2014; Viscardi 2012; Speer 2009; Brochu tion in experimental lung injury (Narimanbekov
et al. 2011). Preterm infants appear to have a and Rozycki 1995).
84 K. Glaser and C. P. Speer
5.5.4.2 Brain Injury comprise ten human receptors, expressed either
Experimental, epidemiological, and immunohis- on the plasma membrane (TLR1, 2, 4, 5, 6) or
tochemical data support a cytokine hypothesis of intracellularly on endoplasmic reticulum and
brain injury considering microglial cytokine endosomal membranes (TLR3, 7, 8, 9, 10) (Glaser
releases the major mediator of white matter dam- and Speer 2013; Takeuchi and Akira 2010; Akira
age (Dammann and Leviton 2014; Strunk 2006). Ligand binding is followed by recruitment
et al. 2014; Girard et al. 2009). Several cytokines, of IL-1 receptor-associated kinases (IRAKs) or
such as TNF-α and IFN-γ, expressed in microglia TNF receptor-associated factor (TRAF)-6 and
and macrophages, have been detected in human subsequent activation of complex signaling cas-
PVL lesions (Khwaja and Volpe 2008). cades culminating in upregulation of
Pro-inflammatory cytokines may be released in pro-inflammatory cytokines, co-stimulatory mol-
response to infection and hypoxia-ischemia, both ecules, and chemokines (Akira 2006; Yamamoto
conditions mutually potentiating harmful effects and Takeda 2010). Recognizing peptidoglycans
(Khwaja and Volpe 2008). Injurious cytokine and LPS, respectively, TLR2 and TLR4 provide
effects comprise inhibition of oligodendrocyte an innate immune response against the most com-
differentiation, generation of ROS, induction of mon pathogens involved in CA and neonatal sep-
glial apoptosis, and myelin degeneration (Khwaja sis and have been associated with inflammatory
and Volpe 2008; Berger et al. 2012). Moreover, disorders of prematurity (Glaser and Speer 2013;
TNF-α and IL-6 have been shown to increase O’Hare et al. 2013; Kemp 2014). In animal
BBB permeability and to disrupt BBB integrity models of CA, LPS-induced cytokine synthesis
(Berger et al. 2012). In a rat model of perinatal directly correlated with TLR4 expression and sub-
brain damage, neuroinflammatory response to sequent activation of NF-KB and enhanced secre-
LPS and hypoxia-ischemia was characterized by tion of TNF-α, IL-1β, IL-6, and IL-8 (Kramer
downregulated anti-inflammatory cytokines and et al. 2002; Harju et al. 2005). Animal models
predominance of IL-1β release in preterm-like and in vitro data provide evidence of a gestational
brains, while term-like brains presented with age-dependent expression of TLRs and
stronger pro- and anti-inflammatory responses, TLR-related molecules on inflammatory as well
including both Il-1β and TNF-α releases (Brochu as non-inflammatory cells (Glaser and Speer
et al. 2011). Of note, postnatal systemic adminis- 2013; Harju et al. 2001; Hillman et al. 2008;
tration of IL-1ra led to decreased long-term gliosis Kollmann et al. 2012; Zhang et al. 2015).
and myelin degeneration and protected against Maturation-dependent TLR activation and TLR
functional defects associated with perinatal brain signaling might render the immature lung and
injury (Girard et al. 2012). In neonatal rat and brain more susceptible to injurious exogenous
mouse model of inflammation-induced brain and endogenous stimuli of pro-inflammation
injury, administration of IL-10 reduced white mat- (Khwaja and Volpe 2008; Kollmann et al. 2012).
ter damage following CA or neonatal sepsis TLR signaling is tightly controlled by a number of
(Mesples et al. 2003; Pang et al. 2005). exo- and endogenous regulatory molecules (Akira
2006), including IL-1 receptor-associated kinase
(IRAK)-M, which inhibits TLR-mediated NF-kB
5.5.5 Pattern Recognition Receptors activity, leading to significantly reduced
LPS-induced TNF-α and IL-6 synthesis (Wesche
Activation of PMNs and PBMCs is mediated by et al. 1999).
pattern recognition receptors (PRRs), which rec-
ognize structurally stable microbial membrane 5.5.5.1 Lung Injury
components (Takeuchi and Akira 2010). PRRs Maturation-dependent expression of TLR4 in
display a complex system of sentinel receptors lung tissue and lung fibroblasts has been demon-
including cell-associated receptors, such as strated (Glaser and Speer 2013; Harju et al. 2001).
TLRs (Takeuchi and Akira 2010). TLRs currently In a mouse model of fetal lung development,
5 Prenatal and Postnatal Inflammatory Mechanisms 85
activation of TLR2 and TLR4 inhibited expres- inflammation (Khwaja and Volpe 2008; Bhandari
sion of fibroblast growth factor (FGF)-10, leading 2010). Moreover, ROS are generated upon
to abnormal saccular airway morphogenesis dem- hyperoxia or reoxygenation by free iron and the
onstrating many features of the BPD phenotype cell-bound xanthine-oxidase system. Very imma-
(Benjamin et al. 2007). TLR4-mediated inflam- ture preterm infants are particularly susceptible to
matory response was associated with altered air- hyperoxia-induced organ damage due to a pro-
way fibronectin expression, potentially inhibiting found deficiency in antioxidant enzyme activity
distal airway branching and alveolarization (Saugstad 2005). Animal experiments confirmed
(Prince et al. 2005). In adult animal models, that oxidative stress may be a crucial event in the
LPS-induced activation and overexpression of initiation of both pulmonary and brain inflamma-
TLR4 was accompanied by heightened sensitivity tion (Khwaja and Volpe 2008; Kramer
to LPS and enhanced fibrosis (He et al. 2009). On et al. 2002), with oxygen radicals exerting direct
the contrary, surfactant proteins (SP) A and D toxic effects on bronchoalveolar and brain paren-
were shown to beneficially modulate TLR2 and chymal structures, such as lipid peroxidation,
TLR4 expression, to upregulate the regulatory inactivation of protective antiproteases,
protein IRAK-M and to inhibit NF-kB activation upregulation of MMPs, and direct toxicity to
in experimental lung inflammation (Nguyen pre-OLs (Khwaja and Volpe 2008; Saugstad
et al. 2012; Bersani et al. 2013). 2005; Bhandari 2010; Gerber et al. 1999).
5.5.5.2 Brain Injury 5.5.6.1 Lung Injury
Activation of TLR2 and TLR4 has been shown to Data from in vitro studies, animal experiments,
contribute to hypoxic-ischemic and LPS-induced and clinical observations indicate an imbalance of
neonatal brain injury (Eklind et al. 2005; Stridh proteases and protease inhibitors contributing to
et al. 2011). Moreover, TLRs seem to be involved preterm lung injury (Speer et al. 1993; Altiok
in microglial activation and the subsequent gen- et al. 2006). Following elastolytic damage,
eration of ROS and RNS toxic to pre-OLs increased concentrations of various markers of
(Khwaja and Volpe 2008). In fetal and neonatal tissue destruction were detected in airway secre-
rat model, administration of LPS induced cerebral tions and urine of preterm infants (Speer 2006a,
expression of CD14 and TLR4, sensitizing the 2009). Of note, elastase and neutral proteases
immature brain to a second hit, such as hypoxic- were shown to prime macrophages for increased
ischemic injury (Strunk et al. 2014). In neonatal release of toxic oxygen metabolites (Speer
mice, activation of the TLR1/2 complex was et al. 1984). At sites of inflammation, neutrophil
shown to induce choroid plexus transcription of and macrophage-released proteases, such as elas-
TNF-α and influx of white blood cells into the tase, β-glucuronidase, myeloperoxidase, cathep-
CSF, potentially reflecting disturbances in choroid sin, MMPs, and others, play an essential role in
plexus barrier function (Stridh et al. 2013). A role the destruction of the alveolar-capillary unit and in
for tissue-released endogenous TLR ligands has extracellular matrix remodeling (Bhandari 2010).
been discussed in the amplification of ischemic Similarly, overexpression of MMPs might cause
brain injury (Volpe 2008). disruption of the extracellular matrix. High con-
centrations of MMPs were detected in airway
secretions of infants with BPD (Cederqvist
5.5.6 Oxygen Radicals et al. 2001). Moreover, protective levels of tissue
and Proteolytic Mediators inhibitors of MMPs were rather low in infants
with BPD (Cederqvist et al. 2001), and blocking
Exposure to high inspiratory oxygen concentra- of MMP-9 was shown to reduce hyperoxia-
tions causes direct oxidative cell damage due to derived lung injury in fetal mice (Chetty
increased production of ROS released by neutro- et al. 2008). In the context of overexpression of
phils, macrophages, and microglia at sites of IL-1β in a bi-transgenic mouse model, MMP-9
86 K. Glaser and C. P. Speer
played a protective role, and MMP-9 deficiency, (MRI) studies, infants with BPD showed an
on the contrary, further exaggerated perturbation increased lung water content and were susceptible
of lung morphogenesis (Lukkarinen et al. 2009). to gravity-induced collapse of the lung (Adams
et al. 2004). In mechanically ventilated infants
5.5.6.2 Brain Injury with RDS, a simultaneous activation of clotting,
Oxidative stress is an important component of fibrinolysis, kinin-kallikrein system, and the com-
early injury to the neonatal brain. Human brain plement system was observed (Speer 2006a), indi-
and experimental studies point to a maturation- cating that injury to the pulmonary vascular
dependent vulnerability of pre-OLs to ROS endothelium may subsequently promote neutro-
attack, presumably due to a delay in the develop- phil and platelet activation and may induce pul-
ment of enzymes of the superoxide dismutase monary as well as systemic inflammation and
complex (Khwaja and Volpe 2008). Aiming at activation of the clotting system.
reducing oxidative damage to the neonatal brain,
a number of potential therapeutic strategies have 5.5.7.2 Brain Injury
been subject to research, including ROS scaven- Periventricular white matter injury, which is
gers, lipid peroxidation, and nitric oxide synthase now the most common cause of brain injury in
inhibitors (Chew and DeBoy 2015). preterm infants, is characterized by microglial
activation, axonal damage, damage to the devel-
oping subplate neurons, and disturbance of
5.5.7 Microvascular and Tissue white matter fiber tracts (Kaindl et al. 2009).
Integrity MRI-based techniques provide evidence of
additional involvement of telencephalic gray
Inflammation and inflammatory mediators have matter and long tracts in perinatal brain injury,
detrimental effects on the microvascular integrity probably due to apoptotic transmigrating neu-
of the immature lung and on cytoarchitecture and rons (Kaindl et al. 2009).
tissue integrity of preterm white and gray matter
(Speer 2009; Kaindl et al. 2009).
5.5.8 Modulators of Angiogenesis
5.5.7.1 Lung Injury and Growth Factors
Increased alveolar-capillary permeability is a
pathognomonic feature of early stages of lung Several key regulators of angiogenesis have been
inflammation and has been associated with a dete- identified mediating vascular development and,
rioration of lung function (Speer 2006a, 2009). A thus, affecting parenchymal organ development.
variety of lipid mediators, such as leukotrienes, VEGF is a key regulator of angiogenesis (Hines
prostacyclin, platelet-derived factor, and and Sun 2014). It is essential and critical for
endothelin-1, detected in airways of infants with vascular development and exists in high concen-
BPD, seem to directly affect the alveolar-capillary trations in heavily vascularized tissues (Thebaud
unit (Speer 2006b). Within 1 h after initiation of and Abman 2007; Bhandari 2010).
mechanical ventilation, protein leakage into the
alveoli and airways of preterm infants was 5.5.8.1 Lung Injury
documented (Jaarsma et al. 2004). Moreover, a Alveolar simplification is the typical pathological
drastic increase in albumin concentrations in air- finding in lung tissues from animal models and
way secretions was reported at a postnatal age of infants with BPD being caused by apoptosis of
10–14 days in preterm infants who later devel- cells critical for alveolar and vessel formation
oped BPD, significantly contributing to alveolar (Jobe 2011). Increasing evidence suggests that
edema, inactivation of the surfactant system, and pulmonary blood vessels actively promote normal
deterioration of lung function (Groneck alveolar development and contribute to the main-
et al. 1994). In magnetic resonance imaging tenance of alveolar structures (Thebaud and
5 Prenatal and Postnatal Inflammatory Mechanisms 87
Abman 2007). Perturbation of VEGF signaling result in structural remodeling of the lung, includ-
has been implicated in impaired lung parenchy- ing altered extracellular matrix formation as well
mal development and long-term lung injury, dem- as impaired alveolarization and angiogenesis.
onstrating an essential role of intrapulmonary Data from baboon, mouse, and rabbit models of
vascular structures on lung parenchymal develop- neonatal lung injury confirmed potentiated airway
ment (Reyburn et al. 2012; Thebaud and Abman inflammation and cytokine expression following a
2007; Kunig et al. 2006). While VEGF levels combination of hyperoxia and mechanical venti-
were shown to be significantly increased in new- lation (Varughese et al. 2003; Wilson et al. 2005;
born rabbits following exposure to prolonged Brew et al. 2011).
hyperoxia, decreased VEGF levels and VEGF
signaling were reported in the same setting in a 5.5.8.2 Brain Injury
premature fetal baboon model of BPD (Bhandari VEGF has been shown to be expressed in the
and Elias 2006). Significantly lower levels of central nervous system after hypoxic-ischemic
VEGF were found in preterm infants, who devel- brain injury. It has been presumed a key modula-
oped BPD, compared to infants who recovered tor in the process of brain repair by regulating
from ventilator- and hyperoxia-induced lung angiogenesis, neuronal cell proliferation, and
injury (D’Angio and Maniscalco 2002). migration (Fan et al. 2009; Guo et al. 2016).
Decreased VEGF signaling has been considered VEGF knockout mice showed severe impair-
a potential mechanism in the pathogenesis of ments in vascularization, neuronal migration,
reduced pulmonary capillary volume and and survival. On the contrary, VEGF
impaired alveolarization. In extremely preterm overexpression seems to confer beneficial
animals developing BPD, impaired expression of neuroprotective effects in mouse model, resulting
VEGF, its angiogenic receptors, and angiopoietin from inhibition of apoptotic pathways (Chew and
were shown to contribute to dysmorphic micro- DeBoy 2015). In animal models, late administra-
vasculature and disrupted alveolarization tion of exogenous VEGF 48 h after hypoxia-
(Thebaud et al. 2005; Thomas et al. 2008). In ischemia resulted in enhanced angiogenesis and
newborn rats, treatment with recombinant human functional performance, while administration 1 h
VEGF as well as VEGF gene therapy promoted after insult enhanced BBB permeability and
angiogenesis indicating a potential preventive increased ischemic lesion (Chew and DeBoy
strategy (Kunig et al. 2006; Thebaud 2015). The cytokine erythropoietin (EPO) has
et al. 2005). Adverse stimuli inhibiting pulmonary been shown to play a vital role in neural differen-
angiogenesis may significantly disturb and disrupt tiation and neurogenesis in early brain develop-
secondary septation characteristic of BPD ment and to exert antiapoptotic and anti-
(Thebaud and Abman 2007). In a rat model of inflammatory features in the central nervous sys-
neonatal lung injury, antenatal LPS administration tem. It is expressed by neurons, glial cells, and
resulted in arrest of alveolarization (Ueda cerebral endothelial cells (Chew and DeBoy
et al. 2006). In preterm lambs a similar, time- 2015). In different animal models of neonatal
and dose-dependent effect was observed (Kramer brain injury, both treatment with EPO prior to
et al. 2001). Data from mouse model suggest that hypoxic-ischemic injury and administration of
inflammation may induce abnormal angiogenesis EPO after hypoxia-ischemia attenuated injurious
in the developing preterm lung by upregulation of lesions (Chew and DeBoy 2015).
angiogenic CC chemokines, such as MIP-1α and
MCP-1 (Miller et al. 2010). Of note, intra-
amniotic LPS led to increased levels of the 5.5.9 Repair Mechanisms
angiostatic chemoattractants IFN-γ -inducible
protein (IP)-10 and monokine in preterm lamb Inflammation-induced tissue injury may be
lungs (Kallapur et al. 2003). Even inflammation followed by tissue repair which has only partially
in the absence of infection has been shown to been studied in neonatal lung and brain injury.
88 K. Glaser and C. P. Speer
5.5.9.1 Lung Injury glutamatergic receptor N-methyl-D-aspartate
The inflammatory process seems to result in the (NMDA) were shown to enhance ischemia-
induction of transforming growth factor (TGF)-β induced endogenous self-repair mechanisms by
that limits inflammatory reactions and plays a key increasing survival rates and differentiation of
role in mediating tissue remodeling and repair newly generated pre-OLs into mature oligoden-
(Bartram and Speer 2004). As a counter player drocytes (Li et al. 2015).
to fibroblast growth factor-β and IL-1β, both low-
ering elastin mRNA in human lung fibroblasts,
TGF-β seems to increase elastin by transcriptional 5.5.10 Genetic Predisposition
and posttranscriptional mechanisms (Kuang to Inflammation
et al. 2007). Hyperoxia-induced increased levels
of TGF-β may contribute to impaired and simpli- Individual infants may be particularly susceptible
fied alveolarization characteristic of BPD (Zhao to sustained inflammation. Genetic factors may
et al. 1997). In preterm animals, increased expres- significantly contribute to the variance in risk for
sion of TGF-β inhibited normal lung development disorders of prematurity. Genetic background of
and promoted fibrosis (Speer 2006a). A reduced severe courses may be different from mild and
expression of connective tissue growth factor moderate diseases, and associated genetic varia-
(CTGF), which is responsible for various down- tions may vary by ethnicity. Twin concordance
stream actions of TGF-β and second important studies have pointed to a relevant impact of
key mediator in the induction of pulmonary fibro- genetic risk, and current research has focused on
sis, was found in a sheep model of BPD identifying genetic factors contributing to height-
(Kunzmann et al. 2008). Moreover, low concen- ened risk of intrauterine infection, preterm birth,
trations of hypoxic-inducible factor, keratinocyte and inflammatory disorders, such as BPD (Lal and
and hepatocyte growth factors, all thought to par- Ambalavanan 2015). Genetic predisposition
ticipate in normal lung development and tissue might comprise, e.g., variability in cytokine
regeneration after lung injury, were detected in and chemokine response, imbalance toward exag-
infants with BPD (Danan et al. 2002; Lassus gerated pro-inflammatory responses, and poly-
et al. 2003). morphisms in key regulators of
pro-inflammatory signaling, antioxidants, and
5.5.9.2 Brain Injury modulators of angiogenesis (Lal and
PVL in preterm infants is characterized by loss of Ambalavanan 2015; Yu et al. 2016). Gene poly-
pre-OLs (Khwaja and Volpe 2008). Both the morphisms may confer an increased risk of altered
subventricular zone and the white matter are vaginal flora, ascending infections and preterm
considered to be main sources of oligodendro- birth (Genc and Onderdonk 2011). In BPD, how-
cytes derived from endogenous glial progenitor ever, candidate gene studies, genome-wide asso-
cells (Curtis et al. 2007). The latter were shown ciation studies, exome sequencing, integrative
to differentiate into mature glial cells and to omics analysis, and pathway analysis did not
migrate into injured white matter lesions for identify genetic variations significantly and con-
repair (Curtis et al. 2007). In a neonatal rat sistently associated with the disease
model of PVL, ischemia activated those endog- (Yu et al. 2016; Huusko et al. 2014).
enous self-repair mechanisms. However, repair
capacity was found to be limited, and shortened
survival of newly generated glial cells was 5.6 Conclusion
observed (Li et al. 2015). Recently,
UDP-glucose, an endogenous agonist of G There is profound evidence that a complex inter-
protein-coupled receptor 17 (GPR17), the play of pre- and postnatal pro-inflammatory con-
neurotrophic factor glial cell line-derived ditions, primarily comprising oxygen toxicity,
neurotrophic factor (GDNF), and blockade of mechanical ventilation, and pre- and postnatal
5 Prenatal and Postnatal Inflammatory Mechanisms 89
infection, initiates and perpetuates an adverse injury in a murine model of bronchopulmonary dyspla-
inflammation in the structural and functional sia. Pediatr Res 69:312–318
Baier RJ, Majid A, Parupia H, Loggins J, Kruger TE
immature organs of preterm infants. An initial (2004) CC chemokine concentrations increase in respi-
injury, also referred to as “first hit,” activates ratory distress syndrome and correlate with develop-
early immune responses directed to pathogen ment of bronchopulmonary dysplasia. Pediatr
clearance and/or tissue repair. Functional immatu- Pulmonol 37:137–148
Barton SK, Moss TJ, Hooper SB, Crossley KJ, Gill AW,
rity in early and late immune responses, in antiox- Kluckow M et al (2014) Protective ventilation of pre-
idant enzymes and protease system, in key term lambs exposed to acute chorioamnionitis does not
regulators of homeostasis, in growth factors of reduce ventilation-induced lung or brain injury. PLoS
angiogenesis, and in repair mechanisms may pro- One 9:e112402
Bartram U, Speer CP (2004) The role of transforming
mote an injurious inflammatory response, charac- growth factor beta in lung development and disease.
terized by rapid accumulation of neutrophils and Chest 125:754–765
macrophages or diffuse microglial activation, Benjamin JT, Smith RJ, Halloran BA, Day TJ, Kelly DR,
respectively. An arsenal of inflammatory mediators Prince LS (2007) FGF-10 is decreased in
bronchopulmonary dysplasia and suppressed by Toll-
might subsequently affect tissue integrity with like receptor activation. Am J Physiol Lung Cell Mol
imbalance of pro-inflammatory and anti-inflamma- Physiol 292:L550–L558
tory mechanisms favoring pro-inflammation. Berger I, Peleg O, Ofek-Shlomai N (2012) Inflammation
Adverse postnatal conditions may further aggravate and early brain injury in term and preterm infants. Isr
Med Assoc J 14:318–323
the ongoing inflammation, as “second” or “third Bersani I, Speer CP (2012) Nosocomial sepsis in neonatal
hit.” Both neonatal lung and brain injury have intensive care: inevitable or preventable? Z
been related to maturation-dependent factors under- Geburtshilfe Neonatol 216:186–190
lying a particular vulnerability. As a devastating Bersani I, Kunzmann S, Speer CP (2013) Immunomodu-
latory properties of surfactant preparations. Expert Rev
consequence, normal lung and brain development Anti Infect Ther 11:99–110
may be compromised with lifelong consequences. Bhandari V (2010) Hyperoxia-derived lung damage in pre-
Seeking for strategies to prevent or ameliorate BPD term infants. Semin Fetal Neonatal Med 15:223–229
and WMD in high-risk infants, we still need a Bhandari V, Elias JA (2006) Cytokines in tolerance to
hyperoxia-induced injury in the developing and adult
deeper insight into the pathogenesis of inflamma- lung. Free Radic Biol Med 41:4–18
tory events. So far, we do not know whether, and to Blackwell TS, Hipps AN, Yamamoto Y, Han W, Barham
what extent, a preterm infant at risk will face the WJ, Ostrowski MC et al (2011) NF-kappaB signaling
given sequence of adverse inflammation, since the in fetal lung macrophages disrupts airway morphogen-
esis. J Immunol 187:2740–2747
orchestra of confounding pre- and postnatal factors, Boghossian NS, Page GP, Bell EF, Stoll BJ, Murray JC,
genetic susceptibility, and “window of vulnerabil- Cotten CM et al (2013) Late-onset sepsis in very low
ity” may differ from infant to infant. birth weight infants from singleton and multiple-
gestation births. J Pediatr 162:1120–1124, 1124 e1121
Bose CL, Dammann CE, Laughon MM (2008)
Bronchopulmonary dysplasia and inflammatory bio-
References markers in the premature neonate. Arch Dis Child
Fetal Neonatal Ed 93:F455–F461
Adams EW, Harrison MC, Counsell SJ, Allsop JM, Bose CL, Laughon MM, Allred EN, O’Shea TM, Van
Kennea NL, Hajnal JV et al (2004) Increased lung Marter LJ, Ehrenkranz RA et al (2013) Systemic
water and tissue damage in bronchopulmonary dyspla- inflammation associated with mechanical ventilation
sia. J Pediatr 145:503–507 among extremely preterm infants. Cytokine
Akira S (2006) TLR signaling. Curr Top Microbiol 61:315–322
Immunol 311:1–16 Brehmer F, Bendix I, Prager S, van de Looij Y,
Altiok O, Yasumatsu R, Bingol-Karakoc G, Riese RJ, Reinboth BS, Zimmermanns J et al (2012) Interaction
Stahlman MT, Dwyer W et al (2006) Imbalance of inflammation and hyperoxia in a rat model of neo-
between cysteine proteases and inhibitors in a baboon natal white matter damage. PLoS One 7:e49023
model of bronchopulmonary dysplasia. Am J Respir Brew N, Hooper SB, Allison BJ, Wallace MJ, Harding R
Crit Care Med 173:318–326 (2011) Injury and repair in the very immature lung
Backstrom E, Hogmalm A, Lappalainen U, Bry K (2011) following brief mechanical ventilation. Am J Physiol
Developmental stage is a major determinant of lung Lung Cell Mol Physiol 301:L917–L926
90 K. Glaser and C. P. Speer
Brochu ME, Girard S, Lavoie K, Sebire G (2011) Devel- inducible factor-1alpha expression in brain develop-
opmental regulation of the neuroinflammatory ment and neonatal hypoxic-ischemic brain injury.
responses to LPS and/or hypoxia-ischemia between Brain Res Rev 62:99–108
preterm and term neonates: an experimental study. Garcia-Munoz Rodrigo F, Galan Henriquez G, Figueras
J Neuroinflammation 8:55 Aloy J, Garcia-Alix Perez A (2014) Outcomes of
Cai Z, Pang Y, Lin S, Rhodes PG (2003) Differential roles very-low-birth-weight infants exposed to maternal clin-
of tumor necrosis factor-alpha and interleukin-1 beta in ical chorioamnionitis: a multicentre study. Neonatol-
lipopolysaccharide-induced brain injury in the neonatal ogy 106:229–234
rat. Brain Res 975:37–47 Garcia-Ramallo E, Marques T, Prats N, Beleta J,
Cederqvist K, Sorsa T, Tervahartiala T, Maisi P, Kunkel SL, Godessart N (2002) Resident cell chemo-
Reunanen K, Lassus P et al (2001) Matrix kine expression serves as the major mechanism for
metalloproteinases-2, -8, and -9 and TIMP-2 in tracheal leukocyte recruitment during local inflammation. J
aspirates from preterm infants with respiratory distress. Immunol 169:6467–6473
Pediatrics 108:686–692 Genc MR, Onderdonk A (2011) Endogenous bacterial
Chetty A, Cao GJ, Severgnini M, Simon A, Warburton R, flora in pregnant women and the influence of maternal
Nielsen HC (2008) Role of matrix metalloprotease-9 in genetic variation. BJOG 118:154–163
hyperoxic injury in developing lung. Am J Physiol Gerber CE, Bruchelt G, Stegmann H, Schweinsberg F,
Lung Cell Mol Physiol 295:L584–L592 Speer CP (1999) Presence of bleomycin-detectable
Chew LJ, DeBoy CA (2015) Pharmacological free iron in the alveolar system of preterm infants.
approaches to intervention in hypomyelinating and Biochem Biophys Res Commun 257:218–222
demyelinating white matter pathology. Neurol. pii: Girard S, Kadhim H, Roy M, Lavoie K, Brochu ME,
S0028-3908(15)00266-X. https://doi.org/10.1016/j. Larouche A et al (2009) Role of perinatal inflammation
neuropharm.2015.06.008. [Epub ahead of print] in cerebral palsy. Pediatr Neurol 40:168–174
Curtis MA, Kam M, Nannmark U, Anderson MF, Axell MZ, Girard S, Sebire H, Brochu ME, Briota S, Sarret P, Sebire G
Wikkelso C et al (2007) Human neuroblasts migrate to (2012) Postnatal administration of IL-1Ra exerts
the olfactory bulb via a lateral ventricular extension. neuroprotective effects following perinatal inflamma-
Science 315:1243–1249 tion and/or hypoxic-ischemic injuries. Brain Behav
D’Alquen D, Kramer BW, Seidenspinner S, Marx A, Immun 26:1331–1339
Berg D, Groneck P et al (2005) Activation of umbilical Glaser K, Speer CP (2013) Toll-like receptor signaling in
cord endothelial cells and fetal inflammatory response neonatal sepsis and inflammation: a matter of orches-
in preterm infants with chorioamnionitis and funisitis. tration and conditioning. Expert Rev Clin Immunol
Pediatr Res 57:263–269 9:1239–1252
D’Angio CT, Maniscalco WM (2002) The role of vascular Goldenberg RL, Andrews WW, Goepfert AR, Faye-
growth factors in hyperoxia-induced injury to the Petersen O, Cliver SP, Carlo WA et al (2008) The
developing lung. Front Biosci 7:d1609–d1623 Alabama Preterm Birth Study: umbilical cord blood
Dammann O, Leviton A (2014) Intermittent or sustained Ureaplasma urealyticum and Mycoplasma hominis cul-
systemic inflammation and the preterm brain. Pediatr tures in very preterm newborn infants. Am J Obstet
Res 75:376–380 Gynecol 198(43):e41–e45
Danan C, Franco ML, Jarreau PH, Dassieu G, Chailley- Groneck P, Gotze-Speer B, Oppermann M, Eiffert H,
Heu B, Bourbon J et al (2002) High concentrations Speer CP (1994) Association of pulmonary inflamma-
of keratinocyte growth factor in airways of prema- tion and increased microvascular permeability during
ture infants predicted absence of bronchopulmonary the development of bronchopulmonary dysplasia: a
dysplasia. Am J Respir Crit Care Med sequential analysis of inflammatory mediators in
165:1384–1387 respiratory fluids of high-risk preterm neonates. Pedi-
Dommergues MA, Patkai J, Renauld JC, Evrard P, atrics 93:712–718
Gressens P (2000) Proinflammatory cytokines and Guo H, Zhou H, Lu J, Qu Y, Yu D, Tong Y (2016) Vascular
interleukin-9 exacerbate excitotoxic lesions of the new- endothelial growth factor: an attractive target in the
born murine neopallium. Ann Neurol 47:54–63 treatment of hypoxic/ischemic brain injury. Neural
Dong Y, Speer CP (2015) Late-onset neonatal sepsis: Regen Res 11:174–179
recent developments. Arch Dis Child Fetal Neonatal Hallman M, Curstedt T, Halliday HL, Saugstad OD, Speer CP
Ed 100:F257–F263 (2013) Better neonatal outcomes: oxygen, surfactant and
Eklind S, Mallard C, Arvidsson P, Hagberg H (2005) drug delivery. Preface. Neonatology 103:316–319
Lipopolysaccharide induces both a primary and a sec- Harju K, Glumoff V, Hallman M (2001) Ontogeny of toll-
ondary phase of sensitization in the developing rat like receptors Tlr2 and Tlr4 in mice. Pediatr Res
brain. Pediatr Res 58:112–116 49:81–83
Ericson JE, Laughon MM (2015) Chorioamnionitis: impli- Harju K, Ojaniemi M, Rounioja S, Glumoff V, Paananen R,
cations for the neonate. Clin Perinatol 42:155–165, ix Vuolteenaho R et al (2005) Expression of toll-like
Fan X, Heijnen CJ, van der Kooij MA, Groenendaal F, receptor 4 and endotoxin responsiveness in mice during
van Bel F (2009) The role and regulation of hypoxia- perinatal period. Pediatr Res 57:644–648
5 Prenatal and Postnatal Inflammatory Mechanisms 91
Hartling L, Liang Y, Lacaze-Masmonteil T (2012) Kim KS (2003) Pathogenesis of bacterial meningitis: from
Chorioamnionitis as a risk factor for bronchopulmonary bacteraemia to neuronal injury. Nat Rev Neurosci
dysplasia: a systematic review and meta-analysis. Arch 4:376–385
Dis Child Fetal Neonatal Ed 97:F8–F17 Kim CJ, Romero R, Chaemsaithong P, Chaiyasit N, Yoon
He Z, Zhu Y, Jiang H (2009) Inhibiting toll-like receptor BH, Kim YM (2015) Acute chorioamnionitis and
4 signaling ameliorates pulmonary fibrosis during acute funisitis: definition, pathologic features, and clinical
lung injury induced by lipopolysaccharide: an experi- significance. Am J Obstet Gynecol 213:S29–S52
mental study. Respir Res 10:126 Kolb M, Margetts PJ, Anthony DC, Pitossi F, Gauldie J
Hillman NH, Moss TJ, Nitsos I, Kramer BW, Bachurski CJ, (2001) Transient expression of IL-1beta induces acute
Ikegami M et al (2008) Toll-like receptors and agonist lung injury and chronic repair leading to pulmonary
responses in the developing fetal sheep lung. Pediatr Res fibrosis. J Clin Invest 107:1529–1536
63:388–393 Kollmann TR, Crabtree J, Rein-Weston A, Blimkie D,
Hillman NH, Nitsos I, Berry C, Pillow JJ, Kallapur SG, Thommai F, Wang XY et al (2009) Neonatal innate
Jobe AH (2011) Positive end-expiratory pressure and TLR-mediated responses are distinct from those of
surfactant decrease lung injury during initiation of ven- adults. J Immunol 183:7150–7160
tilation in fetal sheep. Am J Physiol Lung Cell Mol Kollmann TR, Levy O, Montgomery RR, Goriely S (2012)
Physiol 301:L712–L720 Innate immune function by Toll-like receptors: distinct
Hines EA, Sun X (2014) Tissue crosstalk in lung develop- responses in newborns and the elderly. Immunity
ment. J Cell Biochem 115:1469–1477 37:771–783
Hogmalm A, Bry M, Strandvik B, Bry K (2014) IL-1beta Korzeniewski SJ, Romero R, Cortez J, Pappas A,
expression in the distal lung epithelium disrupts lung Schwartz AG, Kim CJ et al (2014) A “multi-hit”
morphogenesis and epithelial cell differentiation in fetal model of neonatal white matter injury: cumulative con-
mice. Am J Physiol Lung Cell Mol Physiol 306:L23–L34 tributions of chronic placental inflammation, acute fetal
Huusko JM, Karjalainen MK, Mahlman M, Haataja R, inflammation and postnatal inflammatory events. J
Kari MA, Andersson S et al (2014) A study of genes Perinat Med 42:731–743
encoding cytokines (IL6, IL10, TNF), cytokine recep- Kramer BW, Moss TJ, Willet KE, Newnham JP, Sly PD,
tors (IL6R, IL6ST), and glucocorticoid receptor Kallapur SG et al (2001) Dose and time response after
(NR3C1) and susceptibility to bronchopulmonary dys- intraamniotic endotoxin in preterm lambs. Am J Respir
plasia. BMC Med Genet 15:120 Crit Care Med 164:982–988
Inatomi T, Oue S, Ogihara T, Hira S, Hasegawa M, Yamaoka Kramer BW, Kramer S, Ikegami M, Jobe AH (2002)
S et al (2012) Antenatal exposure to Ureaplasma species Injury, inflammation, and remodeling in fetal sheep
exacerbates bronchopulmonary dysplasia synergistically lung after intra-amniotic endotoxin. Am J Physiol
with subsequent prolonged mechanical ventilation in Lung Cell Mol Physiol 283:L452–L459
preterm infants. Pediatr Res 71:267–273 Kramer BW, Ladenburger A, Kunzmann S, Speer CP,
Jaarsma AS, Braaksma MA, Geven WB, van Oeveren W, Been JV, van Iwaarden JF et al (2009) Intravenous
Bambang Oetomo S (2004) Activation of the inflam- lipopolysaccharide-induced pulmonary maturation
matory reaction within minutes after birth in ventilated and structural changes in fetal sheep. Am J Obstet
preterm lambs with neonatal respiratory distress syn- Gynecol 200:195 e191–110
drome. Biol Neonate 86:1–5 Kroon AA, Wang J, Huang Z, Cao L, Kuliszewski M,
Jobe AH (2011) The new bronchopulmonary dysplasia. Post M (2010) Inflammatory response to oxygen and
Curr Opin Pediatr 23:167–172 endotoxin in newborn rat lung ventilated with low tidal
Jones CA, Cayabyab RG, Kwong KY, Stotts C, Wong B, volume. Pediatr Res 68:63–69
Hamdan H et al (1996) Undetectable interleukin (IL)-10 Kuang PP, Zhang XH, Rich CB, Foster JA,
and persistent IL-8 expression early in hyaline mem- Subramanian M, Goldstein RH (2007) Activation of
brane disease: a possible developmental basis for the elastin transcription by transforming growth factor-beta
predisposition to chronic lung inflammation in preterm in human lung fibroblasts. Am J Physiol Lung Cell Mol
newborns. Pediatr Res 39:966–975 Physiol 292:L944–L952
Kaindl AM, Favrais G, Gressens P (2009) Molecular Kunig AM, Balasubramaniam V, Markham NE,
mechanisms involved in injury to the preterm brain. Seedorf G, Gien J, Abman SH (2006) Recombinant
J Child Neurol 24:1112–1118 human VEGF treatment transiently increases lung
Kallapur SG, Jobe AH, Ikegami M, Bachurski CJ (2003) edema but enhances lung structure after neonatal
Increased IP-10 and MIG expression after intra- hyperoxia. Am J Physiol Lung Cell Mol Physiol
amniotic endotoxin in preterm lamb lung. Am J Respir 291:L1068–L1078
Crit Care Med 167:779–786 Kunzmann S, Seher A, Kramer BW, Schenk R, Schutze N,
Kemp MW (2014) Preterm birth, intrauterine infection, Jakob F et al (2008) Connective tissue growth factor
and fetal inflammation. Front Immunol 5:574 does not affect transforming growth factor-beta
Khwaja O, Volpe JJ (2008) Pathogenesis of cerebral white 1-induced Smad3 phosphorylation and T lymphocyte
matter injury of prematurity. Arch Dis Child Fetal Neo- proliferation inhibition. Int Arch Allergy Immunol
natal Ed 93:F153–F161 147:152–160
92 K. Glaser and C. P. Speer
Lal CV, Ambalavanan N (2015) Genetic predisposition to birth in neonatal respiratory distress syndrome. Pediatr
bronchopulmonary dysplasia. Semin Perinatol Res 40:484–489
39:584–591 Nanthakumar N, Meng D, Goldstein AM, Zhu W, Lu L,
Lassus P, Heikkila P, Andersson LC, von Boguslawski K, Uauy R et al (2011) The mechanism of excessive intes-
Andersson S (2003) Lower concentration of pulmonary tinal inflammation in necrotizing enterocolitis: an
hepatocyte growth factor is associated with more immature innate immune response. PLoS One 6:
severe lung disease in preterm infants. J Pediatr e17776
143:199–202 Narimanbekov IO, Rozycki HJ (1995) Effect of IL-1
Lee Y, Kim HJ, Choi SJ, Oh SY, Kim JS, Roh CR blockade on inflammatory manifestations of acute
et al (2015) Is there a stepwise increase in neonatal ventilator-induced lung injury in a rabbit model. Exp
morbidities according to histological stage (or grade) Lung Res 21:239–254
of acute chorioamnionitis and funisitis?: effect of ges- Nguyen CN, Schnulle PM, Chegini N, Luo X, Koenig JM
tational age at delivery. J Perinat Med 43:259–267 (2010) Neonatal neutrophils with prolonged survival
Leviton A, Allred EN, Kuban KC, Hecht JL, Onderdonk secrete mediators associated with chronic inflamma-
AB, O’Shea TM et al (2010) Microbiologic and his- tion. Neonatology 98:341–347
tologic characteristics of the extremely preterm Nguyen HA, Rajaram MV, Meyer DA, Schlesinger LS
infant’s placenta predict white matter damage and (2012) Pulmonary surfactant protein A and surfactant
later cerebral palsy. The ELGAN study. Pediatr Res lipids upregulate IRAK-M, a negative regulator of
67:95–101 TLR-mediated inflammation in human macrophages.
Levy BD, Serhan CN (2014) Resolution of acute inflam- Am J Physiol Lung Cell Mol Physiol 303:L608–L616
mation in the lung. Annu Rev Physiol 76:467–492 Normann E, Lacaze-Masmonteil T, Eaton F,
Levy O, Wynn JL (2014) A prime time for trained immu- Schwendimann L, Gressens P, Thebaud B (2009) A
nity: innate immune memory in newborns and infants. novel mouse model of Ureaplasma-induced perinatal
Neonatology 105:136–141 inflammation: effects on lung and brain injury. Pediatr
Li WJ, Mao FX, Chen HJ, Qian LH, Buzby JS (2015) Res 65:430–436
Treatment with UDP-glucose, GDNF, and memantine O’Carroll SJ, Kho DT, Wiltshire R, Nelson V, Rotimi O,
promotes SVZ and white matter self-repair by endoge- Johnson R et al (2015) Pro-inflammatory TNFalpha
nous glial progenitor cells in neonatal rats with ische- and IL-1beta differentially regulate the inflammatory
mic PVL. Neuroscience 284:444–458 phenotype of brain microvascular endothelial cells.
Lozano SM, Newnam KM (2016) Modalities of mechani- J Neuroinflammation 12:131
cal ventilation: volume-targeted versus pressure- O’Hare FM, William Watson R, Molloy EJ (2013) Toll-
limited. Adv Neonatal Care 16:99–107 like receptors in neonatal sepsis. Acta Paediatr
Lukkarinen H, Hogmalm A, Lappalainen U, Bry K (2009) 102:572–578
Matrix metalloproteinase-9 deficiency worsens lung Paananen R, Husa AK, Vuolteenaho R, Herva R,
injury in a model of bronchopulmonary dysplasia. Kaukola T, Hallman M (2009) Blood cytokines during
Am J Respir Cell Mol Biol 41:59–68 the perinatal period in very preterm infants: relationship
Martin RJ, Fanaroff AA (2013) The preterm lung and of inflammatory response and bronchopulmonary dys-
airway: past, present, and future. Pediatr Neonatol plasia. J Pediatr 154:39–43 e33
54:228–234 Pang Y, Rodts-Palenik S, Cai Z, Bennett WA, Rhodes PG
May M, Marx A, Seidenspinner S, Speer CP (2004) Apo- (2005) Suppression of glial activation is involved in the
ptosis and proliferation in lungs of human fetuses protection of IL-10 on maternal E. coli induced neona-
exposed to chorioamnionitis. Histopathology tal white matter injury. Brain Res Dev Brain Res
45:283–290 157:141–149
Mesples B, Plaisant F, Gressens P (2003) Effects of Prince LS, Dieperink HI, Okoh VO, Fierro-Perez GA,
interleukin-10 on neonatal excitotoxic brain lesions in Lallone RL (2005) Toll-like receptor signaling inhibits
mice. Brain Res Dev Brain Res 141:25–32 structural development of the distal fetal mouse lung.
Miller JD, Benjamin JT, Kelly DR, Frank DB, Prince LS Dev Dyn 233:553–561
(2010) Chorioamnionitis stimulates angiogenesis in Reyburn B, Martin RJ, Prakash YS, MacFarlane PM
saccular stage fetal lungs via CC chemokines. Am J (2012) Mechanisms of injury to the preterm lung and
Physiol Lung Cell Mol Physiol 298:L637–L645 airway: implications for long-term pulmonary out-
Morley CJ (2010) CPAP and low oxygen saturation for come. Neonatology 101:345–352
very preterm babies? N Engl J Med 362:2024–2026 Ricard JD, Dreyfuss D, Saumon G (2001) Production of
Murch SH, Costeloe K, Klein NJ, MacDonald TT (1996a) inflammatory cytokines in ventilator-induced lung
Early production of macrophage inflammatory protein- injury: a reappraisal. Am J Respir Crit Care Med
1 alpha occurs in respiratory distress syndrome and is 163:1176–1180
associated with poor outcome. Pediatr Res 40:490–497 Sarelius IH, Glading AJ (2015) Control of vascular perme-
Murch SH, Costeloe K, Klein NJ, Rees H, McIntosh N, ability by adhesion molecules. Tissue Barriers 3:
Keeling JW et al (1996b) Mucosal tumor necrosis e985954
factor-alpha production and extensive disruption of Saugstad OD (2005) Oxidative stress in the newborn – a
sulfated glycosaminoglycans begin within hours of 30-year perspective. Biol Neonate 88:228–236
5 Prenatal and Postnatal Inflammatory Mechanisms 93
Schmitz T, Ritter J, Mueller S, Felderhoff-Mueser U, Chew in hyperoxia-induced lung injury: evidence that angio-
LJ, Gallo V (2011) Cellular changes underlying genesis participates in alveolarization. Circulation
hyperoxia-induced delay of white matter development. 112:2477–2486
J Neurosci 31:4327–4344 Thomas W, Speer CP (2011) Chorioamnionitis: important
Smith RE (1996) Chemotactic cytokines mediate leuko- risk factor or innocent bystander for neonatal outcome?
cyte recruitment in fibrotic lung disease. Biol Signals Neonatology 99:177–187
5:223–231 Thomas W, Speer CP (2014) Chorioamnionitis is essential
Speer CP (2006a) Inflammation and bronchopulmonary in the evolution of bronchopulmonary dysplasia – the
dysplasia: a continuing story. Semin Fetal Neonatal case in favour. Paediatr Respir Rev 15:49–52
Med 11:354–362 Thomas W, Seidenspinner S, Kawczynska-Leda N,
Speer CP (2006b) Pulmonary inflammation and Kramer BW, Chmielnicka-Kopaczyk M, Marx A
bronchopulmonary dysplasia. J Perinatol 26(Suppl 1): et al (2008) Systemic fetal inflammation and reduced
S57–S62; discussion S63–54 concentrations of macrophage migration inhibitory fac-
Speer CP (2009) Chorioamnionitis, postnatal factors and tor in tracheobronchial aspirate fluid of extremely pre-
proinflammatory response in the pathogenetic mature infants. Am J Obstet Gynecol 198(64):e61–e66
sequence of bronchopulmonary dysplasia. Neonatol- Turunen R, Nupponen I, Siitonen S, Repo H, Andersson S
ogy 95:353–361 (2006) Onset of mechanical ventilation is associated
Speer CP (2011) Neonatal respiratory distress syndrome: with rapid activation of circulating phagocytes in pre-
an inflammatory disease? Neonatology 99:316–319 term infants. Pediatrics 117:448–454
Speer CP, Pabst MJ, Hedegaard HB, Rest RF, Johnston RB Jr Ueda K, Cho K, Matsuda T, Okajima S, Uchida M,
(1984) Enhanced release of oxygen metabolites by Kobayashi Y et al (2006) A rat model for arrest of
monocyte-derived macrophages exposed to proteolytic alveolarization induced by antenatal endotoxin admin-
enzymes: activity of neutrophil elastase and cathepsin istration. Pediatr Res 59:396–400
G. J Immunol 133:2151–2156 Varughese R, Nayak JL, LoMonaco M, O’Reilly MA,
Speer CP, Gahr M, Wieland M, Eber S (1988) Ryan RM, D’Angio CT (2003) Effects of hyperoxia
Phagocytosis-associated functions in neonatal on tumor necrosis factor alpha and Grobeta expression
monocyte-derived macrophages. Pediatr Res in newborn rabbit lungs. Lung 181:335–346
24:213–216 Viscardi RM (2012) Perinatal inflammation and lung
Speer CP, Ruess D, Harms K, Herting E, Gefeller O (1993) injury. Semin Fetal Neonatal Med 17:30–35
Neutrophil elastase and acute pulmonary damage in Viscardi RM (2014) Ureaplasma species: role in neonatal
neonates with severe respiratory distress syndrome. morbidities and outcomes. Arch Dis Child Fetal Neo-
Pediatrics 91:794–799 natal Ed 99:F87–F92
Stoll BJ, Hansen NI, Sanchez PJ, Faix RG, Poindexter BB, Viscardi RM, Muhumuza CK, Rodriguez A, Fairchild KD,
Van Meurs KP et al (2011) Early onset neonatal sepsis: Sun CC, Gross GW et al (2004) Inflammatory markers
the burden of group B Streptococcal and E. coli disease in intrauterine and fetal blood and cerebrospinal fluid
continues. Pediatrics 127:817–826 compartments are associated with adverse pulmonary
Stridh L, Smith PL, Naylor AS, Wang X, Mallard C (2011) and neurologic outcomes in preterm infants. Pediatr
Regulation of toll-like receptor 1 and -2 in neonatal mice Res 55:1009–1017
brains after hypoxia-ischemia. J Neuroinflammation 8:45 Volpe JJ (2008) Postnatal sepsis, necrotizing entercolitis,
Stridh L, Ek CJ, Wang X, Nilsson H, Mallard C (2013) and the critical role of systemic inflammation in white
Regulation of toll-like receptors in the choroid plexus matter injury in premature infants. J Pediatr
in the immature brain after systemic inflammatory stim- 153:160–163
uli. Transl Stroke Res 4:220–227 Vuichard D, Ganter MT, Schimmer RC, Suter D, Booy C,
Strunk T, Doherty D, Jacques A, Simmer K, Richmond P, Reyes L et al (2005) Hypoxia aggravates
Kohan R et al (2012) Histologic chorioamnionitis is lipopolysaccharide-induced lung injury. Clin Exp
associated with reduced risk of late-onset sepsis in Immunol 141:248–260
preterm infants. Pediatrics 129:e134–e141 Wagenaar GT, ter Horst SA, van Gastelen MA, Leijser
Strunk T, Inder T, Wang X, Burgner D, Mallard C, Levy O LM, Mauad T, van der Velden PA et al (2004) Gene
(2014) Infection-induced inflammation and cerebral expression profile and histopathology of experimen-
injury in preterm infants. Lancet Infect Dis 14:751–762 tal bronchopulmonary dysplasia induced by
Takeuchi O, Akira S (2010) Pattern recognition receptors prolonged oxidative stress. Free Radic Biol Med
and inflammation. Cell 140:805–820 36:782–801
Thebaud B, Abman SH (2007) Bronchopulmonary dyspla- Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z
sia: where have all the vessels gone? Roles of angio- (1999) IRAK-M is a novel member of the Pelle/inter-
genic growth factors in chronic lung disease. Am J leukin-1 receptor-associated kinase (IRAK) family.
Respir Crit Care Med 175:978–985 J Biol Chem 274:19403–19410
Thebaud B, Ladha F, Michelakis ED, Sawicka M, Wilson MR, Choudhury S, Takata M (2005) Pulmonary
Thurston G, Eaton F et al (2005) Vascular endothelial inflammation induced by high-stretch ventilation is
growth factor gene therapy increases survival, pro- mediated by tumor necrosis factor signaling in mice.
motes lung angiogenesis, and prevents alveolar damage Am J Physiol Lung Cell Mol Physiol 288:L599–L607
94 K. Glaser and C. P. Speer
Wu YW (2002) Systematic review of chorioamnionitis and bronchopulmonary dysplasia. Am J Obstet Gynecol
cerebral palsy. Ment Retard Dev Disabil Res Rev 177:825–830
8:25–29 Yu KH, Li J, Snyder M, Shaw GM, O’Brodovich HM
Yamamoto M, Takeda K (2010) Current views of toll-like (2016) The genetic predisposition to bronchopulmonary
receptor signaling pathways. Gastroenterol Res Pract dysplasia. Curr Opin Pediatr 28:318–323
2010:240365 Zhang J, Zhou J, Xu B, Chen C, Shi W (2015) Different
Yi M, Jankov RP, Belcastro R, Humes D, Copland I, Shek expressions of TLRs and related factors in peripheral
S et al (2004) Opposing effects of 60% oxygen and blood of preterm infants. Int J Clin Exp Med 8:4108–4114
neutrophil influx on alveologenesis in the neonatal rat. Zhao Y, Gilmore BJ, Young SL (1997) Expression of
Am J Respir Crit Care Med 170:1188–1196 transforming growth factor-beta receptors during
Yoon BH, Romero R, Jun JK, Park KH, Park JD, Ghezzi F hyperoxia-induced lung injury and repair. Am J Physiol
et al (1997) Amniotic fluid cytokines (interleukin-6, 273:L355–L362
tumor necrosis factor-alpha, interleukin-1 beta, and Zlotnik A, Yoshie O (2012) The chemokine superfamily
interleukin-8) and the risk for the development of revisited. Immunity 36:705–716
The Fetus at Risk: Chorioamnionitis
6
Mikko Hallman and Tuula Kaukola
Contents
6.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
6.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
6.3 Diagnosis and Incidence of Chorioamnionitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
6.4 Antenatal Findings in Chorioamnionitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
6.4.1 Specific Infections Associated with
Chorioamnionitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
6.4.2 Inflammation Without Microbes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
6.5 Chorioamnionitis as a Risk Factor for Acute and Chronic Diseases . . . . . . 100
6.5.1 Experimental Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
6.5.2 Pulmonary Consequences of CA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
6.5.3 Neurological Consequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
6.6 Prevention of Morbidity Associated with CA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Abstract inflammatory stress in HCA promotes fetal
Histological chorioamnionitis (HCA) is com- maturity. Previous evidence on increased risk
mon in extremely preterm births. HCA in very of respiratory distress, intraventricular hemor-
preterm births is associated with a low risk of rhage (IVH), bronchopulmonary dysplasia
respiratory distress syndrome (RDS) as the (BPD), necrotizing enterocolitis (NEC), cere-
bral palsy (CP), and poor neurodevelopmental
outcome, compared to gestation controls, has
not been uniformly confirmed. Antenatal ste-
M. Hallman (*) roid that decreases the risk of RDS, IVH, NEC,
Department of Children and Adolescents, Oulu University and CP was rarely given in early studies. Clin-
Hospital, and PEDEGO Research Unit, Medical Research ical CA, defined on the basis of fever, leuko-
Center Oulu, University of Oulu, Oulu, Finland cytosis, and local symptoms, represents
e-mail: mikko.hallman@oulu.fi
10–25% of all HCA cases. Clinical CA is asso-
T. Kaukola ciated with CP in near-term/term pregnancies
Department of Children and Adolescents, Oulu University
Hospital, and PEDEGO Research Center, MRC Oulu, and additional adverse outcomes in very pre-
University of Oulu, Oulu, Finland term pregnancies. HCA combined with
# Springer International Publishing AG, part of Springer Nature 2018 95
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_155
96 M. Hallman and T. Kaukola
intrauterine growth restriction or placental per- with the embryo via a connecting stalk that later
fusion defect strongly associates with neuro- develops into the umbilical cord. By 40 days
logical problems. Causes and consequences of p.c. the embryo is completely surrounded by the
HCA remain to be studied. amniotic cavity and attached via the umbilical cord
to the hemomonochorial placenta (Benirschke
et al. 2012). Upon complete adherence of the fetal
6.1 Salient Points membranes to the decidua at about 20 weeks of
gestation, bacterial inflammation may still pene-
• Chorioamnionitis (CA) is a risk factor of sponta- trate the chorioamnion and contaminate the amni-
neous onset of very preterm birth. Only 10–25% otic fluid (Goldenberg and Culhane 2003; Gravett
of histologic CA (HCA) is presented as clinical et al. 1986).
CA, diagnosed on the basis fever, leukocytosis, In high-risk pregnancies, the protective fetal
and local signs of maternal infection. chorioamnion and placental tissues are challenged
• Microbes and inflammation from cervix, and in multiple ways. They respond by promoting
also from fallopian tubes, endometrium, mater- inflammation that involves mediators with multi-
nal blood, or via amniocentesis spread to ple functions, including defense against microbes,
chorioamnion. Cause-relationship between promoting the fetal maturity and the labor process.
microbes and inflammation is not uniformly Oxidative and proteolytic effects of inflammation
established. are obviously harmful to the developing organ-
• HCA promotes the host defense functions, ism. This chapter focuses on the consequences of
decreasing the risk of respiratory distress syn- chorioamnionitis (CA) in the fetus comparing the
drome (RDS). The benefits are balanced against affected fetuses to the gestation controls.
severe potential adverse effects. The associated
increases in the risks of bronchopulmonary dys-
plasia (BPD) and necrotizing enterocolitis 6.3 Diagnosis and Incidence
(NEC) have not been lately confirmed. of Chorioamnionitis
• HCA may increase the risk of intraventricular
hemorrhage (IVH), cerebral palsy (CP), and Histologic chorioamnionitis (HCA) is character-
adverse cognitive consequences in children ized by mostly polymorphonuclear neutrophil
born very preterm. The adverse effects stand (PMN) infiltration of the placenta, fetal mem-
out in clinical CA, compound placental branes, and/or umbilical cord. Pathological exam
defects, and in intrauterine growth restriction. of the placenta, fetal membranes, and umbilical
• Antibiotics in preterm rupture of fetal mem- cord defines CA (Benirschke et al. 2012; Salafia
branes decrease the risk of CA, and antenatal et al. 1989) (Fig. 1). In most cases HCA is a silent
glucocorticoid in threatened very preterm birth condition. It serves as a biomarker, indicating
may decrease the risk of adverse consequences inflammatory activation at the feto-maternal inter-
of HCA. Fetal-placental infections caused by face that may have diverse consequences includ-
specific microbes are often preventable. ing the induction of labor. CA is a risk factor of
spontaneous preterm birth (PTB).
Analysis of biochemical markers of PMNs in
6.2 Introduction amniotic fluid provides accurate diagnosis of
CA. Interleukin-6 (IL-6), IL-8, and other inflamma-
Infections and inflammatory injuries are the major tory cytokines also are elevated in the amniotic fluid
threats during pregnancy. The extraembryonic tis- (Hallman et al. 1989; Bracci and Buonocore 2003).
sues play important roles in protecting the fetus. However, amniocentesis is not indicated for diagno-
From 10 to 12 days post conception (p.c.), yolk sis of CA. After birth, the inspection of the placenta,
sack and allantois vessels provide nutrition to the its vessels, and the fetal membranes helps to under-
embryo. By 20 days p.c. fetal vessels are discern- stand the pregnancy outcome (Fig. 1a). Placentas
ible in developing placenta. They communicate with severe CA reveal marginal hemorrhages, and
6 The Fetus at Risk: Chorioamnionitis 97
Fig. 1 Study of placenta and fetal membranes for diagno- placenta with CA. Dark exudate is noted in the center near
sis of chorioamnionitis. (a) Diamnionic, dichorionic twin the site of rupture of fetal membranes (A. Page 558.
placenta. Preterm placenta (single clamp), located in fun- Fig. 20.2. From Benirschke C, Burton GJ, Baegren
dus, reveals vessels through visible membranes, RN. Pathology of human placenta. Springer-Verlag Berlin
suggesting no CA. Placenta with marginally inserted cord Heidelberg 2012. B. Page 4. Fig.1.3. Left segment. From
(two clamps) has cloudy appearance suggesting inflamma- Benirschke C, Burton GJ, Baegren RN. Pathology of
tion in fetal membranes. Presumptive diagnoses were con- human placenta. Springer-Verlag Berlin Heidelberg 2012.
firmed by histology. (b) Rolling of fetal membranes is C. Page 568. Fig 20.22. From Benirschke C, Burton GJ,
preferably started from the site of the rupture and proceed- Baegren RN. Pathology of human placenta. Springer-
ing towards the edge, with amnion inside. A segment of the Verlag Berlin Heidelberg 2012)
well-rolled portion is fixed for a day. (c) Membrane roll of
the amniotic surfaces are covered with invisible Clinical CA presents as fever, foul-smelling vag-
white leukocyte-enriched film. Diagnostic speci- inal discharge, uterine tenderness, and laboratory
mens are recovered from three sites: chorionic findings, e.g., leukocytosis or elevated C-reactive
plate, fetal membranes as a roll from the site of protein. Two positive criteria (one clinical, one
spontaneous membrane rupture, and segments of chemical/ laboratory) establish the diagnosis. In
umbilical cord (Benirschke et al. 2012; Salafia clinical CA, elective delivery is considered for
et al. 1989). According to microscopy of fetal mem- fetal indication.
branes, HCA is classified into three grades: (1) mild Prelabor rupture of fetal membranes (PROM)
(5–10 neutrophils per high power field [HPF]), in preterm pregnancy exposes the intra-amniotic
(2) moderate (11–30 neutrophils/HPF), and space to ascending infection and is associated
(3) severe (>30 neutrophils/HPF). All three sites with CA. PROM at term that proceeds to labor
are examined and CA is additionally defined on the and delivery is one presentation of normal labor.
basis of distribution of the inflammation in the three In preterm PROM, labor mostly starts spontane-
sites. ously. In other cases, pregnancy continues without
98 M. Hallman and T. Kaukola
concomitant induction of labor for weeks, and potential roles of normal and abnormal microbial
after delivery the study of placenta often reveals colonization during later fetal development
no HCA. In prolonged PROM, post-PROM preg- remain to be studied (Romano-Keeler and
nancy duration is at least one week. The cases of Weitkamp 2015).
PROM that progress to preterm labor are often Fetal inflammatory response syndrome (FIRS)
considered as clinical CA, although the diagnosis is defined as an increase in IL-6 in cord blood in
is not always confirmed by the histological exam, CA (Yoon et al. 2000). Funisitis is another diag-
and typical maternal symptoms are absent. Unless nostic criterion associated with FIRS. Although
the individual studies carefully describe the dura- FIRS is associated with an increased risk of early
tion, symptoms, and histology associated with postnatal infection, in more recent reports most of
PROM, the comparison of the outcomes between the premature newborn affected by FIRS have
different studies remains problematic. negative blood cultures (>90%). According to a
Despite significant association between HCA regional cohort of 163 preterm Finnish infants,
and spontaneous PTB, neither the specificity nor born before 32 weeks of pregnancy, ~50% of
the sensitivity of prediction is very high (Table 1). HCA cases had FIRS on the basis of elevated
In late-preterm births due to spontaneous onset of levels of IL-6 in cord blood, <10% of infants
labor, HCA is less frequent (10–25%) than in had funisitis, and <5% revealed early sepsis.
extremely preterm spontaneous births (40–60%).
Although preterm labor and birth is often associ-
ated with bacterial colonization of fetal mem- 6.4 Antenatal Findings
branes and amniotic fluid, the dogma of sterile in Chorioamnionitis
intrauterine environment during normal term preg-
nancy has been challenged. The new techniques In term pregnancies, maturation and shortening of
allow identification and classification of genomes the cervix and rupture of fetal membranes expose
from various microbes. Even in elective term the amniotic space to microbes. In the setting of
births without labor, genomes of commensal bac- spontaneous preterm labor, the inflammatory
teria may be detectable in fetal compartment. The mediators appear to play a more prominent role
in the activation of the labor process than in term
Table 1 Prevalence of pregnancy conditions and the inci- labor. However, histological inflammation may
dence of histological chorioamnionitis (HCA) persist for a long period during pregnancy as a
Pregnancy Prevalence % HCA % in given condition with little consequence. HCA and
condition of all births pregnancy condition microorganisms are present in at least 50% of
Term 85–92 2–10 second trimester pregnancy loss cases (Heller
Postterm 1–5 5–15a et al. 2003). It has been postulated that after
Preterm 5–13 15–25 mid-pregnancy when the expanding fetal mem-
Spontaneous 3–9 20–35 branes seal the endometrial cavity, the incidence
onset
of ascending infection becomes less common
PROM 1.5–4 50–80
(Goldenberg et al. 2000).
32–36 weeks 2–7 10–25
Besides microbes and endotoxins, other trigger-
28–32 weeks 0.5–1.2 25–40
<28 weeks 0.3–0.6 40–60
ing agents (factors decreasing the immune tolerance,
No 2–4 5–15 meconium-induced HCA) may play a role in the
spontaneous etiology. In HCA, the amniotic fluid or fetal mem-
onset branes reveal microbes that, however, may also be
a
Meconium in amniotic fluid (50 %) associates with green detected even in elective births without labor using
staining of chorioamnion that contains meconium-laden molecular probes specific for bacteria (Bracci and
macrophages; associated chorioamnionitis suggests infec-
tion. The ranges of the incidence figures are based on
Buonocore 2003; Romano-Keeler and Weitkamp
population studies (Paananen et al. 2009; Andrews 2015; Goldenberg et al. 2000). The most common
et al. 2008; McElrath et al. 2008) microbe in HCA is Ureaplasma urealyticum
6 The Fetus at Risk: Chorioamnionitis 99
(20–40%). The traditional pathogens (Group B early pregnancy (see ▶ Chap. 106, “Toxoplasmo-
Streptococci or GBS, E. coli, Enterococci, Listeria sis in the Fetus and Newborn”). Enteroviruses,
monocytogenes) are less common (2–10%). mumps, and rubella cause distinct placental
The ascending route is the most common in inflammatory lesions.
HCA, and bacterial vaginosis (BV) is a risk Listeria monocytogenes from contaminated
factor. In BV, the incidence of lactobacilli as a food or soil presents as severe necrotizing villitis
normal predominant colonization has decreased with abscesses. The disease is associated with
at the expense of other microbes, including chorioamnionitis and generalized fetal infection
Gardnerella vaginalis, Mobiluncus spp., anaer- that often leads to fetal death or to severe neonatal
obic gram-negative rods, M. hominis, and pneumonia or meningitis. Early-onset GBS causes
Ureaplasma urealyticum. Most of microbes in CA, and amniotic fluid is a growth media of GBS:
BV have also been detected in fetal membranes the reported incidences of CA and funicitis were
and in amniotic fluid. However, BV predicts the 64% and 27%, respectively. The high-risk
risk of preterm birth with a low specificity mothers are frequently heavily colonized with
(Goffinet 2005). Periodontitis is another pro- GBS (vaginal flora, urinary tract, breast milk).
posed risk factor of spontaneous PTB (Sacco In these cases, the risk of early neonatal GBS
et al. 2008). is decreased by intrapartum administration of
antibiotics. The recurrence rate of the carrier
status is high (see Section X: Fetal and Neonatal
6.4.1 Specific Infections Associated Infections). A number of other pathogens have
with Chorioamnionitis been associated with CA, including Neisseria
gonorrhoeae, group A β-hemolytic streptococci,
Placental villi are affected in infections causing Streptococcus penumoniae, and Hemophilus
intrauterine growth restriction (Benirschke et al. influenzae. Gram-negative bacilli, particularly,
2011). Treponema pallidum causes hypercellular E. coli is associated with CA and neonatal menin-
villitis with mononuclear infiltration, sometimes gitis. Salmonellae, Shigella, Clostridium,
necrotizing funicitis or plasma cell rich CA. Can- Fusobacterium, Bacterioides fragilis, and
dida vaginitis is common during pregnancy and Gardnerella vaginalis have been occasionally
infections occasionally cause a serious placental associated with chorioamnionitis and fetal pathol-
and fetal disease. Intrauterine candidiasis is asso- ogy. Clamydia is a common cause of cervicitis.
ciated with clusters of characteristic structures, Conjuctivitis caused by gonococcus and Chla-
surrounded by inflammatory cells in umbilical mydia trachomatis requires mostly local treatment.
cord, placenta, and fetal membranes (see Chlamydia pneumoniae has been shown to infect
▶ Chap. 105, “Fetal Infections: Congenital Syph- extravillous trophoblasts.
ilis and Tuberculosis”). About 1% of women Ureaplasma urealyticum is the most frequently
become infected with Cytomegalovirus (CMV) isolated microbe in CA. Of other mycoplasma
during pregnancy and nearly 50% of cases it is species, Mycoplasma hominis is associated with
passed to her fetus. However, very few manifest pelvic inflammatory diseases. Ureaplasma spp.
congenital CMV, associated with characteristic may cause pneumonia and occasionally bacter-
chronic villitis and severe fetal disease. Typical emia and meningitis in susceptible newborn
placental findings of severe CMV infection infants. The infected infants are reported to have
include plasmacytic villitis, thrombosis of villous increased risk of BPD.
capillaries, necrosis of villous tissues, and The causes of increased susceptibility in
inclusion-bearing cytomegalic cells. Toxoplasma some pregnancies to CA and to specific infec-
gondii is associated with lymphoplasmacytic tions causing characteristic feto-placental dis-
villitis and sclerosis, along with toxoplasma cysts eases remain to be studied. Genetic factors
in amnion/chorion. These findings and the risk of likely influence the individual susceptibility, as
severe fetopathy are particularly evident during some alleles cause defects in innate immunity
100 M. Hallman and T. Kaukola
and others cause specific defects in acquired insult (Rounioja et al. 2005), whereas the
immunity. Environmental risk factors warrant transcellular spreading of inflammation acutely
further investigation. boosts the host defense (Bry et al. 1997; Jobe
et al. 2000). The fetal consequences of CA are
additionally dependent on severity and etiology of
6.4.2 Inflammation Without Microbes the inflammation, as well as multiple, poorly
understood genetic and environmental risk fac-
Villitis of unknown etiology (VUE) is found in tors. CA is traditionally diagnosed by histology.
5–15% of predominantly term placentas. It is asso- Characterization of the process biochemically
ciated with intrauterine growth restriction, fetal (inflammatory cytokines), microbiologically, or
death, and perinatal asphyxia. In VUE, by inspection provides additional information
CD3-positive maternal T lymphocytes gain access that is clinically useful when available shortly
to the villous stroma. Fetal antigen-presenting cells after birth (Thomas and Speer 2011).
(Hofbauer cells) expand and express class II major
histocompatibility complex molecules. Maternal
monocyte-macrophages in the perivillous space 6.5.1 Experimental Data
likely amplify the immune response. VUE may
represent a state combining maternal allograft Introduction of bacterial endotoxin (LPS) or
rejection and graft versus host disease mechanisms proinflammatory cytokine (IL-1) to amniotic
(Kim et al. 2009; Redline 2007). fluid evokes an acute maturation of the surfactant
Meconium that is prevalent in postterm system (Bry et al. 1997; Jobe et al. 2000). This
(20–70%) and term (5–15%) pregnancies associ- cytokine-induced pulmonary epithelial differenti-
ates with green staining of chorioamnion ation enhances the capacity of premature neonatal
containing meconium-laden macrophages and respiratory adaptation. The cytokine effect on
often CA. Longstanding meconium may be asso- lung maturity is additive with that of glucocorti-
ciated with umbilical vascular myonecrosis; typical coid (Jobe et al. 2000). At the same time, LPS or
comorbidities include fetal distress and intrauterine the cytokine cascade induced by the inflammatory
growth restriction (Cimic and Baergen 2015). agent (e.g., IL-8) induces acute airway inflamma-
tion that is likely to spread to lung parenchyma
and systemically (Thomas and Speer 2011). Ante-
6.5 Chorioamnionitis as a Risk natal glucocorticoid protects the preterm fetus
Factor for Acute and Chronic affected by FIRS against vascular insults, stabiliz-
Diseases ing the blood pressure and strengthening endothe-
lial and epithelial barriers after premature birth.
From chorioamnion the inflammation may spread In pregnant rodents, a high dose of LPS to the
transcellularly via amniotic fluid that is swallowed maternal compartment induces an acute fetal per-
into GI tract and in part enters the airways by the fusion defect, illustrated by increased resistance in
fetal breathing movements. The umbilical cord is placental villous perfusion and resulting in
in direct contact with amniotic fluid and with low-output fetal cardiac failure (Rounioja
chorionic plate in placenta. On the other hand, et al. 2005). According to animal data, acute
chorion is highly vascular and in generalized transplacental inflammatory insult may result in
maternal infection her blood provides a direct brain injury, involving activation of pattern rec-
source of infection/inflammation to placental ognition receptors and subsequent innate immune
structures, particularly the villae. In clinical CA, response (Speer 1999). In addition hypoxemia-
transplacental spreading to the fetus prevails. ischemia evokes an inflammatory response
According to experimental studies and clinical (Hagberg et al. 2015). Inflammatory mediators
observations, placental circulation is acutely may gain access into the immature brain as spe-
affected as a result of transplacental inflammatory cific chemokines serving as ligands for their
6 The Fetus at Risk: Chorioamnionitis 101
receptors in the target tissue or promoting ventilation techniques. In contrast, within 24 h after
neutrophil-mediated breakdown of blood–brain a very preterm birth, high levels of specific inflam-
barrier (Anthony et al. 1998). Intracerebral cyto- matory cytokines are evident in non-CA pregnan-
kine storm promotes free radical attack, failure in cies with RDS. Very high levels of cytokines,
oxidative phosphorylation, necrosis, apoptosis, particularly IL-8, after birth associate with the
and brain injury. Immature oligodendrocytes are risk of BPD (Kaukola et al. 2009; Paananen
especially vulnerable (see ▶ Chap. 118, “Inflam- et al. 2009). Modest inflammatory response in CA
mation and Perinatal Brain Injury”). may additionally be due to antenatal glucocorticoid
treatment (Been and Zimmermann 2009; Kramer
et al. 2009). Inappropriately low cytokines and tran-
6.5.2 Pulmonary Consequences of CA sient immune paralysis occasionally complicate
prolonged PROM cases that are born very preterm
The reports of premature patients from the early with severe respiratory distress (sometimes sepsis)
1990s associate CA with adverse outcomes. In and pulmonary hypertension (Aikio et al. 2012).
these studies, clinical CA was overrepresented, Structural immaturity predisposes to “new” BPD
antenatal glucocorticoid was rarely given, and (Thébaud and Abman 2007), suggesting that the
advanced neonatal respiratory care practices respiratory adaptation after extremely preterm birth
were not available. Watterberg reported an asso- is harmful. It is possible that environmental factors,
ciation between CA and a low risk of RDS and a such as the inevitable increase in the oxygen tension
high risk of BPD as studied in 53 preterm infants after birth, still play important interactive roles in
(Watterberg et al. 1996). The risk of BPD is asso- pathogenesis. In infants born after 30 weeks of
ciated with increased tracheal IL-1β levels. Later pregnancy, the development of lung structure is
reports representing the era of antenatal glucocor- more advanced and the risk of BPD is very low,
ticoid and surfactant therapy confirm a despite neonatal respiratory distress.
HCA-associated substantial decrease in the risk
of RDS and no increase in the risk of BPD
(Kaukola et al. 2009; Paananen et al. 2009; Been 6.5.3 Neurological Consequences
and Zimmermann 2009) (Table 2).
Recent cohort studies with larger populations At least half of all children with CP are born at
have additionally found that in very preterm infants term (CP prevalence 1–1.5 per 1000 term born).
the high levels of inflammatory cytokines detected The term-born cases mostly represent hemiplegia
in cord blood in HCA often decrease shortly after and quadriplegia, whereas among infants born
birth and do not associate with adverse pulmonary very preterm, diplegia predominates and CP
consequences (Paananen et al. 2009). This decrease cases are fairly common in this population (4–8
is likely achieved by applying noninvasive, gentle per 100 very preterm) (Sellier et al. 2015;
Table 2 Fetal consequences of chorioamnionitis (CA) or CA with complicating event. Comparison of risk to infants born
preterm with similar gestation and without evidence of CA
Postnatal morbidity Histologic CA +Fetal inflammation +Clinical CA +PROM
Infection " " " "
RDS # ~a or # ~a or # ~a or #
BPD ~a ~ or "a ~ or "a ~ or "a
Severe RDS ~a or # ~a ~a "
IVH ~ or "a ~ or " " "
CP ~or "a ~ or " " "
Adverse cognitive development ~a ~ or " " ~ or "
a
Progress in antenatal and neonatal treatment practices (antenatal glucocorticoid and gentle neonatal cardiopulmonary
treatment practices) has decreased the serious morbidity. Explanations: (~) no reported effect
102 M. Hallman and T. Kaukola
Himmelmann and Uvebrant 2014). The pattern of CP. In a meta-analysis, a significant association
cord blood immunoproteins predicting CP is dif- was found both between clinical CA and CP
ferent as compared between very preterm and (RR 1.9, 95% CI 1.5–2.5) and between clinical
term infants (Kaukola et al. 2004). CA and cystic periventricular leukomalacia
According to a large population-based cohorts, (RR 2.6, 95% CI 1.7–3.9) (Wu 2002).
the incidence of CP among term and preterm Quadriplegia as a separate trait in term and
infants has remained stable, or declined, since the near-term neonates was associated with severe
1970s, suggesting that advances in treatment prac- hypoxic-ischemic insult. In contrast, hemiplegia
tices influence the long-term outcomes (Sellier is associated with brain infarction, and one risk
et al. 2015; Himmelmann and Uvebrant 2014). factor of brain infarction was preterm PROM (Lee
et al. 2005; McElrath et al. 2008).
6.5.3.1 Infants Born Very Preterm
In many but not all studies, CA is a risk factor of
IVH among infants born very preterm (Kaukola 6.6 Prevention of Morbidity
et al. 2006; Andrews et al. 2006; Soraisham Associated with CA
et al. 2009). Despite common use of antenatal
glucocorticoid and more gentle neonatal treatment HCA is diagnosed first after birth. However,
practices, decreasing the risk of IVH, CA has been symptoms of clinical CA strongly suggests HCA
linked to early IVH, emphasizing the role of immu- (sensitivity >80%), and preterm PROM suggests
nological activation in fetus as a pathway to cere- HCA (sensitivity ~50%). Inspection of fetal mem-
bral injury before birth. In populations mostly branes by experienced observer enables the diag-
representing clinical CA, the risk of severe IVH is nosis of HCA with reasonable accuracy (Fig. 1).
increased in preterm infants (Soraisham Stillbirths and spontaneous extremely preterm
et al. 2009). There is also evidence of increased births (<28 weeks) are associated with HCA (sen-
risk of CP and cognitive problems in children born sitivity 40–80%). HCA and FIRS are prevalent in
preterm in clinical CA (Neufeld et al. 2005). stillbirths at the extremes of gestation: <26 weeks
Besides clinical CA, cases of “silent” CA with an and >40 weeks (Gordon et al. 2011).
additional defect in placental perfusion are associ- Prevention of cause is the most effective
ated with abnormal neurological outcome approach. Vaccination programs against rubeola
(Kaukola et al. 2006). According to other reports, have virtually eradicated the virus. Development
infants born with HCA as a whole do not have a of vaccines against other pathogens, such as cyto-
higher frequency of neurodevelopmental problems megalovirus, would offer a tool for prevention.
than the gestation controls (Andrews et al. 2008). Prophylaxis programs against Listeriosis, group B
Streptococci, Toxoplasma, and HIV have met
6.5.3.2 Infants Born Late-Preterm with at least moderate success.
to Term Meta-analysis of randomized controlled trials
A case-control study of a cohort of 200,000 of prophylactic antibiotics in preterm PROM and
infants born at 36 weeks or later in gestation particularly in prolonged (>7 days) PROM has
during the years 1991 and 1998 revealed CA or revealed a decrease in HCA, a decrease preterm
endometritis in 14% of CP cases and 4% of ran- births within 48–168 h, and a decrease in invasive
dom controls, translating CA as an independent treatments (oxygen and surfactant therapies) of
risk factor (OR 3.8, CI 1.4–9.3) of CP the preterm infants (Kenyon et al. 2013; Saccone
(Wu et al. 2003), consistent with other studies. and Berghella 2015). In addition, the treatment
Clinical CA and severe symptoms of infection decreases the risk of abnormal head ultrasound
are associated with increased risk. before the discharge. In trials, the antibiotic often
The diagnosis of silent HCA covered only less has been macrolide; choice of antibiotic depends
than 25% of the CA population, and there was no on the resistance spectrum of individual centers.
detectable association between silent HCA and Co-amoxiclav has been associated with NEC.
6 The Fetus at Risk: Chorioamnionitis 103
Antibiotic prophylaxis in PROM at term has 23-to 32-week preterm newborn infants. J Obstet
offered no detectable benefit. In imminent preterm Gynecol 195:803–808
Andrews WW, Cliver SP, Biasini F et al (2008) Early
birth the antibiotic treatment of parturient with preterm birth: association between in utero exposure
vaginal GBS colonization significantly reduces to acute inflammation and severe neurodevelopmental
the risk of serious pneumonia. In preterm labor disability at 6 years of age. Am J Obstet Gynecol
without clear suspicion of bacterial infection, anti- 198:466.e1–466.e11
Anthony D, Dempster R, Fearn S et al (1998) CXC
biotic treatment has no detectable benefit (Hutzal chemokines generate age-related increases in
et al. 2008). neutrophil-mediated brain inflammation and
Treatment of the high-risk infants colonized by blood–brain barrier breakdown. Curr Biol 8:923–926
Ureaplasma has been suggested. Further random- Been JV, Zimmermann LJ (2009) Histological chorioam-
nionitis and respiratory outcome in preterm infants.
ized trials and studies on potential harmful effects Arch Dis Child Fetal Neonatal Ed 94:F218–F225
of azithromycin and other macrolides are required Benirschke K, Burton GJ, Baergen RN (2011) Infectious
to demonstrate that antimicrobial treatment erad- diseases: specific microorganisms. In: Benirschke K,
icates Ureaplasma spp. and decreases the risk of Burton GJ, Baergen RN (eds) Pathology of the human
placenta. Springer, Berlin/Heidelberg, pp 575–655
BPD (Nair et al. 2014). Benirschke K, Burton GJ, Baergen RN (2012) Pathology
According to a number of observational stud- of the human placenta, 6th edn. Springer, Berlin/Hei-
ies of infants born very preterm, antenatal corti- delberg, pp 27–39, 41–53, 180–190, 355–366
costeroid in HCA is associated with decreased Bracci R, Buonocore G (2003) Chorioamnionitis: a risk factor
for fetal and neonatal morbidity. Biol Neonate 83:85–96
neonatal deaths, lowered incidence of RDS, Bry K, Lappalainen U, Hallman M (1997) Intraamniotic
PDA, and IVH (all grades), periventricular interleukin-1 accelerates surfactant protein synthesis in
leukomalacia, and neonatal seizures. In infants fetal rabbits and improves lung stability after premature
with same gestation and without HCA, the bene- birth. J Clin Invest 99:2992–2999
Cimic A, Baergen R (2015) Meconium-associated umbilical
fits associated with glucocorticoid were less strik- vascular myonecrosis: correlations with adverse outcome.
ing. In clinical CA, antenatal corticosteroid was Pediatr Dev Pathol. 2015 Oct 22. [Epub ahead of print].
associated with a decrease in the risk of intracere- https://doi.org/10.2350/15-06-1660-OA
bral complications (all grades of IVH and Doyle LW1, Crowther CA, Middleton P et al (2009) Mag-
nesium sulphate for women at risk of preterm birth for
periventricular leukomalacia) (Hallman 2015). neuroprotection of the fetus. Cochrane Database Syst
According to a meta-analysis of randomized Rev CD004661. https://doi.org/10.1002/14651858.
trials, magnesium sulfate decreases the risk of CD004661.pub3
CP among preterm infants (Doyle et al. 2009). Goffinet F (2005) Primary predictors of preterm labour.
BJOG 112(Suppl 1):38–47
However, according to post hoc analysis of pre- Goldenberg RL, Culhane JF (2003) Infection as a cause of
term infants born at week 24 or later with clinical preterm birth. Clin Perinatol 30:677–700
CA, magnesium sulfate did not protect against CP, Goldenberg RL, Hauth JC, Andrews WW (2000) Intrauter-
neurodevelopmental delay or deaths, or the risk of ine infection and preterm delivery. N Engl J Med
342:1500–1507
CP in the cohort of 396 children (Kamyar Gordon A, Lahra M, Raynes-Greenow C, Jeffery H (2011)
et al. 2015). Histological chorioamnionitis is increased at extremes of
gestation in stillbirth: a population-based study. Infect
Dis Obstet Gynecol 456728. https://doi.org/10.1155/
2011/456728
References Gravett MG, Hummel D, Eschenbach DA, Holmes KK
(1986) Preterm labor associated with subclinical amni-
Aikio O, Metsola J, Vuolteenaho R et al (2012) Transient otic fluid infection and with bacterial vaginosis. Obstet
defect in nitric oxide generation after rupture of fetal Gynecol 67:229–237
membranes and responsiveness to inhaled nitric oxide Hagberg H, Mallard C, Ferriero DM et al (2015) The role
in very preterm infants with hypoxic respiratory failure. of inflammation in perinatal brain injury. Nat Rev
J Pediatr 161:397–403 Neurol 11:192–208
Andrews WW, Goldenberg RL, Faye-Petersen O Hallman M (2015) The story of antenatal steroid therapy
et al (2006) The Alabama Preterm Birth study: poly- before preterm birth. Neonatology 107:352–357
morphonuclear and mononuclear cell placental infiltra- Hallman M, Bry K, PitkPitk O (1989) Ceramide
tions, other markers of inflammation, and outcomes in lactoside in amniotic fluid: high concentration in
104 M. Hallman and T. Kaukola
chorioamnionitis and in preterm labor. Am J Obstet Paananen R, Husa AK, Vuolteenaho R et al (2009) Blood
Gynecol 161:313–318 cytokines during the perinatal period in very preterm
Heller DS, Moorehouse-Moore C, Skurnick J, Baergen RN infants: relationship of inflammatory response and
(2003) Second-trimester pregnancy loss at an urban bronchopulmonary dysplasia. J Pediatr 154:39–43.e3
hospital. Infect Dis Obstet Gynecol 11:117–122 Redline RW (2007) Villitis of unknown etiology:
Himmelmann K, Uvebrant P (2014) The panorama of noninfectious chronic villitis in the placenta. Hum
cerebral palsy in Sweden. XI. Changing patterns Pathol 38:1439–1446
in the birth-year period 2003–2006. Acta Paediatr Romano-Keeler J, Weitkamp JH (2015) Maternal influ-
103(6):618–624 ences on fetal microbial colonization and immune
Hutzal CE, Boyle EM, Kenyon SL et al (2008) Use of development. Pediatr Res 77:189–195
antibiotics for the treatment of preterm parturition and Rounioja S, R€as€anen J, Ojaniemi M et al (2005) Mecha-
prevention of neonatal morbidity: a metaanalysis. Am J nism of acute fetal cardiovascular depression after
Obstet Gynecol 199:620.e1–620.e8 maternal inflammatory challenge in mouse. Am J
Jobe AH, Newnham JP, Willet KE et al (2000) Effects of Pathol 166:1585–1592
antenatal endotoxin and glucocorticoids on the lungs of Sacco G, Carmagnola D, Abati S et al (2008) Periodontal
preterm lambs. Am J Obstet Gynecol 182:401–408 disease and preterm birth relationship: a review of the
Kamyar M, Manuck TA, Stoddard GJ et al (2015) Magne- literature. Minerva Stomatol 57:233–246, 246–250
sium sulfate, chorioamnionitis, and neurodevelopment Saccone G, Berghella V (2015) Antibiotic prophylaxis for
after preterm birth. BJOG https://doi.org/10.1111/ term or near-term premature rupture of membranes:
1471-0528.13460. [Epub ahead of print] metaanalysis of randomized trials. Am J Obstet
Kaukola T, Satyaraj E, Patel DD et al (2004) Cerebral palsy Gynecol 212:627.e1–627.e9
is characterized by protein mediators in cord serum. Salafia CM, Weigl C, Silberman L (1989) The prevalence
Ann Neurol 55:186–194 and distribution of acute placental inflammation in
Kaukola T, Herva R, Perhomaa M et al (2006) Population uncomplicated term pregnancies. Obstet Gynecol
cohort associating chorioamnionitis, cord inflamma- 73:383–389
tory cytokines and neurologic outcome in very preterm, Sellier E, Platt MJ, Andersen GL et al (2015) Surveillance
extremely low birth weight infants. Pediatr Res of Cerebral Palsy Network. Decreasing prevalence in
59:478–483 cerebral palsy: a multi-site European population-based
Kaukola T, Tuimala J, Herva R et al (2009) Cord study, 1980 to 2003. Dev Med Child Neurol. https://
immunoproteins as predictors of respiratory outcome in doi.org/10.1111/dmcn.12865. [Epub ahead of print]
preterm infants. Am J Obstet Gynecol 200:100.e1–100.e8 Soraisham AS, Singhal N, McMillan DD, Sauve RS, Lee SK
Kenyon S, Boulvain M, Neilson JP (2013) Antibiotics for (2009) Canadian Neonatal Network. A multicenter study
preterm rupture of membranes. Cochrane Database on the clinical outcome of chorioamnionitis in preterm
Syst Rev 12, CD001058. https://doi.org/10.1002/ infants. Am J Obstet Gynecol 200:372.e1–372.e6
14651858.CD001058.pub3 Speer CP (1999) Inflammatory mechanisms in neonatal
Kim MJ, Romero R, Kim CJ et al (2009) Villitis of chronic lung disease. Eur J Pediatr 158(Suppl 1):
unknown etiology is associated with a distinct pat- S18–S22
tern of chemokine up-regulation in the feto-maternal Thébaud B, Abman SH (2007) Bronchopulmonary dyspla-
and placental compartments: implications for con- sia: where have all the vessels gone? Roles of angio-
joint maternal allograft rejection and maternal anti- genic growth factors in chronic lung disease. Am J
fetal graft-versus-host disease. J Immunol 182: Respir Crit Care Med 175:978–985
3919–3927 Thomas W, Speer CP (2011) Chorioamnionitis: important
Kramer BW, Kallapur S, Newnham J, Jobe AH (2009) risk factor or innocent bystander for neonatal outcome?
Prenatal inflammation and lung development. Semin Neonatology 99:177–187
Fetal Neonatal Med 14:2–7 Watterberg KL, Demers LM, Scott SM, Murphy S (1996)
Lee J, Croen LA, Backstrand KH et al (2005) Maternal and Chorioamnionitis and early lung inflammation in
infant characteristics associated with perinatal arterial infants in whom bronchopulmonary dysplasia
stroke in the infant. JAMA 293:723–729 develops. Pediatrics 97:210–215
McElrath TF, Hecht JL, Dammann O et al (2008) Preg- Wu YW (2002) Systematic review of chorioamnionitis and
nancy disorders that lead to delivery before the 28th cerebral palsy. Ment Retard Dev Disabil Res Rev
week of gestation: an epidemiologic approach to clas- 8:25–29
sification. Am J Epidemiol 168:980–989 Wu YW, Escobar GJ, Grether JK et al (2003) Chorioam-
Nair V, Loganathan P, Soraisham AS (2014) Azithromycin nionitis and cerebral palsy in term and near-term
and other macrolides for prevention of infants. JAMA 290:2677–2684
bronchopulmonary dysplasia: a systematic review and Yoon BH, Romero R, Park JS et al (2000) The relationship
meta-analysis. Neonatology 106:337–347 among inflammatory lesions of the umbilical cord
Neufeld MD, Frigon C, Graham AS, Mueller BA (2005) (funisitis), umbilical cord plasma interleukin 6 concen-
Maternal infection and risk of cerebral palsy in term tration, amniotic fluid infection, and neonatal sepsis.
and preterm infants. J Perinatol 25:108–113 Am J Obstet Gynecol 183:1124–1129
Diagnosis of Fetal Distress
7
Silvia Vannuccini, Caterina Bocchi, Filiberto Maria Severi, and
Felice Petraglia
Contents
7.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
7.2 Fetal Distress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
7.2.1 Fetal Oxygenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
7.3 Clinical Diagnosis of Fetal Distress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
7.3.1 Antenatal Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
7.4 Antepartum Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
7.4.1 Biophysical Profile (BPP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
7.4.2 Cardiotocography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
7.4.3 Doppler Examination of Fetal and Placental Circulation . . . . . . . . . . . . . . . . . . . . . . 115
7.5 During Labor Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
7.5.1 Identification of Fetal Distress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
7.5.2 Monitoring of Fetal Heart Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
7.5.3 Monitoring of Fetal Oxygenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Abstract because neurological damage may occur
Fetal distress is a very broad term, which can when the fetal brain is deprived of oxygen.
be used in many clinical situations. Although Antepartum fetal testing is used to assess hyp-
it is difficult to give a precise clinical defini- oxia in high-risk pregnancies and monitoring
tion, obstetricians usually use this term to during labor supplies information on the sta-
indicate that the fetus is becoming hypoxic. tus of the fetus prior to birth. However,
Immediate delivery has to be considered, knowledge of the fetal responses to asphyxia,
together with the known evolution of fetal
heart rate patterns, should allow a more accu-
rate definition of its onset and a more rational
management and timing for intervention.
S. Vannuccini · C. Bocchi · F. M. Severi (*) · F. Petraglia
Obstetrics and Gynecology, Department of Molecular and
Developmental Medicine, University of Siena, Siena, Italy
e-mail: [email protected]; caterina.
[email protected]; fi[email protected]; felice.
[email protected]
# Springer International Publishing AG, part of Springer Nature 2018 105
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_156
106 S. Vannuccini et al.
7.1 Salient Points Transfer of oxygen to the fetus during labor may
be altered by various mechanisms, leading to hyp-
• Fetal distress is a broad term used in many oxic changes and acidosis, such as abnormal perfu-
clinical situations. A precise clinical definition sion within the uteroplacental vasculature or
is difficult and usually indicates that the fetus is compression of the spiral arteries or umbilical cord
becoming hypoxic. during contractions (Leung and Lao 2012). In addi-
• Hypoxia may result from reduced placental per- tion, pregnancy complications, such as hypertensive
fusion due to low pO2 in maternal blood (hyp- disorders, diabetes mellitus (DM), inflammatory
oxemic hypoxia), reduced arterial blood oxygen diseases, chorioamnionitis, preterm labor, and fetal
content due to low fetal hemoglobin concentra- growth restriction (FGR), all may further exaggerate
tion (anemic hypoxia), or reduced blood flow to the compromised blood supply to the fetus during
the fetal tissues (ischemic hypoxia). labor. In an attempt to prevent hypoxic–ischemic
• The identification of at-risk pregnancies and morbidities to the neonate, non-reassuring fetal
their surveillance are currently of high priority heart rate monitoring during labor is one of the
in obstetric practice. Fetal distress and major indications for prompt delivery by
antepartum death can be substantially reduced performing an emergent cesarean delivery.
if fetal surveillance is aimed at the early detec- However, the recognition of risk and the
tion of signs of fetal oxygen deprivation. knowledge of the fetal responses to asphyxia,
• Cardiotocography, Doppler examination of fetal together with the known evolution of fetal heart
and placental circulations, biophysical profile, rate patterns, should allow a more accurate defi-
and amniotic fluid evaluation are various nition of its onset and a more rational management
antepartum tests that allow clinicians to evaluate and timing for intervention. Antepartum fetal test-
fetal oxygenation and fetal well-being. ing is used to assess hypoxia in high-risk preg-
nancies and monitoring during labor supplies
information on the status of the fetus prior to
7.2 Fetal Distress birth (Everett and Peebles 2015).
Fetal distress is a very broad term, which can be
used in many clinical situations. Although it is 7.2.1 Fetal Oxygenation
difficult to give a precise clinical definition,
obstetricians usually use this term to indicate 7.2.1.1 Physiology
that the fetus is becoming hypoxic (Cunningham Oxygenation may be defined as the process of
et al. 2001). Low fetal oxygenation may lead to transporting molecular oxygen from air to the
neonatal morbidity and mortality. Immediate tissues of the body. In the fetus this first involves
delivery has to be considered, because neurolog- oxygen transfer across the placenta; then there is
ical damage may occur when the fetal brain is reversible binding of oxygen to fetal hemoglobin
deprived of oxygen (Weiner et al. 2015). and transport in the fetal blood stream and, finally,
The diagnosis of fetal distress based upon heart oxygen consumption for growth and metabolism.
rate is imprecise, because heart rate patterns are Energy is derived from the combination of oxygen
only a reflection of the efficiency of physiological and glucose to form carbon dioxide and water.
mechanisms which depend on blood flow and oxy- When there is inadequate oxygen supply, the
genation. Furthermore, activity of this control Krebs cycle cannot operate and pyruvate is
mechanism is influenced by the preexisting state converted to lactic acid. This enters the blood
of fetal oxygenation as with chronic placental insuf- and there is a systemic acidosis, unless it is either
ficiency. In fact, fetal hypoxia can occur acutely, for metabolized or excreted. Removal of carbon diox-
instance, as a result of placental abruption, but more ide and protection against acidosis is the reverse
commonly from chronic deterioration of placental mechanism of oxygen delivery through the rapid
function (Everett and Peebles 2015). diffusion, high solubility, and volatility of carbon
7 Diagnosis of Fetal Distress 107
dioxide. In the adult, carbon dioxide is excreted in metabolism of carbohydrates to carbon dioxide
the lungs while bicarbonate and hydrogen ions are (CO2) and water is impaired and metabolism pro-
removed by the kidney. In the fetus, both these ceeds along an anaerobic pathway with produc-
functions are carried out by the placenta (Cun- tion of organic acids, such as lactic acid, which are
ningham et al. 2001). not readily excreted or metabolized. Accumula-
Normal fetal metabolism results in the produc- tion of lactic acid can deplete the buffer system,
tion of acids (carbonic and organic), and despite resulting in metabolic acidosis (Martin 2008).
this, the extracellular pH is kept within a critical Hypoxia may result from:
range due to the efficient buffer mechanisms of
the blood system. This is because the functions of 1. Reduced placental perfusion with maternal
the various fetal organ systems, such as the central blood and a consequent decrease in fetal arte-
nervous system and the cardiovascular system, rial blood oxygen content due to low pO2
may be significantly affected by very small (hypoxemic hypoxia)
changes in pH. The major buffers utilized by the 2. Reduced arterial blood oxygen content due to
fetus for neutralizing hydrogen ion production are low fetal hemoglobin concentration (anemic
plasma bicarbonate and hemoglobin. Inorganic hypoxia)
phosphates and erythrocyte bicarbonate are also 3. Reduced blood flow to the fetal tissues (ische-
potential buffers, although they play a lesser mic hypoxia) (Cunningham et al. 2001)
role in fetal acid–base hemostasis. The amount
of oxygen bound to hemoglobin is not linearly Reduced fetal oxygenation may result from a
related to oxygen tension (pO2). Each type of variety of sources (Table 1) (Regnault et al. 2007).
hemoglobin has a characteristic oxygen dissocia-
tion curve which can be modified by various fac-
Table 1 Causes of reduced fetal oxygenation
tors, such as pH and the concentration of
2,3-diphosphoglycerate (2,3-DPG). For example, Maternal Respiratory insufficiency
when 2,3-DPG rises in response to anemia or Hypotension
Hypertension
hypoxia, it binds to and stabilizes the deoxygen-
Shock
ated form of hemoglobin, resulting in a shift of the
Asthma/bronchospasm
oxygen dissociation curve to the right and there-
Diabetes
fore release of oxygen to the tissues. Although,
Collagen/vascular disease
in vitro, both adult (HbA) and fetal (HbF) hemo-
Hematological disorders
globins have the same oxygen dissociation Hemolytic crisis
curves, adult human blood has a lower affinity Congenital heart diseases
for oxygen than fetal blood because of its greater Placental Abruptio placentae
binding to 2,3-DPG. The higher affinity of fetal Infarction
blood for oxygen helps the transplacental transfer Confined mosaicism
of oxygen. Furthermore, since the P50 of fetal Placenta previa
blood is similar to the umbilical arterial pO2, the Uterine Rupture
fetus operates over the steepest part of the hemo- Hyperstimulation
globin oxygen dissociation curve, and, therefore, Prolonged labor
a relatively large amount of oxygen is released Fetal Arrhythmia
from the hemoglobin for any given drop in pO2 Hydrops
(Cunningham et al. 2001). Myocarditis
Congenital abnormality
Umbilical cord Funicular loop
Compression
7.2.1.2 Hypoxia
Prolapse
Fetal hypoxia is a condition characterized by oxy-
Vasa previa bleeding
gen deficiency in the tissues. Complete oxidative
108 S. Vannuccini et al.
According to placenta role, hypoxic pregnancy trophoblast invasion of the myometrium in early
conditions can be classified into three subtypes: pregnancy, leading to reduced perfusion of the
(1) preplacental hypoxia, where both the mother intervillous spaces. Finally, even with normal pla-
and her fetus will be hypoxic (i.e., high-altitude and cental function, chronic conditions within the
cyanotic maternal heart diseases); (2) uteroplacental fetus can cause acidosis. Anemia from rhesus
hypoxia, where the maternal oxygenation is normal disease, parvovirus infection, thalassemia, or
but the uteroplacental circulation is impaired (i.e., feto-maternal hemorrhage, when severe enough
preeclampsia, placentar insufficiency, etc.); and to reduce fetal hemoglobin concentrations below
(3) postplacental hypoxia, where only the fetus is 40 g/l (equivalent to an oxygen content below
hypoxic (Kingdom and Kaufmann 1997). 2 mmol/l), can lead to a fall in pH. Arteriovenous
Predisposing conditions that may result in shunting in fetal tumors, serious cardiac structural
fetal acid–base status derangement might be abnormalities, or arrhythmias are other conditions
classified as either acute or chronic clinical con- which can lead to chronic acidosis by decreased
ditions of the mother, placenta, and/or fetus oxygenation as a result of reduced feto-placental
(Omo-Aghoja 2014). blood flow (Omo-Aghoja 2014) (Table 1).
Acute maternal conditions may include any
clinical situation that causes hypotension or Fetal Acid–Base Balance in Hypoxia
hypovolemia such as hemorrhage, a vasovagal Hypoxia in fetuses is potentially very hazardous
attack, or epidural anesthesia, with a resultant with an adverse outcome for the neonate because
reduction of maternal blood supply and therefore the fetus normally has a very low PaO2 (approxi-
oxygen delivery to the uterus. Uterine contractions mately 35 mmHg in the umbilical vein) and high
can also interrupt uterine blood flow by a pressure PaCO2 (approximately 42 mmHg in the umbilical
rise and if prolonged, as in hypertonus, may cause vein) (Pipkin 1999). The inherent response there-
hypoxia and acidosis. Acute placental factors, on fore is preferential redistribution of blood to vital
the other hand, include conditions such as abrup- organs, and hence in acute severe fetal hypoxemia,
tion that usually result in the disruption of the there is associated and sustained maintenance of
uteroplacental circulation by separating and tearing blood flow to the brain, the adrenal gland, and the
the uterine spiral arteries from the placenta. Simi- heart at the expense of other tissues. This results in
larly, the blood flow from the placenta to the fetus is activation of peripheral chemoreceptors, with an
often affected during labor and delivery by the increase in sympathetic tone, and in later gestation
umbilical cord compression; this can sometimes there is also an increase in concentrations of circu-
happen before labor if there is reduced liquor or a lating cortisol, catecholamines, angiotensin II, and
true knot in the cord. However, there is significant vasopressin, with a resultant increase in peripheral
reserve because the fetus can compensate by resistance. Following severe hypoxia, there is a
increased oxygen extraction, meaning blood flow shift to anaerobic pathways of metabolism as the
to the fetus must be reduced by at least 50% to “deprived” tissues may not be able to maintain
cause hypoxia (Omo-Aghoja 2014). oxidative phosphorylation. Since the fetus has a
Chronic clinical conditions that have been lesser ability to cope with acid–base disturbances,
associated with fetal acid–base derangement may lactic acidemia can rapidly develop. This shifts the
also be maternal, placental, or fetal. Maternal oxyhemoglobin dissociation curve to the right,
causes of chronic fetal acidosis include reduced with a further reduction in blood O2 content.
oxygenation of maternal blood, as in severe respi- Thus, the resulting vicious circle can quickly result
ratory or cardiac disease, or reduced blood flow to in fetal death. The fetal oxyhemoglobin dissocia-
the placenta, as in connective tissue diseases – for tion curve is left shifted in comparison with the
example, systemic lupus erythematosus – and mother’s because fetal hemoglobin has a lower
preeclampsia. Chronic placental factors usually binding affinity for 2,3-diphosphoglycerate. The
result from impairment of placental transfer of fetus has a high hemoglobin concentration (16 g/
oxygen. This is thought to result from inadequate dl), which also contributes to the relatively high
7 Diagnosis of Fetal Distress 109
oxygen content. The low umbilical PaO2 and fetal the emergence of fetal distress. The final stage is
vasculature pO2 means that although umbilical characterized by a decline in systolic and diastolic
venous blood is approximately 85% saturated fetal cardiac function, secondary to myocardial
(compared with approximately 95% in the adult) ischemia. Moreover, raised atrial contraction results
and has a relatively high oxygen content, the steep in the transmission of atrial pressure waves into the
dissociation curve allows adequate oxygen venous duct and umbilical vein, causing
unloading to the tissues. The high fetal blood end-diastolic umbilical vein pulsation. At this
flow allows equivalent or higher oxygen deliveries stage, reduced or reversed end-diastolic flow veloc-
compared with adults to most tissue beds. How- ity may also be found in pulmonary veins, and
ever, it appears that fetal PaO2 varies inversely with coronary blood flow may become visible with
oxygen consumption, as the capacity to increase increased systo-diastolic flow velocities (“heart
oxygen uptake from the lungs is absent. sparing”). If not delivered, intrauterine death occurs
Fetal PaCO2 is high with approximately 60% usually within a few days (Hutter et al. 2010).
being carried as bicarbonate. As fetal blood is
oxygenated, it releases hydrogen ions, which
combine with bicarbonate and push the equilib- 7.3 Clinical Diagnosis of Fetal
rium toward CO2 and H2O which diffuse Distress
across the placenta, down the concentration gra-
dient for CO2. 7.3.1 Antenatal Surveillance
During hypoxia, the fetal pCO2 rises, increasing
the level of H2CO3 in the fetal blood and giving rise 7.3.1.1 Identification of a Fetus at High
to a respiratory acidosis and a fall in the blood Risk of Distress
pH. The combination of hypoxia, hypercapnia, The identification of at-risk pregnancies and their
and metabolic acidosis constitutes asphyxia. At surveillance are currently of high priority in
any given level of oxygen depletion, the survival obstetric practice. Fetal distress and antepartum
time of the hypoxic fetus will depend primarily on death can be substantially reduced if fetal surveil-
its glycogen reserve. Thus, the well-nourished lance is aimed at the early detection of signs of
fetus can be expected to withstand a standard hyp- fetal oxygen deprivation.
oxic insult better than the growth-retarded fetus. Comprehensive assessment of fetal well-being
involves monitoring of fetal growth, placental
Hemodynamic Consequences to Hypoxia function, central venous pressure, and cardiac func-
At an initial stage, the human fetus may be able to tion. Ultrasound evaluation of the fetus using 2D,
adapt to hypoxia by increasing the blood supply to color Doppler, and pulse-wave Doppler techniques
the brain, myocardium, and upper body and forms the foundation of antenatal diagnosis of
decreasing the perfusion of the kidneys, gastroin- structural anomalies, rhythm abnormalities, and
testinal tract, and lower extremities. This redistri- altered fetal circulation. Accurate and timely pre-
bution of blood allows preferential delivery of natal identification of the fetus at risk is critical for
nutrients and oxygen to the most vital organs. appropriate parental counseling, antenatal diagnos-
Cerebral vasodilatation to spare the brain from tic testing, consideration for fetal intervention, peri-
hypoxic damage leads to a decrease in left ven- natal planning, and coordination of postnatal care
tricular afterload, while systemic arterial vasocon- delivery (Pruetz et al. 2015).
striction of lower body vessels increases right Ultrasound imaging has helped with detection
ventricular afterload. of the vulnerable fetus. The purposes of ultraso-
In fact, an increased middle cerebral artery blood nography studies are (i) to have accurate preg-
flow and a shift of the cardiac output in favor of the nancy dating, to diagnose multiple pregnancies,
left ventricle are shown. With further deterioration and to detect fetal anomalies and (ii) to monitor
of the fetal oxygenation, this protective mechanism fetal growth and to recognize small for gestational
is overwhelmed by the decline in cardiac output and age (SGA) and growth-restricted (FGR) fetuses
110 S. Vannuccini et al.
Fig. 1 Reduced fetal
growth: etiopathogenesis Small for gestational
age (SGA)
Genetic predisposition Pathological factors
75–80% (FGR)
No perinatal risk 20–25%
Utero-placental dysfunction 75–80% Intrinsic causes
(15-20% of the total) 15–20%
Very high perinatal risk (5–10% of the total)
who may be more susceptible to the damaging Table 2 Second trimester: accuracy of multiple parame-
effects of fetal hypoxia. ters in the determination of gestational age
It is not always easy to decide whether a fetus is Weeks BPD HC FL
SGA as a result of genetic causes or if it suffers 12–18 1.19 1.19 1.38
from placental insufficiency and malnutrition 19–24 1.73 1.48 1.80
(fetal growth restriction [FGR]) (Fig. 1), but it is 25–30 2.18 2.06 2.08
important to detect fetuses who did not reach their
growth potential because these fetuses are at sig-
nificant risk of hypoxia, acidosis, and death. This measured obtained by ultrasound has been shown as
condition is also a common cause of premature the best parameter during the first trimester (accu-
delivery, is associated with increased perinatal racy: 5–7 days). This measurement can be made
mortality and morbidity, and is considered synon- between 6 and 13 weeks and gives a very accurate
ymous of “chronic fetal distress.” estimation of the gestational age.
If FGR is suspected, it is important to perform The use of multiple parameters (biparietal
an ultrasound biometric evaluation of the fetus as diameter [BPD], head circumference [HC], trans-
early as possible and then to follow fetal growth verse cerebellum diameter [TCD]) is generally
with serial and repeated (every 2 weeks) ultra- recommended for the determination of gestational
sound investigations. age in the second trimester (Table 2).
Before assessing fetal size, it is necessary to To assess if a fetus has normal growth, the
make an accurate assessment of gestational age. following fetal biometry is used:
1. BPD and HC.
Determination of Gestational Age
2. Abdominal circumference (AC), which is the
and Assessment of Fetal Size
most important measurement in the second half
The accurate assessment of gestational age is very
of pregnancy; it reflects fetal size and weight
important in everyday clinical practice. Fetal body
rather than age [ 3].
measurements reflect the gestational age of the fetus.
3. Femur length (FL), which reflects longitudinal
This is particularly true in early gestation (first and
growth of the fetus.
early second trimester). In patients with an uncertain
last menstrual period, biometric measurements must Repeated measurement of AC is considered
be made as early as possible to date the pregnancy the most sensitive parameter for following fetal
accurately. The embryo crown–rump length (CRL) growth (Table 3).
7 Diagnosis of Fetal Distress 111
When the suspicion of FGR is confirmed, 7.4.1 Biophysical Profile (BPP)
fetal surveillance, placental function, and fetal
behavior measurements should be initiated, and The biophysical profile (BPP) combines the use of
fetal growth should be followed longitudinally CTG with the ultrasound assessment of fetal
with other diagnostic methods (see section movement, fetal tone, fetal breathing movements,
“Antepartum Testing”). and amniotic fluid volume. Each parameter is
scored 0 (abnormal) or 2 (normal) points, with a
7.3.1.2 Identification of Fetal Distress maximum total score of 10 (Table 4). A normal
Fetal distress may be discovered in pregnancy score (8) is reassuring and has a high negative
(“antepartum testing”) or during labor and predictive value and is associated with a low still-
delivery (“intrapartum testing”) using different birth rate (0.8%). A score below 6 is not
approaches. reassuring and is considered borderline. The test
may be repeated as often as daily until delivery,
although most often it is a onetime event or a
7.4 Antepartum Testing weekly event depending on the reason for the
biophysical profile. The test is time consuming
There are various tests that allow clinicians to and labor intensive, but a modified BPP (deepest
evaluate fetal oxygenation and fetal well-being. pool of amniotic fluid and CTG assessment) has
These are described below. been shown to have a similar negative predictive
value as a full BPP (Lalor et al. 2012).
Table 3 SGA: ultrasound diagnostic accuracy Described for the first time by Manning, the
BPP is widely used for antepartum fetal surveil-
Ultrasound Sensitivity Specificity
parameters (range) (%) (range) (%) lance (Manning 1999; Thompson et al. 2012). It
Abdominal 67–86 80–92 can be done in the later stages of pregnancy from
circumference the beginning of the third trimester. The test is
Ratio among 62–82 80–93 more frequently used in cases where the preg-
biometrical nancy is over 40 weeks to ensure fetal well-
parameters
being; in some cases it is performed because of
Fetal weight 64–83 79–96
the presence of high-risk factors. However, a
estimation (FWE)
recent Cochrane review concluded that there is
Table 4 Fetal biophysical profile
Biophysical
variable Normal (score = 2) Abnormal (score = 0)
Fetal tone One or more episodes of active extension with return to Slow extension with return to partial
flexion of fetal limb(s) or trunk (opening and closing of flexion, movement of limb in full
hand considered normal tone) extension, absent fetal movement, or
partially open fetal hand
Gross body Two or more discrete body/limb movements within <2 episodes of body/limb movements
movements 30 min (episodes of active continuous movement within 30 min
considered as a single movement)
Fetal breathing One or more episodes of 20 s within 30 min Absent or no episode of 20 s within
movements 30 min
Qualitative One or more pockets of fluid measuring 2 cm in Either no pockets or largest pocket <2 cm
amniotic fluid vertical axis in vertical axis
volume
Fetal heart rate Two or more episodes of acceleration of 15 bpm and One or more episodes of acceleration of
(FHR) of >15 s associated with fetal movement within 20 min fetal heart rate or acceleration of <15 bpm
within 20 min
Modified from Manning (1999)
112 S. Vannuccini et al.
insufficient evidence to support the use of BPP fetal rectum. This investigation is no longer used
in high-risk pregnancies. The review also as often as it was in the past.
highlighted the possible risks of increased inter-
vention (induction of labor and cesarean section)
against the paucity of evidence of benefit in fetal 7.4.2 Cardiotocography
or neonatal outcomes (Lalor et al. 2008).
Cardiotocography (CTG) is the recording
7.4.1.1 Amniotic Fluid Evaluation (-graphy) of the fetal heartbeat (cardio-) and the
Amniotic fluid volume is an important parameter uterine contractions (-toco-). Recordings are done
for the assessment of fetal well-being. It is a using two separate transducers, one for the mea-
reflection of placental perfusion and normal fetal surement of the fetal heart rate and the other for
blood flow from the placenta and may be measuring uterine contractions.
decreased when there are factors causing growth The CTG trace shows two lines: the upper
restriction (Chauhan et al. 2007). shows the fetal heart rate in beats per minute; the
Although an experienced examiner can lower is a recording of uterine contractions. Inter-
assess the adequacy of the amniotic fluid vol- pretation of the results of the monitoring is com-
ume, an amniotic fluid index (AFI) has been plex, and different patterns can be seen on a CTG
developed to standardize this assessment. This (American College of Obstetricians and Gynecol-
index is obtained by calculating the sum of ogists 2009).
deepest pocket of amniotic fluid in each of the
four quadrants of the uterus. Another technique 1. Baseline rate. The baseline rate should be
is the vertical measurement of the major pocket between 110 and 150 beats per minute (bpm)
(Manning technique: cutoff 10 mm) (Manning and is measured when the fetal heart rate is
2009). stable (i.e., without accelerations and deceler-
During the third trimester, normal amniotic ations). It should be taken over a period of
fluid correlates with an AFI of 10–20 cm. Border- 5–10 min. The rate may change over a period
line values are 5–10 cm for decreased fluid and of time but normally remains fairly constant.
20–24 cm for increased fluid depths (Hebbar 2. Bradycardia. This is defined as a baseline heart
et al. 2015). Pregnancies with decreased amniotic rate of less than 110 bpm. A suspicious brady-
fluid volume are an indication for additional sur- cardia is defined as being between 110 and
veillance and assessment. For some authors, pro- 100, whereas a pathological pattern is below
spective evaluation of amniotic fluid index alone 100. A steep sustained decrease in fetal heart
in low-risk pregnancies does not seem to be a rate is indicative of fetal distress.
good predictor of complications during a preg- 3. Tachycardia. A suspicious tachycardia is defined
nancy or the perinatal period, but others consider when the FHR is between 150 and 170 bpm,
that reduced amniotic fluid volume indicates whereas a pathological pattern is above 170 bpm.
chronic oxygen deficiency: perinatal mortality in Tachycardias can be a response to fever, fetal
pregnancies with oligohydramnios is 50 times infection, fetal movements, tocolytic drugs, and
higher than in pregnancies with normal AFI (Ott use of tea or coffee and occasionally a sign of
2005; Morris et al. 2014). fetal distress (in conjunction with other abnor-
malities). An epidural may also induce a tachy-
7.4.1.2 Amnioscopy cardia in the fetus.
At term, it is possible to visualize the amniotic 4. Baseline variations. The short-term variations
fluid color using amnioscopy. If it is clear, the in the baseline should be between 10 and
liquor is considered normal; if it is colored, there 15 bpm (except during fetal sleep, which
is a possibility of fetal distress because during should be no longer than 60 min). Prolonged
fetal hypoxia there is an increase in fetal intestinal reduced variability along with other abnormal-
peristalsis with the release of meconium from the ities may indicate fetal distress.
7 Diagnosis of Fetal Distress 113
5. Accelerations. This is a transient increase in decelerations lasting more than 2 min but less
the fetal heart rate of greater than 15 bpm for than 10 min, recurrent late decelerations with
at least 15 s. Two accelerations in 20 min are moderate variability, and variable decelera-
required for the trace to be considered “reac- tions with other characteristics such as slow
tive,” i.e., normal. Accelerations are a good return to baseline, overshooting the baseline,
sign as they show fetal responsiveness and or “shoulders.” Reduced FHR variability is the
the integrity of mechanisms controlling the most reliable indicator of fetal compromise. A
heart rate. flat FHR tracing with no variability may reflect
6. Decelerations. These may either be normal or neurologic damage to the fetus that has already
pathological. Early decelerations occur at the occurred.
same time as uterine contractions and are usu- 3. Category III FHR tracings are abnormal and
ally due to fetal head compression and there- indicative of hypoxic risk to the fetus and
fore occur during the first and second stages of possible acidemia. They include either no
labor with descent of the head. They are nor- baseline variability or the presence of recur-
mally benign. Late decelerations begin after rent late decelerations, variable decelera-
the start of a contraction and persist after the tions, bradycardia, or a sinusoidal pattern.
end of a contraction and suggest fetal distress. According to a study by Jackson et al., Cat-
Variable decelerations vary in timing and shape egory I and Category II patterns are com-
with respect to each other and may indicate mon in labor and Category III are unusual.
hypoxia or cord compression. Perinatal morbidity is associated with an
increase in time in Category II during the
The American College of Obstetricians and last 2 h of labor.
Gynecologists (ACOG) developed a new three-
tiered classification of fetal heart rate abnormali- 7.4.2.1 Nonstress Test (NST)
ties and a system for interpreting CTG abnormal- Since its introduction during the 1970s, the
ities (American College of Obstetricians and nonstress test (NST) has remained one of the
Gynecologists 2010). cornerstones of fetal surveillance. It is based on
CTG and it reflects cardiorespiratory regulation of
1. Category I FHR tracings are normal tracings fetal heart: the monitor records fetal heart rate in
which are not associated with fetal asphyxia. conjunction with uterine activity.
They include a baseline heart rate between The purpose of NTS is to try to identify
110 and 160, moderate variability defined as potential fetal compromise as a result of placen-
“fluctuations in the baseline heart rate that are tal insufficiency and hypoxia and to take correc-
irregular in amplitude and frequency of tive action (American College of Obstetricians
6–25 bpm,” no late or variable decelerations, and Gynecologists 2010). It is used to identify
possible early decelerations, and possible signs of fetal distress in all situations in which
accelerations. pregnancy complications may cause harm to the
2. Category II FHR tracings are indeterminate fetus. It can also be performed as a precaution
and include a wide variety of possible tracings when there have been problems complicating a
that do not fit in either Category I or Category previous pregnancy or in the presence of risk
III. The classification of Category II tracings factors (e.g., diabetes, intrauterine growth
includes the following: bradycardia with vari- restriction).
ability, tachycardia, minimal variability, no The test is more frequently done between
variability with no recurrent decelerations, 38 and 42 weeks’ gestation; however, it can be
marked variability, absence of induced accel- used as early as the beginning of the third
erations even after fetal stimulation, recurrent trimester.
variable decelerations with minimal or A normal test is defined as a “reactive” pattern
moderate baseline variability, prolonged that requires a minimum of two accelerations
114 S. Vannuccini et al.
(15 bpm increase from the baseline during 15 s) of fetal heart rate during labor so as to institute
during a 20 min test. A reactive trace after timely intervention to avoid intrapartum
10–20 min is generally regarded as sufficient for hypoxic–ischemic injury. Although CTG was
normality. A “nonreactive” result suggests the initially developed as a screening tool to predict
possibility of fetal distress, requiring further fetal hypoxia, its positive predictive value for
assessment (biophysical profile, a stress test). intrapartum fetal hypoxia is approximately
The predictive value of a nonreactive NST is only 30%. Even though different international
poor when outcome parameters such as fetal classifications have been developed with the aim
death and fetal distress during labor are used. of defining combinations of features that help
A reactive test can be expected to impose a predict intrapartum fetal hypoxia, the false-
tenfold lower risk of intervention for fetal dis- positive rate of the CTG is high (60%). More-
tress during labor than a pregnancy with a over, there has not been a demonstrable
nonreactive test. There is a paucity of good- improvement in the rate of cerebral palsy or
quality evidence regarding antenatal CTG mon- perinatal deaths since the introduction of CTG
itoring. A Cochrane meta-analysis, including into clinical practice approximately 45 years
high-risk pregnancies, found no clear evidence ago. However, there has been a significant
that antenatal CTG improves perinatal outcome increase in intrapartum cesarean section and
(Grivell et al. 2015). operative vaginal delivery rates. Unfortunately,
Indeed, there are wide observer differences in existing guidelines employ the visual interpreta-
the qualitative interpretation of the FHR trace, tion of CTG based on “pattern recognition,”
and agreement between observers is low, espe- which is fraught with inter- and intra-observer
cially for decelerations, which are the most dif- variability. Therefore, clinicians need to under-
ficult pattern to interpret. For this reason, to stand the physiology behind fetal heart rate
eliminate observer variability and to increase changes and to respond to them accordingly,
the accuracy of CTG, a computerized analysis instead of purely relying on guidelines for man-
was developed by Dawes and coworkers (Dawes agement. It is very likely that such a “physiol-
et al. 1995, 1996). Nowadays, the use of ogy-based” approach would reduce unnecessary
the computerized CTG has increased the predic- operative interventions and improve perinatal
tive ability of NST for the diagnosis of outcomes while reducing the need for “addi-
fetal hypoxia during the antepartum period tional tests” of fetal well-being (Pinas and
compared with the traditional CTG – compared Chandraharan 2016).
to computer analysis, observers fail to iden-
tify 36% of FHR traces with at least one 7.4.2.2 Contraction Stress Test (CST)
deceleration. The contraction stress test may be used after a
Computerized CTG monitoring can provide nonreactive NST. This test monitors the response
assessment of short-term variability (STV), of fetal heart rate to uterine contractions. These
which cannot be performed by visual assessment contractions may occur on their own or following
alone. STV has been shown to correlate with the the administration of oxytocin.
fetal metabolic state, and significantly reduced A normal placenta has extra capacity for
STV is closely associated with fetal acidemia transporting oxygen, allowing large amounts of
(Turan et al. 2007). In addition, computerized oxygen to pass easily from the maternal to the
CTG has been shown to reduce perinatal mortality fetal circulation. If the placenta is damaged, less
compared to traditional CTG in the high-risk pop- oxygen may cross. When there are contractions,
ulation (Grivell et al. 2015). the vessels feeding the placenta are squeezed,
The use of continuous intrapartum electronic limiting the blood flow and oxygen delivery. If
fetal heart rate monitoring (EFM) using a the oxygen passage across the placenta drops
cardiotocograph was developed to enable obste- below a certain point, the fetus responds with a
tricians and midwives to analyze the changes specific type of heart rate deceleration, which
7 Diagnosis of Fetal Distress 115
occurs after the peak of a contraction and which is Table 5 The most widely used indices used for studying
known as a “late deceleration.” uteroplacental, placental, and fetal arteries
The contraction stress test is considered “pos- Doppler indices
itive” if there are regular late decelerations. When Systolic/diastolic (S/D) Systolic peak/end-diastolic
no late decelerations occur, the CST is negative, ratio velocity
and this is considered reassuring. A positive CST Resistance index (RI) S-D/S
Pulsatility index (PI) S-D/mean velocity
is a sign that the placenta may not be delivering
adequate amounts of oxygen to the fetus. Given a
positive CST, a pregnancy at term should be deliv- maternal–fetal evaluation in high-risk pregnan-
ered, although this is not necessarily appropriate cies, contributing to a reduction in perinatal mor-
for very premature pregnancies. tality (Alfirevic et al. 2013a), especially in the
Because a contraction stress test takes more management of IUGR. The jeopardized fetus
time to perform than a biophysical profile, it is seems to be at the highest risk of imminent demise
seldom done these days. when Doppler abnormalities are observed in the
arterial and especially venous circulation (ductus
7.4.3 Doppler Examination of Fetal venosus and umbilical vein). The temporal
and Placental Circulation sequence of abnormal Doppler changes in the
peripheral and central circulatory systems of the
Doppler ultrasound provides a noninvasive growth-restricted fetus has been described: early
method for the study of the fetus’s hemodynamic abnormal Doppler findings in the umbilical and
status (Everett and Peebles 2015). The application middle cerebral arteries are followed by the rever-
of Doppler to obstetrical ultrasound provides new sal of flow in the ductus venosus or pulsatile
knowledge about fetal circulatory physiology in umbilical venous flow.
health as well as in those compromised by chronic For this reason the use of Doppler velocimetry
hypoxia because of placental insufficiency. This is of great importance in high-risk pregnancies
functional assessment of fetal well-being is done and in cases of non-reassuring test results.
by observing fetal movements, breathing, muscle
tone, and heart rate. Additionally, the volume of 7.4.3.1 Uteroplacental Vessels
amniotic fluid gives an indirect assessment of the Both the uterine and other uteroplacental vessels
pregnancy. have been studied with Doppler sonography. Uter-
Investigation of the flow patterns of the uterine ine arteries are two symmetrical vessels that bring
and umbilical arteries gives information on flow the oxygenated blood of the mother to the placenta.
through the uteroplacental and feto-placental cir- There are numerous Doppler studies on uterine
culations, respectively. Doppler studies of fetal and spiral arterial flow during normal first-
organs are used to detect the hemodynamic trimester pregnancies which demonstrate a high
rearrangements that occur in response to fetal vascular resistance that progressively disappears
hypoxemia, in particular by insonnation of the during the second trimester as a consequence of
middle cerebral arteries (MCA) and ductus decreased resistance downstream. Decreasing vas-
venosus (DV). cular impedance with gestation (Fig. 2) is probably
The Doppler indices (Table 5) indirectly reflect a consequence of dilatation of spiral arteries
the impedance of the circulation downstream to induced by trophoblast infiltration, hormonally
the point of insonnation, and there is a significant mediated vasodilatation, and a decrease in mater-
association between abnormal Doppler indices nal blood flow viscosity. Thus, changes in uterine
and fetal hypoxia, fetal acidosis, and adverse peri- blood flow are correlated with the development of
natal outcome. complications in later pregnancy: if the process of
Doppler ultrasonography is not routinely trophoblastic invasion of the spiral arteries’ mus-
employed in low-risk pregnancies (Alfirevic cular walls is incomplete, the arteries are still
et al. 2015), but has been extensively used for able to respond to vasoactive stimuli, which results
116 S. Vannuccini et al.
Fig. 2 Uterine artery 0.8
resistance index
0.7 +2ds
0.6
Resistance Index (RI)
0.5
mean
0.4
0.3
–2ds
0.2
0.1
0
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
Gestation (weeks)
in vasoconstriction. In these pregnancies the populations, which does not appear to benefit the
uteroplacental circulation remains in a state of mother or baby (Alfirevic et al. 2015).
high resistance, which causes generalized endothe- Recent studies have shown that Doppler stud-
lial cell injury, compromising vascular integrity ies of the uterine arteries can be useful also during
and an atherosis-like process in the small arteries the third trimester of pregnancy: when both mid-
resulting in vessel occlusion, local ischemia, and dle cerebral artery and uterine arteries show
necrosis. As a consequence of vasoconstriction, a abnormal Doppler indices, the fetus has a signif-
chronic inadequate blood supply to the growing icantly higher rate of poor outcome even in the
placenta leads to a poor outcome (spontaneous presence of normal umbilical indices (Severi
abortion, IUGR, stillbirth, or preeclampsia). et al. 2002).
When an abnormal adaptation of pregnancy
occurs, impedance to flow increases and Doppler 7.4.3.2 Feto-placental Vessels
examination often demonstrates the presence of a The umbilical artery was the first fetal vessel to be
high-resistance index (RI) and/or the presence of evaluated by Doppler velocimetry, and Doppler
an early mono- or bilateral diastolic notch (Becker velocimetry of the umbilical artery (UA) provides
and Vonk 2010). Adverse outcomes associated a noninvasive measure of the feto-placental hemo-
with abnormal uterine artery flow velocity include: dynamic state. In the Doppler assessment of fetal
preeclampsia and fetal growth restriction and its well-being, the UA is the most easily measured
sequelae, mainly fetal distress (O’Gorman parameter and is the mainstay of assessment in
et al. 2016; Valiño et al. 2016; Savasan et al. 2014). small fetuses or those at risk of compromise
For this reason, in high-risk women, accurate (Everett and Peebles 2015; Berkley et al. 2012).
uteroplacental investigation during the first and Umbilical arteries can be identified by Doppler
second trimester of pregnancy allows the clinician ultrasound as early as 6–8 weeks, when the Dopp-
to identify, and therefore to monitor, fetuses at high ler flow velocity profile shows only a systolic
risk of distress. Through the investigation of uter- component. By 20 weeks, all fetuses should
ine artery flow in high-risk pregnancies, it has been have end-diastolic flow in the umbilical vessels.
shown that if the fetus has a normal umbilical flow, As the pregnancy progresses, placental resistance
the compromise in growth will be mild, the risk of shows a progressive decrease during gestation
fetal distress slightly above normal, and the most (Fig. 3), and there is an increasing diastolic flow
common indication for intervention is maternal, velocity. A mature umbilical artery flow velocity
not fetal. Present evidence does not support routine waveform is usually achieved by 28–30 weeks,
Doppler ultrasound for low-risk or unselected but some fetuses, e.g., twins, may show delayed
7 Diagnosis of Fetal Distress 117
Fig. 3 Umbilical artery 1.8
pulsatility index
1.6
1.4 +2ds
Pulsatility Index (Pl)
1.2
mean
1
0.8
–2ds
0.6
0.4
0.2
0
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
Gestation (weeks)
maturation. Several studies have revealed a large arteries becomes evident only when at least 60%
standard deviation up to 26–28 weeks in the of the placental vascular bed is obliterated.
umbilical S/D ratio that reflects variations in pla- Although it may not be a separated entity,
cental development. Eighty percent of the flow absent or reversed diastolic (ARED) flow in the
velocity waveform is a reflection of the resistance umbilical artery has been the subject of a consid-
beyond the point of measurement, but 20% can be erable body of literature. Clinical studies of
a forward flow effect that is reduced in cardiac umbilical arterial flow velocity waveforms in
output changes, arrhythmias, and bradycardia. IUGR have reported a progressive increase in
Abnormality of the pulsatility index (PI) impedance to flow until end-diastolic flow
(the most significant quantitative parameter) has becomes absent and, in extreme cases, reversed.
been correlated with feto-placental vascular This is associated with a high perinatal morbidity
maldevelopment. Changes in umbilical artery and mortality. In pregnancies with ARED flow,
velocity waveforms reflect changes in the placen- the capillary loops in terminal villi are decreased
tal bed vascular resistance. Simply, increased in number, longer, and with fewer branches than
resistance in the placenta results in reduced dia- in normal pregnancies. For this reason, there is a
stolic blood flow velocities. Initially, this is deter- strong association between the ARED velocity
mined quantitatively through increasing PI and hypoxia/acidosis (Gerber et al. 2006).
values. As resistance further increases, qualitative When there is reversed flow, it may be a
changes in the waveform become evident, clinical emergency because most of these fetuses
resulting in intermittently absent end-diastolic will die within 2 weeks. The ARED flow, as a
flow (EDF), progressing to persistently absent test for hypoxia, shows a high sensitivity, spec-
EDF and ultimately reversed EDF, which repre- ificity, positive predictive value, and negative
sents obliteration of >70% of placental tertiary predictive value (Soregaroli et al. 2002). How-
villi. In fact, the primary and secondary branches ever, where flow is continuous throughout dias-
of the umbilical circulation are in place after the tole, only a very high S/D ratio (greater than 4.5)
first trimester, while in the next 3 months there is is associated with hypoxia. Furthermore, the
active proliferation of tertiary branches. Placental observation of ARED flow in the umbilical
histology showed that growth-restricted fetuses artery Doppler surveillance of pregnancies at
with abnormal flow velocity have half as many risk for fetal distress has great clinical impor-
tertiary arterioles as normal fetuses (Kingdom tance, especially in pregnancies associated with
et al. 2000). Pathological studies have demon- fetal growth restriction (Seyam et al. 2002).
strated that increased impedance in the umbilical Umbilical artery Doppler applied to high-risk
118 S. Vannuccini et al.
pregnancies significantly lowers perinatal mor- Measurement by Doppler of the peak systolic
tality, the need for induction of delivery, and the flow velocity (PSV) of the fetal middle cerebral
emergency cesarean section rate (Morris artery (MCA) is a predictor of moderate or severe
et al. 2011). Conversely, the Doppler measure- fetal anemia (Mari 2005) in pregnancies compli-
ment of umbilical artery flow has repeatedly cated by red blood cell isoimmunization or in case
been shown not to be useful in a low-risk or of viral infections such as parvovirus B19. How-
unselected population (Alfirevic et al. 2015) ever, if a raised PSV is detected in a woman
without antibodies or recent viral infection, fetal
7.4.3.3 Fetal Vessels anemia secondary to acute or chronic feto-
Alteration in fetal vessel blood flow reflects an maternal hemorrhage should be considered
important hemodynamic modification that occurs (Cosmi et al. 2012).
in association with IUGR and fetal hypoxemia. In fact, study of this vessel also yields important
The Doppler-detectable modifications in the fetal information for the detection of fetal distress. In
circulation associated with these conditions some growth-restricted fetuses, the cerebral vessels
include increased resistance in both the umbilical are dilated. Usually these are fetuses with reduced
artery (as described before) and fetal peripheral umbilical artery flow velocity. This implies that
vessels, in association with decreased resistance fetuses with mild hypoxia will have dilated cerebral
in the fetal cerebral vessels. vessels as a compensatory response: this explains
Studies of other vascular beds in the fetus, the so-called “brain-sparing” effect seen in FGR
including the cerebral circulation and the central fetus. These changes occur early and may be pre-
arterial and venous systems, have increased the sent for weeks or even months before birth. In FGR
knowledge of compensatory and adaptive mech- fetuses the trend changes of the MCA-PI and
anisms and the time sequence of circulatory MCA-PSV provide more clinical information
changes in the fetus subjected to hypoxia and than one single measurement. A high MCA-PSV
severe growth restriction. predicts fetal distress and perinatal mortality better
than a low MCA-PI. For this reason MCA-PSV
Arterial Compartment might be valuable in the clinical assessment of
The circle of Willis is an easy landmark to identify IUGR fetuses that have abnormal UA Doppler
using ultrasound. Color flow makes it easy to see (Mari et al. 2007; Fig. 4).
the common carotid and the anterior, middle, and The value of MCA Doppler in the prediction of
posterior cerebral arteries. adverse fetal outcome and the assessment of the
Fig. 4 Middle cerebral 2.6
artery pulsatility index +2ds
2.4
mean
2.2 –2ds
Pulsatility Index (Pl)
1.8
1.6
1.4
1.2
1
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
Gestation (weeks)
7 Diagnosis of Fetal Distress 119
“at-risk” fetus has been controversial. Some stud- perinatal death (Figueras et al. 2015). Thus, the
ies have suggested that the assessment of the CPR should be considered as an assessment tool
MCA Doppler is a useful tool, whereas others in fetuses undergoing third-trimester ultrasound
have found poor predictive value. However, in a examination, irrespective of the findings of the
recent metanalysis low MCA-PI appears to be individual umbilical artery and middle cerebral
predictive of impaired fetal well-being assessed artery measurements.
by either acidosis (pH < 7.20) at birth, 5 min
Apgar score <7 or admission to a NICU. Abnor- Fetal Arterial Blood Flow Redistribution
mal MCA is also predictive of an overall compos- The “brain-sparing” effect is a phenomenon
ite measure of adverse perinatal outcome and where fetuses that are hypoxic preferentially per-
perinatal mortality (Morris et al. 2012). Although fuse the brain, heart, and adrenals at the expense
these findings suggest that there is an association of the integument, viscera, gut, and kidneys.
between abnormal MCA and adverse outcomes, Although knowledge of the factors governing
the association is weak. In clinical practice, circulatory rearrangements and their mechanism
MCA alone has limited predictive value for of action is incomplete, it appears that partial
compromised fetal or neonatal well-being. pressures of oxygen and carbon dioxide play a
role, presumably through their action on chemo-
Cerebroplacental Ratio receptors. This mechanism allows preferential
The cerebroplacental ratio (CPR) is emerging as an delivery of nutrients and oxygen to vital organs,
important predictor of adverse pregnancy outcome, thereby compensating for diminished placental
and this has implications for the assessment of fetal resources. However, compensation through cere-
well-being in fetuses diagnosed as small for gesta- bral vasodilatation is limited, and a plateau
tional age (SGA) and those appropriate for gesta- corresponding to a nadir of PI in cerebral vessels
tional age close to term (DeVore 2015). Interest in is reached at least 2 weeks before the onset of late
this assessment tool has been rekindled because of fetal heart rate decelerations (Ferrazzi et al. 2002),
recent reports associating an abnormal ratio with and the development of the fetus is jeopardized.
adverse perinatal events and associated postnatal This suggests that maximal vascular adaptation to
neurological outcome. Fetuses with an abnormal hypoxemia precedes the critical degree of impair-
CPR that are appropriate for gestational age or ment of fetal oxygenation, after which vascular
have late-onset SGA (>34 weeks of gestation) dilatation may be suppressed by the development
have a higher incidence of fetal distress in labor of cerebral edema. An alternative explanation
requiring emergency cesarean delivery, a lower may be that in severe hypoxemia, an increase in
cord pH, and an increased admission rate to the PI is the consequence of alterations in flow due to
newborn intensive care unit when compared with reduced cardiac contractility and to a fall in abso-
fetuses with a normal CPR (Prior et al. 2013, 2015 lute cardiac output. Consequently, arterial vessels
Khalil et al. 2014; Morales-Rosello et al. 2015). are not suitable for the longitudinal monitoring of
Fetuses with early-onset SGA (<34 weeks of ges- growth-restricted fetuses, and cardiac and venous
tation) with an abnormal CPR have a higher inci- velocity waveforms give more information about
dence of the following when compared with fetuses fetal well-being or compromise.
with a normal CPR: (1) lower gestational age at
birth, (2) lower mean birth weight, (3) lower birth Cardiac and Venous Compartment
weight centile, (4) birth weight less than the 10th Cardiac flow is influenced by the modifications of
centile, (5) higher rate of cesarean delivery for fetal arterial impedance to flow. As long as the fetus is
distress in labor, (6) higher rate of Apgar scores less able to compensate for a reduced placental supply
than 7 at 5 min, (7) an increased rate of neonatal by arterial redistribution (a brain-sparing effect),
acidosis, (8) an increased rate of newborn intensive there is preferential myocardial oxygenation,
care unit admissions, (9) higher rate of adverse which delays the development of right heart fail-
neonatal outcome, and (10) a greater incidence of ure despite an increasing afterload. Cerebral
120 S. Vannuccini et al.
vasodilatation produces a decrease in left ventric- atrial systole, seen as absent or reversed a-wave
ular afterload, whereas increased placental and (Baschat et al. 2006).
systemic resistance produce increased right ven- Fetal hypoxemia is associated with reduced
tricular afterload. At this stage, fetal Doppler mea- umbilical venous blood flow, but, despite this
surements show high placental resistance and decrease, a normal PSV in the ductus venosus is
arterial redistribution in the presence of normal maintained. In the growth-restricted fetus, the per-
venous waveforms, and the majority of fetuses centage of umbilical venous blood passing
have normal, reactive heart rate traces and bio- through the ductus venosus is increased from
physical profiles. Progressive changes in the about 40% (in normal fetuses) to about 60%.
venous circulation may indicate failure of the Thus, there is a redistribution of venous blood
compensatory mechanism and herald the devel- flow in favor of the ductus venosus at the expense
opment of right heart failure due to myocardial of hepatic blood flow in growth-restricted fetuses.
hypoxia (Baschat and Harman 2006). Unlike peak velocity during ventricular systole,
Longitudinal studies of deteriorating growth- flow velocities during atrial contraction are
restricted fetuses have shown that PSV and cardiac reduced or even reversed. One may speculate
output gradually decline, suggesting a progressive that increased end-diastolic right ventricular pres-
worsening in cardiac function. Similarly, there is a sure would not influence ductus venosus blood
symmetrical decrease in ventricular ejection force flow velocities during atrial contraction, as flow
at the level of both ventricles, despite the dramati- is preferentially directed through the foramen
cally different hemodynamic conditions present ovale to the left atrium. However, the foramen
downstream of the two ventricles (i.e., reduced ovale is closed during atrial contraction and
cerebral resistances for the left ventricle and blood flow velocity through the foramen ovale
increased splanchnic and placental resistance for decreases to zero.
the right ventricle). This supports a pivotal role of Altered venous flow velocity waveforms are
the intrinsic myocardial function in the compensa- more closely related to intrauterine fetal jeopardy
tory mechanism of the growth-restricted fetus fol- than changes in arterial flow, which may occur
lowing the establishment of the brain-sparing quite early during the course of impaired placental
effect. Ventricular ejection force dramatically function.
decreases in a short time interval (about 1 week), The degree of fetal acidemia can be estimated
showing an impairment of ventricular force close from Doppler measurements of pulsatility in both
to fetal distress. As a consequence, cardiac filling is the arterial system and the ductus venosus. With
also impaired (Severi et al. 2000; Baschat 2011). moderate acidemia (pH between 2 and 4 stan-
Late Doppler changes generally accompany dard deviations from the normal mean for gesta-
metabolic deterioration and are a result of declin- tional age), almost all fetuses have an MCA-PI
ing cardiac function and abnormal organ below 2 standard deviations, whereas there is a
autoregulation. Increasing venous Doppler indi- wide scatter of individual results for the ductus
ces are the hallmark of advancing circulatory venosus, with the majority of measurements being
deterioration since they indicate a decreasing abil- still within the reference ranges. With increasing
ity of the heart to accommodate venous return. severity of hypoxemia and acidemia, ductus
The ductus venosus (DV) waveform is sensitive to venosus PI increases, and, in the most severe
cardiac function, which in turn is adversely cases, velocities with atrial contraction were
affected by chronic severe decrease in substrate/ reduced to zero or even become negative. How-
oxygen availability. In response to hypoxia, the ever, in severe fetal growth restriction, abnormal
DV becomes more dilated, and there is reduced Doppler velocimetry of the ductus venosus is the
flow during ventricular diastole, resulting in only significant parameter associated with perina-
increased DV pulsatility index for veins (PIV), tal death and low 5 min Apgar scores (Baschat
followed by increasingly retrograde flow during 2010; Baschat et al. 2003).
7 Diagnosis of Fetal Distress 121
7.4.3.4 Doppler Findings respectively. However, neurologic impairment at
and the Prediction of Perinatal 2 years of age was 9% and 5%, respectively. In
Risks those for whom delivery timing was based on
Elevations of placental blood flow resistance and reduced CTG STV, perinatal mortality and abnor-
venous Doppler indices frequently progress in mal 2-year outcomes were 7% and 15%, respec-
parallel. The recognition of venous Doppler tively. Although the outcomes were not
changes has led to reexamination of the relation- significantly different between the groups, the
ship between prenatal Doppler findings in growth- study suggests that delivery based on late Doppler
restricted fetuses and perinatal outcome. changes, rather than on reduced CTG STV, may
Previously, delivery was recommended when provide better long-term outcomes, possibly at the
umbilical artery Doppler end-diastolic velocities expense of a small increase in perinatal mortality
were absent or reversed. However, the Growth (Lees et al. 2013, 2015).
Restriction Intervention Trial (GRIT) (Thornton
et al. 2004) showed that if there was early-onset
IUGR, early and preterm delivery were indepen- 7.5 During Labor Surveillance
dent risk factors for adverse neurodevelopment at
2 years of age. Safe prolongation of pregnancy in 7.5.1 Identification of Fetal Distress
these fetuses is therefore critical. Daily biophysi-
cal profile scoring in fetuses with absent or Maternal blood flow to the placenta may be
reversed umbilical artery end-diastolic velocity severely diminished by uterine contractions, so
with strict delivery criteria has been associated the potential for fetal hypoxia increases during
with good outcomes, suggesting that safe prolon- labor. In the last century some asphyxiated fetuses
gation of these pregnancies is indeed possible. It is were noted to have abnormally fast or slow heart
now apparent that prediction of perinatal risk rates, so heart auscultation evolved as a compo-
based on umbilical artery alone, without account- nent of intrapartum care. However, the human ear
ing for venous circulatory changes, is inadequate. is insensitive to subtle changes in rate, so elec-
Prediction of stillbirth and acidemia is signifi- tronic methods of recording have been developed.
cantly enhanced by the addition of venous Dopp- These methods generate paper traces that show
ler findings, irrespective of the umbilical arterial features not obvious on auscultation, including
end-diastolic velocity. This rate increases when the degree of variation of the heart rate and the
the arterial end-diastolic velocity is absent or shape of accelerations and decelerations in rate
reversed but venous Doppler indices are still nor- (the CTG).
mal and increases further when venous Doppler Identification of fetal distress based on fetal
indices become abnormal (predominantly due to heart rate patterns is imprecise, and intrapartum
an increase in the rate of stillbirth). If the preva- Doppler velocimetry was studied as a potential
lence of stillbirth is 25%, abnormal venous Dopp- adjunct to conventional intrapartum fetal monitor-
ler findings have 65% sensitivity and 95% ing, but it was concluded that this technique was a
specificity for the prediction of stillbirth. poor predictor of adverse perinatal outcomes
Depending on the cutoff (2 vs. 3 SD) and the (Cunningham et al. 2001).
combination of veins examined, the sensitivity
for acidemia ranges from 70% to 90% and speci-
ficity from 70% to 80%. 7.5.2 Monitoring of Fetal Heart Rate
The TRUFFLE study has provided clarifica-
tion of outcomes in the cases of IUGR prior to The pattern of the fetal heartbeat during labor is
32 weeks’ gestation. In cases where delivery was often a good indicator of fetal well-being. The
determined by increased DV PIV or absent DV normal fetal heart rate (FHR) is 120–160 bpm. A
a-wave, perinatal mortality was 6% and 10%, normal heart rate suggests that the fetus is
122 S. Vannuccini et al.
receiving enough oxygen from the mother’s electrodes are connected to video screens and a
bloodstream. The typical fetal heart rate pattern printer which produces graphs of the fetal heart
is to slow somewhat during a contraction and rate and “intensity” of the contractions.
increase again at the end of a contraction. Abnor- Internal measurement requires the cervix to be
mal variations in heart rate can indicate decreased at least 2 cm dilated as it involves inserting a
oxygen in the blood and tissues of the fetus that pressure catheter into the uterine cavity, as well
can potentially damage the fetus. The fetal heart as attaching a scalp electrode to the fetal head to
can be monitored either intermittently by auscul- adequately measure the heart rate. Membranes
tation or continuously by CTG. must be ruptured to place the electrodes. The
electrode measures the fetal heart rate. It is used
7.5.2.1 Auscultation with Fetal in some high-risk births if the external monitor
Stethoscope or Doppler shows suspicious results or if external monitoring
Ultrasound Stethoscope is not generating an adequate trace. Internal mon-
The fetal heartbeat and variability can be itoring offers better accuracy of readings than
checked before, during, and after contractions, external monitoring, but there is an increased
either using a Pinard fetal stethoscope or a risk of infection after application of the electrode.
Doppler ultrasound stethoscope, a small hand- The advantage of internal monitoring is that it is
held device which uses sound waves to monitor immediately apparent if the fetal heart rate slows
the heart beat. In low-risk births, the American down, stops, or is slow to recover from contrac-
College of Obstetricians and Gynecologists tions. It can detect reduced oxygen flow due to
(American College of Obstetricians and Gyne- cord compression (more common after rupture of
cologists 2009) suggests monitoring at least the membranes), oxytocin-augmented contrac-
every 30 min during active labor and at least tions, or narcotic- and epidural-related changes
every 15 min during the second stage of labor. in maternal blood pressure.
When risk factors are present, the fetal heart During the first stage of labor, a moderate fetal
should be evaluated every 15 min and every tachycardia may be considered a circulatory
5 min in the second stage. The mother’s abdo- mechanism of adaptation against moderate fetal
men may be also palpated to check for the hypoxia. By contrast, a severe tachycardia is a
strength of contractions. clear sign of fetal hypoxia: it can be associated
with high maternal temperature or fetal cardiac
7.5.2.2 Electronic External or Internal malformations or medications administered to
Monitoring the mother. The same is true for a bradycardia: a
In last decade, approximately 85% of pregnancies moderate bradycardia is considered without clin-
were monitored in labor by continuous cardioto- ical significance, but a marked bradycardia is a
cography, also known as electronic fetal monitor- sign of severe fetal hypoxia.
ing (EFM), making it the most commonly Similar considerations relating to the use of
performed obstetric procedure. CTG apply during the antepartum period for
A handheld Doppler ultrasound probe can be what concerns baseline variability. Accelera-
used to calculate and display, but not permanently tions are, as before labor, an expression of nor-
record, the FHR. Electronic fetal monitors are mality. Early decelerations are not usually a sign
used to both determine the FHR and continuously of fetal distress. They are likely generated by
record it in graphical form. External measurement vagal stimulation due to cephalic compression
means taping or strapping the electrodes to the and are more frequent after rupture of the
maternal abdominal wall, with a small Doppler membranes.
ultrasound heart electrode overlying the fetal Variable decelerations are usually due to
heart, and the contraction electrode measuring umbilical cord compression. They may occur in
the tension of the abdominal wall, an indirect association with fetal distress due to hemody-
measure of the intrauterine pressure. Both namic changes. However, late decelerations are
7 Diagnosis of Fetal Distress 123
a typical expression of fetal hypoxia. Their intrapartum fetal surveillance. Fetal pulse oxime-
timing and shape are directly correlated with try was introduced into clinical practice about
the severity of fetal hypoxia: the time elapsing 30 years ago, but it has only recently been possi-
between the contraction and the deceleration is ble to use it as an additional measure to evaluate
directly proportional to the fetal partial oxygen fetal well-being. It was developed as a less trau-
pressure. matic and invasive method of assessing fetal oxy-
Obviously, in the presence of both late decel- genation than fetal scalp sampling. It allows for
erations and baseline abnormalities, the prognosis the real-time and continuous assessment of the
is more serious. fetus (Klauser et al. 2005; East et al. 2006;
Interpretation of the cardiotocogram is more Bloom et al. 2006; K€uhnert and Schmidt 2004).
difficult during the second stage of labor. In this It uses a probe that sits inside the vagina during
period only a severe and persistent bradycardia is labor. It is possible only if the membranes are
considered of serious prognostic significance, ruptured because the probe has to be placed on
especially when associated with abnormalities in fetal skin.
variability. Fetal oxygen saturation decreases between
If the CTG is normal during labor, intermittent the first and the second stages of labor (from
auscultation may be appropriate. It is considered 60% to 53%): a value of 30% is considered
normal if the FHR is between 120 and 160 bpm. It pathological. A fetal oxygen saturation of 30%
is also suggested that monitoring should be under- for 10 min is associated with acidosis and a poor
taken for 20–30 min every 2 h during labor. fetal outcome. Low values of fetal oxygen satu-
Continuous cardiotocography during labor is ration are associated with an abnormal CTG trace
associated with a reduction in neonatal seizures, (low variability).
but no significant differences in cerebral palsy, There are still controversies about the benefits
infant mortality, or other standard measures of fetal pulse oximetry. Some authors have con-
of neonatal well-being. However, continuous cluded that fetal pulse oximetry during active
cardiotocography was associated with an increase labor provides a more accurate assessment of
in cesarean sections and instrumental vaginal fetal well-being and may reduce the need for
births (Alfirevic et al. 2013b; Larma et al. 2007). interventions. Conversely, a recent Cochrane
For this reason, continuous electronic fetal moni- review showed that the addition of fetal pulse
toring should be reserved for high-risk pregnan- oximetry does not reduce overall cesarean section
cies (Table 6). rates, providing limited support for the use of fetal
pulse oximetry when used in the presence of a
non-reassuring CTG. A better method for the
7.5.3 Monitoring of Fetal evaluation of fetal well-being in labor is required
Oxygenation (East et al. 2014).
7.5.3.1 Pulse Oximetry 7.5.3.2 Fetal Scalp Blood Sampling
Fetal pulse oximetry has been advocated as a A sample of blood from the fetal scalp may be
means of improving the specificity of CTG in tested during labor to determine the acidity of the
blood. This test is called fetal scalp blood sam-
pling (FSBS). If the fetus is not getting enough
Table 6 High-risk pregnancies oxygen, the blood becomes highly acidic.
Abnormalities on intermittent auscultation or at CTG Fetal blood sampling is typically performed
monitoring at the beginning of the labor using a kit. An amnioscope with a light source is
Discolored amniotic fluid used to expose the fetal scalp. The blood is col-
Oxytocin infusion
lected in long, heparinized capillary tubes. The
Fever during labor
test requires that the cervix be dilated at least
Other conditions of pathological labor
2–3 cm and can be difficult to perform.
124 S. Vannuccini et al.
Capillary blood collected from the fetal scalp encephalopathy (sensitivity 50%, PPV 3%)
usually has a pH lower than umbilical venous (Allen et al. 2004).
blood and correlates well with fetal arterial values. Indeed, the degree of technical skill required,
However, scalp edema can result in erroneous cost, need for continuous availability of standard-
results. A scalp pH value of less than 7.20 has ized equipment and trained personnel, and mater-
traditionally been used to represent the critical nal discomfort have precluded the use of this
value for identifying fetal acidosis (Table 7). modality in many labor and delivery units. There-
However, a scalp pH below 7.15 is more repre- fore, fetal scalp blood sampling had a historical
sentative of the tenth percentile and is closer to the importance, but currently there is very limited
threshold currently used in umbilical cord blood scientific evidence to support its use in modern
analysis to define fetal acidemia associated with obstetric practice (Chandraharan 2014).
neurological deficits (Jørgensen and Weber 2014).
In addition, when further testing to assess fetal 7.5.3.3 Fetal Electrocardiography
well-being in labor is indicated, fetal scalp blood A technical system, the fetal heart monitor, mon-
lactate estimation is more likely to be successfully itors the fetal electrocardiogram (ECG) during
undertaken than pH estimation. The smaller vol- labor, as a reflection of fetal myocardial metabo-
ume of blood required for this test, compared with lism and acid–base balance. It can be used as an
the more traditional pH estimation, may improve adjunct to continuous electronic FHR monitoring
sampling rates (East et al. 2015). during labor. The rationale is that fetal acidemia is
The accuracy of intermittent fetal scalp pH associated with fetal ECG ST-segment elevation
assessment for predicting neonatal acidosis and increased T-wave amplitude. The monitor’s
with subsequent neurologic sequelae has been software automatically identifies and analyzes
questioned. It is no longer used in many institu- changes in the T wave and the ST segment of the
tions, although its use can result in fewer cesarean fetal ECG, which is obtained via a spiral electrode
deliveries performed for the indication of attached to the fetal scalp.
non-reassuring fetal status. FSBS was advocated The fetal heart monitor was approved by the
as an “additional test” of fetal well-being to reduce United States Food and Drug Administration as an
the false-positive rate of CTG. The aim was to adjunct to the assessment of non-reassuring FHR
identify the presence of acidosis to differentiate at tracings in pregnancies over 36 weeks of gesta-
least 60% of fetuses who were not hypoxic tion, in labor, with vertex presentation and rup-
from 40% of fetuses who were experiencing tured fetal membranes. Initial FDA approval was
intrapartum hypoxia when the CTG was classified based primarily on European studies that
as “pathological,” in order to avoid unnecessary suggested that fetal ST-segment analysis technol-
operative interventions. ogy reduced the rates of fetal scalp sampling pro-
However, the test has poor sensitivity and pos- cedures and operative deliveries, with a
itive predictive value (PPV) for predicting umbil- significant reduction of neonatal academia and
ical arterial pH <7.0 (sensitivity 35%, PPV 9%). encephalopathy (Ojala et al. 2006; Amer-Wåhlin
The test also has poor sensitivity and PPV for et al. 2001). Thus, this technique appeared to
identifying newborns with hypoxic–ischemic improve the clinician’s ability to discriminate
between fetuses in need of intervention and
those who can be managed expectantly.
Table 7 Recommended fetal management according to However, a recent Cochrane review showed
the pH value obtained by fetal scalp blood sampling
that the modest benefits of fewer fetal scalp sam-
pH value Management plings during labor have to be considered against
pH > 7.25 Repeat test if CTG continues to the disadvantages of needing to use an internal
deteriorate
scalp electrode, after membrane rupture (Neilson
pH 7.21–7.24 Repeat test in 30 min
2015). Indeed, a recent large randomized, con-
pH < 7.20 Aim for delivery within 30 min
trolled trial showed no significant benefit of the
7 Diagnosis of Fetal Distress 125
adjunctive use of ST-segment analysis in reducing information on probability of adverse pregnancy out-
a composite of neonatal outcomes or in reducing come and degree of fetal growth restriction in a
low-risk population. Fetal Diagn Ther 27:78–86
cesarean or operative vaginal deliveries in a pop- Belfort MA, Saade GR, Thom E et al (2015) A randomized
ulation undergoing conventional intrapartum con- trial of intrapartum fetal ECG ST-segment analysis. N
tinuous electronic fetal heart rate monitoring Engl J Med 373:632–641
(Belfort et al. 2015). Berkley E, Chauhan SP, Abuhamad A (2012) Doppler
assessment of the fetus with intrauterine growth restric-
tion. Am J Obstet Gynecol 206:300e8
Bloom SL, Spong CY, Thom E et al (2006) Fetal pulse
oximetry and cesarean delivery. N Engl J Med
References 355:2195–2202
Chandraharan E (2014) Fetal scalp blood sampling during
Alfirevic Z, Stampalija T, Gyte GM (2013a) Fetal and labour: is it a useful diagnostic test or a historical test
umbilical Doppler ultrasound in high-risk pregnancies. that no longer has a place in modern clinical obstetrics?
Cochrane Database Syst Rev 11, CD007529 BJOG 121:1056–1062
Alfirevic Z, Devane D, Gyte GM (2013b) Continuous Chauhan SP, Taylor M, Shields D et al (2007) Intrauterine
cardiotocography (CTG) as a form of electronic fetal growth restriction and oligohydramnios among high-
monitoring (EFM) for fetal assessment during labour. risk patients. Am J Perinatol 24:215–221
Cochrane Database Syst Rev 31(5), CD006066 Cosmi E, Rampon M, Saccardi C et al (2012) Middle
Alfirevic Z, Stampalija T, Medley N (2015) Fetal and cerebral artery peak systolic velocity in the diagnosis
umbilical Doppler ultrasound in normal pregnancy. of fetomaternal hemorrhage. Int J Gynaecol Obstet
Cochrane Database Syst Rev 4, CD001450 117:128e30
Allen RM, Bowling FG, Oats JJ (2004) Determining the fetal Cunningham FG, Gant NF, Leveno KJ et al (2001) Wil-
scalp lactate level that indicates the need for intervention liams obstetrics, 21st edn. McGraw-Hill, New York
in labour. Aust N Z J Obstet Gynaecol 44:549–552 Dawes GS, Moulden M, Redman CW (1995) Computer-
American College of Obstetricians and Gynecologists ized analysis of antepartum fetal heart rate. Am J Obstet
(2009) ACOG Practice Bulletin No. 106. Intrapartum Gynecol 173:1353–1354
fetal heart rate monitoring: nomenclature, interpreta- Dawes GS, Moulden M, Redman CW (1996) Improve-
tion, and general management principles. Obstet ments in computerized fetal heart rate analysis
Gynecol 114:192–202 antepartum. J Perinat Med 24:25–36
American College of Obstetricians and Gynecologists DeVore GR (2015) The importance of the cerebroplacental
(2010) ACOG Practice Bulletin No. 116. Management ratio in the evaluation of fetal well-being in SGA and
of intrapartum fetal heart rate tracings. Reaffirmed AGA fetuses. Am J Obstet Gynecol 213:5–15
2015 Obstet Gynecol 116:1232–1240 East CE, Brennecke SP, King JF et al (2006) The effect of
Amer-Wåhlin I, Hellsten C, Norén H et al (2001) Cardioto- intrapartum fetal pulse oximetry in the presence of a
cography only versus cardiotocography plus ST analy- nonreassuring fetal heart pattern on operative delivery
sis of fetal electrocardiogram for intrapartum fetal rates: a multicenter randomized controlled trial (the
monitoring: a Swedish randomised controlled trial. FOREMOST trial). Am J Obstet Gynecol 194:606.
Lancet 358:534–538 e1–606.e16
Baschat AA (2010) Ductus venosus Doppler for fetal sur- East CE, Begg L, Colditz PB et al (2014) Fetal pulse
veillance in high-risk pregnancies. Clin Obstet Gynecol oximetry for fetal assessment in labour. Cochrane Data-
53:858e68 base Syst Rev 10, CD004075
Baschat AA (2011) Examination of the fetal cardiovascular East CE, Leader LR, Sheehan P et al (2015) Intrapartum
system. Semin Fetal Neonatal Med 16:2–12 fetal scalp lactate sampling for fetal assessment in the
Baschat AA, Harman CR (2006) Venous Doppler in the presence of a non-reassuring fetal heart rate trace.
assessment of fetal cardiovascular status. Curr Opin Cochrane Database Syst Rev 5, CD006174
Obstet Gynecol 18:156–163 Everett TR, Peebles DM (2015) Antenatal tests of fetal
Baschat AA, Gembruch U, Weiner CP et al (2003) Quali- wellbeing. Semin Fetal Neonatal Med 20:138–143
tative venous Doppler waveform analysis improves Ferrazzi E, Bozzo M, Rigano S et al (2002) Temporal
prediction of critical perinatal outcomes in premature sequence of abnormal Doppler changes in the periph-
growth-restricted fetuses. Ultrasound Obstet Gynecol eral and central circulatory systems of the severely
22:240e5 growth-restricted fetus. Ultrasound Obstet Gynecol
Baschat AA, Galan HL, Bhide A et al (2006) Doppler and 19:140–146
biophysical assessment in growth restricted fetuses: Figueras F, Savchev S, Triunfo S et al (2015) An inte-
distribution of test results. Ultrasound Obstet Gynecol grated model with classification criteria to predict
27:41e7 small-for-gestational-age fetuses at risk of adverse
Becker R, Vonk R (2010) Doppler sonography of perinatal outcome. Ultrasound Obstet Gynecol 45:
uterine arteries at 20–23 weeks: depth of notch gives 279–285
126 S. Vannuccini et al.
Gerber S, Hohlfeld P, Viquerat F et al (2006) Intrauterine neurodevelopmental and intermediate perinatal out-
growth restriction and absent or reverse end-diastolic comes in infants with very preterm fetal growth restric-
blood flow in umbilical artery (Doppler class II or III): a tion (TRUFFLE): a randomised trial. Lancet
retrospective study of short-and long-term fetal mor- 385:2162–2172
bidity and mortality. Eur J Obstet Gynecol Reprod Biol Leung TY, Lao TT (2012) Timing of caesarean section
126:20–26 according to urgency. Best Pract Res Clin Obstet
Grivell RM, Alfirevic Z, Gyte GM et al (2015) Antenatal Gynaecol 27:251–267
cardiotocography for fetal assessment. Cochrane Data- Manning FA (1999) Fetal biophysical profile. Obstet
base Syst Rev 9, CD007863 Gynecol Clin North Am 26:557–577
Hebbar S, Rai L, Adiga P et al (2015) Reference ranges Manning FA (2009) Antepartum fetal testing: a critical
of amniotic fluid index in late third trimester of preg- appraisal. Curr Opin Obstet Gynecol 21:348–352
nancy: what should the optimal interval between two Mari G (2005) Middle cerebral artery peak systolic veloc-
ultrasound examinations be? J Pregnancy ity: is it the standard of care for the diagnosis of fetal
2015:319204 anemia? J Ultrasound Med 24:697–702
Hutter D, Kingdom J, Jaeggi E (2010) Causes and mech- Mari G, Hanif F, Kruger M et al (2007) Middle cerebral
anisms of intrauterine hypoxia and its impact on the artery peak systolic velocity: a new Doppler parameter
fetal cardiovascular system: a review. Int J Pediatr in the assessment of growth-restricted fetuses. Ultra-
2010:401323 sound Obstet Gynecol 29:310–316
Jørgensen JS, Weber T (2014) Fetal scalp blood sampling Martin CB Jr (2008) Normal fetal physiology and behav-
in labor – a review. Acta Obstet Gynecol Scand ior, and adaptive responses in the fetus with hypox-
93:548–555 emia. Semin Perinatol 32:239e42
Khalil AA, Morales Rosello J, Morlando M et al (2014) Is Morales-Rosello J, Khalil A, Morlando M et al (2015) Poor
fetal cerebroplacental ratio an independent predictor of neonatal acid-base status in term fetuses with low
intrapartum fetal compromise and neonatal unit admis- cerebroplacental ratio. Ultrasound Obstet Gynecol
sion? Am J Obstet Gynecol 213(54):e1–e10 45:156e61
Kingdom JCP, Kaufmann P (1997) Oxygen and placental Morris RK, Malin G, Robson SC, Kleijnen J et al (2011)
villous development: origins of fetal hypoxia. Placenta Fetal umbilical artery Doppler to predict compromise
18:613–621 of fetal/neonatal wellbeing in a high risk population:
Kingdom J, Huppertz B, Seaward G, Kaufmann P (2000) systematic review and bivariate meta-analysis. Ultra-
Development of the placental villous tree and its con- sound Obstet Gynecol 37:135e42
sequences for fetal growth. Eur J Obstet Gynecol Morris RK, Say R, Robson SC et al (2012) Systematic
Reprod Biol 92:35–43 review and meta-analysis of middle cerebral artery
Klauser CK, Christensen EE, Chauhan SP et al (2005) Use Doppler to predict perinatal wellbeing. Eur J Obstet
of fetal pulse oximetry among high-risk women in Gynecol Reprod Biol 165:141e55
labor: a randomized control trial. Am J Obstet Gynecol Morris RK, Meller CH, Tamblyn J et al (2014) Association
192:1810–1817 and prediction of amniotic fluid measurements for
K€uhnert M, Schmidt S (2004) Intrapartum management of adverse pregnancy outcome: systematic review and
nonreassuring fetal heart rate patterns: a randomized meta-analysis. BJOG 121:686–699
controlled trial of fetal pulse oximetry. Am J Obstet Neilson JP (2015) Fetal electrocardiogram (ECG) for fetal
Gynecol 191:1989–1995 monitoring during labour. Cochrane Database Syst Rev
Lalor JG, Fawole B, Alfirevic Z et al (2008) Biophysical 21(12), CD000116
profile for fetal assessment in high risk pregnancies. O’Gorman N, Tampakoudis G, Wright A et al (2016) Uter-
Cochrane Database Syst Rev 23, CD000038 ine artery pulsutility index at 12, 22, 32 and 36 weeks’
Lalor JG, Fawole B, Alfirevic Z et al (2012) Biophysical gestation in screening for preeclampsia. Ultrasound
profile for fetal assessment in high risk pregnancies. Obstet Gynecol 47:565–572
Wiley, Chichester Ojala K, V€a€ar€asm€aki M, M€akikallio K et al (2006) A
Larma JD, Silva AM, Holcroft CJ et al (2007) Intrapartum comparison of intrapartum automated fetal electrocar-
electronic fetal heart rate monitoring and the identifica- diography and conventional cardiotocography: a
tion of metabolic acidosis and hypoxic-ischemic randomised controlled study. BJOG 113:419–423
encephalopathy. Am J Obstet Gynecol 197:301. Omo-Aghoja L (2014) Maternal and fetal acid–base chem-
e1–301.e8 istry: a major determinant of perinatal outcome. Ann
Lees C, Marlow N, Arabin B, TRUFFLE Group Med Health Sci Res 4:8–17
et al (2013) Perinatal morbidity and mortality in Ott WJ (2005) Reevaluation of the relationship between
early-onset fetal growth restriction: cohort outcomes amniotic fluid volume and perinatal outcome. Am J
of the trial of randomized umbilical and fetal flow in Obstet Gynecol 192:1803–1809
Europe (TRUFFLE). Ultrasound Obstet Gynecol Pinas A, Chandraharan E (2016) Continuous cardioto-
42:400–408 cography during labour: analysis, classification and
Lees CC, Marlow N, van Wassenaer-Leemhuis A, TRUF- management. Best Pract Res Clin Obstet Gynaecol
FLE Study Group et al (2015) Two year 30:33–47
7 Diagnosis of Fetal Distress 127
Pipkin FB (1999) Fetal growth and physiology. In: Seyam YS, Al-Mahmeid MS, Al-Tamimi HK (2002)
Edmonds KD (ed) Dewhurst’s textbook of obstetrics Umbilical artery Doppler flow velocimetry in intrauter-
and gynecology for postgraduates, 6th edn. Blackwell ine growth restriction and its relation to perinatal out-
Science, Oxford, pp 104–112 come. Int J Gynecol Obstet 77:131–137
Prior T, Mullins E, Bennett P et al (2013) Prediction of Soregaroli M, Bonera R, Danti L et al (2002) Prognostic
intrapartum fetal compromise using the role of umbilical artery Doppler velocimetry in growth-
cerebroumbilical ratio: a prospective observational restricted fetuses. J Matern Fetal Neonatal Med
study. Am J Obstet Gynecol 208:124.e1–124.e6 11:199–203
Prior T, Paramasivam G, Bennett P et al (2015) Are fetuses Thompson JL, Kuller JA, Rhee EH (2012) Antenatal sur-
that fail to achieve their growth potential at increased veillance of fetal growth restriction. Obstet Gynecol
risk of intrapartum compromise? Ultrasound Obstet Surv 67:554e65
Gynecol 46:460–464 Thornton JG, Hornbuckle J, Vail A, GRIT Study Group
Pruetz JD, Votava-Smith J, Miller DA (2015) Clinical et al (2004) Infant wellbeing at 2 years of age in the
relevance of fetal hemodynamic monitoring: perinatal Growth Restriction Intervention Trial (GRIT):
implications. Semin Fetal Neonatal Med 20:217–224 multicentred randomised controlled trial. Lancet
Regnault TR, de Vrijer B, Galan HL et al (2007) Develop- 364:513–520
ment and mechanisms of fetal hypoxia in severe fetal Turan S, Turan OM, Berg C et al (2007) Computerized
growth restriction. Placenta 28:714–723 fetal heart rate analysis, Doppler ultrasound and bio-
Savasan ZA, Goncalves LF, Bahado-Singh RO (2014) physical profile score in the prediction of acid-base
Second- and third-trimester biochemical and ultra- status of growth-restricted fetuses. Ultrasound Obstet
sound markers predictive of ischemic placental disease. Gynecol 30:750e6
Semin Perinatol 38:167–176 Valiño N, Giunta G, Gallo DM et al (2016) Uterine artery
Severi FM, Rizzo G, Bocchi C et al (2000) Intrauterine pulsatility index at 30–34 weeks’ gestation in the pre-
growth retardation and fetal cardiac function. Fetal diction of adverse perinatal outcome. Ultrasound
Diagn Ther 15:8–19 Obstet Gynecol 47:308–315
Severi FM, Bocchi C, Visentin A et al (2002) Uterine and Weiner E, Bar J, Fainstein N et al (2015) Intraoperative
fetal cerebral Doppler predict the outcome of third- findings, placental assessment and neonatal outcome in
trimester small-for-gestational age fetuses with normal emergent cesarean deliveries for non-reassuring fetal
umbilical artery Doppler. Ultrasound Obstet Gynecol heart rate. Eur J Obstet Gynecol Reprod Biol
19:225–228 185:103–107
In Vitro Fertilization and Multiple
Pregnancies 8
Maria Angela Rustico, Mariano Lanna, and Enrico Ferrazzi
Contents
8.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
8.2 Epidemiology of Natural Twinning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
8.2.1 Actual Trend . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
8.2.2 Dizygotic Twinning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
8.2.3 Monozygotic Twinning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
8.3 Epidemiology of Iatrogenic Twinning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
8.4 Placentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
8.4.1 Chorionicity and Zygosity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
8.4.2 Monochorionic Placenta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
8.5 Fetal Complications of Twin Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
8.5.1 Miscarriage and Fetal Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
8.5.2 Fetal Growth Restriction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
8.6 Preterm Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
8.6.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
8.6.2 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
8.6.3 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
8.6.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
8.6.5 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
8.6.6 Fetal Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
8.7 Monochorionic-Related Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
8.7.1 Twin-to-Twin Transfusion Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
8.7.2 Twin Anemia-Polycythemia Sequence (TAPS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
8.7.3 Selective Intrauterine Growth Restriction of One Twin (sIUGR) . . . . . . . . . . . . . . 139
8.7.4 Single Intrauterine Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
8.7.5 Twins Discordant for Fetal Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
8.7.6 Twin Reversed Arterial Perfusion (TRAP) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . 141
M. A. Rustico · M. Lanna · E. Ferrazzi (*)
Prenatal Diagnosis and Fetal Surgery Unit, Dept. of
Woman, Mother and Neonate, Buzzi Children’s Hospital
Department of Clinical Sciences, University of Milan,
Milan, Italy
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 129
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_157
130 M. A. Rustico et al.
8.8 Monoamniotic Twinning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
8.9 Cord Occlusion in Monochorionic Twins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Abstract embryo), while monozygotic twinning is
Multiple pregnancies may arise because of largely determined by genetic mechanisms.
modified reproductive strategies (i.e., delayed • Ultrasound techniques are very accurate in
parenthood) and the availability of assisted determining chorionicity and assessing the
reproductive technologies. Dizygotic twinning obstetric risk which is significantly different
rate is affected by different factors (race, in dichorionic and monochorionic twins.
genetic factors, seasonality, maternal age and • Twin pregnancy is always risky for the increased
parity, endogenous gonadotropins, fertility rate of fetal complications and structural anoma-
drugs, and sex of the embryo), while monozy- lies compared to singletons. A monochorionic
gotic twinning is largely determined by genetic twin pregnancy may be complicated by twin-
mechanisms. Ultrasound techniques are very twin transfusion syndrome, selective IUGR,
accurate (100% sensitivity and 99% specific- and twin anemia-polycythemia sequence.
ity) for determining chorionicity and assessing • The death of one twin, which occurs in about
the obstetric risk which is significantly differ- 6% of all MC twin pregnancies, puts the co-
ent in dichorionic and monochorionic twins. twin at greater risk of mortality and morbidity.
The twin pregnancy is associated with an
increased rate of fetal complications, such as
miscarriage and fetal loss, intrauterine growth
restriction (IUGR), and preterm birth. Twins
8.2 Epidemiology of Natural
present with an excess of structural anomalies
Twinning
compared to singletons. All monochorionic
twin pregnancies are at risk of complications
8.2.1 Actual Trend
such as twin-twin transfusion syndrome, selec-
The cultural modifications in women’s
tive IUGR, and twin anemia-polycythemia
reproductive strategies over the past 50 years have
sequence because of the presence of vascular
drastically influenced the demographic scenario.
anastomoses between the circulation of both
Higher levels of education and a desire for eco-
twins on the shared placenta. The death of
nomic and social success, as well as difficulties in
one twin, which occurs in about 6% of all
finding a permanent job, have played a major role in
MC twin pregnancies, puts the co-twin at
modifying the reproductive strategies, as evidenced
greater risk of mortality and morbidity.
by delayed parenthood and the reduction in family
size (Astolfi et al. 2003). In addition to this expected
twinning rate due to advancing maternal age, there
8.1 Salient Points is also evidence that natural twinning has increased
in women who have been exposed to assisted repro-
• Multiple pregnancies arise more frequently duction technologies (Bortolus et al. 1999).
because of modified reproductive strategies
and the availability of assisted reproductive
technologies. 8.2.2 Dizygotic Twinning
• The dizygotic twinning rate is affected by dif-
ferent factors (race, genetic factors, seasonal- In humans, multiple pregnancies arise more fre-
ity, maternal age and parity, endogenous quently from fertilization of two separate oocytes
gonadotropins, fertility drugs, and sex of the (1.2% of pregnancies). The incidence of excessive
8 In Vitro Fertilization and Multiple Pregnancies 131
follicular recruitment is more or less 31% in technologies (ART) have become available.
mothers of dizygotic (DZ) twins. The DZ twinning Because of the higher morbidity and mortality
rate is affected by race, genetic factors, seasonality, associated with twins and particularly triplets,
maternal age and parity, endogenous gonadotro- every effort should be made to reduce the inci-
pins, fertility drugs, and sex of the embryo dence (ESHRE Capri Workshop Group 2000). In
(ESHRE Capri Workshop Group 2000). The inci- Europe, the overall rate of multiple pregnancy in
dence of twin pregnancy also varies from country 2002 was 23% compared to 26% in 2000. This
to country, the highest rates being reported in Nige- reduction has been determined by the transfer of
ria (5%) and the lowest in Japan. In Italy the best fewer embryos, except in Italy where a controver-
estimate of DZ twinning is 1%. It has been sial law obliged the transfer of three embryos until
suggested that genetic predisposition and malnutri- it was recently modified. A similar high preva-
tion may play a role in this different frequency. lence of twinning in ART pregnancies was
Maternal age up to 35–39 years is linked with reported in 2006 in the USA (26%), where such
increasing twinning rates, and this pattern has a policy had not been universally adopted. In the
been attributed to the rise in the level of gonado- USA, the proportion of multiple births attributable
tropins with age (Bortolus et al. 1999). There is a to ovulation induction or ART is 33%. In triplets
slight tendency for twins to have been conceived and higher-order multiple pregnancies this rate
during summer as compared with singletons; and must be even higher.
this may reflect the effect of increased light during
summer on the pineal gland, resulting in melatonin
production, and consequent decreased inhibition 8.4 Placentation
of pituitary follicle-stimulating hormone (FSH)
release (ESHRE Capri Workshop Group 2000). 8.4.1 Chorionicity and Zygosity
Two thirds of spontaneous twin pregnancies are
8.2.3 Monozygotic Twinning dizygotic (DZ), resulting from the fertilization of
two eggs by different spermatozoa, and are therefore
The constant frequency of monozygotic dichorionic (DC). The DC twin placenta of DZ twins
(MZ) pregnancies over time and in different may be composed of separate disks or, alternatively,
areas, and the lack of association between mater- the two placental portions may be fused. Vascular
nal age and frequency of MZ twinning, suggests communications are almost totally absent. The other
that MZ twins are largely determined by genetic third of spontaneous twin pregnancies are monozy-
mechanisms. In fact an excess of monozygotic gotic (MZ), occurring when one single fertilized egg
twins occurs in mothers who are themselves one gives rise to two separate embryos. Of these MZ
of monozygotic twins, whereas there is no evi- pregnancies, a third are DC. The other two thirds
dence for a paternal effect on MZ twinning are monochorionic diamniotic (MCDA), meaning
(Bortolus et al. 1999). that a single placenta serves both embryos and that
vascular communications connecting the twins are
always present. Between 2% and 5% of mono-
8.3 Epidemiology of Iatrogenic chorionic (MC) twins are monoamniotic (MCMA).
Twinning When twinning occurs after approximately 12
days from conception Siamese twins are generated.
There have always been some naturally, or spon- Because of their placental angioarchitecture
taneously, occurring multiple pregnancies (with (Fig. 1), MC twins are more susceptible to addi-
twins being more frequent than triplets, and qua- tional complications than DC twins. In fact,
druplets or even higher multiples being much the presence of vascular anastomoses, which medi-
rarer). However, the frequency has increased ates unidirectional or bidirectional flow between
enormously since assisted reproductive the two circulations, greatly influences intrauterine
132 M. A. Rustico et al.
Fig. 1 Partition of 33% 65% 2%
placentas and chorion,
amniotic sac, and fetuses as
a function from days of
conception in monozygotic
twinning Placentas DICHORIONIC MONOCHORIONIC
Sacs MONOAMNIOTIC
Fetuses SIAMESE
Days 0 3 9 12 15
Fig. 2 Monochorionic
placenta
development and plays a crucial role in causing
those complications specific to MC twins, leading 8.5 Fetal Complications of Twin
to a higher morbidity and mortality than in DC Pregnancy
twins (Benirschke and Kaufmann 2000).
8.5.1 Miscarriage and Fetal Loss
8.5.1.1 Definitions
8.4.2 Monochorionic Placenta The World Health Organization in 2008 reported a
consensus on definitions concerning miscarriage
In multiple pregnancies, ultrasound is a very accu- and fetal loss. Preclinical spontaneous miscar-
rate technique (100% sensitivity and 99% speci- riage: a pregnancy diagnosed only by the detec-
ficity) for determining chorionicity (Fig. 2). In tion of HCG in serum or urine, which does not
twin pregnancies, in the first or early second tri- develop into a clinical pregnancy. Spontaneous
mester, ultrasound examination is mandatory to abortion/miscarriage: the spontaneous loss of a
determine chorionicity in order to assess the clinical pregnancy as diagnosed by ultrasound
obstetric risk which is significantly different in that occurs before 20 completed weeks of gesta-
DC and MC twins (Fig. 3). tional age (18 weeks postfertilization) or, if
8 In Vitro Fertilization and Multiple Pregnancies 133
Fig. 3 (a) Dichorionic twins (lambda sign): chorion and decidua between the two sacs. (b) Monochorionic twins
(T sign), only extraembryonic coelom between the two amniotic membranes
gestational age is unknown, the loss of an embryo/ 16, 18, and 21 account for the most common
fetus of less than 400 g. Vanishing sac(s) or autosomal trisomies in spontaneous pregnancy
embryo(s): spontaneous disappearance of one or losses. Some authors have observed an increased
more gestational sacs or embryos in an ongoing risk of fetal death, and in particular spontaneous
pregnancy, documented by ultrasound. abortion with increasing maternal age, and there is
clear evidence from oocyte donation programs
8.5.1.2 Epidemiology that this risk is associated with the aging of the
The “vanishing twin” phenomenon, which has oocytes (Andersen et al. 2005).
been viewed as part of the general fetal wastage
in human reproduction, suggests that while mul- 8.5.1.4 Diagnosis
tiple conceptions are not rare events, multiple The diagnosis of miscarriage is made by ultrasound
pregnancies are strongly selected against, espe- (US) examination. A biochemical pregnancy is
cially during the early stages of embryonic devel- considered when implantation is revealed on day
opment. The incidence of miscarriage during the 16 by blood test, but there is a negative US scan
first trimester is estimated to be between 10% and result on day 23 (Simón et al. 1999).
20%. The true incidence of vanishing twins is
difficult to assess. Landy and Keith (Landy and
Neith 1998) reviewed the majority of pertinent 8.5.2 Fetal Growth Restriction
studies, most of which described pregnancies con-
ceived as a result of ART. Using these data, it was 8.5.2.1 Definition
estimated that 30% of these twins will ulti- Intrauterine growth restriction (IUGR) is a
mately result in singletons and <10% will end in sonographic diagnosis consisting of either an
a complete abortion. estimated fetal weight below the 5th percentile
of the intrauterine growth chart for gestational
8.5.1.3 Etiology age, or declining abdominal fetal growth below
It is thought that intrinsic abnormalities within the the 5th percentile, or declining more than
embryo are the major reasons for failed concep- 40 centiles from midpregnancy to third trimes-
tions or early fetal death. The most significant ter. Abnormal uterine Doppler velocimetry
intrinsic factor contributing to embryonic loss is and/or an abnormal umbilical Doppler
aberrations in the first meiotic division resulting in velocimetry are considered additional criteria
nondysjunction and aneuploidy. Trisomies 13, 15, of severity (Italian Society of Ultrasound in
134 M. A. Rustico et al.
Obstetrics and Gynecology). In a twin preg- most often defined as the difference in sonographic
nancy, a growth discordance of more than 20% estimated fetal weights expressed as a percentage of
in estimated fetal weight is an index of selective the larger twin’s estimated fetal weight. Growth dis-
growth restriction. crepancy may be mild (<15%), moderate (15–30%),
or severe (>30%). This wide range (from 15% to
8.5.2.2 Epidemiology 30%) is the consequence of clinical neonatal exam-
Neonates from multiple gestations are overrepre- ination. It might help to note that a study by Naeye
sented among preterm and low birth weight (Naeye and Letts 1964) in 1964 showed that the total
infants. Multiple pregnancies weigh less than number of organs and cells is not reduced until
their singleton counterparts. The prevalence of growth discrepancy is more than 25%. However, in
small for gestational age newborns in multiple less severe cases, weight discrepancy is determined
pregnancy is higher than expected in singletons. by a smaller volume of cell cytoplasm. A clinical
Although many variables may influence the refer- diagnosis of growth discordance is better achieved
ence standard, the prevalence of small for gesta- by adding information about fetoplacental conditions
tional fetuses varies between 12% and 47%. to biometric growth curves: for example, amniotic
fluid index, Doppler examination of the umbilical
8.5.2.3 Etiology artery and fetal vessels, computerized analysis of
For most of a pregnancy, twins grow at the same fetal heart rate, maternal complications that fre-
rate as singletons, regardless of chorionicity, up to quently cause placental insufficiency such as gesta-
at least 32 weeks’ gestation. Thereafter, twins tional hypertension and preeclampsia.
show a slower rate of growth (Kingdom et al.
2005). The decreased rate may be related to 8.5.2.5 Consequences
uteroplacental insufficiency. It is thought that, at IUGR has long been known to be associated with
some point in the third trimester, the placenta can perinatal morbidity and mortality. Neonatal mor-
no longer maintain the nutrient requirement of bidity such as meconium aspiration syndrome,
both fetuses. In patients with triplets or high- hypoglycemia, polycythemia, and pulmonary
order multiples, this process occurs earlier. hemorrhage may affect up to 50% of IUGR neo-
When growth restricted fetuses are diagnosed in nates. The high prevalence of IUGR in twin preg-
a twin pregnancy, one should keep in mind the nancies suggests that such patients should be
diverse etiologies of IUGR (such as genetic/chro- included in protocols relating to the management
mosomal problems, fetal anatomical anomalies, of high-risk pregnancies.
placental and cord abnormalities, maternal compli-
cations) rather than assuming that the cause is
uteroplacental insufficiency, which is more frequent 8.6 Preterm Delivery
in twins than singletons. Although IUGR can com-
plicate a pregnancy with growth discordance, the 8.6.1 Definition
latter does not necessarily imply the former unless
growth discordance is less than 20%. It is important Preterm birth (PTB) is defined as a delivery at less
to note that IUGR can affect both twins, leading to than 37 completed weeks’ gestation. This condi-
both twins being small but not discordant. tion can be further divided into late preterm
(33–37 weeks), moderate preterm (28–32
8.5.2.4 Diagnosis weeks), and severe preterm (20–27 weeks).
Knowledge of chorionicity assessed during the first
trimester or by gender discordance is paramount for
managing patients with growth abnormalities. Since 8.6.2 Epidemiology
fetal growth is a dynamic process, serial ultrasound
is helpful in the assessment of fetal growth in patients There is a wide variation in preterm birth rates
with multiple fetuses. In utero growth discordance is between countries, mostly because of different
8 In Vitro Fertilization and Multiple Pregnancies 135
iatrogenic practices. In many states of the confused with the cause of PTB. Efforts should
European Union, about half the children born be made to exclude intrauterine infections and
following multiple births were preterm, account- subclinical chorioamnionitis. Blood and amniotic
ing for between 18% and 25% of preterm birth in tests for infections and abnormalities of fetal heart
each country. The proportion of births before rate should be taken into account. Tocolysis with
37 weeks in twins ranges from 68.4% in Austria Atosiban and bed rest may delay delivery by at
to 42.2% in the Republic of Ireland. This reflects least 48 h, permitting the administration of corti-
different clinical protocols and the consideration costeroids to improve fetal lung maturity. In cases
of twin pregnancies being at high risk and provid- of severe infection, delivery may well be the best
ing parents with leave from work and other social option combined with antibiotic therapy. Opin-
maternal benefits. ions about cervical cerclage vary.
8.6.3 Etiology 8.6.6 Fetal Complications
The etiology of preterm birth depends on multiple Prematurity is the main cause of low birth weight,
factors. The most investigated etiologies both in perinatal mortality, and the most frequent deter-
singletons and twins are infection and maternal minant of neonatal and infant mortality and mor-
stress. Twin pregnancy with its impact on cervical bidity. The following diseases are frequently
integrity is per se a risk factor for ascending infec- associated with prematurity: transient tachypnea
tions. Twin pregnancy is also a risk factor for of the newborn, respiratory distress syndrome,
psychological and physical maternal stress. persistent pulmonary hypertension, respiratory
Other minor risk factors for preterm birth are: failure, temperature instability, jaundice, feeding
cervical incontinence, uterine malformations, difficulties, intraventricular hemorrhage, necrotiz-
infertility, previous preterm birth or intrauterine ing enterocolitis, and brain damage.
fetal death, low social status, and male fetal sex.
8.7 Monochorionic-Related
8.6.4 Diagnosis Complications
High risk for PTB should induce clinicians to A characteristic of all monochorionic twin preg-
make a careful assessment of risk factors and to nancy is the presence of vascular anastomoses
use appropriate diagnostic tests. Among these the between the circulation of both twins on the
evaluation of short cervical length by transvaginal shared placenta (Benirschke 1995).
sonography seems to be the best predictor of PTB. Three types of anastomoses are identifiable:
Infection and other possible direct causes of PTB two superficial ones, artero-arterial anastomoses
should be excluded. Fetal fibronectin in vaginal (AAA) and veno-venous anastomoses (VVA),
secretions may add to the usefulness of cervical which mediate a bidirectional blood flow, and
length measurements. A cervical length 25 mm those that go deep in the cotyledon, artero-venous
at 18 weeks and 22 mm at 24 weeks seems the anastomoses (AVA), which allow unidirectional
best predictors of preterm delivery. flow (Fig. 2).
The difference in type, position, and size
of these anastomoses and the proportion of exten-
8.6.5 Prevention sion of each vascular territory contributes to
bringing about certain complications typical
Cervical length measurement, the fibronectin test, of monochorionic twin pregnancies, including
and the assessment of uterine contractions might twin-twin transfusion syndrome (TTTS), selective
diagnose impending PTB but should not be intrauterine growth restriction (sIUGR), and twin
136 M. A. Rustico et al.
anemia-polycythemia sequence (TAPS) (Lanna The traditional neonatal criteria for diagnosing
et al. 2015). TTTS, based on an inter-twin hemoglobin difference
(>5 g/100 mL) and weight discordance (>20%), do
not apply in utero because similar discrepancies in
8.7.1 Twin-to-Twin Transfusion hemoglobin and birthweight are also found in DC
Syndrome and in MC twins complicated by sIUGR and TAPS,
without TTTS (Denbow et al. 1998).
TTTS is the best-known complication of MC preg- The diagnosis of TTTS is only made by ultra-
nancies, occurring in approximately 10% of cases sound (Fig. 4). In a twin pregnancy with a single
(Lewi et al. 2008). Although hormonal and hemo- placental mass, twins of the same gender, and a thin
dynamic mechanisms may be involved, the current membrane dividing the twins, the crucial ultrasound
interpretation of TTTS is that it is caused by an sign for the diagnosis of TTTS is the combined
imbalance in the blood exchange between one presence of polyuric polyhydramnios in one sac
twin (the donor) and the other (the recipient) via (deepest vertical pocket >8 cm before 20 weeks’
placental anastomoses, due to a relative excess of gestation, >10 cm after 20 weeks’ gestation) and
unidirectional arterio-venous connections not com- oligouric oligohydramnios in the other (deepest ver-
pensated by reverse flow through other anastomo- tical pocket <2 cm) (Fig. 2) (Senat et al. 2004).
ses. When a significant imbalance in blood flow TTTS is classified into five stages using the
occurs, the donor twin becomes hypovolemic and Quintero staging system, based on ultrasound
oliguric, develops severe oligohydramnios and criteria. Stages I or II are when the donor bladder
Doppler signs of placental insufficiency. The recip- is still either visible or empty, in association with the
ient twin shows hypervolemia, polyuria, and poly- polyhydramnios-oligohydramnios sequence. Stage
hydramnios, with cardiac overload, leading in III is when Doppler findings are abnormal for either
severe cases to hydrops (Galea et al. 2008). Without twin, while Stage IV and V are when there is con-
treatment, the prognosis is poor, with perinatal mor- gestive cardiac failure and hydrops in the recipient
tality as high as 90%. In survivors, preterm birth due or the death of one or both twins (Quintero et al.
to polyhydramnios is a major cause of mortality and 1999).
morbidity. At 4 years follow-up, the incidence of Considering the poor survival rate and the risk
cerebral palsy and abnormal neurologic develop- of neurological complications due to antenatal or
ment is 21% in surviving twins with TTTS postnatal injury, treatment should be offered in all
(Lopriore et al. 2003). cases.
Fig. 4 Ultrasonographic evidence of TTTS: on the left the donor twin with anydramnios; on the right the recipient twin
with polyhydramnios
8 In Vitro Fertilization and Multiple Pregnancies 137
In the past, the most common treatment for polycithemia sequence (TAPS)) occurring after
TTTS was serial amnioreduction (AR), which selective or nonselective laser treatment were
works by reducing the risk of preterm delivery related to the persistence of residual small anas-
secondary to uterine distension and possibly also tomoses found in almost 20% of treated pla-
by reopening compensatory placental vascular centas (Lewi et al. 2006) led to a new approach
anastomoses. For MC twin pregnancies compli- named the Solomon technique. Taking inspira-
cated by TTTS before 28 weeks, the International tion from the story of King Solomon, this pro-
Amnioreduction Registry reported an overall sur- cedure involves the coagulation of the entire
vival rate at birth of 78%. In survivors, a central territory between any anastomoses identified
nervous system scan was abnormal in 25% of with the selective procedure, with the aim of
cases at 1 month of life (Mari et al. 2001). obtaining complete dichorionization of the pla-
In more recent years, endoscopic laser coagu- centa (Fig. 5). The Solomon randomized trial
lation of the placental anastomoses, a procedure (Slaghekke et al. 2014a) compared the two sur-
first described by De Lia in 1995, has been gical approaches, selective and Solomon tech-
adopted as an effective treatment for TTTS nique, and demonstrated better outcomes with
because it severs the vascular connections which the latter (Table 1).
are thought to be responsible for the syndrome. Improvement of skills and technique lead to a
The Eurofetus randomized trial Senat et al. better perinatal outcome. In our own experience,
(2004) compared serial amnioreduction with laser perinatal survival has improved from 52% (first
coagulation and demonstrated that laser coagula- 150 cases (Rustico et al. 2012) to 65.1% in the last
tion is the best first-line treatment for TTTS diag- 205 pregnancies treated, with a higher survival
nosed before 26 weeks, with a better neurological rate after the introduction of Solomon technique
outcome than serial amniotic reduction. The rate of (77%).
periventricular leukomalacia in the laser group was Postnatal complications have been described
6% versus 14% in the AR group ( p = 0.002). both in ex-recipient and in ex-donor twin after
laser therapy. The recipient twin, which is
8.7.1.1 Laser Treatment in Twin-to-Twin
Transfusion Syndrome
This procedure is performed with fetoscopy under
local anesthesia. A 3 mm cannula is introduced in
the amniotic sac of the recipient twin under ultra-
sound guidance using a percutaneous approach. A
2 mm fiberscope is then passed through the can-
nula, so that the operator can explore the fetal
surface of the placenta to identify the vascular
connections and perform coagulation with a
400 μm laser fiber.
Two ways of performing the procedure have
been compared: the nonselective technique, that
requires coagulation of all vessels crossing the
insertion of the inter-twin membrane, and the
selective technique, that interrupts only those ves-
sels involved in blood exchange between twins.
The selective technique has proved to have a
better outcome in terms of at least one survivor
Fig. 5 Monochorionic placenta after laser coagulation of
(Quintero et al. 2000).
vascular anastomoses by Solomon technique. The com-
Emerging evidence that the fetal complica- plete dicorionization is evidenced by color dye injection
tions (recurrence of TTTS and anemia – of the vascular territories
138 M. A. Rustico et al.
Table 1 Comparison of different series consisting of more than 100 endoscopic laser coagulations of placental vessels,
performed using different techniques
Median GA Median GA Overall Survivors
N. (weeks) at (weeks) at survival rate (%)
First author cases procedure delivery (%) 2 1 1 0
Hecher et al. 127 20 34 68 54 27 81 19
(2000)
Robyr et al. 101 21 32.1 76 66 22 88 12
(2006)
Huber et al. 200 20 34.3 71 59 24 83 17
(2006)
Quintero 193 20 33.7 77 65 23 88 12
et al. (2000)
Middeldorp 100 21 33 69 58 23 81 19
et al. (2007)
Stirnemann 287 20 32.4 38 42 33 75 25
et al. (2008)
Cincotta et al. 100 21 31 75 66 19 85 15
(2009)
Morris et al. 164 20.4 33.2 62 38 43 85 15
(2010)
Rustico et al. 150 20.6 32.1 52 33 39 72 28
(2012)
Valsky et al. 334 16–26 vs. >26 33 79 68 22 90 10
(2012)
Baud et al. 325 >16 vs. >26 31 72 63 24 87 13
(2013)
Baschat et al. 147 20 31.3 74 60 28 88 12
(2013)
Ruano et al. 102 20 32 63 65 15 80 20
(2013)
Slaghekke 272 20 32 73 62 23 85 15
et al. (2014a)
hypervolemic, may develop right-heart hyper- survivors after laser, are related to unbalanced
trophy with a tricuspid valve regurgitation lead- blood flow and may occur before laser treat-
ing to valvular pulmonary stenosis. This cardiac ment of TTTS. Cerebral palsy affects nearly
abnormality may persist after successful laser 6% of twins after laser; the risk of
treatment because myocardial tissue may have neurodevelopment impairment increases sig-
been already damaged by persistent overload. In nificantly with prematurity (van Klink et al.
selected cases, pulmonary stenosis may be so 2013). Neurological outcome worsens when
severe that balloon valvuloplasty is required laser treatment is performed at advanced gesta-
after birth (Stagnati et al. 2015). Similarly, tional age and with a III/IV Quintero stage of
severe hypovolemia may cause renal insuffi- TTTS.
ciency. In this case, laser treatment can preserve
kidney function in the surviving twin by
establishing a normal circulating volume. 8.7.2 Twin Anemia-Polycythemia
For both twins, neonatal morbidity is mainly Sequence (TAPS)
related to neurological outcome. Most cerebral
lesions result from hemorrhagic or ischemic Postnatal evidence of significant hemoglobin dis-
injury. These lesions, which affect 10% of cordance in some monochorionic twins at birth, in
8 In Vitro Fertilization and Multiple Pregnancies 139
Fig. 6 Monochorionic
placenta of a twin
pregnancy complicated by
twin anemia-polycythemia
sequence (TAPS): in blue
and green the arteries, in red
and yellow the veins. In
detail the small artero-
venous anastomoses
absence of any prenatal sign of TTTS, indicates mandatory. The options for active management
the presence of another complication typical of are selective feticide of the more compromised
these pregnancies: the twin anemia-polycytemia twin, laser coagulation of the residual anastomo-
sequence. ses, or in utero fetal transfusion of the anemic
In recent years, the diagnostic criteria have twin.
been precisely defined, both during the prenatal
and postnatal life of twins (Slaghekke et al. 2010).
In utero, Doppler velocimetry of the middle 8.7.3 Selective Intrauterine Growth
cerebral artery makes it possible to correlate the Restriction of One Twin (sIUGR)
peak velocity value during systole with fetal
hematocrit: prenatal TAPS is defined when a A typical complication of MC twin pregnancies is
MCA-PV value is >1.55 MoM in one twin selective interauterine growth restriction of one
(indicative of anemia) and <0.8 MoM in the twin (sIUGR) which is present in 10% of cases
other twin (indicative of polycytemia). (Lewi et al. 2008).
Postnatal TAPS is defined by a hemoglobin Diagnosis is made in presence of a discordance
discordance between twins >8.0 g /dL and at least in estimated fetal weight of twins 25% or by an
one of the following: reticolocyte count ratio >1.7 estimated fetal weight in one twin 10 percen-
or evidence of an artero-venous anastomoses tile, without the signs of TTTS described above.
<1 mm on placenta surface (Fig. 6). In this small The sIUGR worsens fetal and neonatal out-
anastomoses, the volume of bloodflow between come, since it increases the risk of in utero fetal
twins cannot be as large as in TTTS, so the passage death of one or both twins and the risk of postnatal
of only erythrocytes gives rise to TAPS. complications.
On the basis of these criteria, TAPS compli- Prenatal surveillance of these pregnancies
cates 3–13% of MC twins and can develop after includes Doppler velocimetry of umbilical artery
laser treatment for TTTS, whenever a small anas- to gauge the severity of the condition and, in case
tomoses is left uncoagulated. of deterioration, to identify the best management
In some cases, spontaneous resolution of TAPS option depending on gestational age and parental
can be observed. Whenever there is a progression choice: either selective feticide of the IUGR twin
of sequence, both twins are at risk of death in utero or delivery of both twin.
or of neurologic sequelae (Slaghekke et al. Table 2 shows the postnatal outcome of a series
2014b). For that reason, tailored management is of 140 cases managed at the Fetal Therapy Unit
140 M. A. Rustico et al.
Table 2 Neonatal/infant outcome in monochorionic diamniotic twin pregnancies complicated by sIUGR
sIUGR twin Large twin Total
N (%) N (%) N (%) p-value
Neonatal death 17/140 (12.1)a 9/140 (6.4) 26/280 (9.3) n.s.
Neonatal/infant outcome (N/217)b 97 (44.7) 120 (55.3) 217
Healthy infants 75 (77.3) 107 (89.2) 182 (83.9) 0.03
Neonates/infants with complications 22 (22.7) 13 (10.8) 35 (16.1)
Severe neurologic morbidity 5 (5.2) 6 (5.0) 11 (5.1) n.s.
Spastic bilateral cerebral palsy 2 2 4
Diplegia 2 3 5
Quadriplegia
1 1 2
Bilateral deafness
Moderate neurologic morbidity 2 (2.1) 1 (0.8) 3 (1.4) n.s.
Unilateral deafness 1 0 1
Attention deficit Hyperactivity disorder 1 1 2
Mild neurologic morbidity 6 (6.2) 1 (0.8) 7 (3.2) 0.05
Congenital heart disease 3 (3.1)c 2 (1.7)d 5 (2.3) n.s.
Necrotizing enterocolitis 1 (1.0) 1 (0.8) 2 (0.9) n.s.
Chronic lung disease 2 (2.1) 1 (0.8) 3 (1.3) n.s.
ROP stage III 1 (1.0) 0 (0) 1 (0.5) n.s.
Syndromese 1 (1.0) 1 (0.8) 2 (0.9) n.s.
Other (Intrahepatic bile ducts hypoplasia) 1 (1.0) 0 1 (0.5) n.s
a
Three neonatal deaths of sIUGR twin occurred from cardiac anomaly: Two aortic coarctation (after surgery), One
complete AV block
b
n.43 IUGR twins and 20 large twins were lost in utero
c
One ventricular septal defect, One ostium secundum type atrial septal defect, One aortic coarctation
d
One ventricular septal defect, One pulmonary valve stenosis. All babies had surgery before 1 year of life
e
Neurofibromatosis, affecting both twins
“U. Nicolini” at the V. Buzzi Hospital, Milan to hypoperfusion (Fusi et al. 1991). Sequelae
(Rustico et al. 2016). include ischemic cerebral lesions, periventricular
At follow-up, 13 IUGR and eight large neo- leukomalacia, renal cortical necrosis, and small
nates/infants (9.7% of survivors) showed neuro- bowel atresia. A recent review of all published
logic morbidity. Even though the incidence of series on single IUFDs underlined how chorionicity
severe neurologic morbidity was similar between makes the difference: MC survivor twins run a five
IUGR and large twins, the occurrence of mild times higher risk of dying (15%) than DC twins and
neurodevelopmental impairment was higher in a four times higher risk of neurological sequelae
the IUGR infants ( p = 0.05). (26%) than DC twins (Shek et al. 2014). The risk of
an adverse outcome for the surviving co-twin
depends on the gestational age at the time of intra-
8.7.4 Single Intrauterine Death uterine death and the interval between death and
delivery. In early pregnancy, the death of one twin
In MC twin pregnancies, the death of one twin, frequently causes the death of the other fetus, but
which occurs in about 6% of these pregnancies, severe sequelae in the survivor are less common
puts the co-twin at greater risk of mortality and than at a more advanced gestation. Immediate deliv-
morbidity. The mechanism for this adverse outcome ery after a single intrauterine death only adds the
is blood loss from the dying twin through placental risks of prematurity to the surviving twin. Indeed,
vascular anastomoses. This leads to hypovolemia, damage may occur at the moment of death of the
which may cause the death of the co-twin from co-twin and therefore may not be preventable. Intra-
hypovolemic shock or parenchymal damage due uterine transfusion can be a therapeutic solution but,
8 In Vitro Fertilization and Multiple Pregnancies 141
if the critical moment preceding fetal death is mis- abdominal wall anomalies, and cardiac disorders.
sed, there is no treatment and conservative manage- The prevalence of cardiac defects has been
ment is recommended (Nicolini and Poblete 1999). reported as 2.3% in twins without TTTS, and 7%
Dedicated ultrasonography of the fetal brain and in those with TTTS, compared to 1% in the gen-
magnetic resonance imaging (MRI) 2–3 weeks eral population (Karatza et al. 2002).
after an intrauterine fetal death may provide useful Structural malformations which are not geneti-
information for predicting neurodevelopmental out- cally determined may affect only one of the two
come in the surviving twin. MZ twins. It has been estimated that both twins are
Monochorionic twin survivors of a single affected in less than 20% of cases, while in the
IUFD after laser coagulation of placental anasto- majority of cases only one twin is involved.
mosis for treatment of TTTS, or after a selective When a fetal anomaly affects only one fetus, clini-
feticide, are less exposed to neurological sequelae cians face the dilemma of choosing between expec-
(O'Donoghue et al. 2009). tant management or selective termination of the
At the Fetal Therapy Unit “U Nicolini,” at anomalous fetus. The primary goal is to prevent
V. Buzzi Hospital, Milan, the rate of neurologi- the death of the normal twin. In monochorionic
cal sequelae in monochorionic twin survivors twin pregnancies, selective termination needs to
after spontaneous single IUFD was 16% be performed by ensuring complete and permanent
(13 cases out of 79 pregnancies) higher than occlusion of the umbilical cord of the abnormal
reported in single survivors after laser treatment twin, in order to avoid acute hemorrhage from the
for TTTS (8%, 9 out of 109 treated pregnancies co-twin into the dying fetus, a process which may
with one survivor) or after selective feticide with lead to death or organ damage (Rustico et al. 2005)
bipolar cord coagulation (5%, 7 cases out of Bipolar cord occlusion under ultrasound guidance
128 pregnancies with a survivor twin). In 77% is still considered the best method for selective
of all those cases, prenatal ultrasound and MRI feticide in these cases (Lanna et al. 2012).
detected the brain lesion; in the remaining cases, Between 2004 and 2015, we observed 174 MC
delivery of the baby occurred before MRI could pregnancies with fetal anomaly (in a series of
be performed. 1750 MC twin pregnancies). In this cohort, a
discordant anomaly was detected in 159 (91.4%)
cases. Figure 7 summarizes the type of anomalies
8.7.5 Twins Discordant for Fetal observed.
Anomalies
An excess of structural anomalies is observed in 8.7.6 Twin Reversed Arterial
twins compared to singletons. While the fre- Perfusion (TRAP) Syndrome
quency of malformations in a DZ pregnancy is
similar to that for singletons (2–3%), it is two or Twin reversed arterial perfusion (TRAP)
three times higher than in a MZ pregnancy (Hall sequence, also known as acardiac twinning, is a
2003). The reason is unknown, but it might be rare complication of MC pregnancies which can
considered to be part of a teratogenic process lead to an unfavorable outcome for the normal
during twinning. co-twin. The reported incidence is 1 in 35,000
MZ twins are considered identical, but recent deliveries or 1% of MZ twins. In this condition,
observations have reported that this is not the rule, there is a twin without any functional cardiac
and a number of discordances have been observed tissue and variable developmental disruption (the
for chromosomal anomalies (such as trisomy acardiac twin). The acardiac twin is perfused by
21 and Turner syndrome), single gene disorders, the normal twin (the pump twin) by arterial blood
X-linked diseases (such as Fragile-X, Aicardi’s flowing in a retrograde fashion through a single
syndrome), and structural defects. These struc- superficial artery-to-artery placental anastomoses.
tural defects include malformations of the brain, Poorly oxygenated blood bypasses the placenta,
142 M. A. Rustico et al.
174 MC pregnancies with fetal anomaly
(structural anomaly or abnormal karyotype)
15 (8.6%) Both fetuses with anomaly 159 (91.4%) One fetus with anomaly
10 (66.7%) 5 (33.3%) 151 (95.0%) 8 (5.0%)
Structural anomaly Abnormal karyotype Structural anomaly Abnormal karyotype
2 CHD/CHD 3 trisomy 21/21 54 CNS 6 45 X0
1 CHD/LUTO 1 47 XXY/47 XXY 28 CHD 1 47 XX + mar (18p)
1 CHD/ multiple an. 1 45 X0/45 X0 16 multiple anomal 1 46 XY/47 +5
1CHD/DH 16 urinary tract
2 multiple an/Kidney 14 GE
1 Apert sy/Apert sy 8 skeleton
1LPS/LPS 5 Thorax
1CNS/CNS 4 syndromes
4 Limphatic anom
2 other
Fig. 7 Type of anomalies in a series of 174 MC twin pregnancies (personal experience)
enters the acardiac twin’s circulation at low pres- In a series of 46 cases of TRAP sequence
sure, and preferentially perfuses its lower part. during the period 2004–2013, 18 cases were man-
The blood flow returns to the pump twin via a aged expectantly. In four cases, intrauterine death
single vein-to-vein connection (Benirschke and of both twins occurred before 18 weeks. In three
Kaufmann 2000). The acardiac twin acts as a cases, there was a miscarriage. Eleven cases were
parasite and space-occupying mass, being hemo- delivered near term, with one neonatal death and
dynamically dependent on the other twin. Perina- one baby (where the acardiac fetus was very large,
tal mortality rates reported for the pump twin up to 1.5 kg) had a poor neurological outcome and
range from 35% to 55%. periventricular leukomalacia.
The primary causes leading to poor perinatal In 28 cases, a cord occlusion of acardiac twin
outcome are preterm delivery (because of the con- or interstitial laser was performed. Apart from
tinuing growth of the acardiac fetus) and congestive complications related to the invasive procedures
heart failure (because of the volume of the acardiac (8/28), 18 of the 28 cases (64%) who had in utero
twin’s mass needing to be perfused by the normal treatment are alive and well and free of neurolog-
heart). The deoxygenated blood circulating back to ical complications at postnatal follow-up.
the pump may also cause chronic hypoxia, growth
restriction, and hypoxic ischemic lesions.
In the case of rapid enlargement of the acardiac 8.8 Monoamniotic Twinning
twin mass or signs of cardiac overload in the
pump twin, blockade of the vascular supply to Monoamniotic (MA) twinning is a rare condition,
the parasitic twin is recommended. Possible treat- affecting 2% of all MZ pregnancies. MA twins
ments include intrafetal ablation procedures such share the same placenta and the amniotic sac and
as radiofrequency, interstitial laser, or cord occlu- are at higher risk of structural anomalies, unex-
sion of the acardiac twin. Although no single pected fetal death, and perinatal death (ranging
technique has been conclusively shown to be the from 30% to 70%), compared with MCDA
best, some form of antenatal treatment seems to be twins. The excess fetal loss can be explained by
beneficial, because there is a reported overall umbilical cord entanglement (Fig. 8), and a cru-
pump twin survival rate of 76%. cial cofactor may be acute exsanguination across
8 In Vitro Fertilization and Multiple Pregnancies 143
Fig. 8 Monoamniotic twin
placenta with cord
entaglement: twins were
born at 32 weeks gestation
large placental anastomoses. Recent reviews com- both the arterial and venous blood flow in the
pared the largest series reported and indicate an umbilical cord of the affected twin. Numerous
improvement in perinatal outcome over the years: ways of achieving this have been described in
the fetal loss is 11.4%, but in viable pregnancies the literature. Ligation of the umbilical cord by
after 24 weeks of gestational age mortality rate has fetoscopy has been abandoned because of the
been reported as 2% and is not correlated to the complexity of the procedure and the lengthy
prenatal presence of cord entanglement (Ishii operating time.
2015; Rossi and Prefumo 2013). Based on the Fetoscopic laser coagulation has been
observation that the risk of neonatal death associ- performed as early as 16 weeks but is less effec-
ated with preterm birth at 32 weeks is 1 in 100, the tive at a more advanced gestational age or in
risk for MA twins at this gestational age appears to presence of an edematous cord. The experience
be four times lower. with radiofrequency ablation initially used for the
treatment of TRAP sequence has recently been
extended to non-TRAP fetuses. Ultrasound-
8.9 Cord Occlusion guided bipolar cord coagulation (BCC) can be
in Monochorionic Twins used at a later gestational age and in recent years
has probably become the most common technique
In some MC twin pregnancies complicated by used for selective feticide in complicated MC
TTTS, sIUGR, TRAP sequence, or TAPS the pregnancies.
risk of IUD of one twin can be so high that With a local anesthesia, a 3.3 mm cannula is
selective termination of pregnancy (TOP) can be introduced in the uterine cavity under ultrasound
the last opportunity to save at least one fetus. In guidance. Coagulation is obtained by a power of
some other cases, parents require selective feticide 50 W for 30–40 s with the aim of reducing blood
for a severe discordant anomaly. flow in the placenta of the selected fetus.
The presence of placental vascular anastomo- Whatever the technique, the risk of fetal loss is
ses connecting the two fetal circulations makes it closely correlated to the gestational age at time of
impossible to inject a drug for selective feticide, procedure: after 19 weeks gestational age, the risk of
since there could be leakage into the normal miscarriage and in utero fetal demise of the co-twin
co-twin’s circulation, causing immediate death. diminishes dramatically (Lanna et al. 2012).
The feticide of a MC twin has to be performed Perinatal outcome in the surviving twin is
with at least complete and permanent occlusion of dependent on gestational age at birth: risk of
144
Table 3 Cord occlusion in complicated monochorionic twin pregnancies: pregnancy outcomea
IUD TOP Ab pPROM PD PND Overall
<24 weeks <32 weeks surv
GA (weeks) at procedure n GA (weeks) at delivery median
Indication N. cases median n (%) (%) n (%) n (%) n (%) (range) n (%) n (%)
TTTS 50 22.3 5 (10) 1 (2) 5 5 (10) 15 (30) 33 (25–40) 5 34 (68)
(10) (10)
sIUGR 34 21.6 3 (9) 0 0 2 (6) 9 (26) 33.5 (23.5–40) 2 (6) 29 (85)
Anomaly 59 22.1 7(12) 0 5 (8) 5 (8) 9 (15) 37 (25–41) 4 (7) 43 (73)
TRAP s 6 22 2 (33) 0 1(16) 0 3 (50) 33 (30–37) 0 3 (50)
Total 149 22.1 17 1 (1) 11 12 (7) 36 (24) 34 (23.5–41) 11 109
(11) (7) (7) (73)
TTTS twin-to-twin transfusion syndrome, sIUGR selective intrauterine growth restriction of one twin, GA gestational age, IUD intrauterine death, TOP termination of preg-
nancy, Ab abortion, PD premature delivery, pPROM premature rupture of membrane, PND perinatal death
a
Fetal Medicine Unit, Buzzi Children’s Hospital, Milan (1999–2014). First 118 cases are reported in reference Lanna et al. (2012)
M. A. Rustico et al.
8 In Vitro Fertilization and Multiple Pregnancies 145
premature delivery before 32 weeks is increased damaged survivors after intrauterine death of a mono-
after selective feticide because of pPROM. chorionic twin. Obstet Gynecol 78:517–520
Galea P, Barigye O, Wee L et al (2008) The placenta
In a cohort of 149 pregnancies undergoing contributes to activation of the renin angiotensin sys-
umbilical cord occlusion using bipolar coagulation, tem in twin-to-twin transfusion syndrome. Placenta
preterm delivery occurred in 33% of cases, with a 29:734–742
procedure-to-delivery interval which varied from Hall JG (2003) Twinning. Lancet 362:735–743
Hecher K, Diehl W, Zikulnig L et al (2000) Endoscopic
1 to 22 weeks (median 11 weeks) (Table 3). laser coagulation of placental anastomoses in 200 preg-
A review reported a prevalence of 4–7% of nancies with severe mid-trimester twin-to-twin transfu-
severe neurological lesions in surviving MC sion syndrome. Eur J Obstet Gynecol Reprod Biol
twins (Rossi and Prefumo 2013). This percentage 92:135–139
Huber A, Diehl W, Bregenzer T (2006) Stage-related out-
is lower than expected if compared with neuro- come in twin-twin transfusion syndrome treated by
logical morbidity in surviving twins after the fetoscopic laser coagulation. Obstet Gynecol
spontaneous IUD of the co-twin, which accounts 108:333–337
for 22% of cases. Ishii K (2015) Prenatal diagnosis and management of
monoamniotic twins. Curr Opin Obstet Gynecol
27:159–164
Karatza AA, Wolfenden JL, Taylor MJO et al (2002) Influ-
ence of twin-to-twin transfusion syndrome on fetal
References cardiovascular structure and function: prospective
case–control study of 136 monochorionic twin preg-
Andersen AN, Gianaroli L, Felberbaum R et al (2005) nancies. Heart 88:271–277
Assisted reproductive technology in Europe, 2001. Kingdom CP, Nevi O, Murphy KE (2005) Discordant
Results generated from European registers by growth in twins. Prenat Diag 25:759–765
ESHRE. Hum Reprod 20:1158–1176 Landy HJ, Neith LG (1998) The vanishing twin: a review.
Astolfi P, Ulizzi L, Zonta LA (2003) Changes in twinning Hum Reprod Update 4:177–183
rate: Italy 1950–1996. Hum Reprod 18:207–211 Lanna MM, Rustico MA, Dell’Avanzo M et al (2012)
Baschat AA, Barber J, Pedersen N et al (2013) Outcome Bipolar cord coagulation for selective feticide in com-
after fetoscopic selective laser ablation of placental plicated monochorionic twin pregnancies: 118 consec-
anastomoses vs equatorial laser dichorionization for utive cases at a single center. Ultrasound Obstet
the treatment of twin-to-twin transfusion syndrome. Gynecol 39:407–413
Am J Obstet Gynecol 209:234e.1–234e.8 Lanna MM, Consonni D, Faiola S et al (2015) Color-
Baud D, Windrim R, Keunen J et al (2013) Fetoscopic laser dye injection of monochorionic placentas and
therapy for twin-twin transfusion syndrome before correlation with pregnancy complications. Placenta
17 and after 26 weeks’ gestation. Am J Obstet Gynecol 36:1095–1099
208:197.e1–197.e7 Lewi L, Jani J, Cannie M et al (2006) Intertwin anastomo-
Benirschke K (1995) The biology of the twinning process: ses in monochorionic placentas after fetoscopic laser
how placentation influences outcome. Semin Perinatol coagulation for twin-to-twin transfusion syndrome: is
19:342–350 there more than meets the eye? Am J Obstet Gynecol
Benirschke K, Kaufmann P (eds) (2000) Pathology of the 194:790–795
human placenta. Springer, New York Lewi L, Jani J, Blickstein I et al (2008) The outcome of
Bortolus R, Parazzini F, Chatenoud L et al (1999) The monochorionic diamniotic twin gestations in the era of
epidemiology of multiple births. Hum Reprod Update invasive fetal therapy: a prospective cohort study. Am J
5:179–187 Obstet Gynecol 199:514e1–514e8
Cincotta RB, Gray PH, Gardener G et al (2009) Selective Lopriore E, Nagel HT, Vandenbussche FP et al (2003)
fetoscopic laser ablation in 100 consecutive pregnan- Long term neurodevelopmental outcome in twin-to-
cies with severe twin-twin transfusion syndrome. Aust twin transfusion syndrome. Am J Obstet Gynecol
N Z J Obstet Gynaecol 49:22–27 189:1314–1319
Denbow M, Fogliani R, Kyle P et al (1998) Mari G, Roberts A, Detti L et al (2001) Perinatal morbidity
Haematological indices at fetal blood sampling in and mortality rates in severe twin-twin transfusion syn-
monochorionic pregnancies complicated by feto-fetal drome: results of the International Amnioreduction
transfusion syndrome. Prenat Diagn 18:941–946 Registry. Am J Obstet Gynecol 185:708–715
ESHRE Capri Workshop Group (2000) Multiple gestation Middeldorp JM, Sueters M, Lopriore E et al (2007)
pregnancy. Hum Reprod 15:1856–1864 Fetoscopic laser surgery in 100 pregnancies with severe
Fusi L, McParland P, Fisk N et al (1991) Acute twin-to- twin-to-twin transfusion syndrome in the Netherlands.
twin transfusion: a possible mechanism for brain Fetal Diagn Ther 22:190–194
146 M. A. Rustico et al.
Morris RK, Selman TJ, Harbidge A et al (2010) Fetoscopic flow and outcomes. Ultrasound Obstet Gynecol
laser coagulation for severe twin-to-twin transfusion 8:45–56. https://doi.org/10.1002/uog.15933
syndrome: factors influencing perinatal outcome, learn- Senat M, Deprest J, Bulvain M et al (2004) Endoscopic
ing curve of the procedure and lessons for new centres. laser surgery versus serial amnioreduction for severe
BJOG 117:1350–1357 twin-to-twin transfusion syndrome. N Engl J Med
Naeye RL, Letts HW (1964) Body measurements of fetal 351:136–144
and neonatal twins. Arch Pathol 77:393–396 Shek NW, Hillman SC, Kilby MD (2014) Single-twin
Nicolini U, Poblete A (1999) Single intrauterine death in demise: pregnancy outcome. Best Pract Res Clin
monochorionic twin pregnancies. Ultrasound Obstet Obstet Gynaecol 28:249–263
Gynecol 14:297–301 Simón C, Landeras J, Zuzuarregui JL et al (1999) Early
O’Donoghue K, Rutherford MA, Engineer N et al (2009) pregnancy losses in in vitro fertilization and oocyte
Transfusional fetal complications after single intrauter- donation. Fertil Steril 72:1061–1065
ine death in monochorionic multiple pregnancy are Slaghekke F, Kist WJ, Oepkes D et al (2010) Twin anemia-
reduced but not prevented by vascular occlusion. polycythemia sequence: diagnostic criteria, classifica-
BJOG 116:804–812 tion, perinatal management and outcome. Fetal Diagn
Quintero RA, Moeales WJ, Allen MH et al (1999) Staging Ther 27:181–190
of twin-to-twin transfusion syndrome. J Perinatol Slaghekke F, Lopriore E, Lewi L et al (2014a) Fetoscopic
19:550–555 laser coagulation of the vascular equator versus selective
Quintero RA, Comas C, Bornick PW et al (2000) Selective coagulation for twin-to-twin transfusion syndrome: an
versus non-selective laser photocoagulation of placen- open-label randomised controlled trial. Lancet 383
tal vessels in twin-to-twin transfusion syndrome. Ultra- (9935):2144–2151. https://doi.org/10.1016/S0140-6736
sound Obstet Gynecol 16:230–236 (13)62419-8
Robyr R, Lewi L, Salomon LJ et al (2006) Prevalence and Slaghekke F, van Klink JM, Koopman HM et al (2014b)
management of late fetal complications following suc- Neurodevelopmental outcome in twin anemia-
cessful selective laser coagulation of chorionic plate polycythemia sequence after laser surgery for twin-
anastomoses in twin-to-twin transfusion syndrome. twin transfusion syndrome. Ultrasound Obstet Gynecol
Am J Obstet Gynecol 194:796–803 44:316–321
Rossi AC, Prefumo F (2013) Impact of cord entanglement Stagnati V, Chalouhi GE, Essaoui M et al (2015) Pulmo-
on perinatal outcome of monoamniotic twins: a system- nary stenosis in complicated monochorionic twin preg-
atic review of the literature. Ultrasound Obstet Gynecol nancies: prevalence, management and outcome. Prenat
41:131–135 Diagn 35:1085–1092
Ruano R, Rodo C, Peiro JL et al (2013) Fetoscopic laser Stirnemann JJ, Nasr B, Quarello E et al (2008) A definition
ablation of placental anastomoses in twin-twin transfu- of selectivity in laser coagulation of chorionic plate
sion syndrome using ‘Solomon technique’. Ultrasound anastomoses in twin-to-twin transfusion syndrome
Obstet Gynecol 42:434–439 and its relationship to perinatal outcome. Am J Obstet
Rustico MA, Baietti MG, Coviello D et al (2005) Manag- Gynecol 198:62.e1–62.e6
ing twins discordant for fetal anomalies. Prenat Diagn Valsky DV, Eixarch E, Martinez-Crespo JM et al (2012)
25:766–771 Fetoscopic laser surgery for twin-to-twin transfusion
Rustico MA, Lanna MM, Faiola S et al (2012) Fetal syndrome after 26 weeks of gestation. Fetal Diagn
and maternal complications after selective Ther 31:30–34
fetoscopic laser surgery for twin-to-twin transfusion van Klink JM, Koopman HM, van Zwet EW et al
syndrome: a single-center experience. Fetal Diagn (2013) Cerebral injury and neurodevelopmental
Ther 31:170–178 impairment after amnioreduction versus laser sur-
Rustico MA, Consonni D, Lanna MM et al. (2016) Selec- gery in twin-twin transfusion syndrome: a system-
tive intrauterinbe growth restriction in monochorionic atic review and meta-analysis. Fetal Diagn Ther
twins: changing pattern in umbilical artery Doppler 33:81–89
Intrauterine Growth Restriction:
Obstetric and Neonatal Aspects. 9
Intervention Strategies
Enrico Bertino, Giovanna Oggè, Paola Di Nicola,
Francesca Giuliani, Alessandra Coscia, and Tullia Todros
Contents
9.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
9.2 Normal and Abnormal Fetal Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
9.3 Diagnosis of IUGR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
9.4 Monitoring, Timing and Mode of Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
9.5 Auxological Evaluation of the Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
9.6 Neonatal Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
9.6.1 Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
9.6.2 Asphyxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
9.6.3 Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
9.6.4 Coagulation Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
9.6.5 Thermoregulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
9.6.6 Hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
9.6.7 Polycytemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
9.7 Respiratory Distress Syndrome (RDS) and Bronchopulmonary Dysplasia
(BPD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
9.7.1 Retinopathy of Prematurity (ROP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
9.7.2 Necrotizing Enterocolitis (NEC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
9.8 Long-Term Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
9.8.1 Postnatal Growth Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
9.8.2 Neurological Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
9.8.3 Metabolic Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
9.8.4 Chronic Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
9.8.5 Puberty and Reproductive Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
E. Bertino (*) · P. Di Nicola · F. Giuliani · A. Coscia Abstract
Neonatal Unit, University of Turin, Turin, Italy Normal fetal growth can be altered by several
e-mail: [email protected] pathological processes, including genetic dis-
G. Oggè · T. Todros eases, infections, congenital anomalies, maternal
Maternal-Fetal Medicine Unit, University of Turin, Turin, hypoxia, and inadequate placental exchanges.
Italy The impossibility to reach the fetal genetic
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 147
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_158
148 E. Bertino et al.
growth potential because of placental malfunc- Being born SGA is associated with long-
tion is defined intrauterine growth restriction term unfavorable outcomes such as learning
(IUGR). IUGR causes slowing fetal growth, so difficulties, behavior problems, and develop-
that fetal biometry shifts from a higher to a ment of metabolic syndrome.
significantly lower percentile during gestation, The recognition of intrauterine malnutrition
and it progressively leads to fetal hypoxia, and the monitoring of early postnatal growth
acidemia, multiorgan damage, and death. are of utmost importance for optimum survival
Indeed, IUGR is associated with an excess of and long-term outcomes of SGA infants.
perinatal mortality and short- and long-term
morbidity as well as metabolic syndrome in the List of Abbreviations
adulthood. Prenatal diagnosis and appropriate AGA Appropriate for gestational age
timing of delivery improve neonatal outcomes. BMI Body mass index
When a fetus is found to be small for gesta- BPD Broncopulmonary displasia
tional age (SGA) at prenatal ultrasound, every EUGR Extra uterine growth restriction
effort has to be made to differentiate IUGR GA Gestational age
from other causes of impaired fetal growth. In GH Growth hormone
case of IUGR, the clinical management is crit- INR International mormalized ratio
ically dependent on gestational age at onset. In IUGR Intrauterine growth restriction
early onset IUGR, the timing of delivery has to LGA Large for gestational age
take into account the risks of prolonged intra- NEC Necrotizing enterocolitis
uterine hypoxia versus the complications asso- PI Ponderal index
ciated with preterm birth. In late onset IUGR, PT Protrombin time
early induction of labor is probably the most RDS Respiratory distress syndrome
cost-efficient method to prevent perinatal mor- ROP Retinopathy of prematurity
tality and morbidity. In intermediate-onset SD Standard deviation
IUGR there is a lack of clear evidence about SGA Small for gestational age
the best tool to identify the fetuses that would
benefit of timely delivery.
At birth, neonatal weight, length, and head 9.1 Salient Points
circumference are indicators of the quality and
quantity of intrauterine growth. SGA new- • Normal fetal growth can be altered by several
borns, both preterm and term, have increased pathological processes, including inadequate
perinatal mortality risk and short-term compli- placental exchanges determining intrauterine
cations such as birth asphyxia, infections, growth restriction (IUGR).
hypothermia, hypoglycemia, feeding difficul- • IUGR leads to fetal hypoxia, acidemia, multi-
ties, respiratory distress syndrome, organ damage and death that can only be pre-
bronchopulmonary dysplasia, retinopathy of vented by elective delivery.
prematurity, and necrotizing enterocolitis. • At birth, weight, length and head circumfer-
Even if most term children born SGA expe- ence are indicators of the quality and quantity
rience catch-up growth and achieve a normal of intrauterine growth.
adult height, approximately 10% of them • Small for gestational age (SGA) newborns,
remain shorter than peers born appropriate for both preterm and term, have an increased peri-
gestational age. Preterm SGA infants can take natal mortality risk and a number of unfavor-
four or more years to achieve heights in a able short and long term consequences.
normal range and the majority of them show • The recognition of any growth abnormalities
a postnatal growth deficit at the time of and the monitoring of early postnatal growth
hospital discharge (Extra Uterine Growth are of utmost importance for optimum survival
Restriction, EUGR). and long-term outcomes of SGA infants.
9 Intrauterine Growth Restriction: Obstetric and Neonatal Aspects. Intervention Strategies 149
9.2 Normal and Abnormal Fetal increased risk of hypertension, cardiovascular dis-
Growth ease and type 2 diabetes in the adulthood (Barker
and Osmond 1986; Barker 2006; Kanaka-
Normal fetal growth is a complex process Gantenbein 2010) due to epigenetic mechanisms
depending on cellular hyperplasia, prevailing dur- influencing adaptation to the intrauterine environ-
ing the first half of pregnancy, and cellular hyper- ment (Hanson and Gluckman 2014). It has been
trophy, being prevalent in the second half of demonstrated that prenatal identification of SGA
pregnancy. Defects in fetal growth can therefore fetuses (as a proxy of IUGR) improves neonatal
schematically be attributed to events that inhibit outcomes (Lindqvist and Molin 2005), thus accu-
cellular mitosis (such as chromosomal or genetic rate diagnosis of IUGR is a primary goal of peri-
diseases, infections or ischemia) or to events that natal medicine.
restrict cellular metabolism (such as inadequate Assessment of fetal growth in utero is
placental exchanges, maternal hypoxia due to performed by comparing fetal biometry with the
respiratory, cardiac or hematologic diseases, normal value at that specific GA in the same
maternal under-nutrition). The impossibility to population. To this purpose, three conditions are
reach the fetal genetic growth potential because required:
of a pathologic event is defined intrauterine
growth restriction (IUGR). In case of IUGR the 1. Exact knowledge of GA, i.e., accurate dating of
limitation to maternal-fetal gas and metabolic pregnancy. As the date of conception is usually
exchanges progressively leads to fetal hypoxia unknown, the beginning of the last menstrual
and, when compensating mechanisms fail, to period (LMP) is conventionally adopted as a
fetal acidemia, multi-organ damage and death. surrogate in clinical practice, assuming that
Such a cascade of events can only be interrupted ovulation and conception, occur 2 weeks after
by elective delivery of the fetus. LMP and that pregnancy extends on average
Based on the distribution of fetal and neonatal 280 days (40 weeks) from LMP (Baskett and
anthropometric parameters at each gestational age Nagele 2000). However, many women are not
(GA) in the general population, every fetus and able to reliably report the date of LMP and,
newborn can be defined as small for gestational moreover, the interval from the beginning of
age (SGA) if its biometric measures result below a LMP and conception is subject to considerable
pre-established threshold, large for gestational biologic variation (Nakling et al. 2005). The
age (LGA) when they result above an upper introduction of ultrasound allowed a more
threshold, or appropriate for gestational age accurate estimate of GA, based on the fact
(AGA) if they lay between these pre-defined that the velocity of embryonic growth shows
limits of normality. However, a fetus that is SGA a high degree of uniformity during early preg-
is not necessarily affected by IUGR, as it can be nancy (particularly during the first trimester)
healthy but genetically determined to be smaller (Blaas et al. 1998). Indeed, between 9 and
than the majority of the general population (con- 13 weeks’ gestation, GA can be accurately
stitutional SGA). On the contrary, an AGA fetus estimated by the measure of crown-rump
can actually be suffering from IUGR if its growth length (CRL) which growth is rapid and has a
has slowed so that its biometry has shifted from a rather small inter-individual variability. Later,
higher to a significantly lower percentile during biparietal diameter is typically used for dating,
gestation, but it has not fallen below the threshold as CRL can no longer be measured owing to
of normality (Bardien et al. 2016) (Fig. 1). curling of the growing fetus; however, varia-
IUGR is associated with a significant burden of tion is greater, which results in less accurate
perinatal mortality and neonatal morbidity (Garite assessment of GA. For this reason, first-
et al. 2004; Aucott et al. 2004; Morsing et al. trimester ultrasound estimation of GA is
2011) and impaired neurodevelopmental out- recommended in clinical practice (Kalish
comes (Guellec et al. 2011), as well as the et al. 2004). However, it must be noted that
150 E. Bertino et al.
Fig. 1 Different patterns of fetal growth: (a) SGA fetus fetal abdominal circumference progressively shifting from
with IUGR: fetal abdominal circumference progressively 2 standard deviations above the mean for GA to a lower
shifts from the mean for GA to 2 standard deviations below percentile, without falling below the lower threshold of
the mean for GA, (b) SGA fetus without IUGR: fetal normality; (d) AGA fetus without IUGR: fetal abdominal
abdominal circumference is 2 standard deviations below circumference is between the limits of normality for GA
the mean for GA, but it continues growing on the same and it continues growing on the same trajectory throughout
trajectory throughout gestation; (c) AGA fetus with IUGR: gestation
pathologic processes can influence intrauterine individual fetus as normal or abnormal for
growth even in its earliest stages, including GA relies on the comparison with the normal
very early forms of IUGR (Morin et al. 2005; value of each biometric variable at the same
Thorsell et al. 2008). GA. Several charts have been published,
2. Availability of an adequate fetal growth chart. including different populations and using dif-
The classification of the biometry of an ferent statistical methods; the choice of the
9 Intrauterine Growth Restriction: Obstetric and Neonatal Aspects. Intervention Strategies 151
chart has consequences on the sensitivity and maternal body constitution, and dynamic
specificity of the diagnosis of IUGR. Growth nature of the pathology; under this regard, if
charts can be constructed retrospectively or ultrasound is performed late in pregnancy it
prospectively (in the latter case quality data is has the potential to detect the majority of
improved by strict pre-defined protocols); they cases of abnormal growth, while it is going to
can be cross-sectional (every fetus in the study miss a considerable proportion if it is
population contributes with only one observa- performed earlier, when the deviation from
tion; these studies can provide references for normal growth is still mild or has not occurred
fetal size, but not for fetal growth velocity) or yet. In a recent multicentric cohort study, uni-
longitudinal (every fetus is measured serially versal ultrasound screening at 28 and 36 weeks
over time and its growth velocity is assessed); of GA detected 57% of SGA fetuses with
they can include only healthy individuals birthweight lower than the 10th percentile
(therefore providing standards of how fetuses (vs. 20% of a policy of selective ultrasound
should grow), or they can comprehend the when clinically indicated): even such an inten-
general population (therefore describing refer- sive protocol of monitoring (currently not fea-
ences of how fetuses actually grow in that sible on the general population because of the
specific setting). Recently, international stan- limitation of resources even in high-income
dards for fetal growth were published based on countries) is destined to miss nearly half of all
a prospective, multicenter, population-based SGA (Sovio et al. 2015). Not surprisingly, a
study including 4321 women in optimal health series of papers from a prospective screening
and nutritional status, with singleton preg- study in a single centre, found that ultrasono-
nancy, without major obstetric complications, graphic biometry, combined with maternal
from eight countries (Papageorghiou et al. characteristics and medical history, can iden-
2014). Such approach is based on the assump- tify 44% of all SGA with birthweight lower
tion that when adequate health and nutritional than the 5th percentile born at term if it is
conditions are met, other genetic and environ- performed at 19–24 weeks of GA, versus
mental factors do not have significant influence 58% if it is performed at 30–34 weeks of GA
on intrauterine growth. Conversely, custom- and 70% if it is performed at 35–37 weeks of
ized growth charts are founded on the hypoth- GA (Lesmes et al. 2015; Bakalis et al. 2015;
esis that few genetic and environmental Fadigas et al. 2015). Of course, a program of
variables (namely ethnic group, maternal screening by ultrasound late in pregnancy
height and body mass index, fetal sex and would miss the earliest and most severe cases.
parity) can physiologically modulate fetal
growth, so that the same fetal weight at the
same gestational age would represent a differ-
ent percentile if the fetus is Caucasian or Afri-
can, female or male etc. (De Jong et al. 2000; 9.3 Diagnosis of IUGR
Kase et al. 2012; Rizzo et al. 2016). Which
approach is more efficient for the diagnosis of As discussed above, every fetus can be defined as
IUGR is still debated. SGA if its biometric variables (usually abdominal
3. Accurate measurement of relevant fetal bio- circumference or estimated fetal weight) result
metric parameters. below a pre-established lowest cut-off (e.g.,
Ultrasonographic measurement of fetal 10th, 5th or 3rd percentile or 2 standard deviation
biometry is considered the gold standard for below the mean for GA), LGA when they result
prenatal diagnosis of IUGR. However, ultra- above a highest cut-off (e.g., 90th, 95th, or 97th
sound accuracy is limited by several factors percentile or 2 standard deviation above the mean
related to the operator’s skills, technical char- for GA), or AGA if they lay between the
acteristics of the ultrasound equipment, pre-defined limits of normality. However, such
152 E. Bertino et al.
operation can only provide a cross-sectional mea- This is particularly important when an SGA
sure of the size of the fetus: not all newborns biometry is detected during the first half of
falling below the cut-off are abnormally small pregnancy, a time when placental inadequacy
because of growth restriction, as a proportion of to supply for fetal requirements is unlikely,
them are representing the normal spectrum of fetal and therefore the etiology of the growth defect
growth. has to be searched elsewhere. When anatom-
As growth is a dynamic process, the evaluation ical anomalies are suspected, moreover,
of fetal growth can only be obtained by a longitu- amniocentesis is indicated, for karyotyping,
dinal sequence of biometric measurements during research for specific genetic mutations, or
time. Accordingly, when fetal biometry shifts infectivologic analyses.
from a percentile to a significantly lower one, (b) Uterine artery Doppler velocimetry. Doppler
IUGR can be diagnosed, while the opposite pas- velocimetry tracings obtained from the uter-
sage, to a significantly higher percentile, allow the ine arteries reflect impedance to blood flow in
diagnosis of fetal growth acceleration. the spiral arteries. These vessels are modified
However, ultrasound and Doppler velocimetry by trophoblastic invasion, producing vasodi-
can provide several other clues to help differenti- latation, during the first half of pregnancy.
ate a healthy, constitutional SGA fetus from one Low resistance to flow and high diastolic
that is SGA because of IUGR, even when longi- velocities in the uterine arteries indicate nor-
tudinal assessment is not available: mal trophoblastic invasion, while high resis-
tance to flow and low diastolic velocities
(a) Research for anatomical anomalies. A careful indicate shallow dilatation of the spiral arter-
assessment of fetal anatomy can identify signs ies because of impaired placental invasion
of congenital malformations, chromosomal or (Fig. 2). Therefore the finding of abnormally
genetic diseases and intrauterine infections. high resistance in the uterine arteries is
Fig. 2 Doppler velocimetry tracing of a uterine artery in the third trimester of pregnancy: (a) with normal resistance and
high diastolic velocities; (b) with increased resistance and decreased early-diastolic velocities (arrows)
9 Intrauterine Growth Restriction: Obstetric and Neonatal Aspects. Intervention Strategies 153
strongly suggestive for a placental etiology is both diagnostic of IUGR of placental origin
(Olofsson et al. 1993; Lyall et al. 2013; and prognostic, as its progression is indicative
Figueras and Gratacos 2014) and is associated of worsening hypoxia, risk of fetal damage
with cesarean section for fetal distress, neona- and intrauterine death and need for elective
tal acidosis and neonatal hospitalization delivery.
(Cruz-Martinez et al. 2015). (d) Middle cerebral artery Doppler velocimetry.
(c) Umbilical artery Doppler velocimetry. Umbil- Vasodilatation in the cerebral circulation
ical artery Doppler velocimetry reflects (most easily assessed in the middle cerebral
impedance to blood flow in the fetal side of artery – Fig. 4) is a sign of fetal hemodynamic
placental circulation, i.e., in the villous tree. adaptation to chronic hypoxia, which is
Abnormally high resistance in the umbilical thought to secure oxygenation to the brain,
arteries velocimetry are indicative of substan- to the expense of other organs (brain sparing).
tial placental pathology (McCowan et al. Decreased impedance in the middle cerebral
1987; Todros et al. 1999). Indeed, elevated artery is particularly useful for the identifica-
indices of resistance up to absent or reversed tion of late-onset IUGR, a subgroup of fetuses
end-diastolic flow (ARED) in such vessels, in which umbilical artery flow can be only
correlate with worsening degrees of fetal hyp- mildly altered or even normal, but are still at
oxia and acidosis and increased risk of peri- risk of fetal distress during labor and sub-
natal mortality (Karsdorp et al. 1994; optimal neurobehavioral outcomes (Oros
Nicolaides et al. 1988; Tyrrell et al. 1989) et al. 2011; Eixarch et al. 2008).
(Fig. 3). Hence the finding of elevated imped- (e) Estimated fetal weight. Even when umbilical
ance in the umbilical arteries in an SGA fetus, and middle cerebral artery Doppler assessment
Fig. 3 Doppler velocimetry tracing of an umbilical artery increased resistance and absent end-diastolic velocities;
in the third trimester of pregnancy with (a) increased (c) increased resistance and reversed end-diastolic
resistance but present end-diastolic velocities; (b) velocities
154 E. Bertino et al.
Fig. 4 Doppler velocimetry the middle cerebral artery; (a) visualization of the circle of Willisa with color Doppler;
(b) Doppler velocimetry tracing of the middle cerebral artery
is normal, a very low estimated fetal weight preferentially symmetrical (Campbell and
(calculated by means of different algorithms Thoms 1977). In contrast with this assump-
on the basis of ultrasonographic biometry) is tion, it has been shown that all SGA fetuses
strongly predictive of adverse perinatal out- show some degree of asymmetry although
comes among SGA fetuses, and is therefore such pattern is more common among IUGR
suggestive of IUGR (Savchev et al. 2012). (Todros et al. 1996; David et al. 1995). How-
(f) Pattern of growth. Since the introduction of ever, newborns with low weight and preserved
fetal ultrasonographic biometry, obstetricians length (also referred to as wasting),
classify SGA fetuses as symmetrical (propor- corresponding to asymmetrical SGA fetuses,
tionately small head circumference, abdomi- show a stronger association with poor neona-
nal circumference ad femur length) and tal outcomes including admission to neonatal
asymmetrical (substantial reduction in abdom- intensive care unit, respiratory distress syn-
inal circumference with relatively preserved drome, transient tachypnea and difficulty in
head circumference and femur length) with oral feeding, compared to newborns with low
the believing that IUGR fetuses tend to adopt weight and short length (also referred as
an asymmetric pattern of growth as a conse- stunting), corresponding to symmetrical SGA
quence of brain sparing, while constitutional fetuses (Victora 2015). Therefore asymmetri-
SGA and fetuses with aneuploidies, congeni- cal SGA fetuses should be considered at high
tal infections and malformations are risk of intrauterine damage.
9 Intrauterine Growth Restriction: Obstetric and Neonatal Aspects. Intervention Strategies 155
9.4 Monitoring, Timing and Mode Prematurity (as a result of iatrogenic preterm
of Delivery delivery of fetuses considered to be at high risk
of intrauterine acidemia and demise) is also an
Clinical management of IUGR is critically depen- independent predictor of neonatal mortality and
dent on gestational age at its onset. Early onset severe neonatal complications associated with
IUGR is more easily diagnosed because it tends to abnormal neurodevelopmental outcomes in
rapidly touch extreme degrees of alterations in IUGR fetuses (Baschat et al. 2007, 2009; Tor-
terms of fetal biometry and oxygenation and rance et al. 2010; Soothill et al. 1992; Lees et al.
because of its frequent association with maternal 2013). A multicenter cohort trial conducted
hypertensive diseases. However, the only avail- between 2000 and 2006 in 12 centers of perina-
able therapeutic intervention, i.e., interruption of tal medicine in USA and Europe, reports neona-
pregnancy, is a serious clinical dilemma because it tal outcomes of 604 singleton liveborn with
exposes the fetus to the risks of severe preterm IUGR delivered between 24 and 32 weeks
birth. On the other hand, late onset IUGR, which þ 6 days. Mortality within 28 days of life was
is much more frequent, is more easily missed by 20% while incidence of severe morbidity was
antenatal care, because deviation from normal 36%; however, the rate of neonatal death
fetal growth and hemodynamic function are decreased by 2% per each day of pregnancy
more subtle, while, in this case, the risks of antic- prolongation between 24 and 27 weeks of
ipating delivery appear to be a safer option; how- GA. In contrast, after this threshold Doppler
ever, in light of the growing evidence on the velocimetry of the venous circulation and arte-
perinatal risks of late preterm birth, solid criteria rial pH were the only independent variables pre-
to choose the timing of delivery are lacking. dictive of neonatal mortality, while GA at
Early onset IUGR. Early-onset IUGR (occur- delivery was not a determinant of neonatal sur-
ring before 34 weeks of gestation) is associated vival. Similarly, GA was the main predictor of
with a risk of perinatal mortality as high as 41%, severe neonatal morbidity until 29 weeks, but it
depending on definition, study population and GA was replaced by venous Doppler between 29 and
(Mari et al. 2007). Neonatal short- and long-term 33 weeks (Baschat et al. 2007).
prognosis is mainly determined by three vari- More favorable data on neonatal mortality and
ables: fetal cardiovascular status, birthweight, morbidity are reported by the Trial of Umbilical
and GA at birth (Baschat et al. 2007, 2009; Tor- and Fetal Flow in Europe (TRUFFLE). This is a
rance et al. 2010). randomized clinical trial conducted between 2005
The fetal cardiovascular status, as indicated by and 2010 in 20 European centers, in which
Doppler velocimetry of arterial and venous ves- 503 fetuses with early-onset IUGR (diagnosed
sels and by fetal heart rate tracing, is strictly between 26 weeks and 31 weeks þ 6 days of
related to the fetal acid–base status: hence serial GA) were randomly allocated to be delivered
testing with Doppler ultrasound and fetal heart according to one of three criteria: (1) fetal heart
rate tracings allows to follow the transition from rate criteria (namely reduced short term variation);
fetal normal oxygenation to hypoxemia, hypoxia (2) early abnormalities in the Doppler velocimetry
and acidemia, which in turn appears to be the of the ductus venosus (reduced velocities during
nearest fetal antecedent of perinatal mortality atrial contraction); (3) late abnormalities in the
and infant neurodevelopmental delay (Soothill ductus venosus (absent or reversed velocities dur-
et al. 1992). ing atrial contraction) (Fig. 5). When the short-
Birthweight is the expression of both GA at birth term outcomes of the whole cohort, regardless of
and the severity of fetal malnutrition and correlates the arm of randomization, were analyzed, neona-
with major neonatal morbidity (Baschat et al. 2007) tal mortality before discharge from hospital was
and abnormal neurodevelopment in infancy and 5.5% of all live born, and severe morbidity was
childhood independently of Doppler parameters 24%. Besides GA and birthweight, the major
(Baschat et al. 2009; Torrance et al. 2010). determinant of poor outcome was the occurrence
156 E. Bertino et al.
Fig. 5 Doppler velocimetry tracing of the ductus venosus during atrial contraction; (c) reversed velocities during
in the third trimester of pregnancy with: (a) normal positive atrial contraction. Arrows indicate velocities during atrial
velocities during atrial contraction; (b) reduced velocities contraction
of maternal hypertensive disease, which short- complications associated with preterm birth.
ened the interval between diagnosis of IUGR Unfortunately, there is no single test indicating
and delivery (Lees et al. 2013). the break point, in spite many tests reflecting
In summary, the aim of clinical management of fetal conditions and their deterioration have been
early-onset IUGR fetuses is focused on optimiz- developed in the last decades: fetal arterial and
ing the timing of delivery in order to balance the venous Doppler velocimetry, fetal heart rate trac-
risks of prolonged intrauterine hypoxia versus the ing with computerized analysis of short term
9 Intrauterine Growth Restriction: Obstetric and Neonatal Aspects. Intervention Strategies 157
variability, ultrasound for assessment of fetal related to protocols of clinical management for late
growth and amniotic fluid. The results of the prematurity and not to specific neonatal complica-
TRUFFLE study recently demonstrated that the tions (Boers et al. 2012). Evidence is still lacking
best neurodevelopmental outcome at 2 years in regarding the best monitoring tool to identify those
surviving fetuses is obtained when timing of fetuses that would benefit from early induction of
delivery is based on the integration of results of labor (Tajik et al. 2014). Therefore, in case of
ductus venosus Doppler and fetal heart rate (Lees IUGR after 36 weeks of GA, it appears more rea-
et al. 2015). sonable to choose induction of labor in order to
Late onset IUGR. Late-onset IUGR is not a prevent fetal mortality and neonatal morbidity and
minor clinical issue, because most infants with in order to save the resources needed for intensive
intrauterine growth restriction are born at term fetal monitoring.
(Clausson et al. 1998). Even when diagnosed Intermediate onset IUGR. The time interval
late in gestation, IUGR is associated with between 34 and 36 weeks of GA is the source of
increased risk of perinatal mortality and morbid- the greatest uncertainty in the clinical management
ity, such as fetal distress, hypoglycemia, seizures, of pregnancies complicated by IUGR, as evidence
behavioral problems, cerebral palsy, and cardio- is lacking about risks of chronic intrauterine hyp-
vascular disease (Jarvis et al. 2003; Pulver et al. oxia and preterm birth and the most efficient tools
2009; Boulet et al. 2006; Dijxhoorn et al. 1987). for identifying fetuses at highest risk of intrauterine
Moreover growing evidence suggests that growth compromise. As umbilical artery Doppler is fre-
failure occurring around term is associated with a quently normal in this population, the middle cere-
poorer mental and psychomotor development bral artery velocimetry could be the best marker for
(Skuse et al. 1994). Early delivery by induction impending fetal hypoxia and could be used for
of labor might prevent the detrimental effects of timing delivery. At the moment there is a need for
inadequate nutrition and oxygenation, and indeed clinical research on the subject.
it is the common clinical practice; however, the
excess of mortality and morbidity associated with
late preterm (between 34 an 36 weeks) and early 9.5 Auxological Evaluation
term (between 37 and 38 weeks) birth is increas- of the Newborn
ingly recognized (Shapiro-Mendoza et al. 2008;
Hansen et al. 2008; Engle 2011). Weight, length, and head circumference at birth
A multicenter randomized clinical trial (the Dis- are indicators of the quality and quantity of
proportionate Intrauterine Growth Intervention growth. These variables must be evaluated using
Trial At Term, DIGITAT) compared the effect of standardized instruments and following the tech-
induction of labor and expectant management on a niques required for accurate measurements as
population of 650 women with prenatal diagnosis described by Cameron (2004).
of IUGR after 36 weeks of GA and did not find any In order to identify intrauterine malnutrition,
significant difference in terms of adverse neonatal some anthropometric indexes have been pro-
outcomes (Boers et al. 2010, 2012), caesarean sec- posed. They compare variables, such as body
tions (Boers et al. 2010), and developmental and length and head circumference, which are less
behavioral outcomes at two years of age (van Wyk influenced in cases of malnutrition, to those vari-
et al. 2012). However, expectant management was ables which are more compromised such as body
associated with a higher chance of being born with weight.
severe IUGR, which is a major predicting factor for The most well known is the Rörher ponderal
neurodevelopmental disturbances. On the other index [PI = body weight (grams) 100/length
hand, early induction was associated with a higher (centimeters)3] whose normal value in a full-term
rate of neonatal admission to intermediate care, but newborn lies between 2.2 and 3 (3rd and 97th
such excess of neonatal admissions seemed to be percentile) (Miller 1985). This neonatal body
158 E. Bertino et al.
Table 1 Suggested characteristics for a reliable neonatal Gynecologists (The American Academy of Pedi-
anthropometric chart (Bertino et al. 2007) atrics and the American College of Obstetricians
Preplanned multicenter ad hoc study and Gynecologist 2007) recognize three groups of
Descriptive reference GA and define neonates as follows:
Monoethnic population
Charts specific for gender – Preterm: born before 37 completed weeks (less
Charts specific for single or multiple pregnancy than 259 days)
Charts specific for parity – Full term: born between 37 and 41 weeks þ
Reliable gestational age assessment
6 days (from 259 to 293 days)
Reliable measuring techniques and instruments
– Postterm: born 42 weeks of GA (294 or more
Range of GA from 42 to 24 weeks or less
days)
proportionality index corresponds to the Body As a consequence, nine different classes of
Mass Index (BMI) used in children and adults newborns can be defined.
[BMI= body weight (kg)/length (m)2], and it is The definition of small, appropriate, and large
an indirect measure of soft tissue and inferentially newborn for GA is based on weight. However,
of fat accumulation. similar classes may be defined considering body
At birth, recognition of any growth abnormal- length and head circumference, so that at every
ities or intrauterine malnutrition is of utmost GA, newborns can be defined as having small,
importance for prognostic purposes and in clinical appropriate, and large body length or head
practice. The so-called neonatal anthropometric circumference.
charts or curves are used whereby graphs repre- Consideration of weight, body length, and
sent, at various gestational ages, either the percen- head circumference traditionally allows identifi-
tile values or the mean and standard deviation of cation, among the heterogeneous group of SGA
anthropometric variables considered which are newborns, those infants who are symmetrical
computed on a reference population. A recent (or proportionate) or asymmetrical
commentary defines the characteristics that a reli- (or disproportionate) (Brar and Rutherford
able anthropometric chart should possess to be of 1988).
both epidemiological and clinical use (Table 1) Symmetrical SGA newborns have reduced
(Bertino et al. 2007). weight, body length, and head circumference.
The neonatal anthropometric charts enable the The insult leading to reduced growth occurs
classification of newborns at different gestational early in pregnancy, during the phase of growth
ages based on weight as follows: primarily characterized by cellular hyperplasia,
with consequent reduction in cell number (hypo-
– SGA – Small for Gestational Age: weight plasia) that may limit the subsequent catch-up of
below the 10th centile for GA organ and tissue growth (Vrachnis et al. 2006;
– AGA – Appropriate for Gestational Age: Singer et al. 1991).
weight between 10th and 90th centile for GA Asymmetrical SGA newborns have reduced
– LGA – Large for Gestational Age: weight weight, with normal or less reduced body
above 90th centile for GA length and head circumference. The insult,
leading to reduced growth occurs later, inter-
Some authors set down a cut-off of the 3rd and fering with the delivery of oxygen and nutrition
97th centile among AGA, SGA, LGA newborns during the phase of prevalent cellular hypertro-
or equivalent limits of mean 2 SD (Clayton phy, resulting in reduced cell size (hypo-
et al. 2007). trophy), with the possibility of subsequent
The American Academy of Pediatrics and the catch-up growth (Vrachnis et al. 2006; Singer
American College of Obstetricians and et al. 1991). The weight deficit is principally
9 Intrauterine Growth Restriction: Obstetric and Neonatal Aspects. Intervention Strategies 159
due to a reduction in fat deposition, particularly
during the third trimester of pregnancy. The
disproportion is due to the redistribution of
the blood flow, which occurs in these cases in
the fetus, with preferential perfusion of the
brain, heart, and adrenal glands to the detriment
of other organs, such as the liver, spleen, kid-
neys, thymus, and adipose tissue, whose
growth is more compromised not only as
regards the brain but also body length (Barker
and Hanson 2004). In the case of late noxa, the
biggest reduction in fetal weight growth com-
pared to body length may also be explained by
the different dynamics of their intrauterine
growth: the velocity peak of length growth,
about the 20th week, occurs earlier than the
peak of weight growth (Tanner 1989; Bertino
et al. 1996). At six months of pregnancy the
fetus reaches 70% of its full-term length but
only 25% of its weight.
These newborns, once defined “dysmature,”
often seem to have clinical signs of intrauterine
malnutrition, an “old man” appearance, wrin-
kled and hypoelastic skin, easily liftable and Fig. 6 Wrinkled and hypoelastic skin, easily liftable, and
pliable skinfolds in a IUGR newborn
pliable skinfolds, poorly represented subcutane-
ous tissue, hypotrophic muscular mass, and thin
umbilical cord. When meconium is passed in underlying causes of reduced fetal growth may
utero, there is a yellow-green staining of finger- be more important than evaluating body propor-
nails, skin, and umbilical cord (Fig. 6). Thanks tionality at birth in predicting short- and long-
to better prenatal diagnosis and management of term outcomes of SGA children.
fetal growth restriction, the newborns with all In contrast with the usual assessment based
these features are uncommon nowadays. The solely on weight, a recent paper suggests to clas-
main differences between symmetrical and sify newborns as proportionately or dispropor-
asymmetrical SGA newborns are presented in tionately developed and infants as stunted (short
Table 2. length for age, reflecting linear growth restriction)
Some studies have reassessed the distinction or wasted (low weight for length, or low BMI for
between proportionate and disproportionate age, often reflecting recent weight loss). Although
SGA newborns. It has been suggested that newborn stunting and wasting share some com-
these two classes represent a continuum rather mon determinants, they are distinct phenotypes
than distinct classes (Todros et al. 1996; Kramer with their own risk factors and neonatal progno-
et al. 1989) and that both disproportionate and ses. This distinction could help to prioritize pre-
proportionate fetal growth restriction may start ventive interventions and focus the management
early in pregnancy (17–19 weeks of gestation) of fetal undernutrition (Victora 2015).
(Rasmussen et al. 2006). These observations Growth of the fetus relative to the placenta also
lead to a partial reconsideration of causes, seems to be important. Babies born small but with
timing, and risk of symmetric or asymmetric a relatively large placenta are less likely to show
IUGR. Of course recognizing specific catch-up growth in the 18 months after birth and
160 E. Bertino et al.
Table 2 Symmetrical and asymmetrical SGA newborns (Sources: Vrachnis et al. (2006), Rosenberg (2008), Halliday
(2009))
Symmetric (20–30%) Asymmetric (70–80%)
Onset of fetal Early in gestation Late in gestation (late second trimester or third
growth trimester)
restriction
Pathophysiology Impaired cell hyperplasia Impaired cell hypertrophy
Reduced cell number Reduced cell size
Anthropometry Small birth weight, length, and head Small birth weight, but relative sparing of length
circumference; normal ponderal index and head circumference growth; low ponderal
index
Major clinical Malformations, congenital infections, Asphyxia, meconium aspiration syndrome,
problems increased risk of postnatal neurological and hypoglycemia, polycythemia.
growth impairment Increased risk of type 2 diabetes
Causes • Genetic disorders and syndromes • Impaired uteroplacental function (i.e.,
• Congenital infections preeclampsia, chronic hypertension, long
• Teratogens exposure standing maternal diabetes)
• Substance abuse, fetal alcohol syndrome • Maternal disease (i.e., renal or heart disease,
• Constitutional healthy SGA without IUGR collagen vascular disease, anemia)
• Maternal malnutrition
• Environmental factors (i.e., high altitude)
• Multiple pregnancy
• Substance abuse
have an increased risk of hypertension in adult life A higher mortality rate is reported in SGA
(Casey 2008). preterm infants with abnormal (absent or reversed
end-diastolic flow) umbilical artery Doppler
velocimetry (Shand et al. 2009).
9.6 Neonatal Outcome
9.6.1 Mortality 9.6.2 Asphyxia
Small for gestational age newborns, both pre- Transient diminished placental blood flow during
term and term, have an increased perinatal mor- labor is poorly tolerated by growth-restricted
tality risk (Pallotto and Kilbride 2006; fetuses. Intrauterine chronic hypoxia and limited
Vashevnik et al. 2007). A recent paper has dem- carbohydrate reserves as a consequence of placen-
onstrated that the increased risk of neonatal and tal insufficiency predispose to perinatal asphyxia
infant mortality observed in late preterm (34–36 SGA neonates more than AGA newborns. As a
weeks) and early term (37–38 weeks) SGA result, there is also an increased risk of all clinical
infants persists even when infants dying of con- sequelae of perinatal asphyxia (Rosenberg 2008).
genital anomalies are excluded. In addition to
congenital conditions, birth asphyxia and infec-
tions have a relevant role in neonatal mortality 9.6.3 Infections
whereas sudden infant death syndrome contrib-
utes to infant mortality (Pulver et al. 2009). Recent studies suggest possible interactions
Some other data have indicated that birth weight between immunological function and nutritional
is the predominant factor independently affect- status. Thymic atrophy and prolonged impairment
ing neonatal mortality as well as risk for low of cell immunity have been found in SGA infants
Apgar score and neonatal sepsis during NICU and animal models of intrauterine growth retarda-
stay (Mamopoulos et al. 2015). tion. These subjects also have a more pronounced
9 Intrauterine Growth Restriction: Obstetric and Neonatal Aspects. Intervention Strategies 161
hypogammaglobulinemia compared with AGA hypoglycemia in IUGR infants. In addition,
infants (Bartels et al. 2007). Neutropenia occurs growth-restricted infants have limited fat stores
frequently in infants born to mothers with pre- and do not effectively oxidize free fatty acids and
eclampsia (Snijders et al. 1993). In a recent triglycerides (Sabel et al. 1982). The risk of hypo-
paper, lower counts of leukocytes, total neutro- glycemia is greater during the first few days of life
phils, immature neutrophils, lymphocytes, and when the newborn must adapt to extrauterine life
monocytes were detected in SGA infants not without the placental source of nutrients, but in
related to maternal preeclampsia (median some cases it may persist for weeks (Halliday
birthweight 583 g) suggesting that IUGR may 2009; Pallotto et al. 2004; Rozance 2014).
act as an independent factor for lower counts of
different leukocytes in very immature preterm
infants (Wirbelauer et al. 2010). All these aspects 9.6.7 Polycytemia
result in an increased risk of neonatal infections.
Chronic fetal hypoxia results in increased eryth-
ropoietin production and release by the fetal kid-
9.6.4 Coagulation Disorders ney, with consequent excessive blood red cells
production. Besides, a shift of blood from the
The hepatic dysfunction that results from chronic placental compartment to the fetus during labour
intrauterine hypoxia may lead to a reduction in or a period of fetal asphyxia constitutes important
vitamin-K dependent factors and thrombocytope- causes of polycythemia in IUGR fetuses (Sarkar
nia. Such disorders are usually transient and easily and Rosenkrantz 2008). Polycythemia contributes
corrected. Only occasionally severe bleeding, to the increased risk of pathologies such as hypo-
such as pulmonary hemorrhage, has been reported glycemia, hyperbilirubinemia, and NEC.
(Halliday 2009). In a recent study, prolonged PT
and INR were observed in full-term healthy SGA
neonates, indicating a predisposition to hemor- 9.7 Respiratory Distress Syndrome
rhagic events. However, the newborns included (RDS) and Bronchopulmonary
in the study did not appear to have any clinical Dysplasia (BPD)
symptoms of altered hemostasis (Mitsiakos et al.
2009). The common opinion that the intrauterine stress
associated with IUGR enhances lung maturation
has been challenged in some papers reporting that
9.6.5 Thermoregulation the incidence of RDS is inversely correlated with
birth weight and gestational age (McIntire et al.
SGA infants are at increased risk of hypothermia 1999) and that growth-restricted infants may have
as a consequence of their higher brain weight and the same (Piper et al. 1996) or a higher (McIntire
body surface area in relation to weight as well as et al. 1999; Bernstein et al. 2000; Peacock et al.
to their lower subcutaneous adipose tissue stores, 2013) incidence of RDS than AGA newborns of
including depleted brown fat reserves (Yu and the same gestational age.
Upadhyay 2004). A higher BPD incidence has also been reported
in IUGR preterm infants (Aucott et al. 2004;
Gortner et al. 1999; Lal et al. 2003; Regev et al.
9.6.6 Hypoglycemia 2003; Sharma et al. 2004; Soudée et al. 2014).
BPD has a multifactorial etiology, and there are
Reduced hepatic and skeleton muscle glycogen several hypotheses about its physiopathology in
stores (the predominant source of glucose in the SGA including abnormal intrauterine lung devel-
first hours after birth) and impaired glycogenolysis opment (Lal et al. 2003), oxidative injury in utero,
and gluconeogenesis are the main causes of more severe early lung disease with subsequent
162 E. Bertino et al.
ventilator-induced lung injury, and fetal or neona- infants. Recent trials, however, have shown that early
tal systemic inflammatory response due to chronic enteral feeding in IUGR infants is safe and that
hypoxia (Soudée et al. 2014; Kinsella et al. 2006). human milk exerts a protective role against NEC.
9.7.1 Retinopathy of Prematurity 9.8 Long-Term Outcome
(ROP)
9.8.1 Postnatal Growth Impairment
It has been reported that SGA infants have an
increased risk of developing ROP (Dhaliwal Most term children born SGA experience catch-
et al. 2009; Lundgren et al. 2014). up growth and achieve a normal adult height,
Changes in organ development due to fetal above 2 SD. Approximately 10% of them
hypoxemia, nutrient restriction, and alterated remain shorter than peers born AGA (Clayton
endocrine environment can all contribute to the et al. 2007; Simon et al. 2008). Catch-up growth
pathogenesis (McMillen et al. 2001). SGA infants is typically an early postnatal process. Term SGA
are often sicker than their AGA peers, requiring infants usually experience a period of accelerated
more intensive and prolonged hospital care linear growth during the first 12 months of life
(Yu and Upadhyay 2004). They are therefore (Saenger et al. 2007) and in most cases catch-up
more likely to require supplementary oxygen, growth is complete by two years of age (Clayton
which is a well-documented risk factor for ROP. et al. 2007; Saenger et al. 2007). It is has been
A lower serum concentration of insulin-like suggested that SGA children aged 2–4 years with
growth factor 1, documented in SGA infants, no evidence of catch-up growth and heights less
may as well play a role (Smith 2005). than 2.5 SD should be referred for endocrino-
logical evaluation and could be eligible for GH
treatment (Clayton et al. 2007). The preterm SGA
9.7.2 Necrotizing Enterocolitis (NEC) infants can take 4 or more years to achieve heights
in a normal range (Gibson et al. 2000).
Infants who are growth-restricted in utero are The majority of preterm infants show a post-
considered as having a higher risk of developing natal growth deficit at the time of hospital dis-
NEC, especially if there has been antenatal detec- charge, the so-called Extra Uterine Growth
tion of absent or reversed end-diastolic flow Restriction (EUGR). There is no consensus
velocities in Doppler studies of fetal aorta or among neonatologists regarding the best way to
umbilical artery (Dorling et al. 2005; Ree et al. define EUGR. At present, a definition based on
2014). The underlying mechanism is unclear, but the negative change of SDS from birth to term
increasing thoracic aorta and umbilical artery corrected age is probably the most appropriate
resistance may be associated with alterations in because age at discharge could be biased by dif-
blood flow in the viscera, particularly in the intes- ferent discharge policies over time and between
tine and in the liver. Abnormalities of bowel blood centers. The EUGR is largely due to inadequate
flow persist postnatally, with some recovery dur- postnatal nutrient intake as well as postnatal mor-
ing the first week of life, providing justification for bidities, and it increases with the decrease of ges-
a delayed and careful introduction of enteral feed- tational age at birth (Wit et al. 2006; Bertino et al.
ing (Dorling et al. 2005). Early postnatal evalua- 2009). Studies demonstrate that premature infants
tion of superior mesenteric artery blood flow may with EUGR also have metabolic abnormalities
also be used to identify infants at increased risk of similar to those observed in term SGA children
developing NEC (Murdoch et al. 2006; Bora et al. and these occur irrespectively of whether they are
2009; Bozzetti et al. 2013). SGA or AGA at birth (Hofman et al. 2006).
It is common practice in neonatal intensive care Approximately 10% of very preterm children
units to delay enteral feeding administration for these have heights below 2 SD at 4–5 years of age.
9 Intrauterine Growth Restriction: Obstetric and Neonatal Aspects. Intervention Strategies 163
Fig. 7 Growth of a term
SGA infant after IUGR and
of a preterm AGA infant
with EUGR (Reproduced
with permission from
“Pediatrics”, Vol.
117, Pages e793-5,
Copyright # 2006 by the
AAP)
This percentage is similar to that of term SGA moderate learning difficulties in childhood and
infants who do not show postnatal catch-up adolescence, lower psychological and intellectual
growth (Wit et al. 2006) (Fig. 7). SGA term performance in young adulthood, low social com-
infants suffer from an adverse fetal environment petence and behavior problems when compared
during the last trimester of pregnancy, whereas with AGA infants of the same gestational age
very preterm infants suffer from an adverse post- (Lundgren and Tuvemo 2008; Walker and
natal environment during the first three months, a Marlow 2008; Levine et al. 2015).
time biologically equivalent to the third trimester A recent review suggests the association
of fetal life. Considering these similarities, an between cerebral redistribution based on middle
expert group has recently suggested that the indi- cerebral artery Doppler indices and poorer
cation of GH therapy should be expanded to pre- neurodevelopmental outcome supporting the
term children with EUGR who failed to normalize growing evidence that there is a need to reevaluate
over time (Wit et al. 2006). Several common whether cerebral redistribution should be used as
comorbidities of prematurity are significantly a criterion for delivering late preterm and term
associated with postnatal growth restriction SGA or growth restricted babies, even in the
including medical or surgical NEC, gastrointesti- absence of abnormal Umbilical artery Doppler
nal perforation, and severe retinopathy of prema- (Meher et al. 2015). The most important predictor
turity. These results should help clinicians to of subnormal performance is the absence of catch-
identify those infants at highest risk of adverse up growth in height and/or head circumference
growth outcomes and work to further improve (Clayton et al. 2007; Rosenberg 2008). SGA chil-
these outcomes (Griffin et al. 2015). dren who developed catch-up growth were shown
to have completed successfully higher school
grades and to get higher mean intelligence
9.8.2 Neurological Outcome quotiens scores compared to those who fail to
develop catch-up growth or to those with steady
There is an increasing evidence that being born growth or to children with early catch-down
SGA is independently associated with mild to (Varella and Moss 2015).
164 E. Bertino et al.
Long-term exclusive breastfeeding could help et al. 2005). This reprogramming is adequate to
to prevent some of the neurological sequelae of maintaining gluco-homeostasis in the short term,
being born SGA. Overfeeding with enriched for- when intrauterine nutrient supply is deficient, but
mula could accelerate growth, but it does not seem it predisposes the child to metabolic syndrome in
to be an advantage for the intellectual develop- later life, when nutrient supplies are adequate
ment and could be a drawback in terms of meta- (Halliday 2009; Saenger et al. 2007). Moreover,
bolic and cardiovascular risks (Morley et al. 2004; SGA newborns show postnatal accelerated
Agostoni 2005). It has been suggested that GH growth with rapid weight gain, associated with
treatment may improve IQ in short SGA children, later obesity, which is per se associated with the
but additional data are required (Clayton et al. metabolic syndrome (Maiorana et al. 2007; Nobili
2007; Lundgren and Tuvemo 2008). et al. 2008). Overweight former SGA children
The association between cerebral palsy and have an increased risk of metabolic syndrome
IUGR which has been observed in both term and compared with overweight former AGA children
preterm infants may be due to placental insuffi- (Reinehr et al. 2009). On the other hand, it is
ciency: reduced oxygen or nutrient delivery to the known that poor postnatal growth is associated
fetus may have adverse effects on brain develop- with later poor neurocognitive outcome (Yeung
ment and differentiation (Halliday 2009; 2006).
Lundgren and Tuvemo 2008). The challenge of neonatal nutrition is the
achievement of a “healthy catch-up growth” of
IUGR subjects, based on a nutritional strategy
9.8.3 Metabolic Risk that improves neurodevelopmental outcome
while minimizing long-term metabolic and car-
Since the late 1980s, epidemiological studies have diovascular adverse effects (Nobili et al. 2008).
shown that impaired intrauterine growth is asso-
ciated with later development of the metabolic
syndrome or one of its components (insulin resis- 9.8.4 Chronic Kidney Disease
tance, hyperinsulinemia, impaired glucose toler-
ance or diabetes mellitus type 2, dyslipidemia, As previously described, when resources in utero
arterial hypertension, and obesity). Additionally, are restricted their allocation to the development
some other morbidities have been connected with of the kidney is restricted to guarantee appropriate
the syndrome, such as hypercoagulability, non- development of the brain and heart (Barker and
alcoholic fatty liver disease, renal dysfunction Hanson 2004). The result is a diminished number
(micro- or macroalbuminuria), polycystic ovary of nephrons which predisposes these subjects to
syndrome, endothelial dysfunction, and athero- albuminuria and to the risk of developing chronic
sclerosis leading to increased cardiovascular mor- kidney disease, as well as of hypertension. In
bidity and mortality (Varda and Gregoric 2009). parallel, metabolic syndrome and type 2 diabetes
A number of mechanisms for the development may contribute to renal complications
of metabolic syndrome have been proposed. One (Koleganova et al. 2009).
hypothesis is that the fetus adapts to an adverse
intrauterine environment “reprogramming” the
endocrine-metabolic status, with short-term sur- 9.8.5 Puberty and Reproductive
vival benefits. This process consists mainly of Function
insulin resistance and of reduced insulin secretion
due to impaired development of beta cells. As a In girls born SGA most studies have shown an
result, blood glucose concentration can be increased risk of earlier pubertal development or
maintained for the benefit of brain development normal timing, but with rapid progression
at the expense of less glucose transported to (Hernández and Mericq 2008). These aberrations
peripheral tissue (e.g., muscle and fat) (Barker may result in reduced adult stature. Today there
9 Intrauterine Growth Restriction: Obstetric and Neonatal Aspects. Intervention Strategies 165
are insufficient data to define the risk of ovarian surveillance parameters. Ultrasound Obstet Gynecol
dysfunction, reduced fertility, or early menopause 33:44–50
Baskett TF, Nagele F (2000) Naegele’s rule: a reappraisal.
in females born SGA. On the contrary, most boys BJOG 107:1433–1435
born SGA have normal pubertal timing, but often Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A
heights below the target (Hernández and Mericq (2000) Morbidity and mortality among very-low-birth-
2008) Information about the influence of fetal weight neonates with intrauterine growth restriction.
The Vermont Oxford Network. Am J Obstet Gynecol
growth on gonadal function is scarce, but most 182:198e206
studies have shown that low birth weight is a Bertino E, Di Battista E, Bossi A, Pagliano M, Fabris C,
common risk factor for testicular cancer, hypospa- Aicardi G, Milani S (1996) Fetal growth velocity:
dia, and cryptorchidism (Main et al. 2006). kinetic, clinical, and biological aspects. Arch Dis
Child 74:F10–F15
Bertino E, Milani S, Fabris C, De Curtis M (2007) Neona-
tal anthropometric charts: what they are, what they are
not. Arch Dis Child Fetal Neonatal Ed 92:7–10
References Bertino E, Coscia A, Boni L, Rossi C, Martano C,
Giuliani F, Fabris C, Spada E, Zolin A, Milani S
Agostoni C (2005) Small-for-gestational-age infants need (2009) Weight growth velocity of very low birth weight
dietary quality more than quantity for their develop- infants: role of gender, gestational age and major mor-
ment: the role of human milk. Acta Paediatr bidities. Early Hum Dev 85:339–347
94:827–829 Blaas HG, Eik-Nes SH, Bremnes JB (1998) The growth of
Aucott SW, Donohue PK, Northington FJ (2004) Increased the human embryo. A longitudinal biometric assess-
morbidity in severe early intrauterine growth restric- ment from 7 to 12 weeks of gestation. Ultrasound
tion. J Perinatol 24:435–440 Obstet Gynecol 12:346–354
Bakalis S, Silva M, Akolekar R, Poon LC, Nicolaides KH Boers KE, Vijgen SM, Bijlenga D, van der Post JA,
(2015) Prediction of small-for-gestational-age neo- Bekedam DJ, Kwee A, van der Salm PC, van Pampus
nates: screening by fetal biometry at 30–34 weeks. MG, Spaanderman ME, de Boer K, Duvekot JJ,
Ultrasound Obstet Gynecol 45:551–558 Bremer HA, Hasaart TH, Delemarre FM,
Bardien N, Whitehead CL, Tong S, Ugoni A, McDonald S, Bloemenkamp KW, van Meir CA, Willekes C,
Walker SP (2016) Placental insufficiency in fetuses that Wijnen EJ, Rijken M, le Cessie S, Roumen FJ, Thorn-
slow in growth but are born appropriate for gestational age: ton JG, van Lith JM, Mol BW, Scherjon SA,
a prospective longitudinal study. PLoS One 11:e0142788 DIGITAT study group (2010) Induction versus expec-
Barker DJP (2006) Adult consequences of fetal growth tant monitoring for intrauterine growth restriction at
restriction. Clin Obstet Gynecol 49:270–283 term: randomized equivalence trial (DIGITAT). BMJ
Barker DJ, Hanson MA (2004) Altered regional blood flow 341:c7087
in the fetus: the origins of cardiovascular disease? Acta Boers KE, van Wyk L, van der Post JA, Kwee A, van
Paediatr 93:1559–1560 Pampus MG, Spaanderdam ME, Duvekot JJ, Bremer
Barker DJ, Osmond C (1986) Infant mortality, childhood HA, Delemarre FM, Bloemenkamp KW, de Groot CJ,
nutrition, and ischaemic heart disease in England and Willekes C, Rijken M, Roumen FJ, Thornton JG, van
Wales. Lancet 1:1077–1081 Lith JM, Mol BW, le Cessie S, Scherjon SA, DIGITAT
Barker DJ, Osmond C, Forsén TJ, Kajantie E, Eriksson JG Study Group (2012) Neonatal morbidity after induction
(2005) Trajectories of growth among children who vs expectant monitoring in intrauterine growth restric-
have coronary events as adults. N Engl J Med tion at term: a subanalysis of the DIGITAT RCT. Am J
353:1802–1809 Obstet Gynecol 206:344 e1–344 e7
Bartels DB, Schwab F, Geffers C, Poets CF, Gastmeier P Bora R, Mukhopadhyay K, Saxena AK, Jain V, Narang A
(2007) Nosocomial infection in small for gestational (2009) Prediction of feed intolerance and necrotizing
age newborns with birth weight <1500 g: a multicentre enterocolitis in neonates with absent end diastolic flow
analysis. Arch Dis Child Fetal Neonatal Ed 92: in umbilical artery and the correlation of feed intoler-
F449–F453 ance with postnatal superior mesenteric artery flow. J
Baschat AA, Cosmi E, Bilardo CM, Wolf H, Berg C, Matern Fetal Neonatal Med 22:1092–1096
Rigano S, Germer U, Moyano D, Turan S, Hartung J, Boulet SL, Alexander GR, Salihu HM, Kirby RS, Carlo
Bhide A, Müller T, Bower S, Nicolaides KH, WA (2006) Fetal growth risk curves: defining levels of
Thilaganathan B, Gembruch U, Ferrazzi E, Hecher K, fetal growth restriction by neonatal death risk. Am J
Galan HL, Harman CR (2007) Predictors of neonatal Obstet Gynecol 195:1571–1577
outcome in early-onset placental dysfunction. Obstet Bozzetti V, Tagliabue PE, Visser GH, van Bel F, Gazzolo D
Gynecol 109:253–261 (2013) Feeding issues in IUGR preterm infants. Early
Baschat AA, Viscardi RM, Hussey-Gardner B, Hashmi N, Hum Dev 89(S2):S21–S23
Harman C (2009) Infant neurodevelopment following Brar HS, Rutherford SE (1988) Classification of intrauter-
fetal growth restriction: relationship with antepartum ine growth retardation. Semin Perinatol 12:2–10
166 E. Bertino et al.
Cameron N (2004) Measuring techniques and instruments. neonates: screening by fetal biometry at 35–37 weeks.
In: Nicoletti I, Benso L, Gilli G (eds) Physiological and Ultrasound Obstet Gynecol 45:559–565
pathological auxology. Edizioni Centro Studi Figueras F, Gratacos E (2014) Stage-based approach to the
Auxologici, Firenze, pp 117–159 management of fetal growth restriction. Prenat Diagn
Campbell S, Thoms A (1977) Ultrasound measurement of 34:655–659
the fetal head to abdomen circumference ratio in the Garite TJ, Clark R, Thorp JA (2004) Intrauterine growth
assessment of growth retardation. Br J Obstet Gynaecol restriction increases morbidity and mortality among
84:165–174 premature neonates. Am J Obstet Gynecol
Casey PH (2008) Growth of low birth weight preterm 191:481–487
children. Semin Perinatol 32:20–27 Gibson AT, Carney S, Cavazzoni E, Wales JK (2000)
Clausson B, Cnattingius S, Axelsson O (1998) Preterm and Neonatal and postnatal growth. Horm Res 53:42–49
term births of small for gestational age infants: a Gortner L, Wauer RR, Stock GJ, Reiter HL, Reiss I,
population-based study of risk factors among nullipa- Jorch G, Hentschel R, Hieronimi G (1999) Neonatal
rous women. Br J Obstet Gynaecol 105(9):1011–1017 outcome in small for gestational age infants: do they
Clayton PE, Cianfarani S, Czernichow P, Johannsson G, really better? J Perinat Med 27:484e9
Rapaport R, Rogol A (2007) Management of the child Griffin IJ, Tancredi DJ, Bertino E, Lee HC, Profit J (2015)
born small for gestational age through to adulthood: a Postnatal growth failure in very low birthweight infants
consensus statement of the International Societies of born between 2005 and 2012. Arch Dis Child Fetal
Pediatric ndocrinology and the Growth Hormone Neonatal Ed 101:F1–F6
Research Society. J Clin Endocrinol Metab Guellec I, Lapillonne A, Renolleau S, Charlaluk ML, Roze
92:804–810 JC, Marret S, Vieux R, Monique K, Ancel PY,
Cruz-Martinez R, Savchev S, Cruz-Lemini M, Mendez A, EPIPAGE Study Group (2011) Neurologic outcomes
Gratacos E, Figueras F (2015) Clinical utility of third- at school age in very preterm infants born with severe
trimester uterine artery Doppler in the prediction of or mild growth restriction. Pediatrics 127:e883–e891
brain hemodynamic deterioration and adverse perinatal Halliday HL (2009) Neonatal management and long-term
outcome in small-for-gestational-age fetuses. Ultra- sequelae. Best Pract Res Clin Obstet Gynaecol
sound Obstet Gynecol 45:273–278 23:871–880
David C, Gabrielli S, Pilu G, Bovicelli L (1995) The head- Hansen AK, Wisborg K, Uldbjerg N, Henriksen TB (2008)
to-abdomen circumference ratio: a reappraisal. Ultra- Risk of respiratory morbidity in term infants delivered
sound Obstet Gynecol 5:256–259 by elective caesarean section: cohort study. BMJ
De Jong CL, Francis A, Van Geijn HP, Gardosi J (2000) 336:85–87
Customized fetal weight limits for antenatal detection Hanson MA, Gluckman PD (2014) Early developmental
of fetal growth restriction. Ultrasound Obstet Gynecol conditioning of later health and disease: physiology or
15:36–40 pathophysiology? Physiol Rev 94:1027–1076
Dhaliwal CA, Fleck BW, Wright E, Graham C, McIntosh Hernández MI, Mericq V (2008) Impact of being born
N (2009) Retinopathy of premature in small- for gesta- small for gestational age on onset and progression of
tional age infants compared with those of appropriate puberty. Best Pract Res Clin Endocrinol Metab
size for gestational age. Arch Dis Child Fetal Neonatal 22:463–476
Ed 94:F193–F195 Hofman PL, Regan F, Cutfield WS (2006) Prematurity-
Dijxhoorn MJ, Visser GH, Touwen BC, Huisjes HJ (1987) another example of perinatal metabolic programming?
Apgar score, meconium and acidaemia at birth in small- Horm Res 66:33–39
for-gestational age infants born at term, and their rela- Jarvis S, Glinianaia SV, Torrioli MG, Platt MJ, Miceli M,
tion to neonatal neurological morbidity. Br J Obstet Jouk PS, Johnson A, Hutton J, Hemming K,
Gynaecol 94:873–879 Hagberg G, Dolk H, Chalmers J, Surveillance of Cere-
Dorling J, Kempley S, Leaf A (2005) Feeding growth bral Palsy in Europe (SCPE) collaboration of European
restricted preterm infants with abnormal antenatal Cerebral Palsy Registers (2003) Cerebral palsy and
Doppler results. Arch Dis Child Fetal Neonatal Ed 90: intrauterine growth in single births: European collabo-
F359–F363 rative study. Lancet 362:1106–1111
Eixarch E, Meler E, Iraola A, Illa M, Crispi F, Hernandez- Kalish RB, Thaler HT, Chasen ST, Gupta M, Berman SJ,
Andrade E, Gratacos E, Figueras F (2008) Neurodeve- Rosenwaks Z, Chervenak FA (2004) First- and second-
lopmental outcome in 2-year-old infants who were trimester ultrasound assessment of gestational age. Am
small-for-gestational-age term fetuses with cerebral J Obstet Gynecol 191:975–978
blood flow redistribution. Ultrasound Obstet Gynecol Kanaka-Gantenbein C (2010) Fetal origins of adult diabe-
32:894–899 tes. Ann N Y Acad Sci 1205:99–105
Engle WA (2011) Morbidity and mortality in late preterm Karsdorp VH, van Vugt JM, van Geijn HP, Kostense PJ,
and early term newborns: a continuum. Clin Perinatol Arduini D, Montenegro N, Todros T (1994) Clinical
38:493–516 significance of absent or reversed end-diastolic veloc-
Fadigas C, Saiid Y, Gonzalez R, Poon LC, Nicolaides KH ity waveforms in umbilical artery. Lancet
(2015) Prediction of small-for-gestational-age 344:1664–1668
9 Intrauterine Growth Restriction: Obstetric and Neonatal Aspects. Intervention Strategies 167
Kase BA, Carreno CA, Blackwell SC (2012) Customized Lyall F, Robson SC, Bulmer JN (2013) Spiral artery
estimated fetal weight: a novel antenatal tool to diag- remodeling and trophoblast invasion in preeclampsia
nose abnormal fetal growth. Am J Obstet Gynecol and fetal growth restriction: relationship to clinical
207:218.e1–218.e5 outcome. Hypertension 62:1046–1054
Kinsella JP, Greenough A, Abman SH (2006) Main KM, Jensen RB, Asklund C, Høi-Hansen CE,
Bronchopulmonary dysplasia. Lancet 367:1421–1431 Skakkebaek NE (2006) Low birth weight and male
Koleganova N, Piecha G, Ritz E (2009) Prenatal causes of reproductive function. Horm Res 65:116–122
kidney disease. Blood Purif 27:48–52 Maiorana A, Del Bianco C, Cianfarani S (2007) Adipose
Kramer MS, Mc Lean FH, Olivier M, Willis DM, Usher tissue: a metabolic regulator. Potential implications for
RH (1989) Body proportionality and head and length the metabolic outcome of subjects born Small for Ges-
“sparing” in growth-retarded neonates: a critical tational Age (SGA). Rev Diabet Stud 4:134–146
reappraisal. Pediatrics 84:717–723 Mamopoulos A, Petousis S, Tsimpanakos J, Masouridou S,
Lal MK, Manktelow BN, Draper ES, Field DJ (2003) Kountourelli K, Margioula-Siarkou C, Papouli M,
Chronic lung disease of prematurity and intrauterine Rousso D (2015) Birth weight independently affects
growth retardation: a population-based study. Pediat- morbidity and mortality of extremely preterm neonates.
rics 111:483–487 J Clin Med Res 7:511–516
Lees C, Marlow N, Arabin B, Bilardo CM, Brezinka C, Mari G, Hanif F, Treadwell MC, Kruger M (2007) Gesta-
Derks JB, Duvekot J, Frusca T, Diemert A, Ferrazzi E, tional age at delivery and Doppler waveforms in very
Ganzevoort W, Hecher K, Martinelli P, Ostermayer E, preterm intrauterine growth-restricted fetuses as pre-
Papageorghiou AT, Schlembach D, Schneider KT, dictors of perinatal mortality. J Ultrasound Med
Thilaganathan B, Todros T, van Wassenaer-Leemhuis- 26:555–559
A, Valcamonico A, Visser GH, Wolf H, TRUFFLE McCowan LM, Mullen BM, Ritchie K (1987) Umbilical
Group (2013) Perinatal morbidity and mortality in artery flow velocity waveforms and the placental vas-
early-onset fetal growth restriction: cohort outcomes cular bed. Am J Obstet Gynecol 157:900–902
of the trial of randomized umbilical and fetal flow in McIntire DD, Bloom SL, Casey BM, Leveno KJ (1999)
Europe (TRUFFLE). Ultrasound Obstet Gynecol Birth weight in relation to morbidity and mortality
42:400–408 among newborn infants. N Engl J Med 340:1234–1238
Lees C, Marlow N, van Wassenaer-Leemhuis A, Arabin B, McMillen I, Adams M, Ross J, Coulter CL, Simonetta G,
Bilardo CM, Brezinka C, Calvert S, Derks JB, Owens JA, Robinson JS, Edwards LJ (2001) Fetal
Diemert A, Duvekot JJ, Ferrazzi E, Frusca T, growth restriction: adaptation and consequences.
Ganzevoort W, Hecher K, Martinelli P, Ostermayer E, Reproduction 122:195–204
Papageorghiou AT, Schlembach D, Schneider KTM, Meher S, Hernandez-Andrade E, Basheer SN, Lees C
Thilaganathan B, Todros T, Valcamonico A, Visser (2015) Impact of cerebral redistribution on neurodeve-
GHA, Wolf H, on behalf of the TRUFFLE Group lopmental outcome in small for gestational age or
(2015) The Trial of Randomized Umbilical and Fetal growth restricted babies: a systematic review. Ultra-
Flow in Europe (TRUFFLE) study: two year sound Obstet Gynecol 46:398–404
neurodevelopmental and intermediate perinatal out- Miller HC (1985) Prenatal factors affecting intrauterine
comes. Lancet 385:2162–2172 growth retardation. Clin Perinatol 12:307–318
Lesmes C, Gallo DM, Panaiotova J, Poon LC, Nicolaides Mitsiakos G, Papaioannou G, Papadakis E,
KH (2015) Prediction of small-for-gestational-age neo- Chatziioannidis E, Giougi E, Karagianni P,
nates: screening by fetal biometry at 19–24 weeks. Evdoridou J, Malindretos P, Athanasiou M,
Ultrasound Obstet Gynecol 46:198–207 Athanassiadou F, Nikolaidis N (2009) Haemostatic
Levine TA, Grunau RE, McAuliffe FM, Pinnamaneni R, profile of full-term, healthy, small for gestational age
Foran A, Alderdice FA (2015) Early childhood neonates. Thromb Res 124:288–291
neurodevelopment after intrauterine growth restriction: Morin I, Morin L, Zhang X, Platt RW, Blondel B,
a systematic review. Pediatrics 135:126–141 Bréart G, Usher R, Kramer MS (2005) Determinants
Lindqvist PG, Molin J (2005) Does antenatal identification and consequences of discrepancies in menstrual and
of small-for-gestational age fetuses significantly ultrasonographic gestational age estimates. BJOG
improve their outcome? Ultrasound Obstet Gynecol 112:145–152
25:258–264 Morley R, Fewtrell MS, Abbott RA, Stephenson T,
Lundgren EM, Tuvemo T (2008) Effects of being born MacFadyen U, Lucas A (2004) Neurodevelopment in
small for gestational age on long-term intellectual per- children born small for gestational age: a randomized
formance. Best Pract Res Clin Endocrinol Metab trial of nutrient-enriched versus standard formula and
22:477–488 comparison with a reference breastfed group. Pediatrics
Lundgren P, Kistner A, Andersson EM, Hansen Pupp I, 113:515–521
Holmström G, Ley D, Niklasson A, Smith LE, Wu C, Morsing E, Asard M, Ley D, Stjernqvist K, Marsál K
Hellström A, Löfqvist C (2014) Low birth weight is a (2011) Cognitive function after intrauterine growth
risk factor for severe retinopathy of prematurity restriction and very preterm birth. Pediatrics 127:
depending on gestational age. PLoS One 9:e109460 e874–e882
168 E. Bertino et al.
Murdoch EM, Sinha AK, Shanmugalingam ST, Smith GC, neonatal size, proportion, and outcome. Early Hum
Kempley ST (2006) Doppler flow velocimetry in the Dev 82:683–690
superior mesenteric artery on the first day of life in Ree IM, Smits-Wintjens VE, Rijntjes-Jacobs EG, Pelsma
preterm infants and the risk of neonatal necrotizing IC, Steggerda SJ, Walther FJ, Lopriore E (2014) Nec-
enterocolitis. Pediatrics 118:1999–2003 rotizing enterocolitis in small-for-gestational-age neo-
Nakling J, Buhaug H, Backe B (2005) The biologic error in nates: a matched case–control study. Neonatology
gestational length related to the use of the first day of 105:74–78
last menstrual period as a proxy for the start of preg- Regev RH, Lusky A, Dolfin T, Litmanovitz I, Arnon S,
nancy. Early Hum Dev 81:833–839 Reichman B, Network IN (2003) Excess mortality and
Nicolaides KH, Bilardo CM, Soothill PW, Campbell S morbidity among small-for-gestational-age premature
(1988) Absence of end diastolic frequencies in umbil- infants: a population-based study. J Pediatr
ical artery: a sign of fetal hypoxia and acidosis. BMJ 143:186–191
297:1026 Reinehr T, Kleber M, Toschke AM (2009) Small for ges-
Nobili V, Alisi A, Panera N, Agostoni C (2008) Low birth tational age status is associated with metabolic syn-
weight and catch-up-growth associated with metabolic drome in overweight children. Eur J Endocrinol
syndrome: a ten year systematic review. Pediatr Endo- 160:579–584
crinol Rev 6:241–247 Rizzo G, Prefumo F, Ferrazzi E, Zanardini C, Di
Olofsson P, Laurini RN, Marsál K (1993) A high uterine Martino D, Boito S, Aiello E, Ghi T, SIEOG working
artery pulsatility index reflects a defective development group on fetal biometric charts (2016) The effect of
of placental bed spiral arteries in pregnancies compli- fetal sex on customized fetal growth charts. J Matern
cated by hypertension and fetal growth retardation. Eur Fetal Neonatal Med 3:1–8
J Obstet Gynecol Reprod Biol 49:161–168 Rosenberg A (2008) The IUGR newborn. Semin Perinatol
Oros D, Figueras F, Cruz-Martinez R, Meler E, 32:219–224
Munmany M, Gratacos E (2011) Longitudinal changes Rozance PJ (2014) Update on neonatal hypoglycemia.
in uterine, umbilical and fetal cerebral Doppler indices Curr Opin Endocrinol Diabetes Obes 21:45–50
in late-onset small-for-gestational age fetuses. Ultra- Sabel KG, Olegard R, Mellander M, Hildingsson K (1982)
sound Obstet Gynecol 37:191–195 Interrelation between fatty acid oxidation and control
Pallotto EK, Kilbride HW (2006) Perinatal outcome and of gluconeogenic substrates in small for gestational age
later implications of intrauterine growth restriction. (SGA) infants with hypoglycemia and with
Clin Obstet Gynecol 49:257–269 normoglycemia. Acta Paediatr Scand 71:53–61
Pallotto EK, Woelnerhanssen B, Putt M (2004) Incidence Saenger P, Czernichow P, Hughes I, Reiter EO (2007)
and risk factors for prolonged hypoglycemia in small Small for gestational age: short stature and beyond.
for gestational age infants. Abstract, Society for Pedi- Endocr Rev 28:219–251
atric and Perinatal Epidemiology Sarkar S, Rosenkrantz TS (2008) Neonatal polycythemia
Papageorghiou AT, Ohuma EO, Altman DG, Todros T, and hyperviscosity. Semin Fetal Neonatal Med
Cheikh Ismail L, Lambert A, Jaffer YA, Bertino E, 13:248–255
Gravett MG, Purwar M, Noble JA, Pang R, Victora Savchev S, Figueras F, Cruz-Martinez R, Illa M, Botet F,
CG, Barros FC, Carvalho M, Salomon LJ, Bhutta ZA, Gratacos E (2012) Estimated weight centile as a pre-
Kennedy SH, Villar J, International Fetal and Newborn dictor of perinatal outcome in small-for-gestational-age
Growth Consortium for the 21st Century pregnancies with normal fetal and maternal Doppler
(INTERGROWTH-21st) (2014) International stan- indices. Ultrasound Obstet Gynecol 39:299–303
dards for fetal growth based on serial ultrasound mea- Shand AW, Hornbuckle J, Nathan E, Dickinson JE, French
surements: the Fetal Growth Longitudinal Study of the NP (2009) Small for gestational age preterm infants and
INTERGROWTH-21st Project. Lancet 384:869–879 relationship of abnormal umbilical artery Doppler
Peacock JL, Lo JW, D’Costa W, Calvert S, Marlow N, blood flow to perinatal mortality and neurodeve-
Greenough A (2013) Respiratory morbidity at follow- lopmental outcomes. Aust N Z J Obstet Gynaecol
up of small-for-gestational age infants born very pre- 49:52–58
maturely. Pediatr Res 73:457–463 Shapiro-Mendoza CK, Tomashek KM, Kotelchuck M,
Piper JM, Xenakis EM, McFarland M, Elliott BD, Berkus Barfield W, Nannini A, Weiss J, Declercq E (2008)
MD, Langer O (1996) Do growth-retarded premature Effect of late-preterm birth and maternal medical con-
infants have different rates of perinatal morbidity and ditions on newborn morbidity risk. Pediatrics 121:
mortality than appropriately grown premature infants? e223–e232
Obstet Gynecol 87:169–174 Sharma P, McKay K, Rosenkrantz TS, Hussain N (2004)
Pulver LS, Guest-Warnick G, Stoddard GJ, Byington CL, Comparisons of mortality and pre-discharge respira-
Young PC (2009) Weight for gestational age affects the tory outcomes in small-for-gestational-age and
mortality of late preterm infants. Pediatrics 123: appropriate-for-gestational-age premature infants.
e1072–e1077 BMC Pediatr 4:9
Rasmussen S, Kiserud T, Albrechtsen S (2006) Foetal size Simon D, Léger J, Carel JC (2008) Optimal use of growth
and body proportion at 17–19 weeks of gestation and hormone therapy for maximizing adult height in
9 Intrauterine Growth Restriction: Obstetric and Neonatal Aspects. Intervention Strategies 169
children born small for gestational age. Best Pract Res placental villous angiogenesis in pregnancies compli-
Clin Endocrinol Metab 22:525–537 cated by fetal growth restriction. Obstet Gynecol
Singer DB, Sung CJ, Wigglesworth JS (1991) Fetal growth 93:499–503
and maturation with standards for body and organ Torrance HL, Bloemen MC, Mulder EJ, Nikkels PG,
development. In: Wigglesworth JS, Singer DB (eds) Derks JB, de Vries LS, Visser GH (2010) Predictors
Textbook of fetal and perinatal pathology. Blackwell, of outcome at 2 years of age after early intrauterine
London, pp 11–47 growth restriction. Ultrasound Obstet Gynecol
Skuse D, Pickles A, Wolke D, Reilly S (1994) Postnatal 36:171–177
growth and mental development: evidence for a “sen- Tyrrell S, Obaid AH, Lilford RJ (1989) Umbilical artery
sitive period”. J Child Psychol Psychiatry Doppler velocimetry as a predictor of fetal hypoxia and
35:521–545 acidosis at birth. Obstet Gynecol 74:332–337
Smith LE (2005) IGF-1 and retinopathy of prematurity in van Wyk L, Boers KE, van der Post JA, van Pampus MG,
the preterm infant. Biol Neonate 88:237–244 van Wassenaer AG, van Baar AL, Spaanderdam ME,
Snijders RJ, Abbas A, Melby O, Ireland RM, Nicolaides Becker JH, Kwee A, Duvekot JJ, Bremer HA,
KH (1993) Fetal plasma erythropoietin concentration Delemarre FM, Bloemenkamp KW, de Groot CJ,
in severe growth retardation. Am J Obstet Gynecol Willekes C, Roumen FJ, van Lith JM, Mol BW, le
168:615–619 Cessie S, Scherjon SA, DIGITAT Study Group (2012)
Soothill PW, Ajayi RA, Campbell S, Ross EM, Candy DC, Effects on (neuro developmental and behavioral out-
Snijders RM, Nicolaides KH (1992) Relationship come at 2 years of age of induced labor compared
between fetal acidemia at cordocentesis and subsequent with expectant management in intrauterine growth-
neurodevelopment. Ultrasound Obstet Gynecol restricted infants: long-term outcomes of the
2:80–83 DIGITAT trial. Am J Obstet Gynecol 206:406
Soudée S, Vuillemin L, Alberti C, Mohamed D, Becquet O, e1–406 e7
Farnoux C, Biran V, Baud O (2014) Fetal growth Varda NM, Gregoric A (2009) Metabolic syndrome in the
restriction is worse than extreme prematurity for the pediatric population: a short overview. Pediatric Rev 1:e1
developing lung. Neonatology 106:304–310 Varella MH, Moss WJ (2015) Early growth patterns are
Sovio U, White IR, Dacey A, Pasupathy D, Smith GC associated with intelligence quotient scores in children
(2015) Screening for fetal growth restriction with uni- born small-for-gestational age. Early Hum Dev
versal third trimester ultrasonography in nulliparous 91:491–497
women in the Pregnancy Outcome Prediction (POP) Vashevnik S, Walker S, Permezel M (2007) Stillbirths and
study: a prospective cohort study. Lancet neonatal deaths in appropriate, small and large
386:2089–2097 birthweight for gestational age fetuses. Aust N Z J
Tajik P, van Wyk L, Boers KE, le Cessie S, Zafarmand MH, Obstet Gynaecol 47:302–306
Roumen F, van der Post JA, Porath M, van Pampus Victora CG (2015) Anthropometric characterization of
MG, Spaanderdam ME, Kwee A, Duvekot JJ, Bremer impaired fetal growth. Risk factors for and prognosis
HA, Delemarre FM, Bloemenkamp KW, de Groot CJ, of newborns with stunting or wasting. JAMA Pediatr
Willekes C, van Lith JM, Bossuyt PM, Mol BW, 169(7):e151431
Scherjon SA, DIGITAT Study Group (2014) Which Vrachnis N, Botsis D, Iliodromiti Z (2006) The fetus that is
intrauterine growth restricted fetuses at term benefit small for gestationel age. N Y Acad Sci 1092:304–309
from early labour induction? A secondary analysis of Walker DM, Marlow N (2008) Neurocognitive outcome
the DIGITAT randomised trial. Eur J Obstet Gynecol following fetal growth restriction. Arch Dis Child Fetal
Reprod Biol 172:20–25 Neonatal Ed 93:F322–F325
Tanner JM (1989) Foetus into man, 2nd edn. Castlemead Wirbelauer J, Thomas W, Rieger L, Speer CP (2010) Intra-
Publication, Welwyn Garden City uterine growth retardation in preterm infants 32
The American Academy of Pediatrics and the American weeks of gestation is associated with low white blood
College of Obstetricians and Gynecologist (2007) Stan- cell counts. Am J Perinatol 27(10):819–824
dard terminology for reporting of reproductive health Wit JM, Finken MJ, Rijken M, de Zegher F (2006) Preterm
statistics in the United States. In: Guideline for prenatal growth restraint: a paradigm that unifies intrauterine
care. American Academy of Pediatrics, Elk Grove growth retardation and preterm extrauterine growth
Village retardation and has implications for the small-for-ges-
Thorsell M, Kaijser M, Almström H, Andolf E (2008) tational-age indication in growth hormone therapy.
Expected day of delivery from ultrasound dating versus Pediatrics 117:e793–e795
last menstrual period–obstetric outcome when dates Yeung MY (2006) Postnatal growth, neurodevelopment
mismatch. BJOG 115:585–589 and altered adiposity after preterm birth–from a
Todros T, Plazzotta C, Pastorin L (1996) Body proportion- clinical nutrition perspective. Acta Paediatr
ality of the small-for-date fetus: is it related to 95:909–917
aetiological factors? Early Hum Dev 45:1–9 Yu V, Upadhyay A (2004) Neonatal management of the
Todros T, Sciarrone A, Piccoli E, Guiot C, Kaufmann P, growth-restricted infant. Semin Fetal Neonatal Med
Kingdom J (1999) Umbilical Doppler waveforms and 9:403–409
Late Preterm Infants at Risk
for Short-Term and Long-Term 10
Morbidity and Mortality
Avroy A. Fanaroff
Contents
10.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
10.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
10.3 The Late Preterm Infant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
10.3.1 Incidence and Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
10.4 Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
10.5 Morbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
10.6 Readmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
10.7 Thermal Instability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
10.8 Transient Tachypnea of the Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
10.9 Respiratory Distress Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
10.10 Apnea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
10.11 Feeding Difficulties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
10.12 Jaundice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
10.13 Long-Term Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
10.14 Discharge Planning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
10.15 Summary and Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
Abstract
Late preterm infants (LPIs) represent the larg-
est subpopulation of preterm infants with sig-
nificant short and long-term morbidity and
A. A. Fanaroff (*) even mortality compared to term infants. Dur-
Case Western Reserve University School of Medicine ing birth hospitalization, the major causes of
Rainbow Babies and Children’s Hospital, Cleveland,
OH, USA morbidity encountered in LPIs include
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 171
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_159
172 A. A. Fanaroff
transient tachypnea of the newborn, respiratory during birth hospitalization and post-birth
distress syndrome, persistent pulmonary discharge.
hypertension of the newborn, respiratory fail-
ure, apnea, temperature instability, jaundice,
hypoglycemia, and feeding difficulties, which 10.2 Introduction
result in a longer hospital stay and higher med-
ical costs. In addition, LPIs have a higher prev- Late preterm births were the first group of
alence of congenital malformations which premature infants who neonatologists treated
may contribute to an increased mortality rel- successfully. Over time with the very low birth
ative to term infants. There is a twofold risk weight infants surviving and demanding many
of rehospitalization for LPIs compared with resources, near-term infants were relatively
term infants. Hyperbilirubinemia, feeding ignored and unfortunately were no longer consid-
difficulties, poor weight gain, dehydration, ered to be of high risk by many health care pro-
and apnea are the most common clinical con- viders. The resurgence of interest in this group,
ditions requiring hospital readmission during and their renaming to late preterm resulted from
the first week of postnatal life. Respiratory the recognition that they were indeed the largest
and gastrointestinal disorders are the most subpopulation of preterm infants, and had an
common causes of late readmission during increased mortality when compared to term
the first year of life. Evidence suggests that infants and increased morbidity including tran-
LPIs are at increased risk of adverse neuro- sient tachypnea of newborn (TTNB), respiratory
developmental outcomes and academic diffi- distress syndrome (RDS), persistent pulmonary
culties up to 7 years of age in comparison to hypertension (PPHN), respiratory failure, apnea,
term infants. temperature instability, jaundice, hypoglycemia,
feeding difficulties and a prolonged neonatal
intensive care unit (NICU) stay (Raju et al.
10.1 Salient Points 2006; Engle et al. 2007; Jain 2007, 2008a;
Ramachandrappa and Jain 2009; American Col-
• Late preterm infants are the commonest cause lege of Obstetricians and Gynecologists 2013).
of prematurity and account for the bulk of Furthermore, they have an increased prevalence
preterm births of cognitive and neuro-developmental problems
• Prevention of late preterm births provide the and a greater rate of readmission to hospital in the
best opportunity to reduce the rates of preterm first weeks after discharge than term births.
births Escobar noted that many late preterm infants are
• Late preterm births have significant in hospital never admitted to the NICU (Escobar et al. 2005).
morbidity and a higher mortality when com- A possible explanation is that clinicians may
pared to term infants. The infant mortality rate be making clinical judgments based on infants’
for late preterm infants is at least threefold birth weight only rather than gestation and birth
greater than that of term infants. weight.
• Late preterm infants have significant cognitive Preterm births are both emotionally and finan-
and behavioral problems later in life. These cially costly, taking a toll on the family and
problems are independent of maternal IQ, res- resulting in high direct health care costs due to
idential setting, and socio-demographics. longer hospital stays and hospital readmissions.
• Strategies to decrease the morbidity and mor- Reducing the rate and toll from premature deliv-
tality associated with late preterm infants in eries is both a national and international priority.
addition to prevention of late preterm delivery, Because late preterm deliveries, those between
include management to prevent and treat the 34 and 37 weeks’ gestation, account for about
associated complications of late preterm birth 70% of preterm births, they represent the low
10 Late Preterm Infants at Risk for Short-Term and Long-Term Morbidity and Mortality 173
lying fruit, and are the logical initial target for 16.0% Late preterm: 71.3%
<32 weeks
prevention of prematurity.
5.1%
32 weeks
37.1%
10.3 The Late Preterm Infant 36 weeks
7.7%
33 weeks
Until recently late preterm infants (those delivered
between 34 weeks 0 days and 36 weeks plus 6 days)
were regarded and treated as near-term infants. 13.0%
34 weeks
Consequently the considerable morbidity and mor-
tality in this group of infants was largely unnoticed 21.2%
and disregarded. Recognizing that they indeed are 35 weeks
the largest group of preterm infants with significant
Fig. 1 Distribution of all preterm births, USA 2003
short and long-term morbidity and even mortality,
the terminology has changed to emphasize the pre-
term birth, hence the terminology late preterm, and births from 7.3% to 9.1% of all live births in 2006
closer attention is being paid to this specific class of when there were 387,791 late preterm births in the
infant. As they account for over 70% of preterm USA. Indeed between 1996 and 2006, the rate of
births, utilize excessive resources and as many late infants born late preterm in the US increased more
preterm infants have no identifiable reasons for than 18%. However, there was a slight decline of
their early appearance, they present the best oppor- late preterm infants to 9% in 2007, perhaps
tunity to substantially reduce the rate of preterm reflecting progress in the prevention of late pre-
birth (Raju et al. 2006; Engle et al. 2007; Seikku term delivery. Late preterm infants, more than
et al. 2016; Spong et al. 2011; Hamilton et al. 2016) 34 and less than 37 weeks’ gestation, account for
almost three quarters of preterm births (Fig. 1).
Almost half of these deliveries are by elective
10.3.1 Incidence and Prevention cesarean section, for sound medical reasons and
in the best interest of the mother and fetus.
In the US, premature births increased from 10.6% The American College of Obstetricians and
in 1990 to a high of 12.8% of all live births in Gynecologists has recommended that elective
2006, declining to 12.7% in 2007 and 12.3% in deliveries not be performed before 39 weeks of
2008 (Escobar et al. 2005). In 2013 in the USA, gestation (American College of Obstetricians and
the preterm birth rate declined for the seventh Gynecologists 1999).
straight year to 11.39%; the low birth weight Davidoff examined the changing epidemiol-
(LBW) rate was essentially unchanged at 8.02%. ogy of gestational length among singleton births
The infant mortality rate was 5.96 infant deaths in the USA, from 1992 to 2002 (Davidoff et al.
per 1000 live births in 2013, down 13% from 2005 2006). Analyzing gestational age by mode of
(6.86). The age-adjusted death rate for 2013 was delivery, the distribution of spontaneous births
7.3 deaths per 1000 population, unchanged from shifted to the left, with 39 weeks becoming the
2012. (Osterman et al. 2015). In 2015 there were most common length of gestation in 2002, com-
3.978 million births in the USA, down less than pared with 40 weeks in 1992 (P < 0.001). Deliv-
1% from 2014. The cesarean delivery rate eries at greater or equal to 40 weeks gestation
declined to 32.0% of births in 2015; the preterm markedly decreased, accompanied by an increase
birth rate rose slightly to 9.63% from 2014 to in those at 34–39 weeks. Singleton births with
2015 (Martin et al. 2016). premature/prolonged rupture of the membranes
The rise of preterm births during the last three or medical interventions had similar trends.
decades was primarily due to a rise in late preterm Changes in the distribution of all singleton births
174 A. A. Fanaroff
differed by race/ethnicity, with non-Hispanic Reddy et al. (2009) characterized the delivery
white infants having the largest increase in late indications for late preterm births and their potential
preterm births. impact on neonatal and infant mortality rates. Using
To quantify the adverse neonatal and maternal the 2001 US Birth Cohort Linked birth/death files
outcomes associated with elective term delivery at which contained over three million singleton births,
less than 39 completed weeks of gestation, Clark they categorized delivery indications as follows:
et al. reviewed a cohort of 17,794 deliveries, (1) maternal medical conditions; (2) obstetric com-
including 14,955 (84%) at 37 weeks or greater. plications; (3) major congenital anomalies; (4) iso-
Remarkably, of these term deliveries, 6562 (44%) lated spontaneous labor, vaginal delivery without
were planned, rather than spontaneous (Clark et al. induction and without associated medical/obstetric
2009). Among the planned deliveries, 4645 (71%) factors; and (5) no recorded indication. They noted
were purely elective, and 17.8% of infants deliv- that among 292,627 late preterm births, the first four
ered electively without medical indication at categories (those with indications and isolated spon-
37–38 weeks and 8% of those delivered electively taneous labor) accounted for 77%. The remaining
at 38–39 weeks required admission to a newborn 23% (67,909) were classified as deliveries with no
special care unit compared with 4.6% of infants recorded indication. Factors significantly increasing
delivered at 39 weeks or beyond. Cesarean deliv- the chance of no recorded indication were older
ery rate in women undergoing induction of labor maternal age, race, multiparity, or previous macro-
was not influenced by gestational age but was somic infant of more than 4000 g birth weight. The
highly influenced by initial cervical dilatation neonatal and infant mortality rates were significantly
and parity, ranging from 0% for parous women higher among deliveries with no recorded indication
induced at 5 cm or greater to 50% for nulliparous compared with deliveries secondary to isolated spon-
women at 0 cm. They rightfully concluded that taneous labor but not surprisingly lower compared
elective delivery before 39 weeks’ gestation is with deliveries with an obstetric indication or con-
associated with significant neonatal morbidity genital anomaly. These 23% of late preterm births
and is inappropriate. with no recorded indication for delivery noted on
Oshiro et al. (2009) reported that before initia- birth certificates present a prime opportunity for pre-
tion of a concerted system and multidisciplinary venting late preterm births.
team effort (including information technology The potential for success in this regard is
administrators as well as bedside care providers documented by the Ohio Perinatal Quality Collab-
such as physicians and nurses) with the goal of orative Writing Committee (Donovan et al. 2010).
reducing elective births before 39 weeks, 28% of They sought to reduce scheduled births between
elective deliveries were occurring before 39 com- 36(0/7)–38(6/7) weeks that lack appropriate medi-
pleted weeks of gestation. Within 6 months of cal indication. They collected baseline data for
introducing the program, the rate was down to 60 days from 20 Ohio maternity units and then
10%, and 6 years later through continued educa- mandated recording of an indication for scheduled
tion and a cultural change within the system, the births between 36(0/7) and 38(6/7) weeks gesta-
rate is down to a very acceptable 3%. tion. Deidentified birth data were analyzed cen-
Until 2007 the rate of preterm births has been trally. Rates of scheduled births without a
increasing in the USA, especially for births at documented indication, birth certificate data, and
34 weeks of gestation (late preterm). The causes implementation issues were shared regularly
for these trends remain unclear, but significant among sites. The rate of scheduled births between
contributors to these large numbers of late preterm 36(0/7)–38(6/7) weeks without a documented
births are elective inductions and cesarean deliv- medical indication declined significantly from
eries prior to 37 weeks’ gestation. This is despite 25% to less than 5% in participating hospitals.
evidence and guidelines recommending against Birth certificate data showed inductions without
elective deliveries before 39 weeks without clini- an indication declined from a mean of 13–8%.
cal indication (Seikku et al. 2016). Dating criteria were documented in 99% of charts.
10 Late Preterm Infants at Risk for Short-Term and Long-Term Morbidity and Mortality 175
Thus merely by establishing and applying dating 44 times more likely than term appropriate for
criteria for gestational age and requiring documen- gestational age (AGA) newborns to die in their
tation of the reasons for scheduled birth, the num- first month and 22 times more likely to die in
ber of late preterm deliveries was substantially their first year. Even excluding deaths from
reduced. If we can accomplish this beyond congenital conditions, including birth defects,
36 weeks, there is no reason to believe that it cannot the differences in mortality rate ratios persisted
be extrapolated to 34 weeks and beyond with a for SGA infants, especially those born in the
significant impact on reducing late preterm births. late preterm period.
However, in order to sustain the success, it will be Tomashek et al. (2007) observed that late pre-
necessary for scheduled births to be a part of the term infants were particularly more likely to die in
culture of safety and for mothers to be better edu- the early neonatal period compared with term
cated regarding the risks of late preterm delivery. infants from causes such as respiratory compro-
Bailit et al. (2010), utilizing electronic health mise, maternal complications of pregnancy, and
records, sought to determine maternal and neona- congenital anomalies. They noted that infant mor-
tal outcomes by labor onset type and gestational tality rates were three times higher in late preterm
age. They reviewed 115,528 deliveries from 2002 infants than term infants (7.9 vs. 2.4 deaths per
through 2008 categorized by labor onset type 1000 live births) (Table 1). Because many of the
(spontaneous, elective induction, indicated induc- deaths were caused by life-threatening congenital
tion, unlabored cesarean). Neonatal and maternal malformations, which may have precipitated the
outcomes were calculated by labor onset type and preterm delivery, the plea for prospective docu-
gestational age. mentation of the indications for late preterm deliv-
Neonatal intensive care unit admissions, the eries is timely and appropriate.
need for assisted ventilation, and sepsis improved Kitsommart et al. (2009) compared data on
with each week of gestational age until 39 weeks. 1193 late preterm, the majority of whom were
The babies did better with elective induction, but 36 weeks (44%) followed by 35 weeks (29%)
there was increased risk of mothers requiring a and 34 weeks (27%), respectively, and 8666
hysterectomy in that group (Bailit et al. 2010). term infants. The prevalence of intensive care
admission, respiratory support, pneumothorax,
and mortality in late preterm infants was signifi-
10.4 Mortality cantly higher compared with term infants.
Although only 1% had positive cultures, almost
In 2002, the neonatal mortality rate (deaths among 30% were treated with antibiotics. Despite a low
infants 0–27 days chronologic age) for late pre-
term infants was 4.6 times higher than the rate for Table 1 Complications of prematurity in late preterm
term infants (4.1 vs. 0.9 per 1000 live births, versus term infants
respectively). This difference has actually wid- Frequency late Frequency
ened when compared to 1995 data where there Complication preterm term
was a fourfold difference between late preterm Jaundice 54% 38%
and term infants (4.8 vs. 1.2 per 1000 live births, Sepsis evaluation 37% 13%
Feeding 32% 7%
respectively). This relationship also carries over
difficulties
into infant mortality. In 2002, the infant mortality Receive IV fluids 27% 5%
rate, deaths during the first year of life, for late Hypoglycemia 16% 5
preterm infants was also greater than the infant Temp. instability 10% <0.1%
mortality rate for term infants (7.7 vs. 2.5 per 1000 Apnea 6% <0.1%
live births, respectively) (Hamilton et al. 2016; Mechanical 3.4% 0.9
Clark et al. 2009). ventilation
This is most notable for late preterm small Mortality (2002) 7.9/1000 live 2.4/1000 live
for gestational age (SGA) infants who are births births
176 A. A. Fanaroff
Fig. 2 Proportion with
34 51.7
newborn morbidity during
birth hospitalization 35 25.6
according to gestational age
(From (Shapiro-Mendoza 36 12.1
et al. 2008), with
Gestational age, wk
37 5.9
permission)
38 3.3
39 2.6
40 2.5
41 2.8
34-36 22.2
37-41 3.0
0 10 20 30 40 50 60
Morbidity risk, %
overall mortality rate of 0.8%, the late preterm Table 2 Risk for infant morbidity term versus late pre-
group had a 12-fold higher risk of death. The term (Clark et al. 2009)
increased mortality and morbidity thus confirm Maternal condition RR ratio LPT/term
the high-risk status of late preterm infants. Hypertensive disease 6.1
Diabetes 5.4
Antepartum hemorrhage 5.1
10.5 Morbidity Acute or chronic lung disease 6.1
Maternal infection 4.4
It is estimated that nearly 50% of infants born at Cardiac disease 5.7
34 weeks’ gestation require intensive care; this Renal disease 4.6
number drops to 15% at 35 weeks and 8% at Genital herpes 10.0
36 weeks gestation. In order to identify infants at
the highest risk for life-threatening morbidity and has had prenatal maternal exposure to hyperten-
those most likely to require specialized care, sive disorders of pregnancy and antepartum
Shapiro-Mendoza et al. (2008) classified a new- hemorrhage.
born as having a morbid condition during initial Late preterm infants were seven times more
hospitalization when at least one of the following likely to have newborn morbidity than term infants
three criteria was met: (1) newborn hospital stay (22 vs. 3%) (Fig. 2). Late preterm infants who were
of five nights and any morbidity diagnostic code exposed to antepartum hemorrhage and hyperten-
considered life-threatening, (2) newborn hospital sive disorders of pregnancy (HDP) were especially
stay of five nights and transfer to a higher-level vulnerable. Additionally HDP, diabetes, and
medical facility, and (3) infant death before hos- asthma are associated with an increased risk for
pital discharge. They reported that the risk for indicated or spontaneous preterm birth (Table 2).
newborn morbidity increases twofold with each Decisions regarding the delivery of late pre-
earlier week of gestation, beginning at 38 weeks’ term infants take into account the risks and bene-
gestation until 34 weeks’ gestation (Fig. 2). Late fits to both mother and fetus of prolonging the
preterm infants are at greater risk for newborn pregnancy. Specific standards of care and proto-
morbidity than term infants, especially when cols are necessary for late preterm infants rather
maternal morbidity also is present. This risk than applying those developed for term infants.
seems to be particularly intensified when an infant Furthermore better anticipation, recognition,
10 Late Preterm Infants at Risk for Short-Term and Long-Term Morbidity and Mortality 177
and treatment of women with chronic and during the first year of life. Underwood et al. noted
pregnancy-related health conditions may decrease that the largest cohort of infants readmitted to the
the rates of newborn morbidity in all infants but hospital at least once during the first month of life
especially in late preterm ones. was infants born at 35 week’s gestation, most com-
The major causes of morbidity encountered in monly due to a respiratory illness (Underwood
late preterm infants include transient tachypnea of et al. 2007). The cost of hospital readmission for
the newborn (TTNB), respiratory distress syndrome this cohort of infants approached 100 million
(RDS), persistent pulmonary hypertension of the dollars.
newborn (PPHN), respiratory failure, apnea, tem-
perature instability, jaundice, hypoglycemia, feed-
ing difficulties, and a prolonged neonatal intensive 10.7 Thermal Instability
care unit (NICU) stay. In addition they have a
higher prevalence of congenital malformations Whereas the late preterm infant is better equipped
which, as noted above, may contribute to an than the extremely low birth weight and premature
increased mortality relative to term infants. They infant, they are still vulnerable to cold exposure
are also more likely to develop bloodstream infec- after delivery. Increasing amounts of fat are
tions (Cohen-Wolkowiez et al. 2009) (Table 1). deposited in the final weeks of gestation so they
have less white fat and brown fat accumulation
and maturation, notably the controlling hormones
10.6 Readmission surge at term. Late preterm infants often have
temperature instability, which in turn leads to the
Escobar evaluated the large Kaiser Permanente consideration of sepsis, a sepsis evaluation, and
database which included 33,276 survivors of neo- often the initiation of antibiotic therapy (Wang
natal intensive care with 862 (2.6%) < 34 weeks’ et al. 2004).
gestation, 2153 (6.5%) between 34 and 36 weeks,
and 30,261 (90.9%) of more than 37 weeks (Amer-
ican College of Obstetricians and Gynecologists 10.8 Transient Tachypnea of the
2013). Rehospitalization rates within 2 weeks Newborn
after nursery discharge varied by gestational age
range: 26/862 (3.0%) among babies <34 weeks, A major respiratory disorder in late preterm
94/2153 (4.4%) among babies 34–36 weeks, and infants is transient tachypnea of the newborn
618/30261 (2.0%) among babies 37+ weeks. (TTNB). TTNB is best described as the conse-
Hence there is a twofold risk of rehospitalization quence of delayed and inadequate lung liquid
for late preterm infants compared with term infants, clearance. This self-limiting disease, character-
and jaundice was the major reason for readmission. ized by an increase in respiratory rate, occurs
These data are substantiated by McLaurin (24), more frequently in infants delivered by elective
who reported readmission rates over the first year cesarean section and is thought to result from
of life for late preterm infants were 15%, compared delayed activation of liquid clearance in infants
to 8% in term infants (McLaurin et al. 2009). In not subjected to the stress of labor. Gowen and
particular, late preterm infants are three times more others showed that newborn infants with TTNB
likely to be admitted within the first 15 days after had a transient decrease in amiloride-sensitive
discharge from the birth hospitalization (3.8 nasal epithelial Na+ transport compared with nor-
vs. 1.3%. The most common reasons for early mal newborns, supporting the notion that sub-
readmission are jaundice, feeding difficulties, optimal clearance of liquid is a cause of TTNB.
poor weight gain, dehydration, and apnea. Respi- Infants with TTNB were found to have low nor-
ratory (including bronchiolitis) and gastrointestinal epinephrine but normal epinephrine levels.
disorders are the most common diagnoses for late Lung ultrasound has been a very useful means
readmission ( 15 days after the date of discharge) of establishing the diagnosis of TTNB.
178 A. A. Fanaroff
10.9 Respiratory Distress Syndrome Dudell and Jain (2006) reviewed the ELSO
neonatal registry to study the indications for and
With more liberal use of antenatal corticosteroids outcomes of late preterm infants requiring extra-
commencing in 1994 and the introduction of sur- corporeal membrane oxygenation (ECMO). The
factant in the early 1990s, infant deaths associated cohort comprised 2258 late preterm infants,
with respiratory distress syndrome decreased by representing 14.5% of 15,590 registered neonates.
48% from 1989–1991 to 1995–1997 and then The primary etiology of hypoxic respiratory fail-
decreased by another 18% by 2002–2004 in the ure in late preterm infants treated with ECMO was
USA. The latter mortality reduction was evident at RDS or sepsis as compared to term infants who
28–32 weeks but not 33–36 weeks of gestation were more likely to have aspiration syndromes.
because these infants have not been optimally The overall survival (74%) has not improved over
targeted to receive prenatal corticosteroid prophy- time and was inferior for the late preterm infants
laxis, despite evidence from randomized trials as compared with 87% in the term population.
regarding the safety and efficacy of the treatment
at this gestation. As corticosteroid use is infrequent
beyond 33 weeks’ gestation (15%), “addressing the 10.10 Apnea
knowledge practice gap in corticosteroid use at
33 and 34 weeks should reduce infant morbidity Apnea occurs more frequently in late preterm
and mortality” (Gowen et al. 1988). infants (4–7%) than in term infants (1–2%)
Extrapolating the data from infants born at (Hunt 2006). In the Collaborative Home Infant
24–32 weeks gestation, Joseph et al. (Joseph et al. Monitoring Evaluation (CHIME) study, the
2009) concluded that the number needed to treat recorded rate of apnea (obstructive and central
estimates for 35 weeks (n = 21) and 36 weeks apnea) and bradycardia events was greater in late
(n = 64) of gestation is sufficient to warrant addi- preterm infants versus term infants (Hunt 2006;
tional attention in terms of future research Ramanathan et al. 2001). Late preterm infants
addressing efficacy at these more advanced gesta- may also be at increased risk for sudden infant
tional ages. However meta-analyses reveal nonsig- death syndrome compared to term infants.
nificant protective effects beyond 36 weeks.
Administration of betamethasone to women at
risk for late preterm delivery significantly reduced 10.11 Feeding Difficulties
the rate of neonatal respiratory complications.
The primary outcome (the use of continuous posi- Late Preterm infants may have immature feeding
tive airway pressure or high-flow nasal cannula for mechanics with poor coordination of sucking and
at least 2 h, supplemental oxygen with a fraction of swallowing resulting in limited fluid intake and
inspired oxygen of at least 0.30 for at least 4 h, dehydration, often necessitating intravenous ther-
extracorporeal membrane oxygenation, or mechan- apy. It is also more difficult to establish breast
ical ventilation) or stillbirth or neonatal death within feeding, and there may also be accentuated gas-
72 h after delivery. occurred (11.6%) in the troesophageal reflux in late preterm infants. The
betamethasone group and(14.4%) in the placebo American Academy of Pediatrics (AAP) has
group (Gyamfi-Bannerman et al. 2016). Severe recommended that prior to discharge, it is essential
respiratory complications, transient tachypnea of to establish successful feeding defined as coordi-
the newborn, surfactant use, and bronchopulmonary nated sucking, swallowing, and breathing while
dysplasia also occurred significantly less frequently feeding (Engle et al. 2007). Weight loss should not
in the betamethasone group. There were no signif- exceed 7% of birth weight during birth hospitali-
icant between-group differences in the incidence of zation. If the infant is breastfed, twice daily
chorioamnionitis or neonatal sepsis. Neonatal hypo- documented observation by trained caregivers of
glycemia was more common in the betamethasone successful position, latch, and milk transfer after
group than in the placebo group (24.0% vs. 15.0). birth also should be performed.
10 Late Preterm Infants at Risk for Short-Term and Long-Term Morbidity and Mortality 179
10.12 Jaundice and zones according to the Bhutani nomogram
(Maisels and Kring 1998; Bhutani and Johnson
Hyperbilirubinemia is the most common clinical 2006).
condition requiring hospital readmission during the It has long been accepted that jaundice pro-
first week of postnatal life. Late preterm infants are at gresses in a cephalo-caudal fashion as the total
substantially higher risk for severe hyper- serum bilirubin (TSB) level increases. Kramer
bilirubinemia than infants born at term. Infants born provided the first systematic study of this process
at 36 weeks’ gestation have almost an eightfold by dividing the body into five zones ranging from
increased risk of developing a total serum bilirubin zone 1 (jaundice restricted to the head and neck)
greater than 20 mg per 100 mL (5.2%) versus those to zone 5 (jaundice in the hands and feet). As the
born at 41 or 42 weeks gestation (0.7 and 0.6%, jaundice progressed from the head to the extrem-
respectively) (Newman et al. 1999). Approximately ities, the TSB levels increased, although there
1 in 650–1000 infants >35 weeks’ gestation was a wide range of bilirubin values in each
develops, total serum bilirubin values greater than zone (Bhutani et al. 2008). To evaluate the visual
or equal to 25 mg per 100 mL, and 1 in 10,000 has assessment of jaundice, Keren et al. (Kramer
levels greater than 30 mg per 100 mL. 1969) utilized experienced well-baby nursery
The risk factors for readmission are nurses to visually evaluate newborns for jaun-
documented in Table 3 and are dominated by dice at a mean age of 47 h. The objective was to
gestational age and breast feeding (Maisels and determine whether the pre discharge visual
Kring 1998). The jaundice may be attributed also assessment would help to predict the subsequent
to early discharge, inappropriate follow-up and risk of significant neonatal hyperbilirubinemia,
monitoring, as well as diminished fluid intake defined as a bilirubin level that exceeded or came
related to poor feeding. Late preterm infants within 1 mg/dL of the AAP phototherapy treat-
accounted for 40% of kernicterus in a large series ment threshold (Keren et al. 2009). Those whose
reported by Bhutani and Johnson (2006). All were pre discharge jaundice was seen in zones 4 and
discharged early and breastfed. 5 were five times more likely to develop signif-
Most vaginal deliveries, including the late icant hyperbilirubinemia than those with no
preterm infants, are discharged by 48 h of life, jaundice or jaundice restricted to zone 1. Never-
well before the peak serum bilirubin that is theless, the correlation between cephalocaudal
observed in term infants on day 3–5 and later in progression and the ability to predict the risk of
preterm infants. The peak bilirubin thus occurs hyperbilirubinemia was highly erratic. An
at home. It is therefore necessary to screen the exception was the complete absence of jaundice
bilirubin levels prior to discharge and arrange (zone 0), which was present in only 17% of the
for early follow-up either at home or in the population but had a powerful negative predic-
clinics to prevent catastrophic nonmonitored ele- tive value of 99%. The conclusion is that it is
vation of serum bilirubin. Decisions are made on dangerous to rely on visual assessment of jaun-
the bilirubin levels according to age in hours dice and if there is clinical evidence of jaundice,
then the bilirubin should be measured either
Table 3 Risk of being readmitted for phototherapy chemically or by transcutaneous measurement.
The AAP guidelines are directed at reducing the
Risk factor Odds ratio (vs. 40 weeks)
frequency of severe neonatal hyperbilirubinemia
35–36 weeks 13.2
(levels >17 mg per 100 mL) and bilirubin
37–38 weeks 7.
encephalopathy, in addition to minimizing
Breastfeeding 4.2
Jaundice in nursery 7.
parental anxiety and discontinuation of
Length of stay <72 h 3. breastfeeding and hoping to reduce costs. (Amer-
30,000 discharges from well-baby nursery 1988–1994;
ican Academy of Pediatrics, Subcommittee on
4.2/1000 readmitted for phototherapy (Maisels and Kring Hyperbilirubinemia 2004). The key elements of
1998) the guidelines are presented in Table 4.
180 A. A. Fanaroff
Table 4 AAP Jaundice Guideline The 10 key elements preterm and full-term children for these standard
(Maisels and Kring 1998) measures from ages 4 to 15 years. They concluded
1. Promote and support successful breastfeeding that late preterm infants born otherwise healthy
2. Establish nursery protocols – include circumstances in seem to have no real burdens regarding cognition,
which nurses can order a bilirubin achievement, behavior, and socio-emotional
3. Measure TSB or TcB if jaundiced in the first 24 h
development throughout childhood.
4. Visual estimation of jaundice can lead to errors,
particularly in darkly pigmented infants
Shah et al. (2016) noted that late preterm infants
5. Interpret bilirubin levels according to the infant’s age in demonstrate comparable developmental outcomes
hours to full-term infants (early-term and full-term
6. Infants <38 weeks particularly if breastfed are at high gestation) at 24 months, but demonstrate less opti-
risk mal reading outcomes at preschool and kindergar-
7. Perform risk assessment prior to discharge ten time points. Woyhuler et al. (2015) confirmed
8. Give parents written and oral information that late preterm infants continue to be delayed at
9. Provide appropriate follow-up based on time of kindergarten compared with full term infants
discharge and risk assessment
(FTIs). However a child who tested within the
10. Treat newborns when indicated with phototherapy or
exchange transfusion normal range (>85) at 24 months had an excellent
chance of testing in the normal range at
kindergarten.
Taige (Talge et al. 2010) observed that late
10.13 Long-Term Outcomes preterm birth was associated with an increased
risk of full scale and performance (IQ scores
Until recently, the assumption was that late pre- below 85). Additionally late preterm birth was
term infants carry minimal risk for long-term associated with higher levels of internalizing and
morbidities. Morse et al. (2009) refuted these attention problems. Late preterm birth is associ-
assumptions when they compared prekindergar- ated with behavioral problems and lower IQ at the
ten and kindergarten outcomes among healthy late age of 6, independent of maternal IQ, residential
preterm infants and healthy term infants. setting, and sociodemographics. It remains to be
Outcomes were adjusted for 15 potential con- determined whether these findings relate to
founding maternal and infant variables. They shorter gestational length in utero or ex utero
observed that the risk for developmental delay or (e.g., neonatal complications) factors marked by
disability was 36% higher among late preterm late preterm birth or some combination of these
infants compared with term infants. Furthermore factors.
the risk for retention and disability in kindergarten After a systematic review of 9 electronic data
with need for special education was higher for late bases, examining early childhood outcomes in
preterm infants. The assessment “not ready to start late preterm infants(LPI’s), McGowan et al.
school” was borderline significant. Thus healthy (2011) concluded “Evidence suggests that LPIs
late preterm infants compared with healthy term are at increased risk of adverse developmental
infants face a greater risk of developmental delay outcomes and academic difficulties up to 7 years
and school-related problems up through age of age in comparison to term infants. Of note, an
5 (Jain 2008b). infant control group matched for gestational age
On the other hand, Gurka et al. (2010) applied has not been used; thus, for LPIs, the effect of
11 standard outcomes measuring cognition, neonatal admission on longer-term outcomes has
achievement, social skills, and behavioral/emo- not been fully explored. Systematic measurement
tional problems using the Woodcock-Johnson of early childhood outcomes is lacking, and
Psycho-Educational Battery-Revised and the focused long-term follow-up studies are needed
Child Behavior Checklist, administered repeat- to investigate early childhood development after
edly through age 15 years. They detected no con- late-preterm birth.” There remain gaps in knowl-
sistent significant differences between late edge that urgently need to be addressed.
10 Late Preterm Infants at Risk for Short-Term and Long-Term Morbidity and Mortality 181
10.14 Discharge Planning 10.15 Summary and
Recommendations
Clinicians who care for late preterm infants need
to first recognize and establish that the infant is a In the USA, late preterm infants, defined as infants
late preterm infant. They must be aware of their with a gestational age between 34 and 36 weeks
increased risk for morbidity, mortality, and poten- and 6 days, account for 9% of all births.
tial neuro-developmental problems. They must Late preterm infants have a reported sevenfold
anticipate, screen for, and intervene in an appro- increased risk of morbidity compared to term infants
priate and timely manner for the common prob- during birth hospitalization, which results in a lon-
lems encountered in these vulnerable infants. ger hospital stay and higher medical costs. The most
Prior to hospital discharge, parents need to be common causes of morbidity include hypothermia,
educated that their infant is at increased risk for hypoglycemia, respiratory distress, apnea, hyper-
jaundice, feeding difficulties, hypoglycemia, and bilirubinemia, and feeding difficulties. Late preterm
dehydration. Parents must be taught to recognize infants have a higher mortality than term infants.
these conditions and promptly seek appropriate Readmission rates are two to three times greater for
care following hospital discharge. late preterm compared to term infants. Early
The AAP has established the following guide- readmission (within 15 days of discharge from
lines for discharge criteria for late preterm infants birth hospitalization) includes hyperbilirubinemia,
(Engle et al. 2007): feeding difficulties, poor weight gain, dehydration,
and apnea. During the first year of life, respiratory
Determine the accurate gestational age, and ensure and gastrointestinal disorders are the most common
that there are no abnormalities or medical condition diagnoses for late readmission. Late preterm infants
(i.e., hyperbilirubinemia) that requires further
hospitalization. also have more neurodevelopmental disabilities and
school problems than their term-born peers.
The infant demonstrates physiologic stability by
demonstrating competency in the following:
Thermoregulation defined as an axillary tempera-
ture of 36.5–37.4 C in an open crib. References
Cardiorespiratory control with stable vital signs of a American Academy of Pediatrics, Subcommittee on
respiratory rate less than 60 breaths per minute and Hyperbilirubinemia (2004) Management of hyper-
a heart rate between 100 and 160 beats per minute bilirubinemia in the newborn infant 35 or more weeks
and absence of medical illness of gestation. Pediatrics 114:297–316
American College of Obstetricians and Gynecologists
Passed at least one stool spontaneously (1999) Induction of labor. Practice bulletin, vol 10.
ACOG, Washington, DC
Completed other routine newborn care. This American College of Obstetricians and Gynecologists
includes screening tests (i.e., hearing and disorders (2013) ACOG committee opinion no. 560: medically
that are threatening to life or long-term health), indicated late-preterm and early-term deliveries. Obstet
vaccinations (i.e., hepatitis B vaccine), and prophy- Gynecol 121:908
lactic treatment (i.e., vitamin K prophylaxis). Bailit JL, Gregory KD, Reddy UM et al (2010) Maternal
and neonatal outcomes by labor onset type and gesta-
Assessment of the family and home environment to tional age. Am J Obstet Gynecol 202:245.e1–245e12
identify any risk factors that may impact on the Bhutani VK, Johnson L (2006) Kernicterus in late preterm
health of the infant. infants cared for as term healthy infants. Semin Peri-
natol 30:89–97
Successful training of the parents who have dem- Bhutani VK, Maisels MJ, Stark AR, Buonocore G (2008)
onstrated competency in the care of their infant and Management of jaundice and prevention of severe neo-
the ability to assess for hyperbilirubinemia, feeding natal hyperbilirubinemia in infants > or =35 weeks
difficulties, and dehydration. gestation. Neonatology 94:63–67
Clark SL, Miller DD, Belfort MA et al (2009) Neonatal and
A follow-up visit 24–48 h after discharge is sched- maternal outcomes associated with elective term deliv-
uled with an identified primary care provider. ery. Am J Obstet Gynecol 200:156.e1–156.e4
182 A. A. Fanaroff
Cohen-Wolkowiez M, Moran C, Benjamin DK et al (2009) McLaurin KK, Hall CB, Jackson EA et al (2009) Persis-
Early and late onset sepsis in late preterm infants. tence of morbidity and cost differences between late-
Pediatr Infect Dis J 28:1052–1056 preterm and term infants during the first year of life.
Davidoff MJ, Dias T, Damus K et al (2006) Changes in the Pediatrics 123:653–659
gestational age distribution among U.S. singleton Morse SB, Zheng H, Tang Y, Roth J (2009) Early school-
births: impact on rates of late preterm birth, 1992 to age outcomes of late preterm infants. Pediatrics 123:
2002. Semin Perinatol 30:8–15 e622–e629
Donovan EF, Lannon C, Bailit J et al (2010) A statewide Newman TB, Escobar GJ, Gonzales VM et al (1999)
initiative to reduce inappropriate scheduled births at 36 Frequency of neonatal bilirubin testing and hyper-
(0/7)–38(6/7) weeks’ gestation. Am J Obstet Gynecol bilirubinemia in a large health maintenance organiza-
202:243.e1–243.e8 tion. Pediatrics 104:1198–1203
Dudell GG, Jain L (2006) Hypoxic respiratory failure in the Oshiro BT, Henry E, Wilson J et al (2009) Decreasing elec-
late preterm infant. Clin Perinatol 33:803–830 tive deliveries before 39 weeks of gestation in an inte-
Engle WA, Tomashek KM, Wallman C et al (2007) “late- grated health care system. Obstet Gynecol 113:804–811
preterm” infants: a population at risk. Pediatrics Osterman MJ, Kochanek KD, MF MD, Strobino DM,
120:1390–1401 Guyer B (2015) Annual summary of vital statistics:
Escobar GJ, Greene JD, Hulac P et al (2005) Rehospitalisation 2012–2013. Pediatrics 135(6):1115–1125
after birth hospitalisation: patterns among infants of all Raju TN, Higgins RD, Stark AR, Leveno KJ (2006) Opti-
gestations. Arch Dis Child 90:125–131 mizing care and outcome for late-preterm (near-term)
Gowen CW Jr, Lawson EE, Gingras J et al (1988) Electri- infants: a summary of the workshop sponsored by the
cal potential difference and ion transport across nasal National Institute of Child Health and Human Devel-
epithelium of term neonates: correlation with mode of opment. Pediatrics 118:1207–1214
delivery, transient tachypnea of the newborn, and respi- Ramachandrappa A, Jain L (2009) Health issues of the late
ratory rate. J Pediatr 113:121–127 preterm infant. Pediatr Clin N Am 56:565–577
Gurka MJ, LoCasale-Crouch J, Blackman JA (2010) Long- Ramanathan R, Corwin MJ, Hunt CE et al (2001) Cardio-
term cognition, achievement, socio-emotional, and respiratory events recorded on home monitors: compar-
behavioral development of healthy late-preterm ison of healthy infants with those at increased risk for
infants. Arch Pediatr Adolesc Med 164:525–532 SIDS. JAMA 285:2199–2207
Gyamfi-Bannerman C, Thom EA, Blackwell SC et al Reddy UM, Ko CW, Raju TNK, Willinger M (2009) Deliv-
(2016) NICHD maternal–fetal medicine units network. ery indications at late-preterm gestations and infant mor-
Antenatal betamethasone for women at risk for late tality rates in the United States. Pediatrics 124:234–240
preterm delivery. N Engl J Med 374(14):1311–1320 Seikku L, Gissler M, Andersson S et al (2016)
Hamilton BE, Martin JA, Osterman MJ (2016) Births: Asphyxia, neurologic morbidity, and perinatal mortal-
preliminary data for 2015. Natl Vital Stat Rep 65:1 ity in early-term and postterm birth. Pediatrics 137(6):
Hunt CE (2006) Ontogeny of autonomic regulation in late e20153334
preterm infants born at 34–37 weeks postmenstrual Shah P, Kaciroti N, Richards B et al (2016) Developmental
age. Semin Perinatol 30:73–76 outcomes of late preterm infants from infancy to kin-
Jain L (2007) Morbidity and mortality in late-preterm infants: dergarten. Pediatrics 138
more than just transient tachypnea! J Pediatr 151:445–446 Shapiro-Mendoza CK, Tomashek KM, Kotelchuck M et al
Jain L (2008a) Respiratory morbidity in late-preterm infants: (2008) Effect of late-preterm birth and maternal medi-
prevention is better than cure! Am J Perinatol 25:75–78 cal conditions on newborn morbidity risk. Pediatrics
Jain L (2008b) School outcome in late preterm infants: a 121:e223–e232
cause for concern. J Pediatr 153:5–6 Spong CY, Mercer BM, D’alton M et al (2011) Timing of
Joseph KS, Nette F, Scott H, Vincer MJ (2009) Prenatal indicated late-preterm and early-term birth. Obstet
corticosteroid prophylaxis for women delivering at late Gynecol 118:323
preterm gestation. Pediatrics 124:e835–e843 Talge NM, Holzman C, Wang J et al (2010) Late-preterm
Keren R, Teremont K, Luan X, Cnaan A (2009) Visual birth and its association with cognitive and socio-
assessment of jaundice in term and late preterm infants. emotional outcomes at 6 years of age. Pediatrics
Arch Dis Child Fetal Neonatal Ed 94:F317–F322 126:1124
Kitsommart R, Janes M, Mahajan V et al (2009) Outcomes Tomashek KM, Shapiro-Mendoza CK, Davidoff MJ,
of latepreterm infants: a retrospective, single-center, Petrini JR (2007) Differences in mortality between
Canadian study. Clin Pediatr (Phila) 48:844–850 late-preterm and term singleton infants in the United
Kramer LI (1969) Advancement of dermal icterus in the States 1995–2002. J Pediatr 151:450–456
jaundiced newborn. Am J Dis Child 118:454–458 Underwood MA, Danielsen B, Gilbert WM (2007) Cost,
Maisels MJ, Kring E (1998) Length of stay, jaundice and causes and rates of rehospitalization of preterm infants.
hospital readmission. Pediatrics 101:995–998 J Perinatol 27:614–619
Martin JA, Hamilton BE, Osterman MJ (2016) Births in the Wang ML, Dorer DJ, Fleming MP, Catlin EA (2004) Clinical
United States, 2015. NCHS Data Brief 258:1–8 outcomes of near-term infants. Pediatrics 114:372–376
McGowan JE, Alderdice FA, Holmes VA, Johnston L Woyhaler MCMC, Mao WY, Smith VC (2015) Late pre-
(2011) Early childhood development of late-preterm term infants and neurodevelopmental outcomes at kin-
infants: a systematic review. Pediatrics 127:1111 dergarten. Pediatrics 136:424
Ethical Problems in Neonatal Medicine
11
Otwin Linderkamp
Contents
11.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
11.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
11.3 Survival and Outcome of Extremely Preterm (EP) Infants . . . . . . . . . . . . . . 185
11.3.1 Survival of EP Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
11.3.2 Neonatal Morbidities and Long-Term Outcome in EP Infants . . . . . . . . . . . . . . 186
11.3.3 Prediction of the Outcome of Individual EP Infants . . . . . . . . . . . . . . . . . . . . . . . . . 187
11.4 Laws and Guidelines for the Care at the Limit of Viability . . . . . . . . . . . . . 187
11.5 Quality of Life and the Best Interests of the
Infant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
11.6 Attitudes Toward Extremely Preterm and Critically Sick Neonates . . . . 190
11.7 The Rights of the Newborn and the Parents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
11.8 Informing and Counseling Parents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
11.9 Decision-Making in EP Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
11.10 Withholding and Withdrawing
of Intensive Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
11.10.1 Withholding Versus Withdrawing
of Intensive Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
11.10.2 Withholding Proactive Antenatal Care and Resuscitation After Birth . . . . . . 196
11.10.3 Withdrawing of Intensive Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
11.10.4 Pain- and Stress-Relieving Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
11.11 Severe Asphyxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
11.12 Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
O. Linderkamp (*)
Division of Neonatology, Department of Pediatrics,
University of Heidelberg, Heidelberg, Germany
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 183
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_160
184 O. Linderkamp
Abstract • The rights of newborn babies and parents have
In perinatal and neonatal medicine, the Hippo- to be known in order to establish decision-
cratic Oath can be translated into the responsi- making processes and withholding and with-
bility of the physicians to act in the “best drawal of intensive care.
interests” of the fetus and newborn infant
and to avoid harming the fetus and infant
and also the mother. This implies that the 11.2 Introduction
benefit of treatments should outweigh the
harm and risks of the treatment for the patient. “I will prescribe regimens for the good of my
The decision-making process is extremely patients according to my ability and my judg-
difficult for infants with uncertain prognosis ment and never do harm to anyone.” The Hippo-
such as extremely preterm infants. The cratic oath expressed beneficence and
knowledge of long-term outcome is essential non-maleficence as basic principles of medical
for correct and complete antenatal and post- ethics more than 2000 years ago. Beneficence in
natal counseling of parents and for decision perinatal and neonatal medicine refers to the
processes in the care of the high risk newborn. responsibility of the physicians to act in the
Laws and guidelines are necessary and avail- “best interests” of the fetus and newborn infant.
able for care at the limit of viability, but there Non-maleficence relates to the avoidance of
are different attitudes toward critically ill neo- harm to the fetus and infant but also to the
nates in different countries, in different cen- mother. This implies that the benefit of treat-
ters, and among caregivers in the same center. ments should outweigh the harm and risks of
The decision-making process is articulated in the treatment for the patient.
at least three time points: care of mother and In the newborn infant, benefits are usefully
fetus before birth, initiation or withholding of defined as survival and the ability to live a self-
resuscitation of the infant after birth, and con- determined life. For infants with no chance of
tinuation or withdrawal of neonatal intensive survival, aggressive intensive care is not benefi-
care. Knowledge of newborn and parental cial but harmful and futile, and is, therefore, gen-
rights is the starting point for decisions by erally assumed to be unethical. However, in
physicians from the antenatal until postnatal infants with uncertain prognosis (i.e., high risk
period. of survival with poor quality of life), the decision
is extremely difficult and requires clear ethical
guidelines.
A recent meta-analysis on decision-making in
11.1 Salient Points the best interests of the newborn demonstrated that
prejudices play an important role in the attitudes
• The knowledge of long-term outcome is of (and hence decisions) of caregivers (Bellieni and
great importance for antenatal and postnatal Buonocore 2009). Janvier et al. (2008a) criticized
counseling of parents and for decision pro- that neonatal intensive care is usually far more
cesses in the care of high risk newborn. scrutinized than intensive care of any older patient
• Several models have been developed that con- groups and that children and adults with a poor
sider factors influencing the short- and long- prognosis are more likely to be resuscitated than
term prognosis of high risk newborn and par- newborn infants with the same or a better progno-
ticularly of extremely preterm infants. sis. The authors explain the different attitudes by
• Laws and guidelines are available for care at deficient knowledge about the actual outcomes or
the limit of viability. However, attitudes toward by irrational negative associations with low gesta-
critically sick neonates vary among different tional ages. To avoid decision-making by prejudices
healthcare professions, countries, centers and confirmation bias, evidence-based medical
within a country, and caregivers in one center. ethics applies research results (particularly
11 Ethical Problems in Neonatal Medicine 185
epidemiology) in addition to ethical and legal prin- Table 1 Determinants of the outcome of extremely pre-
ciples to draw conclusions to ethical dilemmas in term (EP) infants
medicine. Fetal factors
Three groups of newborn infants are usually Gestational age
considered in end-of-life decisions: (1) infants at Body weight
or below the gestational age limit of viability, Gender
(2) infants born with congenital anomalies Single or multiple births
incompatible with life, and (3) extremely ill pre- Social status and lifestyle of the mother
Individual maturity and resilience of the fetus
term or full-term infants who might survive with
Antenatal and intrapartum care of the fetus
severe damage of the brain or other vital organs
Maternal transfer to a level III center
after a long period of intensive care. This chapter
Antenatal steroids, tocolysis, antibiotics, etc.
focuses on the extremely preterm (EP) infant and
Cesarean section on fetal indication
reviews some of the important issues, such as Experience in “proactive care” of the mother and the
outcome data, withdrawal and/or withholding EP fetus
life support, role of parents and health care pro- Neonatal factors
viders, economics, and a framework for neonatal Individual maturity, strength, and resilience of the
ethical issues. infant
Sufficient maturity of vital organs for survival (lungs)
and for intact survival (brain, eyes)
Condition of the EP infant at birth and response to
11.3 Survival and Outcome resuscitation within 3–5–10 min.
of Extremely Preterm Stability/instability in the first 12–24 postnatal hours
(EP) Infants Extent and required time of intensive care
Neonatal complications and severe morbidities
11.3.1 Survival of EP Infants (IVH/PVL, ROPNEC, sepsis)
Neonatal and long-term care of EP infants
The knowledge of published survival and long- Experience in resuscitation and neonatal intensive
term outcome data is of great importance for ante- care of EP infants
Availability of adequate equipment, resources, and
natal and postnatal counseling of the parents and
experienced staff around the clock
for the decision process in the care of EP infants. Neonatal developmental care
The prognosis depends on several factors such as Specialized long-term care
gestational age, birth weight, gender, single or Socio-cognitive and learning support
multiple births, prenatal and postnatal care, neona- Policies, attitudes, and individual decisions
tal complications and morbidities, attitudes of the Policies and guidelines concerning the care of EP
caregivers and parents, and on the individual matu- infants
rity and resilience of the fetus and infant (Table 1). Attitudes of the obstetrical and neonatal staff toward
Gestational age is accepted as a major prenatal the care of EP infants
predictor of the prognosis of EP infants (Levene Antenatal decisions of parents and caregivers
(initiation and withholding of intensive care based on risk
2004) since prenatal care (transfer to a perinatal factors of death and long-term sequelae)
center, corticosteroids) and antenatal counseling Postnatal decisions of parents and caretakers
of the parents are mainly based on the gestational (withdrawal of intensive care if the prognosis of the infant
age. Most laws and guidelines on the limit of deteriorates)
viability in EP infants use a defined gestational
age as a limit. However, the estimated gestational
age may deviate by 7 days from the actual A recent review of 20 published studies on
gestational age due to uncertain last menses and survival rates of EP infants born between 1985
errors of prenatal ultrasonography, unless the time and 2008 (Linderkamp 2012) shows that live-
of (in vitro) fertilization is precisely known born preterm infants with a gestational age of
(Skupsi et al. 2010). 22 weeks had an overall survival rate of 8%
186 O. Linderkamp
(145/1791) with no consistent trend to improve- hemorrhage and/or periventricular leukomalacia
ment with time. Survival rates 20% were noted ranged from 9% to 29%, at 24 weeks from 14%
in Japan (Nishida and Sakuma 2009; Kusuda et al. to 28%, and at 25 weeks from 7% to 15%. Infants
2006; Itabashi et al. 2009) and in some single- with 23 weeks’ gestation had a high risk of severe
center studies. In Japan, infants born at 22 weeks’ retinopathy (17–62%) requiring surgical treat-
gestation are principally considered viable and ment. Blindness resulting from retinopathy of
resuscitated. From 2004 to 2007, 1-year survival prematurity (ROP) has, however, become rare
of infants born alive at 22–26 weeks of due to modern laser coagulation techniques.
gestation in Sweden was 70% and ranged from The high risk of EP infants for neurodeve-
9.8% at 22 weeks to 85% at 26 weeks (Marsal and lopmental impairments, such as cerebral palsy
Express Group 2009). The overall survival rate of and cognitive or sensory deficits, is of great con-
infants born at 23 weeks’ gestation was 25% cern to parents, caregivers, and society. Only few
(1361/5383). Eight studies showed improve- national and regional studies present week-by-
ments, and six showed decreases in the survival week outcomes in EP infants (Linderkamp
rates with time. Survival rates above 50% were 2012). Severe disability was noted in 20–22%,
reported for Sweden (Marsal and Express 8–39%, and 11–27% of infants born at 23, 24,
Group 2009) and Japan (Nishida and Sakuma and 25 weeks’ gestation, respectively. No disabil-
2009; Kusuda et al. 2006; Itabashi et al. 2009). ity was seen in 13–33%, 16–56%, and 17–52% in
Preterm infants born at 24 weeks’ gestation infants born at 23, 24, and 25 weeks’ gestation,
showed an overall survival rate of 50% (3796/ respectively. Two Japanese studies showed rela-
7555). A Japanese study on infants born in 2005 tively low rates of neurodevelopmental disability
showed the highest survival rates in the whole- in infants born at 23 weeks’ gestation (32–35%)
country studies (77%) (Itabashi et al. 2009), (Ikeda et al. 2006; Iijima et al. 2009). EP infants
followed by Sweden in 2004–2007 (67%) (Marsal without visible disability in early years are at
and Express Group 2009), England and Wales in considerable risk for a variety of behavioral and
2005 (56%) (Moser et al. 2007), and Norway in educational deficits at school age.
1999–2000 (55%) (Markestad et al. 2005). In There is concern that newly developed treat-
11 time-trend studies, a marked rise of the survival ments and altered attitudes toward EP infants
rates was observed with time. The overall survival improve their survival rate, but that many of the
rate of infants with 25 weeks’ gestation was 68%. additional surviving infants suffer from severe
Japan, Sweden, Norway, and England and Wales disability. A rising prevalence of long-term
reached again high survival rates of 85%, 81%, deficits such as cerebral palsy and poor cognitive
77%, and 76%, respectively. Overall survival outcome was indeed observed in several time-trend
rates increased from 61% in infants born studies on EP infants born in the 1970s and 1980s
mainly in the 1990s to 74% in infants born mainly and in some studies in the mid-1990s and the early
in the early 2000s. Infants born at 26 weeks’ ges- 2000s (Linderkamp 2012; Wilson-Costello et al.
tation had an overall survival rate of 80% 2007). Recent studies showed both increasing sur-
(Linderkamp 2012). vival rates and decreases in the rates of short- and
long-term neurodevelopmental disabilities in EP
infants (Wilson-Costello et al. 2007). The recent
11.3.2 Neonatal Morbidities and Long- improvements of short- and long-term outcomes
Term Outcome in EP Infants are probably the result of a comprehensive antena-
tal and postnatal care philosophy including proac-
Seven recent studies on severe neonatal morbidity tive antenatal care, optimal delivery procedure,
in surviving EP infants <27 weeks presenting competent neonatal care in the delivery room and
week-by-week results have been reviewed the intensive care unit, better long-term care, and a
elsewhere (Linderkamp 2012). At 23 weeks’ positive attitude of more caretakers toward these
gestation, the prevalence of intraventricular patients (Hakansson et al. 2004).
11 Ethical Problems in Neonatal Medicine 187
11.3.3 Prediction of the Outcome weeks’ gestation have an uncertain prognosis, and
of Individual EP Infants infants born at 25 weeks’ gestation have a reason-
able chance to survive without severe disability. The
The prognosis of EP infants depends on several lower limit of viability is currently set at 22–23
factors in addition to the gestational age. weeks and the “gray zone” at 23 0/7–24 6/7 weeks.
Although it is difficult to consider all of these Infants born in the “gray zone” have an uncertain
factors in counseling the parents and in decision- prognosis with high risk of death or survival with
making, obstetricians and neonatologists should severe long-term deficits, but the individual progno-
be aware of the complex risk profile in individual sis depends on a variety of biologic and individual
infants. Several models have been developed that (maturity, strength, and resilience), technologic, and
consider some or several of the factors influencing general care factors (including antenatal proactive
the short- and long-term prognosis of EP infants. care, attitudes of staff, and developmental care in the
Several guidelines include the option of withhold- NICU). The “gray zone” also considers the uncer-
ing treatment if the infant’s condition appears tainty of the assessment of gestational age by
poor immediately after birth. This agrees with approximately 7 days (Skupsi et al. 2010).
the attitude of many neonatologists who want
“to see what the infant looks like” if the infant is
born at the limit of viability (Singh et al. 2007). 11.4 Laws and Guidelines
However, several studies demonstrated that the for the Care at the Limit
infant’s condition at birth (low Apgar scores and of Viability
low heart rates at 1 min and 5 min, need of car-
diopulmonary resuscitation) did not predict poor The World Health Organization (WHO) defines a
outcome in EP infants (Finer et al. 1999; Jankov live birth as “a fetus, whatever its gestational age,
et al. 2000). Thus, the condition at birth is an exits the maternal body and subsequently shows
unreliable predictor of the prognosis of EP infants, any sign of life, such as voluntary movement,
unless resuscitation of more than 3–5 min is heartbeat, or pulsation of the umbilical cord, for
required to stabilize an EP infant. however brief a time” (World Health Organization
Definitions of the limit of viability and of the 1993). The term “live birth” was defined by the
“gray zone” in EP infants (Walter 2005; Seri and WHO mainly for public health, legal, and statistical
Evans 2008; Lagercrantz and Changeux 2009; purposes and should not be used synonymously
Comitato Nazionale per la Bioetica 2008): with “viability.” Signs of life may already be seen
in extremely immature infants born at 20 weeks of
(a) Viability is defined as the possibility to live and gestation and no chance of survival.
survive outside the uterus independent of the The “Born-Alive Infant Protection Act”
risk for severe neurodevelopmental disability. enacted by the US government in 2002 obliges
(b) Viability is determined as a reasonable chance the physician to “protect infants who are born
to survive without “severe and unacceptable” alive at any stage of development.” Enforcement
morbidity (usually defined as severe guidelines to the law issued in 2005 requires the
neurodevelopmental disability). hospital and its medical staff “to perform a med-
(c) Viability is defined as the ability to grow and ical screening examination on that born-alive
develop normally outside the uterus, the abil- infant” and to treat the infant if signs of life are
ity to communicate, and the ability to engage detected (Partridge and Dickey 2009). The legal
in meaningful relationships with others, to conditions in the USA may explain that the guide-
become a child and later achieve independent lines of the American Academy of Pediatrics
moral status and personhood. (MacDonald and American Academy of Pediat-
rics Committee on Fetus and Newborn 2002;
The outcome of infants born at 22 weeks’ gesta- American Academy of Pediatrics 2007) recom-
tion is actually extremely poor; infants born at 23–24 mend withholding life support in infants with
188 O. Linderkamp
22 weeks’ gestation but do not give detailed rec- decision or care according to parental request. At
ommendations for more mature infants. Similar 24 weeks’ gestation, four guidelines regard inten-
guidelines have been issued in Spain (Pignotti and sive care as due according with individual deci-
Donzelli 2008). In Italy, the National Bioethics sions (Wilkinson et al. 2009; Peerzada et al. 2006;
Committee recommends resuscitation of all Miljeteig et al. 2007; Fischer et al. 2009), four as
babies born alive when a possibility of survival generally indicated (Nishida and Sakuma 2009;
exists (Turillazzi and Fineschi 2009). Comitato Nazionale per la Bioetica 2008; Pohlandt
Some national laws define the limit of viability 2008; Österreichische Gesellschaft für Kinder-und
to address primarily the limit of legal abortion Jugendheilkunde 2005). At 25 weeks’ gestation,
(e.g., Japan and Italy, 22 weeks; the Netherlands, most guidelines regard intensive care as “generally
Singapore, and the UK, 24 weeks). In Japan the indicated.” Resuscitation on the basis of gestational
viability limit has been lowered from the previous age has also been criticized (Fanaroff 2008): The
24 weeks’ gestation to 22 completed weeks’ ges- likelihood of a favorable outcome with intensive
tation in 1991 (Motherhood Protection Act) based care can be better estimated by considering four
on surveys of survival rates in EP infants (Nishida factors in addition to gestational age: sex, exposure
and Sakuma 2009). As a result of the legislation in to antenatal corticosteroids, single or multiple
Japan, intensive care is provided to all EP infants births, and birth weight (Tyson et al. 2008).
born at 22 weeks’ gestations (Iijima et al. 2009).
In most western countries, as well as in Japan
and Australia, guidelines regarding the limit of 11.5 Quality of Life and the Best
viability have been established by medical Interests of the Infant
organizations in agreement with national laws
and court rulings (Nishida and Sakuma 2009; Assessments of the quality of life, the harm/ben-
Comitato Nazionale per la Bioetica 2008; efit ratio, and the best interests of the infant are
MacDonald and American Academy of Pediatrics often made to decide whether it is appropriate to
Committee on Fetus and Newborn 2002; Pignotti begin or to continue intensive care. In the
and Donzelli 2008; Lui et al. 2006; Nuffield Coun- decision-making process, the estimated quality
cil on Bioethics 2006; Wilkinson et al. 2009; of life corresponds to the probable benefit
Peerzada et al. 2006; Miljeteig et al. 2007; Rijken resulting from medical care, and the best interests
et al. 2007; Pohlandt 2008; Österreichische Gesell- are deducted from the harm/benefit ratio. Parents
schaft für Kinder-und Jugendheilkunde 2005; and professional caregivers are particularly
Dehan et al. 2001; Fischer et al. 2009). The guide- concerned with the risk of “brain damage” and
lines usually present recommendations for the care what it means for the child. In the newborn infant,
of infants with extremely poor, uncertain, and fairly quality of life is usually related to the estimated
good prognosis. No country recommends resusci- future health and development. There are several
tation of infants with gestational age below concerns with the definition of the future quality
22 weeks. For infants of 22 weeks’ gestation, of life in preterm and severely sick neonates:
guidelines of five countries recommend “comfort
care only” (MacDonald and American Academy of The future quality of life is usually estimated from
Pediatrics Committee on Fetus and Newborn 2002; risk factors such as gestational age, birth
Pignotti and Donzelli 2008; Lui et al. 2006; weight, gender, signs of brain damage in ultra-
Peerzada et al. 2006; Rijken et al. 2007). The sound scans, and other complications during
other guidelines propose individual decisions intensive care. Quality of life is thus estimated
based on parental request or the infant’s condition from individual factors that are compared with
at birth. For infants with 23 weeks’ gestation, three statistical data studied in a cohort of infants
countries recommend “comfort care only” (Lui with similar risk factors. The epidemiological
et al. 2006; Rijken et al. 2007; Dehan et al. 2001), approach is objective but uncertain for the
while the other guidelines recommend individual individual child.
11 Ethical Problems in Neonatal Medicine 189
The meaning of an estimated future quality of life Long-term or future potential interests of the
in infants cannot be judged by the infants infant: these are usually defined as good or
themselves but is estimated by the families, acceptable long-term outcome.
the caregivers, and the society. It includes
effects of the health status on lifestyle in the In addition to the infant’s interests, familial,
children and their families, the quality of life communal, and public (moral and legal) interests
probably experienced by the child, and the play a role (Hester 2007; Kopelman 2007). The
value placed by the public, the family, and the family members have their own interests and
child on compromised health states. incorporate religious and cultural values. Com-
The uncertainty of the estimation of the future munal or social interests consider cultural beliefs
quality of life is difficult to bear for many about the value of disabilities, concerns for dig-
parents and caregivers, as the consequence of nity, and respect. Public interests include protec-
the judgment may be the death of the infant. tion of citizens from abuse or neglect. Medical
This is admitted in some countries but cannot care of newborn infants has to be compatible
avoid the suspect of a conflict of interests: with moral and legal duties to incapacitated
some parents can overestimate babies’ future individuals.
disability, or they cannot accept even a Pain and suffering from intensive care proce-
low-grade handicap that, on the other hand, dures (present quality of life) are related to the risk
the baby might bear. for long-term suffering and burden (future quality
Life-and-death decisions based on the judgment of life). If the infant has no chance of survival,
of the quality of life have been regarded dis- intensive care will merely prolong pain and suf-
criminatory against handicapped persons. fering, and natural death may be in the best inter-
Many disabled persons might consider their ests of the baby. If the outcome of the infant is
quality of life as good or acceptable. Some uncertain, but most likely associated with poor
can argue that the decision to withhold or with- health and development, the best interests will
draw intensive care is only made in infants be judged from both the present pain and suffering
with anticipated disability that will probably (intensive care) and the estimated future suffering
lead to intolerable suffering and burden and and burden.
inability to interact with others, but some Financial considerations should not play a
authors do not agree. role in the judgment of the best interests of an
infant with uncertain prognosis by the caregivers
Several national laws, decrees, court rulings, and the society. The best interest concept is
and guidelines request that any decision made on mainly applied in uncertain situations but may
behalf of a person lacking decision-making capac- be uncertain itself. What is the probability of
ity must be in the person’s “best interests.” Three survival of an individual infant? What is a rea-
major interests of the premature or sick neonate sonable, an acceptable, and an unacceptable
have been defined (Hester 2007; Kopelman 2007; long-term outcome? Kipnis (2007) defined three
Chiswick 2008): types of uncertainty in the estimation of the out-
come: the vagueness of the definition of “intol-
Interests in the neonate’s health: reasonable care erable deficits,” the uncertainty of whether a
using recognized standards of care and appro- baby will benefit from an intensive care interven-
priate individualized care measures have to be tion or be harmed by it, and the inability to
provided. determine the harm-to-benefit ratio of (some-
Immediate (short-term) interests of the infant: times aggressive and painful) intensive care mea-
pain and suffering, harm, and indignity should sures. Moreover, the application of the best
be avoided by the selection of appropriate ther- interest standards may be flawed by limited
apeutic measures (e.g., developmental care, knowledge or lack of consensus about treatment
pain treatment, comforting care). choices, conflicts of interests, personal beliefs,
190 O. Linderkamp
bias and prejudice, lack of empathy, ignorance, among different health professions, among differ-
or disregard of persons’ rights and duties ent countries and regions, among various centers
(Bellieni and Buonocore 2009; Kopelman 2007). of a country or region, and among different care-
Critics of the “best interests” concept argue givers in one center (Hakansson et al. 2004;
that it is vague, open to abuse, and permits Bilgen et al. 2007; Cuttini et al. 2009). Moreover,
decision-makers to do whatever they think is attitudes of caregivers and parents may deviate
best. Decisions may be made in the interests of considerably. Attitudes of obstetricians and pedi-
the parents and caregivers rather than in the best atricians were similar in most studies, while
interests of the infant. To overcome the uncer- nurses in some countries tended to be more
tainties of the best interests of an individual infant, prone than physicians to withhold resuscitation
it has been suggested that a best interests’ standard in the delivery room and to consider parental
should incorporate what a reasonable person of opinion regarding subsequent treatment choices
good will would want or consider acceptable in than physicians (Miljeteig et al. 2007; De Leeuw
similar circumstances (“reasonable person stan- et al. 2000; Lavin et al. 2006). Nurses frequently
dard” (Hester 2007; Kopelman 2007)). Physicians underline the suffering of the newborn, whereas
and other health professionals should be aware physicians often stress uncertainty in treatment
that in clinical practice, it is impossible to know outcome (van Zuuren and van Manen 2006).
the true best interests of an infant or to define the The EURONIC study group revealed that most
ideal best interests for an infant. The consideration caregivers in seven European countries would
of evidence-based facts, the clinical intuitions at limit intensive care in EP infants with fatal/termi-
predicting the outcome of an infant, has been nal illness, but that 45–60% of the responders
found useful in one study (Meadow et al. 2002). from Germany, Italy, and Spain would not set
In some countries the decision to withhold or limits in case of poor neurological prognosis
withdraw intensive care in an infant is up to the (Cuttini et al. 2009). Moreover, the attitude
parents. The best interests of the infant should be toward “explicit involvement” of parents in
judged jointly by the parents and the physicians. decision-making varied between 10% (France)
The physicians do not make the final decision but and >90% (UK). If the physicians wished to
rather provide the parents with all the information discontinue intensive care of an infant with poor
they need to make an explicit decision. This infor- prognosis, approximately 50% would continue
mation includes the probable outcome, the neces- intensive care at parental request.
sary intensive care procedures to achieve this Bellieni and Buonocore (2009) reviewed atti-
outcome, and the anticipated burden (including tudes of caregivers concerning the best interests
the social and financial burden). of the newborn. They conclude that several aspects
Saigal and colleagues reported in a cohort of of the personal (age, gender, having own
adults who were born extremely low birth weight, children, fear of litigation), social, religious, and
survivors had no difference in self-ratings of professional background (position, experience,
health-related quality of life (HRQOL) when knowledge, number of cots) influence the attitudes
compared with normal birth weight controls of the caregivers. Religious convictions play an
(Saigal et al. 2006; Wyatt 2007). important role in the attitudes toward care of EP
or severely critically infants independent of the
denomination (Bilgen et al. 2007; Lam et al. 2009).
11.6 Attitudes Toward Extremely Janvier and colleagues demonstrated that atti-
Preterm and Critically Sick tudes toward the care of EP or critically sick
Neonates newborn infants deviate markedly from the atti-
tudes toward older children and adults with simi-
Attitudes of caregivers toward withholding and lar or worse prognosis (Janvier et al. 2008a, b).
withdrawing intensive care of EP and critically Asked if they would resuscitate patients with
sick infants with uncertain prognosis vary identical outcome (50% risk of death and 50%
11 Ethical Problems in Neonatal Medicine 191
risk of severe neurodevelopmental disability in caregivers toward the care of a high-risk infant is
survivors), 69% of the respondents would resus- an important determinant of the prognosis. If
citate an EP infant, 87% a full-term neonate, and some physicians or nurses think that an EP or
97% a two-month-old infant. The authors con- severely sick infant is not viable, they might
clude that EP infants are considered “morally treat the baby that way, resulting in self-fulfilling
different from older children” (Janvier et al. prophecy. Education of all staff involved in pre-
2007) and speculate that the majority of the natal and postnatal care of high-risk infants about
respondents had either irrational negative associ- the actual outcomes using valid epidemiological
ations with low gestational ages or they were data and elimination of irrational negative associ-
unaware of actual outcomes (Janvier et al. 2008c). ations with low gestational age or other risk fac-
Table 2 summarizes several indications that tors are important prerequisites for a good
neonates, in particularly EP infants, are valued outcome of high-risk infants.
differently from older children and adults. A pos-
itive attitude of all prenatal and postnatal
11.7 The Rights of the Newborn
Table 2 Facts and causes of devaluation of the lives of
and the Parents
preterm and full-term infants
- The fetus has almost no rights in utero but suddenly
Mercurio distinguishes three rights of the new-
becomes a citizen after birth born, the right to life, the right to mercy, and the
- Termination of pregnancy is legal in many countries right to justice or fair treatment (Mercurio 2009).
even after the limit of a preterm’s viability The right to life is part of many national consti-
- The extremely preterm infant is frequently described as tutions and includes the right to appropriate
“living fetus” or “fetal infant,” thereby implying the same medical treatment. He defined the right to
lack of rights for the newborn infant as for the fetus
mercy as “a right not to be subjected to pain or
- Infants of older mothers or mothers conceived by
in vitro fertilization are often called “precious” or discomfort that is very unlikely to yield benefit.”
“irreplaceable” children in contrast to apparently less The right to justice or fair treatment includes the
precious other infants (e.g., of very young mothers). This right to equal medical treatment independent of
relativity of the value of a preterm infant is unthinkable
age, ethnicity, income, etc. Different attitudes to
for a critically sick child
- Some ethicists believe that newborn infants lack
the care of preterm, full-term, and older infants
“personhood” (personality) and consciousness and are (Janvier et al. 2008c) violate this right, if they
thus comparable with an animal rather than with a human influence the care. The right to justice and equal
child or adult treatment includes the use of proper epidemio-
- There is widespread belief that the bonding of infant and logical data in the decision to treat or not to treat
mother is less in newborn infants than in older infants and
children and even less in premature infants an EP infant.
- Many caretakers are unaware of actual outcomes of Most countries grant parents the legal rights to
extremely preterm infants and overestimate mortality and decide on behalf of their minor children including
disability rates and the costs of care the general upbringing, the education, the religion,
- Irrational negative associations with low gestational and medical treatment decisions. The parents have
ages are frequent in caregivers and the public.
the right to get all available information on the
Confirmation bias results in the selection of arguments
(and research results) that confirm the assumption of poor condition of their sick child and on therapeutic
prognosis of extremely preterm infants options for their child. After they have received
- Uncertainty of a prognosis (e.g., extreme prematurity, all necessary information, the parents have the
intracranial hemorrhage, severe asphyxia, or right to select from the therapeutic options but
malformations) may justify withholding and withdrawal
of treatment in a neonate but not in an older infant or child
also to refuse treatment or to have the infant trans-
- The informed decision process of the parents requires ferred to another hospital. It would be inappropri-
reliable information at a time when the caretakers ate to override parents’ wishes, since they are
themselves are still depending on subjective usually motivated by their infant’s best interest,
interpretation of benefits, risks, and burdens of the infant have natural authority over their child, express
192 O. Linderkamp
religious views in their opinion, and bear the bur- the counseling physicians are sure that the parents
den of treatment decisions (Dare 2009). have understood the information, options of care
On the other hand, the parents do not have the (inclusive withholding and withdrawing of inten-
right to refuse necessary and reasonable treat- sive care) should be presented to the parents. Both
ment. Thus, parents’ rights are rebuttable when parents should be present at the consultation,
their decisions pose a significant risk to the life or unless the father is legally or for other reasons
well-being of the infant (Dare 2009). “Parents not involved. In this case the mother should be
have a right to make martyrs of themselves, but given the possibility to have a confidant involved.
not of their children” (Mercurio 2009). Moreover, If the mother is underage or incapacitated, the
parents have no right to demand treatment that is mother’s parents may share the authority with
of no benefit to the child. Without perceived ben- their daughter (Ladd and Mercurio 2003).
efit to the child, the parental right to decide is Antenatal counseling may be necessary for
outweighed by the child’s right to mercy women with a high risk of delivering an EP or
(Mercurio 2009). These limitations of parental critically sick infants within days or weeks and for
authority in decision-making for their preterm or women with imminent delivery of a high-risk
sick infants do not justify to bar parents from baby. The prenatal consultation is a collaborative
accurate information about the long-term progno- process that should involve obstetricians and mid-
sis, resuscitation, and treatment options. In many wives, neonatologists and neonatal nurses, and
hospitals parents still have limited informed input, (if necessary) pediatric subspecialists, pediatric
even if the infant is born in the “gray zone” of surgeons, and genetic counselors (Griswold and
viability (Cuttini et al. 2009; Harrison 2008). Fanaroff 2010). Communication among various
specialists is of great importance to avoid incon-
sistent and contradictory information and counsel-
11.8 Informing and Counseling ing (Halamek 2003). A shared decision between
Parents parents and physicians requires a trusting relation-
ship between parents and caregivers. The parents
Guidelines in many countries give parents the should be encouraged to consult their family doc-
major responsibility for the decision-making in tor or other health professionals outside the hos-
EP infants in the gray zone. This responsibility pital, discuss their situation with relatives and
requires comprehensive and accurate information friends, and be offered support by clergy, psychol-
on the prognosis of the infant and treatment ogist, or social worker.
options before and after birth. The first antenatal consultation is usually
The major purposes of antenatal and postnatal performed by the obstetrician and/or midwife
counseling are (Bellieni and Buonocore 2009) to and focuses on antenatal treatments (selection of
inform the parents accurately about the condition, hospital, tocolysis, corticosteroids, cesarean sec-
the reasonable treatment options, and the progno- tion). Parents should be given accurate informa-
sis of the fetus or the newborn infant and (Janvier tion about the chance of their infant surviving and
et al. 2008a) to assist the parents with decision- surviving without severe disability. Many physi-
making (Walter 2005; Halamek 2003; Batton cians believe that the amount of specific medical
2009). The consultations have to be honest, fair, information is too much for the parents. However,
compassionate, and sensitive to the culture and parents have the right to receive the same infor-
religion, the level of understanding, and the phys- mation as the physicians to make far-reaching
ical and psychological condition of the mother decisions for their child. Framing of the informa-
and the father. Translation services may be neces- tion may influence the decision of the parents:
sary for parents not proficient in the national lan- Persons who were informed on the prognosis of
guage. Senior physicians together with other an EP infant born at 23 weeks’ gestation as having
experienced staff should perform the consulta- a chance of intact survival chose resuscitation of
tions in a spirit of fairness and compassion. If an EP infant more often than parents who were
11 Ethical Problems in Neonatal Medicine 193
given prognosis as risk of death and disability In countries where the decision is given to the
(Hayward et al. 2008). parents, there is controversy as to whether counsel-
A neonatologist should become involved as ing of parents should be directive or nondirective
early as possible to describe the anticipated imme- (Batton 2009). In nondirective counseling, infor-
diate and long-term problems after birth, short- mation on outcome data is given (including the
term and long-term prognosis, the expected extent uncertainty of the data) without recommendation
of resuscitation, and subsequent intensive care. for the decision, and parents are asked to decide
Current information on outcome data of EP whether they want their infant resuscitated after
infants should include the prognostic relevance birth. This gives the parents full authority but also
of the gestational age, birth weight, gender, mul- the entire responsibility for a life-or-death decision.
tiple births, and prenatal care (Tyson et al. 2008; They might feel left alone with their decision,
Leversen et al. 2011). Moreover, the parents worries, and emotions and may later regret their
should be informed on local care possibilities decision and feel guilty. Kaempf et al. (2009) dem-
and on local outcome data in comparison with onstrated that shared authority of the staff and
referral centers. Statistical outcome data pre- parents using clear guidelines for counseling is
sented in counseling should include risk of well accepted by the parents.
death and risk of survival with severe/moderate/ For many parents detailed information on the
mild impairments (including their meanings). It prognosis and discussion of treatment options are
should also be mentioned that “normal” surviv- less important than religion-, spirituality-, and
ing infants are at risk of a variety of behavioral hope-guided decision-making (Boss et al. 2008).
and educational deficits. Financial obligations These parents may be reluctant to make a decision
are of little importance in counseling and resus- but may prefer to leave “things in God’s hands”
citation in most countries (Martinez et al. 2006) and want everything done. Different moral and
but should be considered if the prognosis of the religious attitudes may be a source of conflicts
infant is poor and the financial costs for the between physicians and parents. Dunn (1990)
family are high. proposed to ask five questions, particularly if the
The anticipated quality of life, pain, and suf- views and decisions of the parents do not agree
fering of the infant from intensive treatments but with the medical staff:
also the burden for the family should be
addressed. Moreover, the parents should be Do the parents understand the clinical condition
informed about the option to withdraw intensive and prognosis of their child?
care if the treatment becomes futile. During the Do they wish or should they consult others before
consultation, the attitudes and preferences of the finally making up their minds?
parents should be evaluated to assess the best Do they require more time?
interests of the infant as judged by the parents. Is their decision a loving, caring one made in the
An experienced neonatal nurse should explain interests of their child?
nursing procedures in the NICU (including feed- Are they asking to pull life-saving treatment only
ing of mother’s milk, kangaroo care, developmen- for their baby’s interest?
tal care) and (if possible) give the mother and/or Is their decision a reasonable one in the interests of
the father a tour of the NICU. If possible, the their child, and, if in doubt, is it so unreasonable
consulting neonatologist(s) and neonatal nurse(s) as to request them to seek other medical advice
should be part of the resuscitation team in the or for me to take legal steps to take the child into
delivery room and the initial intensive care team care under the protection of the courts?
for the infant. If this is not possible, the counselors
have to make sure that the resuscitation team is Breaking bad news is particularly challenging
informed on the decisions made before delivery and requires the sensitivity and communication
and does not oppose to the decisions, unless the skills of the physician. If bad news is given with
situation has changed considerably. warmth and affection and parents are treated with
194 O. Linderkamp
respect and sensitivity, most parents will have care, suffering and burden from long-term impair-
positive memories and will be grateful to the ments in relation to probable long-term outcome)
staff involved (Henley and Judith Schot 2008). should be estimated and considered in decision-
making. Most guidelines consider only severe
disability leading to intolerable suffering and bur-
11.9 Decision-Making in EP Infants den and/or inability to interact with others as
justification for withholding and withdrawal of
Decisions concerning the care of EP infants may life-sustaining treatment. Whether suffering and
be required at three times: burden resulting from intensive care and disability
are intolerable has to be decided by the parents.
1. Care of the mother and the fetus before birth. However, the decision to withhold or withdraw
Parents and physicians have to decide whether intensive care is primarily a medical decision for
antenatal proactive care is provided (transfer of which the doctor bears ultimate moral and legal
the mother to a perinatal center, tocolysis, ante- responsibility.
natal corticosteroids, cesarean section on fetal The major concern of an end-of-life decision is
indication). that the outcome of an individual infant is esti-
2. Initiation or withholding of resuscitation of the mated from statistical data determined in a group
infant after birth. The decision as to whether of (more or less) representative infants studied
the infant will be resuscitated is made before several years earlier. Because of the uncertainty
birth but may be changed according to the of the prognosis, some authors are strictly against
infant’s condition and the infant’s response to any end-of-life decision made before birth but
resuscitation. The decision to provide proac- rather opt for an individualistic approach based
tive antenatal care is usually combined with the on the infant’s clinical condition and initial
decision to resuscitate the infant and vice response to intervention at birth (Turillazzi and
versa. Fineschi 2009). However, most authors agree that
3. Continuation or withdrawal of neonatal inten- “extending intensive care to all of the most imma-
sive care. Reorientation of care may be consid- ture infants would entail considerable suffering,
ered if provisional care of an infant with resource use, and cost in order to benefit only
assumed poor prognosis has been unsuccessful a small proportion of infants” (Leversen et al.
or if the prognosis deteriorated (e.g., large 2011). This can be considered as a utilitarian
cerebral bleeding with inactive electric brain viewpoint, but it is the logical consequence of
activity). The decision to withdraw intensive dealing with an uncertain situation in which judg-
care in some countries should be made jointly ment and decision have to be made in the assumed
by parents and staff. best interests of the individual infant.
When parents are involved in end-of-life deci-
The reasons for end-of-life decisions have to sion, the following scenarios may occur after birth
agree with national or hospital guidelines. Pallia- in infants whose prognosis was uncertain before
tive care treatments (e.g., analgesic drugs) have to birth:
be compatible with national laws and court deci-
sions. In most guidelines no or small chance of 1. If a joint decision of parents and physicians has
survival (“futility” of treatment) and no or small been made before birth to resuscitate the infant,
chance of survival without severe disability are resuscitation of the infant should usually be
recognized conditions. The entire team (including tried even when the condition of the infant is
subspecialists as pediatric neurologists, etc.) and severely compromised at birth.
(as required) the Ethical Committee should 2. If a joint end-of-life decision of parents and
become involved in the end-of-life decision. physicians has been made before birth, resusci-
If the prognosis is uncertain, the harm-to-ben- tation of the infant will usually not be attempted.
efit ratio (i.e., pain and suffering from intensive If the infant appears viable (spontaneous
11 Ethical Problems in Neonatal Medicine 195
respiration), resuscitation should be started parents request to withdraw treatment, while the
within 1–2 min to avoid severe hypoxia. team sees a realistic chance of survival without
3. If no joint decision of parents and physicians severe disability and wishes to continue intensive
has been made before birth because the mother care, intensive care should generally be continued.
was already in active labor when admitted to
the hospital or because of other reasons (e.g.,
language), the neonatologist must decide on 11.10 Withholding and Withdrawing
behalf of the infant and should in case of of Intensive Care
doubt resuscitate the baby until the parents
can be involved in the decision. 11.10.1 Withholding Versus
Withdrawing of Intensive Care
Parents differ in their request to be supported in
their decision by the staff. Some parents want staff In various studies end-of-life decisions preceded
to suggest to them what to do, while others wish to death in 70–80% of dying newborn infants
receive the necessary information but prefer to (Hentschel et al. 2006; Verhagen et al. 2009b).
make decisions independently or with the support Principally three ways of ending or limiting inten-
of family, friends, family doctor, or religious sive care are possible with the intention to shorten
adviser (Henley and Judith Schot 2008). Although the life of a patient: (Bellieni and Buonocore 2009)
most parents wish support, the staff members have withholding of resuscitation and intensive care after
to avoid any devaluation of parental autonomy birth, (Janvier et al. 2008a) withdrawing of life
and self-worth. “Most parents want to feel guided, support, and (Levene 2004) withholding of addi-
assisted and listened to, but not directed or con- tional therapies (e.g., antibiotics, vasoactive drugs).
trolled, and certainly not abandoned” (Henley and The third way is preferred by many professionals
Judith Schot 2008). Parents will usually make and parents but may result in survival with addi-
concerned and loving decisions in their infant’s tional damage (e.g., from sepsis, hypoxia).
interests. Although probably not uncommon, withholding of
In countries where the decision to withhold or additional therapies is rarely mentioned in reports on
withdraw intensive care is taken with the essential end-of-life decisions (Hentschel et al. 2006).
statement of the parents, the main causes of con- Several guidelines see no moral or ethical dif-
flicts between parents and physicians are different ference between withholding and withdrawing
opinions of the condition and best interests of the intensive care (Walter 2005; American Academy
infant, insensitive behavior and communication of of Pediatrics 2007; Nuffield Council on Bioethics
the team, and religious convictions of the parents 2006; Wilkinson et al. 2009; Fischer et al. 2009;
that forbid withdrawal of life-sustaining treatment Verhagen et al. 2009b). Some authors explicitly opt
(Tripp and McGregor 2006; Verhagen et al. for withdrawal rather than withholding life support,
2009a). Parents usually make concerned and lov- since “provisional” treatment allows for evaluation
ing decisions in their infant’s interests. A Dutch of the clinical condition of the infant, including the
analysis of disagreements in end-of-life decisions actual gestational age and body weight, and the
demonstrated that conflicts within the team reaction to resuscitation and intensive care (Fischer
occurred in 4% and between the team and the et al. 2009; Verhagen et al. 2009b). Boyle (2004)
parents in 12% of the cases. All conflicts were describes the widespread American attitude: “If the
resolved by postponing the end-of-life decision treatment in question never is started, no one will
until consensus was achieved (Verhagen et al. benefit. If it is started, some may benefit, and it can
2009a). When treatment is clearly futile, the phy- be withdrawn from those whom it does not bene-
sicians can decide to stop intensive care without a fit.” During “provisional” intensive care, a harm-
decision of an Ethics Committee or court in some to-benefit ratio can be estimated repeatedly to
countries (Isaacs et al. 2006). In case of conflict determine whether it is appropriate to continue or
between parents and neonatologists, that is, the not. Some national guidelines (e.g., Swiss)
196 O. Linderkamp
recommend “provisional care” of EP infants born reasonable to decide either for both active antena-
at a gestational age in the “gray zone” (Fischer et al. tal care and postnatal resuscitation or for neither of
2009). these active approaches, unless the postnatal con-
However, some religious convictions allow dition of the infant requires reorientation of the
withholding, but not withdrawing, of life support decision made before birth. Some parents might
(Tripp and McGregor 2006). Furthermore, for prefer a passive approach before delivery but
many caregivers and parents, it is psychologically active life support when the infant appears viable
more difficult to withdraw than to withhold inten- after birth. Even for preterm infants with a gesta-
sive care measures. The EURONIC study demon- tional age below the limit of viability, an experi-
strated that neonatologists in Italy, Spain, France, enced neonatologist should be present or
and Germany consider it more acceptable to with- immediately available at birth to confirm or to
hold than to withdraw mechanical ventilation, reorient the medical decision made before birth.
whereas in the Netherlands, the UK, and Sweden, However, a joint decision of the parents and phy-
more than 93% of the neonatologists would with- sicians made before delivery should not be
draw intensive care in selected circumstances reversed after birth without marked change in
(Cuttini et al. 2009). Reasons for reluctance to the expected clinical situation.
withdraw intensive care include fear of legal con- When resuscitation is futile, compassionate
sequences, increasing emotional attachment of par- care must be provided as for babies whose inten-
ents and infants with time, and feeling of active life sive care is discontinued. The baby may be placed
ending or even killing by extubation and applica- on the breast of the mother and die in peace. If the
tion of pain- and stress-relieving drugs. baby suffers, an analgesic and/or sedative drug
On the other hand, for some parents the death of should be given. An appropriate religious cere-
their child may be more bearable if the neonatal mony should be offered and organized.
team has “tried everything” and “gave him or Since EP infants requiring more than 3–5 min
her every chance” (Mercurio 2009). Moreover, a of resuscitation have a poor prognosis (Singh et al.
period of intensive care allows some time for the 2007; Finer et al. 1999; Jankov et al. 2000; Janvier
parents and siblings to meet the child, to perform and Barrington 2005), the ILCOR guidelines (The
baptism or other religious ceremonies, and to touch International Liaison Committee on Resuscitation
and cuddle the baby. The infant may die in the arms (ILCOR) 2006) suggest to stop resuscitation “if
of the parents, and the family has time to grieve with there are no signs of life after 10 min of continu-
their child and to mourn in dignity. Some parent- ous and adequate resuscitative efforts.” In clinical
infant bonding may relief the mourning sorrow. practice 10 min may, however, be a rather brief
These possible emotional benefits must be weighed resuscitation time, since ventilation and other
against painful intensive care measures and the use resuscitation measures are not always adequate
of intensive care resources (Wyatt 1999). (The International Liaison Committee on Resus-
citation (ILCOR) 2006). A framework of care of
extremely preterm infants derived from various
11.10.2 Withholding Proactive guidelines and personal experience of the author
Antenatal is shown in Table 3.
Care and Resuscitation After
Birth
11.10.3 Withdrawing of Intensive Care
Proactive antenatal care (transfer to a center, cor-
ticosteroids, cesarean section on fetal indication) The decision to withdraw intensive care is usually
improves the prognosis of an EP infant to the level made in several steps:
of a 1–2 weeks more mature infant (Itabashi
et al. 2009; Hakansson et al. 2004; Fischer et al. 1. The medical decision of treatment futility or
2009; Leversen et al. 2011). It is therefore intolerable long-term suffering is made
11 Ethical Problems in Neonatal Medicine 197
Table 3 Framework of care of extremely preterm infants 4. Intensive care is reoriented to compassionate
(<26 weeks’ gestation) and palliative care. If possible, the baby is
General considerations cared for in a private family room. Invasive
Extremely preterm infants deserve the best state-of-the- procedures, blood sampling, and any other
art care to attain the best possible outcomes. Withholding painful or stressing interventions should be
treatment because the hospital cannot provide the
appropriate care is unacceptable. If experienced avoided or minimized. Maintaining dignity,
obstetricians and neonatologists are not available at the warmth, skin contact (kangaroo care), and
hospital, the mother has to be transferred to a specialized relief of pain and stress are basic elements of
center. If a transport is not possible, the most experienced palliative care (Walter 2005; Carter 2004). A
local staff should be involved and get advice from a
specialized center family-centered care philosophy is an optimal
Accurate estimation of gestational age (as a major basis for neonatal intensive care and for the
determinant of the prognosis) is extremely important. care of a dying infant. Family members and
Moreover, body weight, gender, and multiple births friends are given time and opportunity to stay
influence the prognosis and should be considered in with the infant, to touch, and cuddle the baby.
antenatal counseling of the parents
5. Withdrawal of life-sustaining treatment should
Parents’ rights to comprehensive information and
explicit involvement in decisions about antenatal care take place in an unhurried, private, and digni-
(transfer to level III center, tocolysis, corticosteroids, fied manner. In the presence of the parents,
cesarean section) and postnatal care of their preterm tubes and electrodes are removed, and the
infant born before or in the “gray zone” (23–24 weeks’
infant dies in the arms of the parents. Pain-
gestation) have to be respected
A decision before birth not to resuscitate or to resuscitate
and stress-relieving drugs should be given,
may have to be reconsidered after birth due to inaccurate and the bronchial and gastric tube should be
prenatal estimation of gestational age and individual sucked to avoid vomiting and choking
variation of the maturity and viability of the infant. The (if possible, before the parents enter the
heart rate response of the baby to ventilation within 3–5
( 10) min is a better indicator of the prognosis than the
room). A nurse and a physician (with a good
clinical condition at birth relationship to the parents and the child) should
be present until the infant has died and should
see the family from time to time thereafter.
collectively by the NICU team and other sub- 6. The staff shows empathy and supports the
specialists (e.g., pediatric neurologist, cardiol- family in their grief. Mementos of the infant
ogist, or surgeon). such as photos and video recordings, arm-
2. The parents are informed on the prognosis of bands, the clothes, a footprint, and a strand of
their infant and explicitly involved in the judg- hair may be given to the parents. Parents
ment of the best interests of their infant. More- should be supported with funeral arrangements
over, the parents are informed about options to and formalities such as death certificate. Some
prevent pain and suffering when their baby countries allow taking the dead baby home for
dies, and they are involved in the decision of some time before the funeral. Further consul-
appropriate pain- and stress-relieving treat- tations (outside the NICU!) should be offered.
ment. Parents are supported in seeking advice Information about bereavement and parent
by medical professionals outside the hospital, groups should be provided.
friends, and religious advisers. In some coun-
tries parents are requested to take an active role
in this decision. 11.10.4 Pain- and Stress-Relieving
3. If parents and caregivers agree on the decision Drugs
to withdraw intensive care, a time is set for
ending intensive care (usually assisted ventila- For intensively treated newborn infants with a
tion). The parents decide whether they wish good prognosis, indications and dosages of pain-
baptism or other religious rituals in correspon- reducing drugs are carefully adjusted to avoid
dence to their faith. serious side effects. After an end-of-life decision
198 O. Linderkamp
has been made, side effects are of little impor- 10 min following birth demonstrated that 69–98%
tance, and the dosages can be increased to reach died and all surviving infants developed severe
complete elimination of pain and stress. More- (89–100%) or moderate neurodevelopmental dis-
over, pain- and stress-relieving drugs are indicated ability (Byrne et al. 2008). This is why some justify
to minimize pain and suffering resulting from the cessation of resuscitation after 10 min (The Inter-
removal of tubes, lines, and electrodes and from national Liaison Committee on Resuscitation
dying itself. Several authors recommend adminis- (ILCOR) 2006), unless resuscitation was not ade-
tration of an adequate dose of opiate analgesia quate. If a baby develops signs of severe hypoxic-
(morphine or analogues) together with a sedative ischemic encephalopathy with poor long-term
(e.g., benzodiazepine) as part of humane care. prognosis, a decision (jointly made by the parents
Although the required high dosages of analgesics and physicians) to withdraw intensive care is justi-
and sedatives may cause respiratory depression fied by some authors (Boyle 2004).
and shorten the life of the infant, their use is
considered legal in most countries as long as the
primary intention of the physicians is relief of pain 11.12 Malformations
and suffering and not shortening the life of the
infant (Provost et al. 2004). Malformation may justify withholding of postnatal
The administration of lethal dosages of drugs resuscitation if the malformation is not compatible
with the intention to hasten death is illegal in most with life or if there is a high risk of death or if
countries. In the Netherlands, “non-voluntary therapy burden is not bearable. The harm-to-benefit
euthanasia” is considered acceptable in selected ratio (i.e., pain and suffering from early interven-
infants for whom death appears to be in the infants’ tions in relation to the probable outcome) may be
best interests but who are presently not dependent considered in the estimation of the best interests of
on life support. The Groningen Protocol for Eutha- the infant. Table 4 lists lethal malformations.
nasia in Newborns gives detailed guidelines that Termination of pregnancy for fetal malforma-
are far more restricted than most guidelines and tion is liberally implemented in many countries.
recommendations for withholding or withdrawing After birth the best interests of viable infants with
of intensive care (Verhagen and Sauer 2005). In malformations have to be judged individually for
fact, only 4% of infants with end-of-life decision each infant, each malformation, and the probable
(born in the Netherlands from 2005 to 2006) died long-term sequelae of the malformation. After
from drugs given with the intention to hasten death birth, treatment decisions are primarily based
(Verhagen and Sauer 2005). on the best interests of the infant (and not pri-
marily on the authority of the mother). This sud-
den change in authority is difficult to understand
11.11 Severe Asphyxia for many parents. Infants with Down syndrome
pose particular dilemma for parents and physi-
Stillborn infants do not breathe and show no other cians. On the one hand, the major purpose of
evidence of life (such as beating of the heart, prenatal screening is to detect trisomy 21 and to
pulsation of the umbilical cord, definite move- terminate pregnancy if the fetus suffers from
ment of voluntary muscles). If the infant shows
signs of maceration, the infant has died at least Table 4 Lethal malformations (according to the US
12 h before birth. A fresh stillborn infant may American Birth Defect Center)
have died hours or minutes before birth. If the Trisomy 13
fetal heartbeat was heard shortly before birth or Trisomy 18
fetal heartbeat was not monitored, resuscitation Anencephaly
should be started. Acranium
Four studies on the outcome of infants with Bilateral renal agenesis (Potter syndrome)
severe asphyxia defined by Apgar score 0 at Bart’s hydrops fetalis
11 Ethical Problems in Neonatal Medicine 199
Down syndrome; on the other hand, there is Finer NN, Tarin T, Vaucher YE et al (1999) Intact survival
general agreement that the diagnosis of Down in extremely low birth weight infants after delivery
room resuscitation. Pediatrics 104:e40
syndrome is no indication for withholding resus- Fischer N, Steurer MA, Adams M et al (2009) Survival
citation even if the infant suffers from severe rates of extremely preterm infants (gestational age <26
cardiac or other malformations (Rennie and weeks) in Switzerland: impact of the Swiss guidelines
Leigh 2008). for the care of infants born at the limit of viability. Arch
Dis Child Fetal Neonatal Ed 94:F407–F413
Griswold KJ, Fanaroff JM (2010) An evidence-based
overview of prenatal consultation with a focus on infants
born at the limits of viability. Pediatrics 125:e931–e937
References Hakansson S, Farooqi A, Holmgren PA et al (2004)
Proactive management promotes outcome in
American Academy of Pediatrics (2007) Noninitiation or extremely preterm infants: a population-based compar-
withdrawal of intensive care for high-risk newborns. ison of two perinatal management strategies. Pediatrics
Pediatrics 119:401–403 114:58–64
Batton DG, Committee on Fetus and Newborn (2009) Halamek LP (2003) Prenatal consultation at the limits of
Clinical report—Antenatal counseling regarding resus- viability. NeoReviews 4:e153–e156
citation at an extremely low gestational age. Pediatrics Harrison HT (2008) The offer they can’t refuse: parents
124:422–427 and perinatal treatment decisions. Semin Fetal Neona-
Bellieni CV, Buonocore G (2009) Flaws in the assessment tal Med 13:329–334
of the best interests of the newborn. Acta Paediatr Hayward MF, Murphy RO, Lorenz JM (2008) Message
98:613–617 framing and perinatal decisions. Pediatrics 122:109–118
Bilgen H, Topuzoglu A, Kuscu K et al (2007) End-of-life Henley A, Judith Schot J (2008) The death of a baby
decisions in the newborn period: attitudes and practices before, during or shortly after birth: good practice
of doctors and nurses. Turk J Pediatr 51:248–256 from the parents’ perspective. Semin Fetal Neonatal
Boss RD, Hutton N, Sulpar LJ et al (2008) Values parents Med 13:325–328
apply to decision-making regarding delivery room Hentschel R, Lindner K, Krueger M, Reiter-Theil S (2006)
resuscitation for high-risk newborns. Pediatrics Restriction of ongoing intensive care in neonates:
122:583–589 a prospective study. Pediatrics 118:563–569
Boyle RJ (2004) Ethical issues in the care of the neonate. Hester DM (2007) Interests and neonates: there is more to
NeoReviews 5:e471–e476 the story than we explicitly acknowledge. Theor Med
Byrne S, Szyld E, Kattwinkel J (2008) The ethics of Bioeth 28:357–372
delivery-room resuscitation. Semin Fetal Neonatal Iijima S, Arai H, Ozawa Y et al (2009) Clinical patterns in
Med 13:440–447 extremely preterm (22 to 24 weeks of gestation) infants
Carter BS (2004) Comfort care principles for the high-risk in relation to survival time and prognosis. Am J Peri-
newborn. NeoReviews 5:e484–e490 natol 26:399–406
Chiswick M (2008) Infants at borderline viability: ethical Ikeda K, Hayashida S, Hokuto I (2006) International per-
and clinical consideration. Semin Fetal Neonatal Med spectives: recent outcomes of ultrapreterm and
13:8–15 extremely low-birth weight infants. Neo Reviews 7:
Comitato Nazionale per la Bioetica (2008) I grandi pre- e511–e516
maturi. Note bioetiche. [EP babies. Bioethical notes]. Isaacs D, Kilham H, Gordon A et al (2006) Withdrawal of
www.governo.it/bioetica neonatal mechanical ventilation against the parents’
Cuttini M, Casotto V, Vonderweid U et al (2009) Neonatal wishes. J Paediatr Child Health 42:311–315
end-of-life decisions and bioethical perspectives. Early Itabashi K, Horiuchi T, Kusuda S et al (2009) Mortality
Hum Dev 85:S21–S25 rates for extremely low birth weight infants born in
Dare T (2009) Parental rights and medical decisions. Japan in 2005. Pediatrics 123:445–450
Pediatr Anesth 19:947–952 Jankov RP, Asztalos EV, Scidmore MB (2000) Favourable
De Leeuw R, Cuttini M, Nadai M et al (2000) Treatment neurological outcomes following delivery room cardio-
choices for extremely preterm infants: an international pulmonary resuscitation of infants 750 g at birth.
perspective. J Pediatr 137:608–616 J Paediatr Child Health 36:19–22
Dehan M, Gold F, Grassin M et al (2001) Dilemmes Janvier A, Barrington KJ (2005) The ethics of neonatal
éthiques de la période périnatale: recommendations resuscitation at the margins of viability: informed con-
pour les decisions de fin de vie. Arch Pediatr 8:407–419 sent and outcomes. J Pediatr 147:579–585
Dunn PM (1990) Life saving intervention in the neonatal Janvier A, Bauer KL, Lantos JD (2007) Are newborns
period: dilemmas and decisions. Arch Dis Child morally different from older children? Theor Med
65:557–558 Bioeth 28:413–425
Fanaroff AA (2008) Extremely low birthweight infants-the Janvier A, Lantos J, Deschènes M et al (2008a) Caregivers
interplay between outcomes and ethics. Acta Paediatr attitudes for very premature infants: what if they knew?
97:144–145 Acta Paediatr 97:276–279
200 O. Linderkamp
Janvier A, Leblanc I, Barrington KJ (2008b) The best- Meadow W, Frain L, Ren Y et al (2002) Serial assessment
interest standard is not applied for neonatal resuscita- of mortality in the neonatal intensive care unit by algo-
tion decisions. Pediatrics 121:963–969 rithm and intuition: certainty, uncertainty, and informed
Janvier A, Leblanc I, Barrington KJ (2008c) Nobody likes consent. Pediatrics 109:878–886
premies: the relative value of patients’ life. J Perinatol Mercurio MR (2009) The ethics of newborn resuscitation.
28:821–826 Semin Perinatol 33:354–363
Kaempf JW, Tomlinson MW, Campbell B et al (2009) Miljeteig I, Markestad T, Norheim OF (2007) Physicians’
Counseling pregnant women who may deliver use of guidelines and attitudes to withholding and with-
extremely premature infants: medical care guidelines, drawing treatment for extremely premature neonates in
family choices, and neonatal outcomes. Pediatrics Norway. Acta Paediatr 96:825–829
123:1509–1515 Moser K, Macfarlane A, Chow YH et al (2007) Introducing
Kipnis K (2007) Harm and uncertainty in newborn inten- new data on gestation-specific infant mortality among
sive care. Theor Med Bioeth 28:393–412 babies born in 2005 in England and Wales. Health Stat
Kopelman LM (2007) The best interests standard for Q 35:13–27
incompetent or incapacitated persons of all ages. Nishida H, Sakuma I (2009) Limit of viability in Japan:
J Law Med Ethics 35:187–196 ethical consideration. J Perinat Med 37:457–460
Kusuda S, Fujimura M, Sakuma I et al (2006) Morbidity Nuffield Council on Bioethics (2006) Critical care deci-
and mortality of infants with very low birth weight in sions in fetal and neonatal medicine: ethical issues,
Japan. center variation. Pediatrics 118:e1131–e1139 London. www.nuffieldbioethics.org/neonatal-medicine
Ladd RE, Mercurio MR (2003) Deciding for neonates: Österreichische Gesellschaft für Kinder-und
whose authority, whose interests? Semin Perinatol Jugendheilkunde (2005) Erstversorgung von
27:488–494 Frühgeborenen an der Grenze der Lebensfähigkeit.
Lagercrantz H, Changeux JP (2009) The emergence of Monatsschr Kinderheilkd 7:711–715
human consciousness: from fetal to neonatal life. Partridge JC, Dickey BJ (2009) Decision-making in neo-
Pediatr Res 65:255–260 natal intensive care: interventions on behalf of preterm
Lam HS, Wong SPS, Liu FYB et al (2009) Attitudes infants. NeoReviews 10:e270–e278
toward neonatal intensive care treatment of preterm Peerzada JM, Schollin J, Håkansson S (2006) Delivery
infants with a high risk of developing long-term dis- room decision-making for extremely preterm infants
abilities. Pediatrics 123:1501–1508 in Sweden. Pediatrics 117:1988–1995
Lavin JP, Kantak A, Ohlinger J et al (2006) Attitudes of Pignotti MS, Donzelli G (2008a) Perinatal care at the
obstetric and pediatric health care providers toward threshold of viability: an international comparison of
resuscitation of infants who are born at the margins of practical guidelines for the treatment of extremely pre-
viability. Pediatrics 118:S169–S176 term births. Pediatrics 121:e193–e198
Levene M (2004) Is intensive care for very immature Pohlandt F (2008) Leitlinie zur Frühgeburt an der Grenze
babies justified? Acta Paediatr 93:149–152 der Lebensfähigkeit des Kindes. Monatsschr
Leversen KT, Sommerfelt K, Rønnestad A et al (2011) Kinderheilkd 156:798–802
Prediction of neurodevelopmental and sensory out- Provost V, Deliens L, Cools F et al (2004) A classification
come at 5 years in Norwegian children born extremely of end-of-life decisions in neonates and infants. Acta
preterm. Pediatrics 127:e630–e638 Paediatr 93:301–305
Linderkamp O (2012) Survival and outcome of extremely Rennie JM, Leigh B (2008) The legal framework for end-
preterm infants in the 90s and early 2000s. Acta of-life decisions in the UK. Semin Fetal Neonatal Med
Paediatr (in press) 13:296–300
Lui K, Bajuk B, Foster K et al (2006) Perinatal care at the Rijken M, Veen S, Walther FJ (2007) Ethics of maintaining
borderlines of viability: a consensus statement based on preterm infants. Pediatr Child Health 17:58–63
a NSW and ACT consensus workshop. Med J Aust Saigal S, Stoskopf B, Pinelli J et al (2006) Transition of
185:495–500 extremely low birthweight infants from adolescence to
MacDonald H, American Academy of Pediatrics Commit- young adulthood. Pediatrics 118:1140–1148
tee on Fetus and Newborn (2002) Perinatal care at the Seri I, Evans J (2008) Limits of viability: definition of the
threshold of viability. Pediatrics 110:1024–1027 gray zone. J Perinatol Suppl 1:S4–S8
Markestad T, Kaaresen PI, Ronnestad A et al (2005) Early Singh J, Fanaroff J, Andrews B et al (2007) Resuscitation
death, morbidity, and need of treatment among in the “gray zone” of viability: determining physician
extremely premature infants. Pediatrics 15:1289–1298 preferences and predicting infant outcomes. Pediatrics
Marsal K, Express Group (2009) Survival of extremely 120:519–526
preterm infants after active perinatal care in Sweden. Skupsi DW, McCullough B, Levene M, Chervenak FA
JAMA 301:2225–2233 (2010) Improving obstetric estimation of outcomes of
Martinez AM, Partridge JC, Yu V et al (2006) Physician extremely premature infants: an evolving challenge.
counselling practices and decision-making for J Perinat Med 38:19–22
extremely preterm infants in the Pacific Rim. J Paediatr The International Liaison Committee on Resuscitation
Child Health 41:209–214 (ILCOR) (2006) Consensus on science with treatment
11 Ethical Problems in Neonatal Medicine 201
recommendations for pediatric and neonatal patients: Wilkinson AR, Ahluwalia J, Cole A et al (2009)
neonatal resuscitation. Pediatrics 117:e978–e988 Management of babies born extremely preterm at less
Tripp J, McGregor D (2006) Withholding and withdrawing than 25 weeks of gestation: a framework for clinical
of life sustaining treatment in the newborn. Arch Dis practices at the time of birth. Arch Dis Child Fetal
Child Fetal Neonatal Ed 91:F67–F71 Neonatal Ed 94:F2–F5
Turillazzi E, Fineschi V (2009) How old are you? Newborn Wilson-Costello D, Friedman H, Minich N et al (2007)
gestational age discriminates neonatal resuscitation Improved neurodevelopmental outcomes for extremely
practices in the Italian debate. BMC Med Ethics 10:19 low birth weight infants in 2000–2002. Pediatrics
Tyson JE, Parikh NA, Langer J et al (2008) Intensive care 119:37–45
for extreme prematurity-moving beyond gestational World Health Organization (1993) International classifica-
age. N Engl J Med 358:1672–1681 tion of diseases (ICD), vol 2, 10th rev edn. World
Verhagen E, Sauer PJJ (2005) The Groningen protocol- Health Organization, Geneva, Switzerland
euthanasia in severely ill newborns. NEJM 352:959–992 Wyatt JS (1999) Neonatal care: withholding or withdrawal
Verhagen AAE, de Vos M, Dorscheidt JHHM et al (2009a) of treatment in the newborn infant. Baillieres Best Pract
Conflicts about end-of-life decisions in NICUs in the Res Clin Obstet Gynaecol 13:503–511
Netherlands. Pediatrics 124:e112–e119 Wyatt J (2007) End-of-life decisions, quality of life and the
Verhagen AAE, Dorscheidt JHHM, Engels B et al (2009b) newborn. Acta Pædiatr 96:790–791
End-of-life decisions in Dutch neonatal intensive care van Zuuren FJ, van Manen E (2006) Moral dilemmas in
units. Arch Pediatr Adolesc Med 163:895–901 neonatology as experienced by health care practi-
Walter FJ (2005) Withholding treatment, withdrawing tioners: A qualitative approach. Med Health Care
treatment, and palliative care in the neonatal intensive Philos 9:339–347
care unit. Early Hum Dev 81:865–872
Care of Extremely Low-Birth-Weight
Infants and Timing of Discharge. 12
Information and Psychosocial
Intervention in Neonatology
Fabio A. Mosca, Monica Fumagalli, Maria Elena Bolis, and
Massimo Agosti
Contents
12.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
12.2 Basic Approach to the Care of Extremely Low Birth Weight Infants:
An Outline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
12.2.1 Delivery Room and First Hour of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
12.2.2 Admission to NICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
12.2.3 Long-Term Morbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
12.3 Timing of Discharge and Problems of Home Care in ELBW Infants . . . . 207
12.3.1 Timing of Home Discharge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
12.3.2 Special Care Needs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
12.3.3 Rehospitalization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
12.3.4 Safe Transportation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
12.4 Information and Psychosocial Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
12.4.1 Preterm Birth and Family Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
Abstract advanced and meticulous procedures and pro-
The welcoming and assistance services of birth tocols, to a more humanitarian vision of the
have evolved in the last decades. In western birth issue.
countries, birth at hospital went from a medi- Prevention procedures have been
cal-sanitary assistance, aimed to guarantee the established to promote attachment and bond-
best security in hospital with more and more ing from the delivery room until discharge: the
respect and promotion of birth physiology, the
early and prolonged contact with the infant
F. A. Mosca (*) · M. Fumagalli
through the “skin to skin” technique immedi-
NICU, Department of Clinical Sciences and Community
Health, Fondazione IRCCS Ca’ Granda Ospedale ately after birth, and the promotion of rooming-
Maggiore Policlinico Milano, Università degli Studi di in practice, which is essential for the beginning
Milano, Milan, Italy of breastfeeding and bonding.
e-mail: [email protected]
It has ever more clearly emerged the role of
M. E. Bolis · M. Agosti the emotional and psychological support of
Neonatology and NICU – Maternal and Child Department,
motherhood and the need to provide psycholog-
Ospedale ”F del Ponte”, Varese, Italy
e-mail: [email protected] ical services in the obstetric wards, in nurseries,
# Springer International Publishing AG, part of Springer Nature 2018 203
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_161
204 F. A. Mosca et al.
and in all those “risky” contexts such as Neona- 12.1 Salient Points
tal Intensive Care Units (NICU), for extremely
low birth weight infants (ELBW). • ELBW infants are at high risk for acute com-
In fact ELBW infants are at high-risk for plications and long-term morbidities.
mortality, morbidities, and long-term compli- • Optimizing perinatal and postnatal care from
cations. Optimizing perinatal and postnatal the first minutes of life is essential to improve
care is essential to improve their outcome and the outcome of ELBW infants.
a better understanding of pathophysiological • Timing of discharge has to be defined
mechanisms involved in respiratory, cardiac, according to physiologic criteria and a safe
and cerebral injury is crucial to implement home discharge plan has to be established
new preventive strategies. with the family.
Nevertheless an active and early involve- • Follow-up programs and early intervention
ment of parents in the infant’s care is also strategies have to be implemented in order to
greatly advisable. Specific guidelines to support improve long-term outcome.
the parents in these critical areas were created, in • Prevention procedures have been established
order to limit the traumatic effects connected to to promote attachment and bonding as much as
prematurity and pathologic births. NICU wards possible.
have increasingly promoted the early contact • NICU wards have increasingly favored the
and involvement of parents, which allow the early contact and involvement of parents, so
bonding not to be totally compromised by that the bonding is not totally compromised by
long separation, prolonged medicalization, and long separation, prolonged medicalization, and
parental experiences. parental experiences.
Time of home discharge has to be carefully • It has emerged ever more clearly the impor-
planned together with parents since ELBW tance of the emotional and psychological sup-
infants are often discharged with some port of parenthood and the need to provide
unresolved medical problems so an individual- psychological services.
ized, close, home-care plan has to be devel-
oped for these babies.
Long-term sequelae are mainly represented
by neurodevelopmental disorders, neurosensory 12.2 Basic Approach to the Care of
deficits, growth failure, and bronchopulmonary Extremely Low Birth Weight
dysplasia. Long-term follow-up programs are Infants: An Outline
recommended in order to early identify those
babies who may benefit from intervention Advances in perinatal and neonatal medicine have
programs. increased the survival rate of extremely low birth
After hospital discharge, specific inter- weight (ELBW) infants in the last decades
vention models have been designed to sup- (McCarthy 2015), but they are also at high-risk
port parenthood and to promote the parent’s for morbidities and long-term sequelae. Optimiz-
ability to take care of his own and his child’s ing perinatal and postnatal care is essential to
health. improve their outcome.
In addition to psychological therapy, new ELBW infants represent an inhomogeneous
types of services have been created as mutual population being constituted by two different
self-help groups of parents and home visits groups of premature newborns with different
service. underlying pathogenetic mechanisms: very pre-
The diffusion of these intervention models has mature babies and intrauterine growth restricted
generated a significant improvement in the pro- infants (IUGR) with higher gestational age but
tection of parenthood and ELBW development. small for gestational age.
12 Care of Extremely Low-Birth-Weight Infants and Timing of. . . 205
12.2.1 Delivery Room and First Hour of 12.2.2 Admission to NICU
Life
On admission to NICU, body temperature and
The first hours of life of ELBW infants are crucial body weight should be measured to correct
and several problems can arise in this time and hypothermia or maintain normothermia and to
develop at NICU admission, during the neonatal optimize fluid management.
period and later in childhood. Sick ELBW infants need close monitoring
At birth, careful attention to the maintenance of of arterial blood pressure, blood gases, serum
body temperature is essential. The most effective glucose, and electrolytes. Insertion of an umbil-
interventions seem to be gentle drying and occlu- ical arterial catheter is useful to avoid pain and
sive wraps (polyethylene wraps or polyurethane discomfort. Arterial lines should be removed as
bags), associated with hats. In spite of these pro- soon as they are no longer necessary. The use of a
cedures, low temperatures are common on admis- double lumen umbilical venous catheter may be
sion and surveillance of temperatures in the useful for the administration of fluid, drugs, and
delivery room and during transport should be blood products. After the first week of life a
identified as quality improvement initiatives percutaneous central venous catheter should be
(Laptook et al. 2009). dedicated to infusion of parenteral nutrition
Most of ELBW infants need some kind of (PN).
respiratory assistance in the delivery room to The skin of prematurely born ELBW infants is
enhance lung fluid clearance, establish functional poorly effective as an epidermal barrier. Distur-
residual capacity (FRC), and maintain lung aera- bances in temperature regulation and water bal-
tion (Hooper et al. 2016). ance, as well as infection can occur because of
It is important to adequately tailor respiratory poor epidermal barrier function and the excessive
assistance in order to both prevent lung hyperin- use of adhesives. The routine prophylactic use of
flation (avoiding excessively high pressure) and emollients is not recommended (Edwards et al.
maintain an effective lung recruitment (applying 2004).
positive end-expiratory pressure). The best respi- In spite of progress in respiratory assistance
ratory strategy to support ELBW infants is still due to new treatment options available and tech-
debated (Wiswell 2011). nological developments, respiratory distress syn-
The use of continuous positive airway pressure drome (RDS) remains a significant problem for
(CPAP) in spontaneously breathing infants seems ELBW infants, being associated with a high num-
to reduce the need of mechanical ventilation ber of complications, particularly BPD (Stoll et al.
(Nowadzky et al. 2009); however, only marginal 2015).
benefits have been shown in reducing the com- The lung of preterm infants is biochemically
bined outcome of death or bronchopulmonary immature and highly vulnerable to injury. For this
dysplasia (BPD) compared to intubation and reason the optimal respiratory approach should
endotracheal ventilation (Schmölzer et al. 2013). aim to gently open and ventilate the lung, pre-
Accurate monitoring of heart rate and oxygen venting the damage due to barotrauma or atelec-
saturation as soon after birth as practicable is tasis (Dargaville and Tingay 2012).
recommended (Wyllie et al. 2015). Different lung protective ventilation strategies
Delayed umbilical cord clamping has received have been suggested to minimize lung injury,
increasing attention in the management of ELBW including patient triggered or synchronized venti-
infants at birth as it seems to be beneficial and lation, volume targeted ventilation (VTV),
safe, being associated with improved hemody- INSURE strategy (INtubation, SURfactant
namic stability, reduced need for red blood cell Extubation to NCPAP), high frequency ventila-
transfusion, and decreased rates of intraventricu- tion (HFV) (including both high frequency oscil-
lar hemorrhage (Oh et al. 2011). latory ventilation (HFOV) and high frequency jet
206 F. A. Mosca et al.
ventilation (HFJV)), and permissive hypercapnia long-term outcomes, although it correlates with
(PH) (Reiterer et al. 2016). neurodevelopment (Ho et al. 2015).
Also a high number of noninvasive respiratory After birth, water and electrolytes should be
support options are now available both as primary supplied to ELBW infants to avoid dehydration
treatment in infants with an adequate spontaneous and hypertonicity. There should be close monitor-
breathing drive or for post-extubation (DeMauro ing of body weight (every 12–24 h), urine output
et al. 2014). and osmolarity (every 12–24 h), and plasma elec-
The optimal timing for surfactant administra- trolytes (mainly sodium and potassium). ELBW
tion remains debated. A policy of early rescue infants show limited nutritional reserves and
surfactant should be standard in infants with immaturity of nutrient absorption in the face of
RDS; however, there might be cases in which high nutritional demands. For this reason, many
surfactant should be administered in delivery ELBW infants experience postnatal growth retar-
room such as in infants requiring urgent intuba- dation in spite of total PN and early enteral feed-
tion for stabilization (Stevens et al. 2007). ing. The main objectives of nutritional support are
INSURE might be considered in infants who to maintain body stores and to assure adequate
fail NCPAP. Minimally invasive surfactant can be postnatal growth, avoiding metabolic complica-
considered as an alternative to INSURE in unit tions and side effects. ELBW infants should
with appropriate expertise (Dargaville et al. 2013; receive glucose and amino acid infusion soon
Kribs et al. 2015). after birth to maintain normoglycemia and ade-
The most frequent cardiovascular problem in quate protein levels. Within the second day of life,
ELBW infants is represented by patent ductus lipids and electrolytes may be administered. Total
arteriosus (PDA). PDA has been related to pul- PN should be associated with early enteral feeding
monary function impairment, prolonged ventila- to limit complications associated with PN, mainly
tor dependency, and development of BPD. cholestasis and sepsis. Metabolic acidosis may
However, definition (clinical and/or echocardio- become a problem with the progression of PN
graphic) of hemodynamically significant PDA, and its correction is still debated.
and timing and type of treatment are still debated Structural and functional immaturity of the gas-
(Hamrick and Hansmann 2010). trointestinal tract may limit early enteral feeding.
ELBW infants present a high risk to develop Minimal enteral feeding (trophic feeding at
brain lesions and later neurodevelopmental disor- 10–20 mL/kg/day) should be started as soon as
ders. Imaging the preterm brain of ELBW infants is possible after achieving clinical stability to stimu-
part of clinical routine practice and sequential cra- late normal functional development of the gastro-
nial ultrasound (cUS) scans from birth up to term intestinal tract. Its progression will be determined
corrected age (TCA) should be performed to detect by feeding tolerance, which is normally reduced in
the typical lesions occurring in preterm infants ELBW infants. Feeding strategies depend on the
(germinal matrix-intraventricular hemorrhage, cys- experience of caregivers and should be aimed at the
tic periventricular leukomalacia) which correlate establishment of enteral feeding, avoiding feeding
with adverse motor prognosis (de Vries et al. 2013). intolerance and necrotizing enterocolitis. Enteral
Magnetic resonance imaging (MRI) has been volume is increased gradually with close monitor-
demonstrated to be superior to cUS in identifying ing for abdominal distension, vomiting, or
minor brain abnormalities occurring in the white increased volume of gastric aspirates, especially if
matter and cerebellum, as well as minor degrees of bile-stained or hemorrhagic. When feeding intoler-
germinal matrix-intraventricular hemorrhage ance is diagnosed, enteral feeding should be
undetected by cUS (Plaisier et al. 2015; Roelants- reduced or stopped. Breast milk is preferred to
van Rijn et al. 2001). premature formulae for both trophic and enteral
However, indication to MRI at TEA in ELBW feeding, but when it is insufficient to achieve nor-
infants should be discussed with parents as there is mal postnatal growth, milk fortifiers should be
no evidence that brain MRI at TCA ameliorates added. Multicomponent fortification of human
12 Care of Extremely Low-Birth-Weight Infants and Timing of. . . 207
milk is associated with short-term improvements in needed before recommending their use in clinical
weight gain, linear and head growth, but without practice (Santos and Tristram 2015).
evidence of long-term benefit (Dutta et al. 2015;
Koletzko et al. 2014).
Infection is a major cause of mortality and 12.2.3 Long-Term Morbidities
morbidity for ELBW infants. The incidence of
early-onset sepsis (EOS) (<72 h) is less than 5% ELBW infants are at high risk for neurodeve-
with a mortality up to 50%, mainly for ELBW lopmental impairment associated with acquired
infants born after premature rupture of mem- severe brain lesions. However, minor cognitive,
branes and/or chorioamnionitis. Prenatal treat- behavioral, and academic developmental disor-
ment of chorioamnionitis and prevention of ders have been observed also in children without
group B streptococcal infection has changed the overt brain injury at conventional neuroimaging
distribution of pathogens of EOS with an increas- performed during the neonatal period. Preterm
ing rate of gram-negative bacterial sepsis (Stoll et infants, during their stay in the NICU, also face a
al. 2011). period of stressful environment (exposure to pain,
Taking a careful prenatal history, timely diag- light and sounds, forced maternal separation),
nosis (based on clinical signs, microbiological and which may negatively impact early brain devel-
biochemical tests) and therapy (empirical use of opment and subsequent neurobehavioral out-
antibiotics) are important for the prevention and comes. In this context, early intervention
treatment of EOS and its complications. programs based on the concept of “individualized
Late-onset sepsis (LOS) affects 20–50% of care” have proved to be effective in promoting
ELBW infants and the mortality rate varies from brain maturation and neurodevelopmental out-
20% to 80%, depending on the causal pathogen come (Spittle et al. 2015).
(Stoll et al. 2010). A neurodevelopmental follow-up has to be
The main risk factors for LOS are the use of established in order to early identify those babies
central lines, mechanical ventilation, and par- who may benefit from long-term intervention
enteral nutrition. The clinical diagnosis of LOS programs.
is more difficult in ELBW infants because of ELBW infants may also develop neurosensorial
nonspecific clinical features and a lack of sen- deficits: hearing impairment is associated with ill-
sitive diagnostic tests. Thus, many of these ness and with the use of ototoxic drugs and a
infants receive several courses of antibiotics hearing screening program is mandatory in these
and antifungals during their hospital stay. Care- babies. Retinopathy of prematurity (ROP) is a
ful monitoring of a neonatal unit can help guide common morbidity in preterm infants and it is
empirical antibiotic therapy and limit antibiotic more severe in ELBW infants, potentially leading
resistance. to blindness (Wallin and Eriksson 2009).
Strategies to prevent late-onset infections Although recent insights into pathogenesis and
include hygiene measures, cautious use of prevention, BPD continues to be one of the most
indwelling devices, early human milk administra- common complications affecting ELBW infants.
tion, the use of central line bundles, and antibiotic
stewardship. Fluconazole prophylaxis may be
indicated in ELBW infants hospitalized in 12.3 Timing of Discharge and
NICUs with a high incidence of fungal infections. Problems of Home Care in
There is some medical evidence supporting the ELBW Infants
use of probiotics and prebiotics in the prevention
of LOS in preterm infants, without adverse ELBW infants are considered high-risk infants
effects. However, clarifications regarding type of who are often discharged with unresolved medical
probiotic/prebiotic, dosing regimens for different problems requiring special care, respiratory and/
weight classes, and long-term outcomes are still or nutritional support after discharge.
208 F. A. Mosca et al.
At the time of discharge from NICU, parents of consistent with the schedule recommended for
preterm infants often question their ability to care full-term infants (Saari and Committee on Infec-
after babies without the support of NICU staff. An tious Diseases 2003).
individualized home-care plan and a close follow- During the respiratory syncytial virus (RSV)
up have to be developed for these babies before season palivizumab should be given before dis-
discharge from NICU and programs that provide charge to high-risk neonates according to the
continuity of care at home need to be national recommendations (American Academy
implemented, making the transition from hospital of Pediatrics Subcommittee on Diagnosis and
to home life safely. Management of Bronchiolitis 2006).
12.3.1.3 Neonatal Screening Programs
12.3.1 Timing of Home Discharge
Newborn metabolic screening should be com-
pleted and reviewed before discharge.
According to the guidelines of the American
Research data have shown that infants in the
Academy of Pediatrics (Committee on Fetus and
NICU are at highest risk of having neural hearing
Newborn 2008) timing of home discharge should
loss. Therefore, a hearing test should be
be based on physiologic criteria rather than body
performed before discharge in high-risk babies
weight.
and a long-term careful monitoring for hearing
Physiologic stability and the acquisition of the
loss, with subsequent appropriate audiological
following competencies are considered essential
management, is essential after discharge.
to allow home discharge: (1) respiratory control;
(2) thermal stability in home environment; (3)
competent oral feeding (by breast or bottle) for 12.3.1.4 Parental Education
an appropriate growth. An active program of parental involvement in the
infant’s care should be established by caregivers
12.3.1.1 Respiratory Control as soon as possible during the hospital stay in
Significant apneas of prematurity can persist up to order to teach parents to handle the baby and let
43 weeks’ postmenstrual age (PMA). After stop- them acquire skills and competence needed to
ping methylxanthines administration, babies who take care of their infant at home.
have experienced problematic apneas should have Breast milk should be strongly promoted as
an event-free period of 5–7 days before discharge. the optimal diet also for ELBW infants and
It is known that the prone position improves oxy- soon after birth mothers should be encouraged
genation, while the nonprone position decreases to provide milk for their own infants. After
the incidence of sudden infant death syndrome discharge, mothers should be supported to
(SIDS) (Task Force on Sudden Infant Death Syn- continue breastfeeding or to give their own
drome 2005; Blair et al. 2006). The association expressed milk; considerable psychological
between prone sleeping and SIDS among ELBW benefits of breastfeeding have been also
infants is equal to or even stronger than the associ- described.
ation among those born at term. Therefore, prior to Before discharge a planned follow-up program
discharge, babies should spend a period of weeks should be offered to the parents by an identified
in the supine position monitoring the occurrence of primary care physician who will take the respon-
desaturation events and mothers should be strongly sibility of the baby’s care after discharge. Individ-
advised by caregivers during hospitalization to ualized discharge and follow-up plans are
maintain supine sleeping position once at home. important to assure safe and effective care at
home and to minimize avoidable hospital
12.3.1.2 Immunization readmissions. In order to help parents to cope
Preterm infants should receive routine with the baby’s needs at home additional support
recommended vaccines at a chronological age may be provided by home nursing care.
12 Care of Extremely Low-Birth-Weight Infants and Timing of. . . 209
12.3.2 Special Care Needs 12.3.2.2 Nutritional Support
Competent breast or bottle feeding supporting
12.3.2.1 Ventilatory Suppor appropriate growth is advocated before discharge.
Approximately 30% of surviving ELBW infants Nevertheless, the use of a feeding tube at home may
(Jensen et al. 2015) still need oxygen therapy be considered when feeding is the last issue pre-
beyond 36 weeks of postmenstrual age. Babies cluding home discharge. A safe home management
with BPD may require long-term oxygen supple- of feeding tube can be assessed for a limited time
mentation or respiratory support to maintain oxy- period by well-trained parents; when the baby does
gen saturation at an acceptable level (suggested not improve in oral feeding skills, a gastrostomy
range 93–95%) (Trzaski et al. 2012; Thoracic should be performed to guarantee safe and effective
Society of Australia and New Zealand et al. gastric nutrition. During gastrostomy feeding oral
2008). nutrition must be stimulated as removal of naso/
In order to shorten hospital stay, home respira- orogastric tube reduces discomfort during suction
tory support should be considered for these and may improve oral feeding skills (Mills and
babies. Humidified high flow nasal cannulae Davies 2012; Abrams and American Academy of
(HHFNC) have been suggested as post-discharge Pediatrics, Committee on Nutrition 2013).
ventilatory support although evidence of benefits Infants with short bowel syndrome due to pre-
compared to low-flow oxygen supplementation is or postnatal damage of the gut require total PN
still missing. when there is insufficient bowel length of sufficient
Some infants may require oxygen supplemen- quality for enteral independncy, which, in turns,
tation for months or even years and discontinua- further depends also on the site of gut resected
tion should be considered when infants and the presence or absence of the ileocaecal
consistently maintain target saturation in room valve. If total PN is likely to be needed long-term,
air; however, weaning from supplemental oxygen home administration has to be planned to give these
should be gradual to avoid worsening of pulmo- children a better quality of life. Home total PN
nary hypertension. requires medical devices and intense home nursing
For infants who cannot be weaned from assisted for surveillance of central venous catheter related
ventilation home ventilation may be necessary. In problems until parents achieve competency and
this case a tracheostomy has to be performed before independency (Batra et al. 2013).
discharge and a special education for parents and
qualified home care are needed. Respiratory sup-
12.3.3 Rehospitalization
port may range from CPAP, to fully ventilator-
supported breathing. Both short and long term
ELBW infants have a high rate of readmission in
respiratory support requirements vary depending
the first years of life (almost 50%), mainly due to
on the underlying disease and indication for
respiratory illness, with the highest incidence in
tracheostomy.
babies <25 weeks’ gestation, with BPD, living
High-risk newborns may require pulse
with other children, first discharged during the
oxymetry or apnea monitoring after discharge.
RSV season or belonging to socially disadvan-
Although criteria to home apnea monitoring
taged groups. The identification of associated
vary widely among NICUs, recommendations
risk factors can be useful to define high-risk
for home monitoring include babies presenting
groups of babies at discharge needing close fol-
mild episodes of apnea not requiring stimula-
low-up and surveillance (Morris et al. 2005).
tion, having a feeding tube in situ, and requir-
ing oxygen supplementation or ventilatory
assistance. 12.3.4 Safe Transportation
The use of home monitoring is not indicated to
prematurely discharge babies who do not demon- When positioned in a safety car seat premature
strate maturity of respiratory control. babies and ELBW infants have an increased
210 F. A. Mosca et al.
risk of airway obstruction (Bull and Engle increased sense of solitude, the investments that
2009). changed because of the baby and the social pres-
The potential risk of respiratory compromise is sures connected with the parental task. Besides the
strictly related to anthropometric parameters happiness and the satisfaction that every birth
(weight and length) and neurologic maturity as necessarily gives to the parents, it is frequent to
well as to the associated medical conditions, espe- find also the inconvenience, mostly by mothers,
cially BPD. A car seat evaluation should be characterized by depression, anxiety, insecurity,
performed before discharge in newborns at risk fragility, and possibly by more serious psychopa-
for obstructive apnea, including babies with hypo- thologies (Song et al. 2015).
tonia (related to genetic or neuromuscular disor- It has emerged in recent years the importance
ders), micrognathia or previous cardiac surgery. of the support of the emotional and sentimental
Parental education about the proper infant’s posi- sphere connected to the birth and it is essential to
tion in the car seat is necessary to minimize the start psychological services in the obstetric wards,
risk of respiratory impairment. A car bed may be in nurseries, and in all those “risky” contexts such
indicated for infants who present apnea or as Neonatal Intensive Care Units (NICU, see
decrease in oxygen saturation when positioned below) especially (Lassi et al. 2014). Specific
semi-reclined, unless evidence is not clear. guidelines to support the parents in these critical
areas were created, in order to limit the traumatic
effects connected to prematurity and pathologic
12.4 Information and Psychosocial births. NICU wards are working on the contact
Intervention and on the involvement of parents, so that the
bonding is not totally compromised by long sep-
The welcoming and assistance services of birth aration, prolonged medicalization, and parental
have evolved in the last decades. In western coun- experiences (Shaw et al. 2013a). Latest scientific
tries, birth at hospital went from a medical-sanitary studies in various areas, such as neurology, psy-
assistance, aimed to guarantee the best security in chology, and pedagogy, show more importance to
hospital with more and more advanced and metic- the perinatal phase and to the first year of life. In
ulous procedures and protocols, to a more human- the neuroscience field, it was clearly demonstrated
itarian vision of the birth issue (National Health that the first child’s relational experiences, joined
Service, UK 2007). This evolution is witnessed by with the potential deriving from the genetic inher-
the spread of a different cultural approach to mater- itance, are crucial to the architecture of the human
nity, characterized by supportive methodologies brain and to his development (Newman et al.
for parents, methodologies that are adopted by 2015). In the psychological field, researches and
obstetricians, neonatologists, and pediatricians theories on attachment highlighted how the qual-
(World Health Organization 2011). ity of the welcoming of birth and of the relation-
In order to support mother and neonate, it is ship between the baby and her/his parents are
relevant to guarantee an intimate and prolonged crucial for growth, deeply influencing the senti-
contact to the couple since the very first moments mental and emotional life, the construction of the
of life in the delivery room, during hospital stay, sense of identity, and the development of the
and until discharge. Considering the birth as a interactive capacities and of the cognitive compe-
multidimensional event attention moved to the tences (Bowlby 1969).
perinatal period, which goes from pregnancy to Many authors’ studies (Stern and Bruschweiler-
the first months of life of the baby (Chalmers et al. Stern 1998; Winnicott 1987) on motherhood,
2001). It is important to stress the difficulties of instead of maternity, underlined that the assump-
the couples to cope with the changes imposed by tion of the parental identity does not coincide with
the taking of the parental role: from the economic, the birth of the baby, but requires a long time to
working, organizational problems to the psycho- mature and for the woman it represents a moment
logical issues related to the living conditions, the of evolutional “crisis,” characterized by a deep
12 Care of Extremely Low-Birth-Weight Infants and Timing of. . . 211
reorganization of her own psychic and emotional context, and culture of belonging (World Health
set. Lastly, researches in the socioeconomic field Organization 2013). Moreover, considering the
are significant as well: they showed how the pre- great sociocultural mutations in families, in
ventive interventions during the early first infancy which the father’s role in western countries is
are cheaper than the following treatment interven- becoming more important in child care, services
tions in social, educational, and therapeutic areas. to parents have changed in a new triadic perspec-
Because of that, investing in quality services ori- tive, welcoming not only the mothers’ emotions
ented to early infancy enables societies to save a lot but also the male need to find models of father-
of money in the long term (Weissbourd 1991). hood, as the old ones are no longer suitable
This perspective led to increased interest in the (Fivaz-Depeursinge and Corboz-Warnery 1999).
safeguard of birth as “common good” and brought New supportive methodologies to parenthood
about a new awareness in operators, of their own leave the old model (grounded on prescription
role and responsibility in sustaining such an and teaching the parents their duties) behind:
important and delicate process. In fact, there is they include father figures more and the keyword
plenty of evidence that the environment surround- is empowerment, a concept which has become
ing every woman – from the earliest moments of widespread in service terminology, referring to
labor and delivery – influences and eases the the task of helping parents to reinforce them-
development of parenthood and bonding. Recog- selves. This type of intervention is founded on
nizing women’s need to engage with supportive the idea that the transition to parenthood, the
and welcoming figures determined a change in passage from maternity to motherhood is a pro-
considering assistance: assistance is care, taking cess of personal maturation which cannot be
care of the woman who “learns to take care of her taught nor prescribed: it can only be facilitated
own neonate.” The newborn needs this kind of and protected from negative interferences. After
approach to face his entry into this world; the hospital discharge, starting from the awareness of
mother needs it too, in order to guarantee it. nowadays families’ needs, a new kind of services
Therefore, prevention measures should be used is created among parents to offer support to each
to make attachment and bonding possible: the other. This opportunity promotes and facilitates
respect and promotion of physiology of birth, the exchange between peers, the sharing of expe-
letting him come to the world instead of making riences and common problems, the exchange of
him come to the world, fostering an early and practical solutions drawn from direct experience.
prolonged contact with the baby, through the In fact the absence of any kind of judgment allows
“skin to skin” technique since from the delivery to normalize one’s own feelings, to give a mean-
room and through the rooming in, which is essen- ing to one’s own behavior, so that everyone can
tial for the beginning of breastfeeding and bond- enrich his own inner world with others’ experi-
ing, providing parenthood with a support even ences. This method has turned out to significantly
after discharge. This kind of interventions cannot improve parents’ self-esteem, autonomy, exper-
ignore the uniqueness of every single family unit, tise, and their perception to be active main char-
thinking of a one-to-one assistance and creating acters of their own lives.
individualized programs aimed at promoting the Offering home care to the new mother right
mother’s ability to take care of her own and her after delivery is another particularly recom-
child’s health, depending on their specific needs. mended supportive protocol to parenthood
In contrast to the rigid standardized procedures of (Ammerman et al. 2012; Sweet and Appelbaum
traditional assistance to birth, it is extremely 2004); over the last years, it has been experienced
important to have flexibility and to offer a person- by family consultants and local institutions in this
alized response to every woman’s, every child’s, field. A common element among new mothers is
every family’s specific needs, which may be dif- the acknowledge of difficulties faced during the
ferent from each others because of their own per- postpartum, when physical and psychological
sonal stories, individual characteristics, social tasks turn out to be arduous (such as regaining
212 F. A. Mosca et al.
energy after delivery, reprocessing the experience, supportive interventions in depression during
readjusting the body, beginning of breastfeeding, pregnancy and after childbirth, based on interna-
getting to know the baby, finding a new poise for tional guidelines which classify their symptoms
the couple, reorganizing family life and its and give recommendations for both prevention
rhythms) because of the lacking of that function and pharmacological-psychotherapic treatment.
of protection, support, and help, once offered by In recent years the development of preventive
the family and neighborhood. and supportive intervention models for maternity,
Home care support has proved to be particu- implemented especially in situations of increasing
larly effective in critical situations such as prob- fragility and great “risk,” has shown a significant
lematic families, in which a baby’s arrival was not effect in terms of preventing severe psychological
consciously chosen, in which either there is a issues and to protect and promote infant’s growth.
social and psychological awkwardness (drug
addicted parents, parents with psychiatric dis-
eases, with personal stories of deprivation, single, 12.4.1 Preterm Birth and Family Care
underage, migrants, etc.) or a pathological birth
occurred. For these mothers, for these parents, the Even hospitalization of the premature infant in
perspective of raising a child in such conditions NICU is considered as a “psychological crisis”
turns out to be strenuous and it can result in high in the family, causing feelings of powerlessness
psychopathological risks, affecting the formation and stress, especially for mothers (Woodward et
of the bonding and child’s growth, as a plentiful al. 2014; Shaw et al. 2013b). Survival rates for
scientific literature shows. Home-care is thought small preterm infants have improved, especially
in a wider project on the single family unit and it those of very low birth weight infants (VLBW).
often combines with other sorts of intervention, Although the birth of an infant with VLBW poses
which may be social, clinical, educational, in the a considerable challenge to parents, there is little
knowledge that the needs of those families who information about how it affects family stress. For
have multidimensional problems cannot be faced an event like preterm birth, different sources of
with unidimensional action. Besides these home parental stress have been identified. One of the
care services, clinical intervents with individual most important is early separation of the mother
psychotherapies are synergically developing, with and infant, which may adversely affect attachment
various goals, depending on the level of critical between the mother-child dyad. Consequently,
issues. One of the main focuses concerns consul- feelings of anxiety and depression are frequent
tations and psychological treatments offered to in mothers of preterm infants and appear to be
parents in the baby’s first years, to either over- more intense during the hospitalization of the
come difficult times or improve their well-being. child in the neonatal intensive care unit. Maternal
These are the so-called parent trainings, strategies depression has been associated with impairment
of intervention on parenthood with a therapeutic of child cognitive, emotional, and behavioral
approach, though different from a real psycho- development. Early maternal depression or other
therapy, as they are shorter (8–10 appointments); psychological symptoms may have varying
they are aimed at strengthening and enriching effects on preterm infants. The relationship of
parents’ abilities, at raising a different manner of maternal mental health on parenting behavior is
“viewing things,” at making them gain more important for preterm populations because mater-
awareness of their roles and learning new ways nal psychological status and other social factors
of engaging with their own children (Lundahl (e.g., socioeconomic status, maternal substance
et al. 2006). A second group of interventions abuse, multiple birth, or other life stressors) have
concerns clinical treatment of parent-child rela- been found to correlate with childhood emotional
tionship at the earliest stages, since a maternal and mental well-being in children of school
figure is utterly fundamental for the baby’s mental age, who were of low birth weight or preterm.
health. A third group consists of preventive and Signs of parental distress can emerge during
12 Care of Extremely Low-Birth-Weight Infants and Timing of. . . 213
hospitalization, which is why staff should adopt a Several models have explored how parents cope
holistic approach to understanding the uniqueness with having their baby in the neonatal unit. Vari-
of each family and provide appropriate support. ous mechanisms are seen, however, and a single is
If a problem is diagnosed during pregnancy, not appropriate for all parents. Some coping strat-
parents should be forewarned. If this does not egies include trying to gain a deeper understand-
occur, most women and their partners will not ing of the problems, establishing a degree of
give serious consideration to the possibility of control over the situation, seeking social support
preterm delivery or illness in their newborn baby from other people, and escaping from or minimiz-
and admission to a neonatal unit. Parents are unfa- ing the apparent severity of the situation. These
miliar with the potentially complex problems their mechanisms are used to varying degrees by indi-
infant faces and there is uncertainty about the vidual parents. There is a systematic difference
future. A lack of understanding and uncertainty between mothers and fathers. Mothers tend to
are major sources of stress. In addition, maternal look for support from others and to search for an
health is often compromised at this time. Mother explanation for what has happened, whereas
and baby are separated when the infant is admitted fathers are more likely to try to minimize the
to the neonatal unit, and this may last many situation, often by concentrating on supporting
months. Although in some hospitals a visit to the their partner.
neonatal unit is a routine part of antenatal care, the A better understanding of the sources of stress
neonatal unit is generally an alien environment for and how parents try to cope allows appropriate
most parents. Units are often noisy, bright, and interventions for the family. A complex network
hot. They can be overcrowded and parts will be of structural, practical, social, and psychological
“high tech.” Parents rarely know the neonatal unit interventions can promote acceptance by mothers
staff before their baby is admitted, and the lan- and fathers of this challenging event (Morey and
guage and behaviors they encounter can contrib- Gregory 2012; Kraljevic and Warnock 2013).
ute to an overwhelming feeling of isolation. The When designing neonatal units, great emphasis
sickest preterm infants may be in hospital for is placed on effective layout, lighting, and noise
many months, and visiting can be difficult, (Brumberg and Shah 2015) reduction. Facilities
exhausting, and a financial drain for parents, espe- for families to stay close to their baby are usually
cially as neonatal services become more central- provided, and rooms for parents allow mothers
ized. All these factors put strain on the parents’ and fathers to relax and meet other parents. Play
relationship: a relationship is more likely to break- areas for siblings have been incorporated into
down during the months after preterm delivery. some units. This more “family-orientated”
Some couples, however, feel the experience approach to care is helped by less restrictive vis-
makes their relationship closer, at least initially. iting policies in neonatal units (Welch et al. 2016;
Generally, stress and anxiety are higher in mothers Cano Giménez and Sánchez-Luna 2015); most
than in fathers, and lessen with the passage of time. units allow parents and siblings open access if
For some parents, the stress experienced is similar they comply with local infection control mea-
to that seen in adults diagnosed with post-traumatic sures. Thus a more sensitive approach could affect
stress disorder. High levels of stress may last faster bonding between mother and sick newborn
beyond the first year of their infant’s life, and the (i.e., 24/24 open access to NICU, kangaroo
level and duration of stress may not be directly mother-care, promotion of maternal/human milk).
related to how preterm or how sick their baby Prenatal counseling is an aspect on which
was. In addition to high levels of stress and anxiety, many units are currently engaged, especially if a
these parents are more prone to clinical depression, prenatal diagnosis has been made. Members of the
which may be difficult to recognize. neonatal team meet with parents before the birth
Responses and feelings similar to those of a to discuss a likely admission and the approach that
classic grief reaction can be encountered: shock, will be taken for the infant’s problems. Parents are
denial, anger, guilt, acceptance, and adjustment. encouraged to visit the unit before their baby is
214 F. A. Mosca et al.
born to familiarize themselves with the environ- with senior staff during the weeks after the death,
ment and the staff. After delivery, it is good prac- and contact with a bereavement support worker or
tice to discuss medical and nursing issues in detail group may all help the process. Most families
with parents to inform and, when possible, to begin to come to terms with the death during the
involve them in decision making from an early first year – not forgetting the child but adjusting to
stage. Parents should be informed as soon as pos- life without him or her. Bereaved parents often
sible about investigation results and any change in need factual information that may help explain
clinical condition. After overcoming their first why their baby has died. Without autopsy, impor-
moments of confusion and fear, parents can also tant information can be missed, and in many neo-
help with the care of their preterm baby. This may natal units, postmortem examination is always
extend beyond simple but important measures, considered and offered to the parents if appropri-
including “skin-to-skin” contact (Mörelius et al. ate. High pro- file cases where there have been
2015), providing skilled care such as tube feeding, procedural inadequacies and anxieties about
toileting practices, and joining intensive “devel- organ retention have contributed to a decrease in
opmental care” programs. Parents of other pre- the number of autopsies carried out. Additionally,
term babies can give support through “buddy” there has been a natural reluctance by parents to
programs or informally. Counseling through authorize further “suffering” for their infant and a
external organizations or formal support can be lack of awareness of the questions that remain
helpful even for families whose babies are not unanswered.
critically ill. This can involve various profes- Discharge home, although an exciting time for
sionals, such as psychologists, social services, families, can also be a time of extreme anxiety,
religious advisers, and ethics committees. Written and so a formal approach to “discharge planning”
information about the neonatal unit, describing is often adopted. Mothers “room in” with their
specific conditions or procedures may be useful. baby to promote bonding, establish feeding, and
Routine contact between the neonatal unit and learn practical skills that might be needed. Sup-
social services may allow financial support to be port for the family in the community once the
provided for the parents. infant is discharged can also be arranged, includ-
Despite intensive treatment and full medical ing specialist neonatal nurses, primary care health
support, patients in a neonatal unit may die. staff (e.g., health visitors, general practitioners),
Although there are substantial differences social workers, and national or local family sup-
between countries and cultures, a decision to port groups. Although managing the immediate
limit active treatment may be considered because stress of discharge home is important, it should be
of the inevitability of death or a prognosis that recognized that although practical issues may
indicates a very poor quality of life. Death, how- become easier with the passage of time, for some
ever it comes about, is a desperate time for families considerable levels of stress and anxiety
affected families. In some cases, parents want to remain long after the discharge itself. Psycholog-
be involved in decision making at these times. ical support should be an integral part of neonatal
They need full and frank information, given in a follow-up programs.
compassionate manner by experienced staff who Parents and families of babies who are admit-
know the family and their baby. In most cases, the ted to a neonatal unit are exposed to a variety
decision to stop or limit treatment is made with of stressors and may face extremely difficult
senior medical and nursing staff. Family, friends, decisions in unique and unfamiliar situations.
and external bodies (such as religious leaders and Many studies suggest that current VLBW follow-
support groups) do not often have a substantial up programs might benefit from the addition of
role in the decision to withdraw treatment but psychological and family services to traditional
contribute to family support afterwards. Mothers neurodevelopmental assessment programs, partic-
and fathers may differ in the way they grieve and ularly during the neonatal period and up to infant
cope with their loss. Mementoes, formal contact age of 2 years. Ten percent of mothers of infants
12 Care of Extremely Low-Birth-Weight Infants and Timing of. . . 215
with VLBW reported severe symptoms of psycho- Committee on Fetus and Newborn (2008) Hospital discharge
logical distress during the neonatal period, five of the high-risk neonate. Pediatrics 122:1119–1126
Dargaville PA, Tingay DG (2012) Lung protective venti-
times the rate for term mothers, while almost one lation in extremely preterm infants. J Paediatr Child
third of mothers of infants with VLBW had clini- Health 48(9):740–746
cally significant levels of depression and anxiety. Dargaville PA, Aiyappan A, de Paoli AG, Kuschel CA,
For mothers of high-risk infants with VLBW, sig- Kamlin CO, Carlin JB, Davis PG (2013) Minimally
invasive surfactant therapy in preterm infants on con-
nificant symptoms recurred when the child was tinuous positive airway pressure. Arch Dis Child Fetal
2 years old. The neonatal period affords an oppor- Neonatal Ed 98:F122–F126
tunity to identify mothers who are most at risk DeMauro SB, Millar D, Kirpalani H (2014) Noninvasive
using standardized, simple screening techniques. respiratory support for neonates. Curr Opin Pediatr 26
(2):157–162
Such identification and referral for treatment may Dutta S, Singh B, Chessell L, Wilson J, Janes M,
prevent the development of more severe symp- McDonald K, Shahid S, Gardner VA, Hjartarson A,
toms, which can interfere with effective parenting Purcha M, Watson J, de Boer C, Gaal B, Fusch C
while the provision of social support may also (2015) Guidelines for feeding very low birth weight
infants. Forum Nutr 7(1):423–442
effectively buffer distress. By targeting this support Edwards WH, Conner JM, Soll RF (2004) The Effect of
appropriately, staff on neonatal units can provide a Prophylactic Ointment Therapy on Nosocomial Sepsis
more complete package of care. Rates and Skin Integrity in Infants With Birth Weights
of 501 to 1000 g. Pediatrics 113(5):1195–1203
Fivaz-Depeursinge E, Corboz-Warnery A (1999) The pri-
mary triangle: a developmental systems view of
mothers, fathers, and infants. Basic Books, New York
References Hamrick SEG, Hansmann G (2010) Patent ductus arteriosus
of the preterm infant. Pediatrics 125:1020–1030
Abrams SA, American Academy of Pediatrics, Committee Ho T, Dukhovny D, Zupancic JA, Goldmann DA, Horbar
on Nutrition (2013) Calcium and vitamin D require- JD, Pursley DM (2015) Choosing wisely in newborn
ments of enterally fed preterm infants. Pediatrics 131 medicine: five opportunities to increase value. Pediat-
(5):e1676–e1683 rics 136(2):e482–e489
American Academy of Pediatrics Subcommittee on Diagnosis Hooper SB, Te Pas AB, Kitchen MJ (2016) Respiratory
and Management of Bronchiolitis (2006) Diagnosis and transition in the newborn: a three-phase process. Arch
management of bronchiolitis. Pediatrics 118:1774–1793 Dis Child Fetal Neonatal Ed 101(3):266–271
Ammerman RT, Putnam FW, Chard KM, Stevens J, Van Jensen EA, DeMauro SB, Kornhauser M, Aghai ZH,
Ginkel JB (2012) PTSD in depressed mothers in home Greenspan JS, Dysart KC (2015) Effects of multiple
visitation. Psychol Trauma ventilation courses and duration of mechanical ventila-
Batra A, Beattie RM (2013) Management of short bowel tion on respiratory outcomes in extremely low-birth-
syndrome in infancy. Early Human Development weight infants. JAMA Pediatr 169(11):1011–1017
89:899–904 Koletzko B, Poindexeter B, Uauy R (eds) (2014) Nutri-
Blair PS, Ward Platt M, Smith IJ, Fleming PJ, CESDI tional care of preterm infants: scientific basis and prac-
SUDI Research Group (2006) Sudden infant death tical guidelines. Karger, Basel
syndrome and sleeping position in pre-term and low Kraljevic M, Warnock FF (2013) Early educational and
birth weight infants: an opportunity for targeted inter- behavioral RCT interventions to reduce maternal symp-
vention. Arch Dis Child 91:101–106 toms of psychological trauma following preterm birth:
Bowlby J (1969) Attachment and loss, vol. I, attachment. a systematic review. J Perinat Neonatal Nurs 27
Hogarth Press, London (4):311–327
Brumberg HL, Shah SI (2015) Born early and born poor: Kribs A, Roll C, Göpel W, Wieg C, Groneck P, Laux R, Teig
an eco-bio-developmental model for poverty and pre- N, Hoehn T, Böhm W, Welzing L, Vochem M, Hoppenz
termbirth. J Neonatal Perinatal Med 8(3):179–187 M, Bührer C, Mehler K, Stützer H, Franklin J, Stöhr A,
Bull MJ, Engle WA (2009) Safe transportation of preterm Herting E, Roth B, NINSAPP Trial Investigators (2015)
and low birth weight infants at hospital discharge. NonintubateLung-protective ventilatorytional therapy in
Pediatrics 123:1424–1429 extremely preterm infants: a randomized clinical trial.
Cano Giménez E, Sánchez-Luna M (2015) Providing par- JAMA Pediatr 169:723–730
ents with individualised support in a neonatal intensive Laptook AR, Salhab W, Bhaskar B, Neonatal Research
care unit reduced stress, anxiety and depression. Acta Network (2009) Admission temperature of low birth
Paediatr 104(7):e300–e305 weight infants: predictors and associated morbidities.
Chalmers B, Mangiaterra V, Porter R (2001) WHO princi- Pediatrics 119:e643–e649
ples of perinatal care: the essential antenatal, perinatal, Lassi ZS, Salam RA, Das JK, Bhutta ZA (2014) Essential
and postpartum care course. Birth 28:202–207 interventions for maternal, newborn and child health:
216 F. A. Mosca et al.
background and methodology. Reprod Health 11(Suppl Santos RP, Tristram D (2015) A practical guide to the
1):S1 diagnosis, treatment, and prevention of neonatal infec-
Lundahl BW, Risser HJ, Lovejoy MC (2006) A meta- tions. Pediatr Clin N Am 62:491–508
analysis of parent training: moderators and follow-up Schmölzer GM, Kumar M, Pichler G, Aziz K, O’Reilly M,
effects. Clin Psychol Rev 26:86–104 Cheung PY (2013) Non-invasive versus invasive respi-
McCarthy M (2015) Outcomes in extremely preterm US ratory support in preterm infants at birth: systematic
infants improve, study finds. BMJ 351:h4851 review and meta-analysis. BMJ 347:f5980
Mills RJ, Davies MW (2012) Enteral iron supplementation Shaw RJ, Sweester CJ, St John N, Lilo E, Corcoran JB, Jo
in preterm and low birth weight infants. Cochrane B, Howell SH, Benitz WE, Feinstein N, Melnyk B,
Database Syst Rev 3:CD005095 Horwitz SM (2013a) Prevention of postpartum trau-
Mörelius E, Örtenstrand A, Theodorsson E, Frostell A matic stress in mothers with preterm infants: manual
(2015) A randomised trial of continuous skin-to-skin development and evaluation. Issues Ment Health Nurs
contact after preterm birth and the effects on salivary 34(8):578–586
cortisol, parental stress, depression, and breastfeeding. Shaw RJ, St John N, Lilo EA, Jo B, Benitz W, Stevenson
Early Hum Dev 91(1):63–70 DK, Horwitz SM (2013b) Prevention of traumatic
Morey JA, Gregory K (2012) Nurse-led education mit- stress in mothers with preterm infants: a randomized
igates maternal stress and enhances knowledge in controlled trial. Pediatrics 132(4):e886–e894
the NICU. MCN Am J Matern Child Nurs 37 Song JE, Kim T, Ahn JA (2015) A systematic review of
(3):182–191 psychosocial interventions for women with postpartum
Morris BH, Gard CC, Kennedy K, For the NICHD Neo- stress. Joggn 44(2):183–192
natal Research Network (2005) Rehospitalization of Spittle A, Orton J, Anderson PJ, Boyd R, Doyle LW (2015)
extremely low birth weight (ELBW)infants: are there Early developmental intervention programmes pro-
racial/ethnic disparities? J Perinatol 25:656–663 vided post hospital discharge to prevent motor and
National Health Service, UK (2007) Antenatal and postna- cognitive impairment in preterm infants. Cochrane
tal mental health. Clinical management and service Database Syst Rev (11):CD005495
guidance, Nice Clinical Guideline 45, developed by Stern, DN, Bruschweiler-Stern N (1998) The birth of a
The National Collaborating Centre for Mental Health mother: how the motherhood experience changes you
Newman L, Sivaratnam C, Komiti A (2015) Attachment forever. Basic Books
and early brain development – neuroprotective inter- Stevens TP, Harrington EW, Blennow M, Soll RF (2007)
ventions in infant–caregiver therapy. Transl Dev Psy- Early surfactant administration with brief ventilation vs
chiatry 3:28647 selective surfactant and continued mechanical ventila-
Nowadzky T, Pantoja A, Britton JR (2009) Bubble contin- tion for preterm infants with or at risk for respiratory
uous positive airway pressure, a potentially better prac- distress syndrome. Cochrane Database Syst Rev 4:
tice, reduces the use of mechanical ventilation among CD003063
very low birth weight infants with respiratory distress Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR,
syndrome. Pediatrics 123:1534–1540 Walsh MC, Hale EC, Newman NS, Schibler K, Carlo
Oh W, Fanaroff AA, Carlo WA, Donovan EF, WA, Kennedy KA, Poindexter BB, Finer NN,
McDonald SA, Poole WK, Eunice Kennedy Shriver Ehrenkranz RA, Duara S, Sánchez PJ, O’Shea TM,
National Institute of Child Health and Human Goldberg RN, Van Meurs KP, Faix RG, Phelps DL,
Development Neonatal Research Network (2011) Frantz ID 3rd, Watterberg KL, Saha S, Das A, Higgins
Effects of delayed cord clamping. J Perinatol RD, Eunice Kennedy Shriver National Institute of
31(Suppl 1):S68–S71 Child Health and Human Development Neonatal
Plaisier A, Raets MM, Ecury-Goossen GM, Govaert P, Research Network (2010) Neonatal outcomes of
Feijen-Roon M, Reiss IK, Smit LS, Lequin MH, extremely preterm infants from the NICHD neonatal
Dudink J (2015) Serial cranial ultrasonography or Research network. Pediatrics 126:443–456
early MRI for detecting preterm brain injury? Arch Stoll BJ, Hansen NI, Sánchez PJ, Faix RG, Poindexter BB,
Dis Child Fetal Neonatal Ed 100(4):F293–F300 Van Meurs KP, Bizzarro MJ, Goldberg RN, Frantz ID
Reiterer F, Schwaberger B, Freidl T, Schmölzer G, Pichler 3rd, Hale EC, Shankaran S, Kennedy K, Carlo WA,
G, Urlesberger B (2016) Lung-protective ventilatory Watterberg KL, Bell EF, Walsh MC, Schibler K,
strategies in intubated preterm neonates with RDS. Laptook AR, Shane AL, Schrag SJ, Das A, Higgins
Paediatr Respir Rev S1526–0542(16)30121 RD, Eunice Kennedy Shriver National Institute of
Roelants-van Rijn AM, Groenendaal F, Beek FJ, Eken P, Child Health and Human Development Neonatal
van Haastert IC, de Vries LS (2001) Parenchymal brain Research Network (2011) Early onset neonatal sepsis:
injury in the preterm infant: comparison of cranial the burden of group B streptococcal and E. coli disease
ultrasound, MRI and neurodevelopmental outcome. continues. Pediatrics 127:817–826
Neuropediatrics 32(2):80–89 Stoll BJ, Hansen NI, Bell EF, Walsh MC, Carlo WA,
Saari TN and the Committee on Infectious Diseases (2003) Shankaran S, Laptook AR, Sánchez PJ, Van Meurs KP,
Immunization of preterm and low birth weight infants. Wyckoff M, Das A, Hale EC, Ball MB, Newman NS,
Pediatrics 112:193–198 Schibler K, Poindexter BB, Kennedy KA, Cotten CM,
12 Care of Extremely Low-Birth-Weight Infants and Timing of. . . 217
Watterberg KL, D’Angio CT, DeMauro SB, Truog WE, Weissbourd B (1991) Family resource and support pro-
Devaskar U, Higgins RD, Eunice Kennedy Shriver grams: changes and challenges in human services.
National Institute of Child Health and Human Develop- Prev Hum Serv 69–85
ment Neonatal Research Network (2015) Trends in care Welch MG, Halperin MS, Austin J, Stark RI, Hofer MA,
practices, morbidity, and mortality of extremely preterm Hane AA, Myers MM (2016) Depression and anxiety
neonates, 1993–2012. JAMA 314:1039–1051 symptoms of mothers of preterm infants are decreased
Sweet MA, Appelbaum MI (2004) Is home visiting an at 4 months corrected age with family nurture inter-
effective strategy? A meta-analytic review of home vention in the NICU. Arch Womens Ment Health 19
visiting programs for families with young children. (1):51–61
Child Dev 75(5):1435–1456 Winnicott DW (1987) Babies and their mothers. Free
Task Force on Sudden Infant Death Syndrome (2005) The Association Books/Addison-Wesley, London/Reading
changing concept of sudden infant death syndrome: Wiswell TE (2011) Resuscitation in the delivery room:
diagnostic coding shifts, controversies regarding the lung protection from the first breath. Respir Care 56
sleeping environment, and new variables to consider (9):1360–1367
in reducing risk. Pediatrics 116:1245–1255 Woodward LJ, Bora S, Clark CA, Montgomery-Hönger
Thoracic Society of Australia and New Zealand, Fitzgerald A, Pritchard VE, Spencer C, Austin NC (2014)
DA, Massie RJH, Nixon GM, Jaffe A, Wilson A, Lan- Very preterm birth: maternal experiences of the neo-
dau LI, Twiss J, Smith G, Wainwright C, Harris M natal intensive care environment. J Perinatol 34(7):
(2008) Infants with chronic neonatal lung disease: rec- 555–561
ommendations for the use of home oxygen therapy. World Health Organization (2011) A global review of the
Med J Aust 189(10):578–582 key interventions related to reproductive, maternal,
Trzaski JM, Hagadorn JI, Hussain N, Schwenn J, newborn and child health. WHO-Partnership for Mater-
Wittenzellner C (2012) Predictors of successful discon- nal, Newborn & Child Health, Geneve
tinuation of supplemental oxygen in very low-birth- World Health Organization (2013) WHO recommenda-
weight infants with bronchopulmonary dyplasia tions on postnatal care of the mother and newborn.
approaching neonatal intensive care unit discharge. WHO, Geneve
Am J Perinatol 29(2):79–86 Wyllie J, Perlman JM, Kattwinkel J, Wyckoff MH, Aziz K,
de Vries LS, Benders MJ, Groenendaal F (2013) Imaging Guinsburg R, Kim HS, Liley HG, Mildenhall L, Simon
the premature brain: ultrasound or MRI? Neuroradiol- WM, Szyld E, Tamura M, Velaphi S, Neonatal Resus-
ogy 55(Suppl 2):13–22 citation Chapter Collaborators (2015) Neonatal resus-
Wallin L, Eriksson M (2009) Newborn individual devel- citation: 2015 international consensus on
opment care and assessment program (NIDCAP): cardiopulmonary resuscitation and emergency cardio-
a systematic review of the literature. Worldviews vascular care science with treatment recommendations.
Evid-Based Nurs 6:54–69 Resuscitation 95:e169–e201
The Process of Decision-Making in
Neonatology 13
Endla K. Anday and Michael Spear
Contents
13.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
13.2 The Process of Decision-Making . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
13.3 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
13.4 The Neuroscience of Decision-Making . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
13.5 Steps in Decision-Making . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
13.5.1 Recognize the Moral Dimension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
13.5.2 Recognize the Parties Involved . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
13.5.3 Parental Decision-Making . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
13.5.4 The Physician’s Role . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
13.6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
Abstract challenges to the families and healthcare pro-
Advances in the field of neonatal–perinatal viders. The dilemma surrounding the complex-
medicine over the past 40 years have resulted ity of the decision-making process is based on
in marked improvement in survival and out- a number of factors including the rights of the
come of the prematurely born and critically ill child as an individual, the values of the family
infant. While the overall reduction in mortality and the healthcare personnel, the cultural influ-
and morbidity for infants is favorable, deci- ences, and the moral and ethical standards that
sions regarding the care provided to newborns impact the way physicians practice medicine
at the threshold of viability and those with and their approach to end-of-life decision-
complex medical, surgical, and potentially making. As an adjunct to help facilitate the
lethal congenital anomalies continue to present process of decision-making, the role of neona-
tal palliative care has increased over the last
few years. In fact, the field of pediatric pallia-
E. K. Anday (*) · M. Spear tive care and neonatal palliative care is rela-
Department of Pediatrics, Drexel University College of
Medicine, St. Christopher’s Hospital for Children, tively new and will provide added benefit to
Philadelphia, PA, USA healthcare providers and families as they are
e-mail: [email protected]; michael. confronted with difficult decisions.
[email protected]
# Springer International Publishing AG, part of Springer Nature 2018 219
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_162
220 E. K. Anday and M. Spear
13.1 Salient Points abnormalities; and neonates suffering from pro-
found intrapartum and postnatal insults present dif-
• Parents generally should be considered the ficult moral, ethical, cultural, and social challenges
spokesperson for determining the best interest for both families and caregivers in regard to provid-
of the child. ing or withholding life supportive measures. The
• A medical team should seek the opinions of decision to withhold or terminate treatment for an
parent(s), both prior to and following delivery infant is based on defining the issues central to this
of a child identified as extremely high risk for process, including the values and rights of the infant
adverse outcome. as an individual, the values of the family and the
• Following birth, a period of transition to extra- medical caregivers, the cultural influences, and the
uterine life should be offered to allow for the societal values that shape the moral arguments that
stabilization and evaluation of the infant to affect one’s judgment. Part of the challenge resides
assess the degree of significant intervention in the complexity of defining who is or should be
likely to be required. responsible for making difficult decisions resulting
• Palliative care is a useful adjunct in counseling, in the death of a newborn since fundamentally this
before and after birth, parents of infants with type of decision is at odds with human nature even
potentially lethal anomalies. Palliative care in situations where the end of life would mean no
teams should also support neonatologists in further suffering for the infant.
stressful clinical situations in perinatal period. The goal of this chapter is to consider some of
• The neonatal palliative care team can assist in the issues confronting the clinician charged with
resolving conflict resolution between the practicing the art of medicine in the context of a
healthcare professionals and the family or certain degree of medical uncertainty and the
between members of the healthcare team in a implications for medical decision-making. The
highly charged setting. role of neonatal palliative care as an adjunct in
counseling prospective parents or parents of
infants with potentially lethal anomalies and/or
13.2 The Process of Decision-Making for provision of care in under circumstances that
are deemed futile has increased. In-depth discus-
When one prevents one’s emotions from overtaking sions of ethical problems and guidelines for the
one’s rationality it is called reason. care of the extremely low birth weight infant will
When one prevents one’s rationality from overtak- be covered in other chapters of this book.
ing one’s emotions it is called compassion.
When one can do both it is called wisdom.
Ancient Chinese saying
13.4 The Neuroscience of Decision-
Making
13.3 Introduction
Viner has stated that “Human behavior, in general is
not under the constant and detailed guidance of
In the past 40 years, tremendous progress has careful and accurate hedonic calculations, but is the
occurred in the care of the neonatal patient. An product of an unstable and irrational complex of
in-depth understanding of fetal and neonatal phys- reflex actions, impulses, instincts, habits, customs,
iology and the molecular basis of pathological pro- fashion, and hysteria” (Viner 1925). Clearly, one
cesses, concurrent with advancements in would hope and expect that Viner’s perspective of
biomedical technology, have impacted favorably human behavior is not relevant to the process
upon the survival of the newborn. However, involved in making decisions to provide or withhold
extremely premature infants at the threshold of treatment for infants. Cognitive neuroscience sup-
viability; infants diagnosed with potentially lethal ports that a variety of processes are essential to
congenital malformations, including chromosomal integrate novel incoming stimuli for decision-
13 The Process of Decision-Making in Neonatology 221
making in situations of uncertainty such as those options for actions, deciding what actions to take
pertaining to life-sustaining medical treatment. and factual emotional outcomes (Damasio 2007).
When considering options about incoming informa- Thus, the evolution of the human PFC is inti-
tion, the key individuals involved must demonstrate mately related to the emergence of human moral-
flexibility to account for various outcomes, con- ity, allowing for the motivational mechanisms to
stantly monitor incoming information as it relates be integrated with an exceptional power to predict
to the ultimate goal state or decision, and evaluate outcomes from a large repository of experiential
the risk–benefit ratio for various decision-making wisdom. Coupled to semantic knowledge, cultural
options (Gazzaniga et al. 2002). But medical deci- and situational factors become integrated into the
sions are not simply the rational calculation of ben- neural substrate to weigh the motivational rele-
efit versus burden. The individuals involved often vance of different behavioral choices in social
consider past experiences and values as well as situations. Clearly then, through a complex inter-
future outcomes of their decisions as part of the action of biological and cultural factors, the
basis for that choice. As such, a certain degree of human moral mind emerges and integrates cogni-
individuality is defined that contributes to decision- tion to emotion and motivation, forming the
making, particularly when one considers the emo- framework for decision-making.
tional influences on this process.
In humans, emotions influence decision-making.
Internal cues and external contextual information 13.5 Steps in Decision-Making
can positively or negatively impact the emotional
state surrounding the decision-making process. The 13.5.1 Recognize the Moral Dimension
emotional evaluation of an action’s consequences
guides the individual who must be able to provide a From a philosophical approach, neonatal medicine
basis for making certain choices (Bechara et al. has been practiced to provide specialized and inten-
2000). Social neuroscience supports that the neuro- sive care measures aimed at improving the health
anatomical substrate involved in complex decision- and survival of premature and critically ill newborns.
making in humans involves the integration of con- But how are these goals affected when the curative
textual social knowledge represented as event model is inadequate such as with infants diagnosed
knowledge in the prefrontal cortex (PFC); social with anencephaly or with the delivery of a 22-week
semantic knowledge, stored in the anterior and pos- gestational age infant; what do the goals become?
terior temporal cortex; and motivational and basic And why is decision-making in this context so dif-
emotional states, which depend on cortical–limbic ficult? Consider the situation wherein prenatally a
circuits (Casebeer 2003a; Miller and Cohen 2001). mother is diagnosed carrying a fetus with severe
While certain perceptual and emotional abilities potentially lethal congenital anomalies; the physi-
have been shown to be shared by humans and cian is put into a unique situation in medicine in
other animals, morality and are a product of evolu- which he/she contemplates withholding support in a
tionary pressures specific to the human species that human being that the physician has never even seen!
have shaped social cognitive and motivational Or contemplate the situation of the 23-week gesta-
mechanisms into uniquely human forms of experi- tional age infant with bilateral grade III intracranial
ence and behavior (Casebeer 2003b). Experiments bleeds and pneumoperitoneum trapped in NICU
using functional MRI in humans have identified that biomedical technology, hanging on to a thread of
decision-making involving intelligence and com- life and without reasonable expectation for improve-
plex resolution activates the ventral and medial ment without incurring unnecessary pain and suffer-
aspect of the prefrontal cortex (VMPFC) (Greene ing; when is enough really enough? Compound the
et al. 2001). Activation of the VMPFC appears to dilemma with both parental and physicians’ attitudes
signify that wisdom required in the decision-making toward life-saving technology and death, which
process comes from categorizing and organizing have been shown in numerous studies to vary with
past experiences from many situations and involves race and ethnicity and are thought to result from
222 E. K. Anday and M. Spear
complex interactions of factors including access to or movement of voluntary muscles is to be con-
medical care, communication styles, family involve- sidered a person and granted full protection under
ment in decision-making, trust in physicians, and the U.S. Constitution” (Born-Alive Infants Pro-
religious background (Boss et al. 2008). tection Act 2001). The Act provides that even a
Each healthcare dilemma reminds caregivers of fertilized ovum, embryo, and fetus of any gesta-
their limitations, including uncertainty, the human tion are to be considered coequal with regard to
predicament, lack of knowledge, and decision- protection from harm. While it was widely under-
making abilities. All of these are tempered by the stood to be an antiabortion legislation, the Act
moral constraints under which we act. These are altered the definition of the words, “person,”
the difficult situations which, based on individual “human being,” “child,” and “individual.”
social, cultural, ethical, and moral differences, Although the law did not impose a new standard
make it highly unlikely that we will all agree. of medical care upon physicians nor change
Nevertheless, within the context of providing care existing law, it altered the physician’s norm of
to the high-risk neonate, the best interest of the deferring to parental discretion regarding the ini-
child must be kept foremost in the minds of the tiation or discontinuation of medical treatment for
caretakers and the professional staff and form the the extremely premature infant. However, the
basis for decisions related to the care of that infant. American Academy of Pediatrics (AAP) and the
Neonatal Resuscitation Program Steering Com-
mittee issued an opinion that it would not affect
13.5.2 Recognize the Parties Involved day-to-day neonatal medical practice and stan-
dards. In fact, the Committee clearly stated
13.5.2.1 The Infant in His/Her Own Right that “decisions about withholding or dis-
as an Individual continuing medical treatment that is considered
The infant born at the threshold of viability or one futile may be considered by the medical care
who has potentially lethal congenital anomalies providers in conjunction with the parents. . . .
has no voice of its own; it depends on decisions Those newly born infants who are deemed appro-
made by a surrogate, most often its mother and/or priate to not resuscitate or to have medical support
family members to advocate on its behalf. Under withdrawn should be treated with dignity and
ideal circumstances, prenatal diagnosis and respect, and provided with “comfort care” mea-
counseling allow for effective communication sures” (Am Acad of Ped Neonatal Resuscitation
between parents and physicians, and a reasonable Prog Steering Comm 2003).
approach to initiating or withholding resuscitation Consider the Baby Doe Law, passed in 1984 in
can be achieved based on the prognosis and risk the United States, that sets forth specific guide-
versus benefit of treatment. During this decision- lines for the treatment of seriously ill or disabled
making process, the value of the infant’s life is newborns and dictates what must be done for a
being judged. However, there may be disagree- child regardless of the wishes of the parents
ments between the medical care providers and (Baby Doe Law 1984). Withholding treatment
surrogates where, in the opinion of the provider, is considered neglectful unless an infant is irre-
the infant’s best interest is not being served and in versibly comatose or the treatment is futile in
which the surrogate’s decision should be overrid- terms of the infant’s survival, but “quality of
den (American Academy of Pediatrics, Commit- life” is not a reason for withholding medical
tee on Bioethics 1994). In 2001, the Senate and care. As a result of this law, hot lines were set
House of Representatives of the US Congress up for anonymous reporting of alleged abuse
passed the “Born Alive Infant Protection Act.” such as withholding of medical care to seriously
Specifically, the Act provides that any “member ill newborns leading to intrusions into the hospi-
of the species homo sapiens at any stage of devel- tals that were disruptive and ultimately found
opment that is expelled or extracted from the unwarranted. This Act was overturned in the
mother who then breathes or has a beating heart Federal Courts in 1987.
13 The Process of Decision-Making in Neonatology 223
Two laws, each illustrating potential conflicts think may be quite different than what the family
between two or more values and the rights of the or child might choose.
child as a distinct entity, contrasted to the rights of In the face of uncertainty and inability to pre-
parental decision-making as the surrogate for the dict outcome for an individual infant, there will
infant. Even more intriguing is the observation usually be differences of opinion regarding out-
that, in spite of legal and ethical standards requir- come, viability, and treatment futility. Those who
ing resuscitation when it is considered to be in a bear the ultimate burden of the decision ought to
patient’s best interest, the newborn infant and have the major role in the decision-making when
particularly the preterm baby are devalued in com- outcomes are very uncertain. Simply put, once a
parison to older patients with comparable survival physician has determined that an infant has no
and morbidity outcomes (Janvier et al. 2008). In a realistic expectation of survival based on the evi-
questionnaire describing eight neurologically dence at hand, parents should be informed and
incompetent patients with potentially equivalent given the opportunity to withhold initiating treat-
adverse neurological outcomes who required ment (e.g., prenatally diagnosed infant with tri-
resuscitation (24-week preterm, term infant, somy 18 and complex congenital heart disease) or
2-month-old infant, 7-year-old child, 14-year- given the option of withdrawing the life-
old, 35-year-old, 50-year-old patient, and an supporting interventions (e.g., 23-week gesta-
80-year-old subject), respondents were asked tional age ELBWI with bilateral grade IV IVH
whether they would comply with the families’ and necrotizing enterocolitis totalis). When faced
wishes if resuscitation was refused. The families’ with such a difficult moral decision, parents often
refusal of resuscitation was accepted most fre- will look to the physician for advice and counsel-
quently for the 80-year-old subject and the ing. The Committee on Bioethics of the American
24-week-old premature infant, even though the Academy of Pediatrics has advocated for a shared
majority of the respondents thought that resusci- decision-making model whereby the physician
tation was indicated for the 24-week-old infant has an ethical duty to seek and respect information
but not the 80-year-old patient. Since the decision regarding parental preferences and values in
was not made on the basis of outcome or what was exchange for providing the parent with medical
perceived to be in the infant’s best interest, there information (Leuthner 2001). A nondirective
seems to be a different value placed on life at the approach to counseling parents is advocated to
extremes. While the root of this devaluation is not allow parents to choose a course of action based
clear, it may be attributable to anthropologic, cul- on their own personal values. While the transfer of
tural, social, and evolutionary factors. information from physician to parent should be
unbiased, the manner in which information is
communicated may have a framing effect on the
13.5.3 Parental Decision-Making parental decision. The recent study by Haward
et al. examined message framing and perinatal
Regardless of the concept of provision of care, it is decisions and demonstrated that the manner in
essential that parents understand the implications which parents received prognostic information,
of the nature of aggressive care in situations where i.e., framed as mortality data versus survival
they “want everything done” for their infant, and data, affected their treatment preference indepen-
physicians must be willing and prepared to rec- dent of religiousness, parental status, and beliefs
ommend withdrawal of support in futile situa- regarding the sanctity of life (Haward et al.
tions. Throughout this process, the infant must 2008). In subtle ways, framing bias can inadver-
be afforded compassion and comfort. What is tently affect the process of parental decision-
good for critically ill newborns and who deter- making at a time when decisions dependent on
mines this? The presence of numerous voices in moral values that deal with the consequences of
deliberations about newborn patient care presses life and death occur in close proximity to physi-
this question. What we as healthcare professionals cian counseling.
224 E. K. Anday and M. Spear
However, for some parents noninitiation of helpful in the decision-making process for the phy-
or withholding life-sustaining treatment is a sician; however, most decisions are not based
psychologically and morally impossible choice; purely on a utilitarian approach.
they may want treatment withdrawn or not ini- During the course of refining the practice of
tiated so their child does not suffer but do not neonatal medicine, a wealth of information relat-
want the responsibility of making that decision ing to the care of the critically ill newborn has
because they do not want to give up hope. been accumulated, not only in the United States,
Under these circumstances, a “left unasked but but worldwide. A number of NICU guidelines
not unaddressed” approach may allow transition and statements have been developed to establish
of aggressive, futile care to care that is based norms and reference points in an effort to assist
upon medical indications (Paris et al. 2006). physicians in the day-to-day management of dif-
For example, instead of asking a parent if they ficult situations including withholding or termi-
want to initiate dopamine infusion for their nating life-sustaining therapy, but these may at
infant with bilateral grade IV IVH and refrac- times be of limited use in the discussion of risks,
tory hypotension, and giving them false hope, benefits, and other options with the parents and
one can explain that everything reasonable has families (American Academy of Pediatrics
been done for their baby and that keeping their (AAP) and American College of Obstetricians
infant comfortable now and holding their baby and Gynecologists (ACOG) 2012; Bell 2007).
is the best one can do at this time. In this Although objective outcome data are available
manner, the parents are not tormented with to many clinical populations, for a given infant
decisions fraught with anguish, ambiguity, and in many situations, the chance of a certain
doubt, and guilt. There comes a time when outcome may be either 0 or 100% (Watchko
“there is no need to compound the suffering of 1986; Pignotti and Donzelli 2008). The recom-
the patient by prolonging it, nor that of the mendations by the International Liaison Com-
parents by insisting they must make a decision mittee on Resuscitation for guidelines on
as fate has already decreed” (Paris et al. 2006). neonatal resuscitation support the “do-not-resus-
citate” order on evidence-based justification for
the extremely low birth weight infant <23 weeks
13.5.4 The Physician’s Role and <400 g and confirmed trisomies 13, 16, and
18 (International Liaison Committee on Resus-
At the time of delivery of an extremely premature citation 2006). However, upon review of incor-
infant or one with potentially lethal congenital rect information, diagnosis, or prognosis about a
anomalies, it may be difficult for a physician to specific situation, the guidelines provide for the
predict for parents what the outcome will be: opportunity of a trial of therapy with the option
possibilities range from death soon after delivery of subsequent withdrawal of support. The Gro-
to survival with severe disabilities to intact sur- ningen protocol wherein end-of-life decisions for
vival. Similarly, an infant might have an initial newborns utilizing euthanasia under strict proto-
postnatal course that would favor a reasonable col are an acceptable choice in situations where
outcome, only to suffer a devastating event in there is severe and sustained suffering without
the NICU where the prognosis is poor. The phy- relief is considered (Verhagen and Sauer 2005).
sician is placed in a situation of weighing the Newborns are classified into three categories
benefits and burdens of ongoing support for the depending on the severity of their condition:
infant under conditions of medical uncertainty Group 1 are infants who are expected to die in
and communicating information in an effective spite of invasive medical care and are actively
manner to the parents, keeping in mind that the removed from support to be held by the parent(s);
decision is in keeping with legal and organizational Group 2 are infants who survive birth but are
guidelines. The roles of authoritative statements, expected to have poor quality of life and who
professional policies, and recommendations can be cannot survive without the assistance of invasive
13 The Process of Decision-Making in Neonatology 225
technology; and Group 3 are patients who could shaping individual professional lives and human
eventually survive without technology but who interactions.
suffer severe, sustained pain and a life without
hope of improvement. Of the three groups, 13.5.4.1 Neonatal Palliative Care
Group 1 is least likely to present a dilemma. In in the NICU: A New Role
Group 2 patients, quality-of-life issues form the The role of neonatal palliative care has increased
basis for the decision-making, and in this situa- over the last few years. In the field of pediatric
tion, it is critical to maintain the best interest of palliative care, neonatal palliative care is rela-
the child in consideration and involve the opinion tively new. There are several clinicians in the
of the parent(s). However, the decision should medical and nursing field, however, who have
not rest solely with the parent; discontinuation of been writing about this area for over a decade.
support must be in concert with the physician The same resistance that is experienced in other
together with the parent(s). At all times, the infant areas of palliative care has also been seen in this
should be kept comfortable and without pain. patient population. Neonatologists, like other
The last Group presents the most difficult physician specialists, feel they have been doing
situation because it is a judgment call that death this care without the services of a palliative care
would be more humane than continuation of life. team and wonder about the added benefit. They
A passive approach to allowing “nature to take its feel they handle these difficult conversations well,
course” and withholding creature comforts, such and those that remain unenlightened are some-
as nutrition, can lead to a period of severe suffer- what resistant.
ing until death. Alternatively, deliberate termina- Yet when neonatal palliative care is closely
tion of life or euthanasia with the use of examined, it provides the same aid in decision-
medications to end the suffering is considered making and other services that it provides in the
illegal. The article by Verhagen and Sauer adult and pediatric arena. Mancini et al. define
(2005) discussed the Groningen protocol in neonatal palliative care as “the active, total, holis-
regard to strict reporting and review of each case tic approach to care, focused on enhancing the
of proposed active termination of life to ensure quality of life for the baby and their family while
that acceptance of this practice will not allow recognizing potential or inevitable death” (Man-
erosion of moral norms where other undesirable cini 2013). The team can provide a multidis-
qualities in newborns can be used as justification ciplinary approach in decision-making. Different
to end their lives. perspectives can help in the decision-making pro-
Physicians and parents may have different cess tremendously. The view of nursing and social
interpretations of what is discussed and what deci- work is incredibly valuable in this process, as
sions are made during prenatal counseling, in the those disciplines detect issues that physicians
delivery room, and following the delivery of an may be unaware of. Another key value the team
infant. Studies support that it is the parents’ per- possesses is time. The consultant can focus on the
ception that physicians do not always address one or two families that need intensive support in
values that parents consider important in the decision-making. Some of the key questions they
counseling they provide (Rebagliato et al. 2000; ask are to assess what the parents’ current under-
Lorenz 2005; Ishii et al. 2013; Stoll et al. 2010). standing of their infant’s illness is, what they are
Specific parental values such as hope, spirituality, hoping for, and what are they willing to do to
and religion are often not incorporated in the achieve their goals. Then they help determine
discussions and may contribute to confusion what is the most important to the family; is it
about what has been discussed and what decisions prolongation of life at any cost, or providing the
have been made (Paris 2005; Curlin et al. 2007; best quality of life, in a supportive but
Williams et al. 2009). To ignore these questions is nonaggressive intervention strategy?
to fail to recognize the significant influence that The other key component of neonatal palliative
these values and cultural influences have had in care includes the perinatal component of this care.
226 E. K. Anday and M. Spear
If the process of decision-making begins prior to is officially consulted, and they can either meet
the birth of an infant with potentially chronic or with the family in concert with the attending, by
life-threatening diagnoses, the parents are more way of introduction, or meet separately. The key
capable of acquiring the necessary understanding initial questions for the team to ask are:
needed to make the difficult decisions ahead.
They are empowered to participate in a less 1. What has your healthcare team told you about
acute environment to develop a “birth plan” for our role?
the delivery room, and beyond, should the infant 2. What is your understanding of your child’s
survive. illness?
In particular, in delivery room primary pallia- 3. What are you most worried about?
tive care has been found in one study to be incon- 4. What are you most hoping for?
sistent, and caregivers in that scenario often need 5. What are you willing to do to achieve those
high support during this stressful time. Primary goals?
palliative care given by the direct caregivers
includes goals of care conversation, symptom These questions will align the team with the
management, and bereavement. Many of the family’s wishes and current thinking and will best
staff in this situation feel ill prepared to handle yield a successful partnership. The team continues
this emotionally charged situation (Carter 2015). to meet with the family on a regular basis. The
Given this study, this lends strength for the palli- regularity is defined based on the family’s needs.
ative care to begin in the perinatal period, long Contact can be daily, several times a week, or as
before delivery, so that staff and the patient’s needed by the family or medical team. The key to
family are well prepared. an effective consult is the understanding that the
An additional role for the palliative care team consultation is a process, not one visit. It takes
has been described as “directive counseling” time to build a successful alliance between the
(Garten 2015). It is sometimes necessary for the team and family. The stakes are often high and
caregivers to be more directive in guiding the trust is not always instantaneous.
family through the difficult decisions at end of In summary, neonatal palliative care can pro-
life. Oftentimes, the parents may prefer more vide an extra layer of support for families and staff
clear guidance through removal technology that as well, in facilitating the difficult decision-
is no longer effective. This decision can be tre- making needed during the perinatal period,
mendously difficult for parents, and there is sup- extending through the NICU stay and beyond.
portive literature that some families may prefer
this burden of choice be lifted from them.
Laing has discussed the importance of conflict 13.6 Summary
resolution in the NICU regarding difficult
decision-making (Garten 2015). He correctly Ours is a global society in which one must be
sites that conflict can arise in this highly charged increasingly aware of the different value systems
setting. This conflict can occur between the in multicultural societies across nations. While a
healthcare professionals and the family or deeper understanding of the cognitive and brain
between members of the healthcare team. One of mechanisms that guide human behavior is of gen-
the additional roles of a neonatal palliative care eral interest, the moral and ethical decisions that are
team is to help with this conflict resolution. By made regarding withholding or withdrawing care
being somewhat outside the immediate conflict, to an infant provoke anxiety and guilt that come
the team can help understand each person’s view- with responsibility for making difficult decisions.
point and offer observation and clarification of the When evidence-based guidelines are available as a
key issues, in order to move beyond the conflict. frame of reference, one may choose to work within
Practically, in order to utilize a team effectively, a set of guidelines; however, these must be indi-
the consultative model is most effective. The team vidualized for each circumstance. Prognosis can
13 The Process of Decision-Making in Neonatology 227
change rapidly from the time of birth to the delivery delivery room resuscitation for high-risk newborn.
room resuscitation; the likelihood of “reasonable Pediatrica 122(3):583–589
Carter B (2015) End of life decision for newborns: an ethical
outcome” should be reevaluated at each junction. and compassionate process? Arch Dis Child Fetal
Implicit in the decision-making is the assumption Neonatal Ed 101(2):F92–93. doi10.1136/archdischild -
that parental counseling has occurred. Parental 2015.309380
wishes regarding the extent of intervention initially Casebeer WD (2003a) Moral cognition and its neural con-
stituents. Nat Rev Neurosci 4:840–846
should almost always be honored until further Casebeer WD (2003b) Natural ethical facts: evolution,
determination by the medical team supports the connectionism, and moral cognition. MIT Press, Cam-
futility of further care. In the absence of a reason- bridge, MA
able expectation of a steady improvement and in Curlin FA, Lawrence RE, Chin MH, Lantos JD (2007)
Religion, conscience, and controversial clinical prac-
the presence of significant pain and suffering, with- tices. N Engl J Med 356(6):593–600
drawal or withholding life-sustaining medical or Damasio A (2007) Neuroscience and ethics: intersections.
surgical treatment is a decision that takes the best AJOB 7(1):3–10
interest of the baby in consideration. In the end, the Garten L (2015) Primary palliative care in the delivery
room: patients’ and medical personnel’s perspectives.
goal of care for the newborn must be focused upon J Perinatol 35:1000–1005. IA L (2013) Conflict reso-
the best interests of the child. lution in end-of-life decisions in the neonatal unit.
In the Hippocratic Corpus, medicine is defined Semin Fetal Neonatal Med 83–87
as having three roles: “To do away with the suf- Gazzaniga RB, Ivry RB, Mangun GR (2002) Cognitive
neuroscience: the biology of the mind, 2nd edn. Norton
fering of the sick, to lessen the violence of their & Company, New York
diseases, and to refuse to treat those overmastered Greene JD, Sommerville RB, Nystrom LE, Darley JM
by their diseases, realizing that in such cases med- et al (2001) An fMRI investigation of emotional
icine is powerless” (Hippocrates 1977). In the engagement in moral judgment. Science 293:
2105–2108
end, perhaps decision-making may best be sum- Haward MF, Murphy RO, Lorenz JM (2008) Message fram-
marized by the Jesuit ethicist, Father John Paris, ing and perinatal decisions. Pediatrica 122:109–118
“The best one can do is to make a human judg- Hippocrates (1977) The art. In: Reiser SJ, Dyck AJ, Curran
ment based on probabilities” (personal WJ (eds) Ethics in medicine: historical perspectives and
contemporary concerns. MIT Press, Cambridge, MA,
communication). pp 6–7
International Liaison Committee on Resuscitation (2006)
The International Liaison Committee on Resuscitation
(ILCOR) consensus on science with treatment recom-
References mendations for pediatric and neonatal patients: neona-
tal resuscitation. Pediatrica 117(5):978
Am Acad of Ped Neonatal Resuscitation Prog Steering Ishii N, Kono Y, Yonemoto N et al (2013) Outcomes of
Comm (2003) Born-alive infant protection act of infants born at 22 and 23 weeks’ gestation. Pediatrica
2001 public law no 107-207. Pediatric 111:680 132(1):62–71
American Academy of Pediatrics (AAP) and American Janvier A, Leblanc MD, Barrington KJ (2008) The best-
College of Obstetricians and Gynecologists (ACOG) interest standard is not applied for neonatal resuscita-
(2012) Guidelines for perinatal care, 7th edn. Elk Grove tion decisions. Pediatrica 121(5):963–969
Village (IL) Leuthner S (2001) Decisions regarding resuscitation of the
American Academy of Pediatrics, Committee on Bioethics extremely premature infant and models of best interest.
(1994) Guidelines on forgoing life-sustaining medical J Perinatol 21(3):193–198
treatment. Pediatrica 93(3):532–536 Lorenz JM (2005) Prenatal counseling and resuscitation
Baby Doe Law (1984) USCA Title 42 Chapter 67 Sec 510a decisions at extremely premature gestation. J Pediatr
(http://frwebgate6.access.gpo.gov/cgi-bin/waisgate.cgi?) 147(5):567–568
Bechara A, Damasio H, Damasio AR (2000) Emotion, Mancini A (2013) Training neonatal staff for the future in
decision making and the orbitofrontal cortex. Cereb neonatal palliative care. Semin Fetal Neonatal Med
Cortex 10(3):295–307 18:111–115
Bell EF (2007) Noninitiation or withdrawal of intensive care Miller EK, Cohen JD (2001) An integrative theory of pre-
for high-risk newborns. Pediatrica 119(2):401–403 frontal cortex function. Annu Rev Neurosci 24:167–202
Born-Alive Infants Protection Act (2001) 107th congress Paris JJ (2005) Resuscitation decisions for “fetal infants”.
1st session HR 2175. 1–38 http://thomas.loc.gov/ Pediatrica 115(5):1415
Boss RD, Hutton N, Sulpar LJ, West AM et al (2008) Paris JJ, Graham N, Schreiber MD, Goodwin M (2006)
Values parents apply to decision-making regarding Approaches to end-of-life decision-making in the
228 E. K. Anday and M. Spear
NICU: insights from Dostoevsky’s The Grand Inquis- NICHD Neonatal Research Network. Pediatrica
itor. J Perinatol 26:389–391 126(3):443–456
Pignotti MS, Donzelli G (2008) Perinatal care at the thresh- Verhagen AA, Sauer PJ (2005) End-of-life decisions in
old of viability: an international comparison of practical newborns: an approach from the Netherlands.
guidelines for the treatment of extremely preterm births Pediatrica 116:736–739
121(1);e193–198. Viner J (1925) The utility concept in value theory and its
Rebagliato M, Cuttini M, Broggin L et al (2000) Neonatal critics. J Pol Econ 33:369–387
end-of-life decision making: physicians’ attitudes and Watchko JF (1986) The tragic vision: acknowledging
relationship with self-reported practices in 10 European limits and uncertainty. J Perinatol 6(1):39–43
countries. JAMA 284(19):2451–2459 Williams C, Cairnie J, Fines V, Patey C et al (2009) Con-
Stoll BJ, Hansen NI, Bell EF, Eunice Kennedy Shriver struction of a parent-derived questionnaire to measure
National Institute of Child Health and Human Devel- end-of-life care after withdrawal of life-sustaining
opment Neonatal Research Network et al (2010) Neo- treatment in the neonatal intensive care unit. Pediatrica
natal outcomes of extremely preterm infants from the 123(1):e87–e95
Follow-Up Outcomes of High-Risk
Infants 14
Neil Marlow
Contents
14.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
14.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
14.3 Cognition and Very Preterm Birth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
14.4 Behavioral Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
14.5 Motor Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
14.6 Somatic Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
14.7 Adult Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
Abstract consideration. This chapter will briefly review
Despite the emphasis on major disabling con- these areas and signpost further reading.
ditions, most survivors of very preterm or
extremely preterm birth have mild or no
impairments as they enter childhood. Along- 14.1 Salient Points
side the major conditions discussed in ▶ Chap.
133, “Epidemiology of Adverse Cerebral Out- • The relationship between impaired outcome
come of Newborns,” a range of important cog- rises almost exponentially with decreasing ges-
nitive, behavioral, and motor problems are tational age, and the risk of problems becomes
now well recognized and persist into adult much greater as gestation falls below 32 weeks.
life. Alongside these are rarely considered • Cognitive impairments may manifest as poor
important issues relating to lung function and attainment at school. Infants born prematurely
cardiovascular health that also require score lower in tests of reading and mathemat-
ics. Several executive processes plateau in
middle childhood, and in these areas preterm
N. Marlow (*)
Institute for Women’s Health, University College London,
London, UK
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 229
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_163
230 N. Marlow
children may “catch up” with normally devel- below 32 weeks. The effect of brain injury and
oping children, but at a later age. developmental changes found after very preterm
• When children born prematurely reach school birth is complex (Volpe 2009). Understanding the
age, deficits in working memory and the speed neuropsychological deficits that underpin this
of processing information have been reported. relationship may point to potential areas of inter-
These appear to underpin a range of executive vention and allow better understanding of the
deficits, leading to poor school attainment and pathways of abnormal development.
behavioral difficulties. These are specific areas Other organ systems other than the brain are
targetting educational strategies, rather than significantly affected by preterm birth. In particu-
using more general interventional strategies. lar lung function may be impaired, particularly in
• Behavioral problems may put preterm infants relation to gestational age, with superimposed
at risk of bullying at school age, prompted by lung injury following neonatal treatment. Under-
physical differences (small size, reduced lung standing the relationship of treatment strategies to
function, etc.) and an internalized emotional later outcomes and the implication of measured
phenotype. Bullying may be responsible for deficits in lung function to adult prognosis is only
some emotional stress in early adolescence now becoming apparent. Similar issues in rela-
and should be enquired after. tionship to vascular function and cardiovascular
• Multiple studies have demonstrated an excess risk to growth and final height pertain and will be
of motor problems among very preterm chil- discussed.
dren, in addition to a formal diagnosis of cere-
bral palsy.
• Excess cardiovascular risk with increased arte- 14.3 Cognition and Very Preterm
rial blood pressure has been reported. Birth
• Childhood growth may also be compromised,
but the effect of the adolescent growth spurt General measures of intelligence are valuable
requires further study. indicators of attainment in childhood and adult
life and are clearly related to prematurity as
described above. IQ is a summative measure of
14.2 Introduction general cognitive function, and many studies have
shown increasing deficit with reducing gestational
Initial research in the first half of the twentieth age (Fig. 2). Understanding the factors that lead to
century seemed to point to there being no deficit this deficit is important. “Cognition” comprises a
from being born very preterm, but with large series of executive processes that combine to pro-
population studies and improving survival <34 duce the final IQ. Many groups have evaluated
weeks of gestation it became apparent that out- aspects of executive function and memory, which
come was a continuum, with increasing problems reveal more specific impairments (Mulder et al.
being identified at the lowest gestations. The 2009; Aarnoudse-Moens et al. 2009), which in
breakpoint at around 32 weeks identified by turn can be evaluated against brain imaging and
Wolke et al. (see ▶ Chap. 133, “Epidemiology of function to elucidate etiology and their role in
Adverse Cerebral Outcome of Newborns,” generating neuropsychological outcomes more
Section 5) has been qualified in more recent data- accurately than using a single global measure
base association studies, where the relationship such as IQ.
between impaired outcome rises almost exponen- Earlier studies revealed that very preterm chil-
tially with decreasing gestational age, for exam- dren found sequential tasks easier in contrast to
ple, in special educational needs (MacKay et al. simultaneous tasks, indicating challenges with
2010) (Fig. 1). Hence the risk of problems at more dealing with complex tasks that would be better
mature gestations, although elevated, is relatively processed as a series of tasks, a principle easily
small and becomes much greater as gestation falls adapted into the classroom.
14 Follow-Up Outcomes of High-Risk Infants 231
Fig. 1 Relationship between the risk of special educational needs and gestational age at birth (note “y” axis is a log scale)
(MacKay et al. 2010) permission required (PLoS Medicine)
Several executive processes plateau in mid- prime areas at which to direct educational strat-
dle childhood, and in these areas preterm chil- egies, rather than seek more general interven-
dren may “catch up” with typically developing tional strategies.
children, but at a later age. In contrast, other Cognitive impairments may manifest as poor
executive functions seem to diverge from typi- attainment at school. Educational tests of reading
cal development in preterm populations over and mathematics, for example, demonstrate lower
late childhood/adolescence. Hence the pattern scores, particularly so in mathematics. Investigat-
of differences seen is related to both the age of ing the underlying causes for this has revealed that
the child and the gestational age of the cohort, the same executive deficits, working memory/pro-
rendering comparative studies challenging cessing speed, rather than the educational concept
(Mulder et al. 2009). This area is further com- of “dyscalculia” are indeed responsible for these
plicated by the emergence and focusing of exec- (Simms et al. 2015). Hence it is not surprising that
utive processes over the preschool years, such very preterm children have a higher rate of special
that early attempts to detail them before school needs at school (Fig. 1), resulting from impaired
age may not be entirely successful (Scherif cognitive functioning, as well as the major dis-
2010). More recently, critical deficits in work- abling conditions described in ▶ Chap. 133, “Epi-
ing memory and the speed of processing of demiology of Adverse Cerebral Outcome of
information at school age have been reported, Newborns.” In keeping with this, final school
which appear to underpin a range of executive attainment may be at lower grades compared to
deficits (Mulder et al. 2011a) and lead to poor children born at term. Within the Danish system
school attainment (Mulder et al. 2010) and the proportion failing to complete “basic school-
behavioral difficulties (Mulder et al. 2011b). It ing” rises in a similar fashion to that shown in
seems clear that these very specific areas may be Fig. 1 (Mathiasen et al. 2010).
232 N. Marlow
Fig. 2 Bubble plot of the relationship between IQ and the cohort (regression line and 95% confidence intervals
gestational age at birth. The size of the bubble indicates shown) (Kerr-Wilson et al. 2012) permission required
relative study size and the position the mean gestation of (J Public Health)
It must be emphasized that not all survivors of However, as neonatal care improves, general cog-
extremely or very preterm birth have such prob- nitive scores appear to have improved for
lems. Risk of impairment may be elevated over extremely preterm children (Moore et al. 2012),
the relatively low rate seen in typically developing suggesting that at least some of the answer lies in
children, but a high proportion of very preterm optimizing neonatal outcomes.
children function normally. The challenge is to
identify those who will go on to develop func-
tional impairment and to provide effective inter- 14.4 Behavioral Outcomes
ventions to enhance outcomes. Many studies in
infancy have attempted to do this with varying Very preterm children are at risk of developing a
effects, but few persist beyond early childhood broad series of behavioral problems, which has
(Spittle et al. 2015; Spittle 2015). At present, it been characterized as the preterm behavioral phe-
seems unclear as to what should be the targets for notype. This is manifest as increased proportion of
such interventions, which ages are most suscepti- children with an internalized phenotype, namely
ble to intervention, and what strategies are most inattentive-type ADHD, autistic symptoms, and
effective. Part of the issue is the bias towards emotional difficulties, such as anxiety (Johnson
social disadvantage in populations of children and Marlow 2011; Johnson and Wolke 2013).
entered into such trials. Risk factor profiles for This contrasts with the predominance of external-
poor cognitive outcomes include male sex, greater ized behaviors such as ADHD (combined and
degrees of immaturity, and a range of markers of overactivity subtypes) in the general population.
social disadvantage (Linsell et al. 2015), none of Many studies use the Child Behavior Checklist
which suggest susceptibility to intervention. with results showing remarkable consistency
14 Follow-Up Outcomes of High-Risk Infants 233
across countries, particularly in the social, identified early and children supported appropri-
thought, and attention domains (Hille et al. ately. In a recent study, neurological dysfunction
2001; Farooqi et al. 2013). This consistency (using Touwen’s neurological examination),
between studies seems to confirm the phenotype. IQ, attention, and processing speed mediated
There is a general excess of symptoms among the relationship between preterm birth and
children in these specific areas, associated with motor impairment (Van Hus et al. 2014), emphasiz-
increased numbers of children with disorders, and ing the interrelationship between all neurocognitive
prevalence again rises with decreasing gestational and behavioral outcomes in these populations.
age at birth. Many more children demonstrate Comprehensive psychometric assessment should
increased symptom scores than present with dis- always accompany motor assessment.
orders. Deficits in working memory and pro-
cessing speed seem to explain the excess of
behavioral problems in 10–11-year-old children 14.6 Somatic Outcomes
(Mulder et al. 2011b), promoting speculation of
different origins of disordered behavior among Alongside brain-based outcomes, key deficits in
preterm populations, compared with the general lung function appear to be the commonest adverse
population. outcomes. Among extremely preterm children,
At least some of this behavioral profile may BPD is common, but outcomes for those without
make such individuals at risk of bullying at school moderate/severe neonatal BPD also appear
age, promoted by physical differences (small size, impaired. At 11 years, scores for those without
reduced lung function, etc) and the internalized BPD showed on average a 0.5SD deficit and those
emotional phenotype. Bullying may be responsi- with BPD showed 1.5SD deficit in FEV1 which
ble for some of the emotional distress in early did not completely correct after bronchodilator.
adolescence (Wolke et al. 2015) and should be This respiratory impairment is manifest in fre-
enquired about. quent hospitalizations over the first years of life
The key question remains as to how such child- and an increased risk of being assigned a diagno-
hood symptoms are manifest in adult life. Few sis of asthma and receiving treatment (Lum et al.
studies have followed sufficient numbers into 2011). These findings are important as they indi-
adult life to understand how the transition affects cate reduced performance in early adult life, on
this spectrum. In database association studies which the well-described age-related decline in
there is evidence of increased prevalence of con- function is based. Maintaining good childhood
ditions and psychotrophic medication use, but respiratory health, promoting exercise, and
these are somewhat difficult to interpret. avoiding cigarette smoke seem particularly
important in this group of individuals (Fig. 3).
Alongside lung function deficits, very pre-
14.5 Motor Function term children appear to be at excess cardiovas-
cular risk, manifest as elevated group means
Multiple studies have demonstrated an excess of of systolic and diastolic blood pressure consis-
motor problems among very preterm children, set- tently among studies in late childhood/early
ting aside a formal diagnosis of cerebral palsy. adolescence. We have also demonstrated in-
These are manifest by impaired scores on a range creased augmentation pressures in central arter-
of motor competence and impairment scales. In a ies, particularly related to lung function (Bolton
recent systematic review of childhood studies in et al. 2012) which suggests early emergence of
very preterm or very low birthweight children, the cardiovascular risk may be related to combined
odds of a score <5th percentile on the Movement- cardiorespiratory factors, as a result of prema-
ABC were 6.3 (95% CI 4.4–9.1) and 5–15th per- turity. The extent to which this is manifest in
centile 8.7 (3.4–22) (Edwards et al. 2011). Develop- adult life as part of the metabolic syndrome is
mental coordination disorder (DCD) should be unclear and requires further study.
234 N. Marlow
a Baseline b Post bronchodilator
4 4
2 2 ULN
FEV1 Z-score
0 0
–2 –2 LLN
–4 –4
–6 –6
EP+BPD EPnoBPD Classmate EP+BPD EPnoBPD Classmate
Fig. 3 Forced Expiratory Volume (FEV1) with and with- controls using contemporary standards (Fawke et al.
out pretreatment with bronchodilator in 11-year-old chil- 2010). Permission required
dren born before 26 weeks of gestation compared to
Childhood growth may similarly be above. In a cohort from Liverpool, UK, Cooke
compromised, but the effect of the adolescent showed generally favorable outcomes for a well-
growth spurt does require some further study. characterized group of individuals who had a
Hack and colleagues demonstrated significant range of childhood problems (Cooke 2004), as did
catch up growth for females between 8 and Saigal in her well-studied group from Hamilton,
20 years of age in their very low birthweight Ontario (Saigal et al. 2006). More recently Saigal
cohort, but not for males, in some part due to the has reported outcomes in the fourth decade for her
excess of small for gestational age individuals in group. There was an excess of reduced employment
their birthweight defined cohort (Hack et al. 2003). prospects, reduced earnings, and a greater need for
social support compared to controls. They demon-
strated fewer risk-taking behaviors, more health
14.7 Adult Outcomes problems, and lower self-esteem (Saigal et al. 2016).
The challenges of neonatal care for this vulner-
As very preterm populations now reach early adult able group of individuals is thus apparent and
life, there is interest in the further progress of pre- emphasizes the critical need to provide ongoing
term populations across the range of areas of func- data from more current cohorts exposed to mod-
tion described above. Poorer group performance at ern neonatal intensive care, which is very different
school may lead to reduced employment and earn- now than 30 years ago and may show signs that
ing potential, but the extent to which these findings outcomes may not be as compromised for such a
are confounded by social disadvantage must be large proportion as it is appears to have been.
determined. In Hack’s classic study (Hack et al.
2002), very low birthweight young adults at
20 years of age had reduced attainment but fewer References
adverse social consequences, such as cigarette, rec-
reational drug, and alcohol use. This may be a Aarnoudse-Moens CS, Weisglas-Kuperus N, van
Goudoever JB et al (2009) Meta-analysis of
manifestation of the relative poor socialization of
neurobehavioral outcomes in very preterm and/or
this group of individuals. Other studies have identi- very low birth weight children. Pediatrics 124
fied persistence of many of the outcomes described (2):717–728
14 Follow-Up Outcomes of High-Risk Infants 235
Bolton CE, Stocks J, Hennessy E et al (2012) The EPICure Moore T, Hennessy EM, Myles J et al (2012) Neurological
study: association between hemodynamics and lung and developmental outcome in extremely preterm chil-
function at 11 years after extremely preterm birth. J dren born in England in 1995 and 2006: the EPICure
Pediatr 161(4):595–601 e2 studies. BMJ 345, e7961
Cooke RW (2004) Health, lifestyle, and quality of life for Mulder H, Pitchford N, Hagger M et al (2009) Develop-
young adults born very preterm. Arch Dis Child 89 ment of executive function and attention in preterm
(3):201–206 children: a systematic review. Develop Neuropsychol
Edwards J, Berube M, Erlandson K et al (2011) Develop- 34(4):393–421
mental coordination disorder in school-aged children Mulder H, Pitchford N, Marlow N (2010) Processing speed
born very preterm and/or at very low birth weight: a and working memory underlie academic attainment in
systematic review. J Dev Behav Pediatr 32(9): very preterm children. Arch Dis Child Fetal Neonatal
678–687 Ed 95:F267–F272
Farooqi A, Hagglof B, Serenius F (2013) Behaviours Mulder H, Pitchford NJ, Marlow N (2011a) Processing
related to executive functions and learning skills at speed mediates executive function difficulties in very
11 years of age after extremely preterm birth: a Swedish preterm children in middle childhood. J Int
national prospective follow-up study. Acta Paediatr 102 Neuropsychol Soc 17:1–10
(6):625–634 Mulder H, Pitchford NJ, Marlow N (2011b) Inattentive
Fawke J, Lum S, Kirkby J et al (2010) Lung function and behaviour is associated with poor working memory
respiratory symptoms at 11 years in children born and slow processing speed in very pre-term children
extremely preterm: the EPICure study. Am J Respir in middle childhood. Br J Educ Psychol 81
Crit Care Med 182(2):237–245 (Pt 1):147–160
Hack M, Flannery DJ, Schluchter M et al (2002) Outcomes Saigal S, Stoskopf B, Streiner D et al (2006) Transition of
in young adulthood for very-low-birth-weight infants. extremely low-birth-weight infants from adolescence
N Engl J Med 346(3):149–157 to young adulthood: comparison with normal birth-
Hack M, Schluchter M, Cartar L et al (2003) Growth of weight controls. JAMA 295(6):667–675
very low birth weight infants to age 20 years. Pediatrics Saigal S, Day KL, Van Lieshout RJ et al (2016) Health,
112(1 Pt 1):e30–e38 wealth, social integration, and sexuality of extremely
Hille ET, den Ouden AL, Saigal S et al (2001) Behavioural low-birth-weight prematurely born adults in the fourth
problems in children who weigh 1000 g or less at birth decade of life. JAMA Pediatr 170(7):678–686
in four countries. Lancet 357(9269):1641–1643 Scherif G (2010) Attention trajectories, mechanisms and
Johnson S, Marlow N (2011) Preterm birth and childhood outcomes: at the interface between developing cogni-
psychiatric disorders. Pediatr Res 69(5 Pt 2):11R–18R tion and environment. Dev Sci 13:805–812
Johnson S, Wolke D (2013) Behavioural outcomes and Simms V, Gilmore C, Cragg L et al (2015) Nature and
psychopathology during adolescence. Early Hum Dev origins of mathematics difficulties in very preterm chil-
89(4):199–207 dren: a different etiology than developmental
Kerr-Wilson CO, Mackay DF, Smith GC et al (2012) Meta- dyscalculia. Pediatr Res 77(2):389–395
analysis of the association between preterm delivery Spittle A (2015) Early intervention cognitive effects not
and intelligence. J Public Health 34(2):209–216 sustained past preschool. J Pediatr 166(3):779
Linsell L, Malouf R, Morris J et al (2015) Prognostic Spittle A, Orton J, Anderson PJ et al (2015) Early devel-
factors for poor cognitive development in children opmental intervention programmes provided post hos-
born very preterm or with very low birth weight: pital discharge to prevent motor and cognitive
A systematic review. JAMA Pediatr 169(12): impairment in preterm infants. Cochrane Database
1162–1172 Syst Rev 11, CD005495
Lum S, Kirkby J, Welsh L et al (2011) Nature and severity of Van Hus JW, Potharst ES, Jeukens-Visser M et al (2014)
lung function abnormalities in extremely pre-term chil- Motor impairment in very preterm-born children: links
dren at 11 years of age. Eur Respir J 37(5):1199–1207 with other developmental deficits at 5 years of age. Dev
MacKay DF, Smith GC, Dobbie R et al (2010) Gestational Med Child Neurol 56(6):587–594
age at delivery and special educational need: retrospec- Volpe JJ (2009) Brain injury in premature infants: a com-
tive cohort study of 407,503 schoolchildren. PLoS Med plex amalgam of destructive and developmental distur-
7(6), e1000289 bances. Lancet Neurol 8(1):110–124
Mathiasen R, Hansen BM, Andersen AM et al (2010) Wolke D, Baumann N, Strauss V et al (2015) Bullying of
Gestational age and basic school achievements: a preterm children and emotional problems at school age:
national follow-up study in Denmark. Pediatrics 126 cross-culturally invariant effects. J Pediatr 166(6):
(6):e1553–e1561 1417–1422
Early Markers of Poor Outcome
in Neonatal Medicine 15
Fabrizio Ferrari, Licia Lugli, Elisabetta Garetti,
Isotta Guidotti, Marisa Pugliese, and Laura Lucaccioni
Contents
15.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
15.2 Poor Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
15.2.1 Cerebral Palsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
15.2.2 Mental Retardation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
15.3 Traditional Neurological Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
15.4 Early Markers of Cerebral Palsy: The Role of
General Movements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
15.4.1 Diplegia and Tetraplegia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
15.4.2 Hemiplegia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
15.4.3 Dyskinetic CP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
15.5 Neuroimaging Predictors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
15.5.1 Cerebral Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
15.5.2 MRI Abnormalities and Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
15.5.3 Cognitive Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
15.6 Visual Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
15.7 Hearing Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
15.8 The International Classification of Functioning . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
Abstract neurodevelopmental disability and who may
A major issue for neonatologists and develop- benefit from neurological follow-up and early
mental neurologists is the identification of intervention strategies.
those infants who are at risk of subsequent The incidence of major disabilities has
decreased in very preterm and extremely pre-
term infants, although nearly half of the popu-
F. Ferrari (*) · L. Lugli · E. Garetti · I. Guidotti · lation suffers from minor disabilities as
M. Pugliese · L. Lucaccioni learning disabilities, cognitive defects, atten-
Neonatal Intensive Care Unit, Department of Medical and tion deficit/hyperactivity disorders, and behav-
Surgical Sciences of the Mother, Children and Adults,
University of Modena and Reggio Emilia, Modena, Italy ioral problems, especially at school age.
e-mail: [email protected] Neuroimaging needs to be accompanied by
# Springer International Publishing AG, part of Springer Nature 2018 237
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_164
238 F. Ferrari et al.
an accurate clinical assessment of the func- factors include neonatal encephalopathy, multiple
tional repertoire of the infant, which varies pregnancy, infection and inflammation, and a
according to the stage of development. variety of genetic factors.
CP is in part a developmental diagnosis, and it
is based on the description of motor signs that are
15.1 Salient Points disabling; such a clinical diagnosis is not easy to
make, especially early in development. CP is
• Poor outcomes comprise severe, moderate, and divided into three major types to describe different
mild deficits. movement impairments; this classification also
• A variety of standardized examination tools reflects the areas of the brain that are damaged
have been developed to detect neurological (Bax et al. 2005). The three major types are:
abnormalities and determine their course dur-
ing the neonatal period and later on during the Spastic CP: Children with this type of CP are
first 2 years of life. hypertonic and have a neuromuscular condition
• General movements represent a reliable and stemming from damage to the corticospinal tract
sensitive method in the neonatal period and or the motor cortex. Spastic CP is further clas-
early infancy for predicting normal and abnor- sified by topography dependent on the region of
mal motor outcome, particularly cerebral palsy. the body affected: spastic hemiplegia with one
• The use of MRI, both in preterm and term side being affected, spastic diplegia with the
infants, is a powerful t ool with high prognostic lower extremities affected and less upper-body
value. spasticity, and spastic tetraplegia with all four
• The combination of MRI and neurodeve- limbs affected equally. Monoplegia, paraplegia,
lopmental assessments may increase the prog- and triplegia may be used to refer to specific
nostic value of each tool, helping the manifestations of the spasticity.
identification of infants at risk for later neuro- Ataxic CP: Symptoms can be caused by damage
logical impairment. to the cerebellum; some individuals have
hypotonia and tremors, and motor skills
might be affected, as well as balance, espe-
15.2 Poor Outcome cially while walking.
Athetoid CP/dyskinetic: This is characterized by
Outcome can be categorized into severe and mixed tone and sometimes by hypotonia
moderate-to-mild deficits. Severe deficits com- (hypotonia will usually occur before 1 year of
prise CP, mental retardation (developmental quo- age; the muscle tone will be increased with age
tient of less than 70), and severe visual or hearing and progress to hypertonia). People with
impairment. Severe deficits can be detected within athetoid CP have trouble holding themselves
the first 2 years of life. Moderate-to-mild deficits, in an upright, steady position for sitting or
however, are often not detected until school age walking and often show involuntary move-
(Marlow et al. 2005). ments. The damage occurs to the extrapyrami-
dal motor system and/or pyramidal tract and to
the basal ganglia (BG) (Rosenbaum et al.
15.2.1 Cerebral Palsy 2005; Palisano et al. 1997).
Cerebral palsy (CP) is a major disability which is In 2004, an international meeting on the defini-
defined as a group of disorders of movement and tion and classification of CP was held in Bethesda.
postural control caused by a nonprogressive The major addition to the classic Bax and Mutch
defect or lesion of the developing brain. The lead- et al. (Rosenbaum et al. 2005) definitions involved
ing prenatal and perinatal risk factors for CP are emphasis on the accompanying developmental dis-
birth weight and gestational age, but other risk turbances that accompany neurodevelopmental
15 Early Markers of Poor Outcome in Neonatal Medicine 239
disabilities: these are often functionally more A hearing impairment or deafness is a full or
important than the developmental motor disorders partial decrease in the ability to detect or under-
that are, by definition, the hallmark of CP stand sounds. It can be classified as conductive or
(Rosenbaum et al. 2005). The severity of CP is sensorineural hearing loss (Dubowitz et al. 1998;
nowadays classified according to the Gross Motor Romeo et al. 2009).
Function Classification System (GMFCS) for
cerebral palsy: it is a reliable and predictive 15.2.2.2 Minimal Neurological
internationally adopted method of scoring gross Dysfunction
motor function in children with CP (Palisano Nearly half of very preterm (VP) and extremely
et al. 1997). preterm (EP) infants suffer from minor disabil-
The revised and expanded version of the ities. The term “minor motor problems” indicates
GMFCS describes the movement ability of chil- a wide spectrum of motor disorders other than CP;
dren with CP in one of five ordinal levels across “minor” does not mean “minimal,” as a relevant
five age bands, with emphasis on the child’s typ- proportion of the preterm infants will develop
ical performance in different settings. Children at academic and behavioral problems at school age.
level I perform the same activities as their Early-onset disorders consist of abnormal general
age-matched peers but with some difficulty in movements (GMs), transient dystonia, and pos-
speed, balance, and coordination, while children tural instability; these conditions usually fade dur-
at level V have difficulty controlling their head ing the first months. They were underestimated in
and trunk posture in most positions and achieving the past; recently, qualitative assessment of GMs
any voluntary control of movement. The GMFCS using. Prechtl’s method has become a major item
has been incorporated recently into most CP reg- of the neurological examination. Late-onset dis-
istry data sets, so there are few studies comparing orders include developmental coordination disor-
the distribution of GMFCS levels in CP popula- der (DCD) and/or minor neurological dysfunction
tion cohorts or assessing changes in levels over (MND): both terms cover partly overlapping
time (Palisano et al. 2008). problems. Simple MND (MND-1) and complex
MND (MND-2) can be identified, and MND-2
gives a higher risk for learning and behavioral
15.2.2 Mental Retardation disorders. A relationship between the qualities of
GMs and MND in childhood has been recently
Mental retardation (MR) or intellectual disabil- described. The Touwen infant neurological exam-
ity is defined as a disability that involves signif- ination (TINE) can reliably detect neurological
icant limitations both in intellectual functioning signs of MND even in infancy. However, the
and in adaptive behavior, which covers many prognostic value of these disorders requires fur-
everyday social and practical skills. This dis- ther investigations. Anyway the high rate of
ability originates before the age of 18 years MNDs and their association with an increased
and encompasses a wide range of conditions, risk for learning difficulties justify their screening
types, and levels. in case of (even moderate) prematurity. Moreover,
children born extremely preterm are at high risk
15.2.2.1 Visual Disability and Hearing for intellectual disability (ID), learning disabilities
Impairment (LD), executive dysfunction, and special educa-
Visual disability is the impairment of visual func- tional needs (SEN), but little is understood about
tioning even after treatment and/or standard the comorbidity of intellectual and learning dis-
refractive correction, with a visual acuity in the abilities in this population. A recent study showed
better eye of less than 6/18 for low vision and 3/60 that extremely premature children with comorbid
for blindness or with a visual field of less than ID/LD had significantly poorer neuropsychologi-
10 degrees from the point of fixation (according to cal abilities and curriculum-based attainment than
the WHO definition). extremely premature children with an isolated
240 F. Ferrari et al.
disability or no disabilities. LD were associated periventricular densities can be associated with
with a three-times increased risk for SEN. There- both normal and abnormal neurodevelopment. A
fore, as extremely premature children are at high high correlation between the HINE at 3 months
risk for comorbid intellectual and learning disabil- and the developmental quotient at 24 months was
ities, education professionals should be aware of found. The high predictive value of the HINE
the complex nature of EP children’s difficulties across the first year of life was probably granted
and the need for multi-domain assessments to by the effective combination of different groups of
guide intervention (Arnaud et al. 2007; Ferrari items for each age period. Indeed, although a
et al. 2012; Johnson et al. 2016). number of items were found to be consistently
among the most predictive ones (movement qual-
ity, quantity, and lateral tilting), other items
changed across time. Tone items (ventral suspen-
15.3 Traditional Neurological sion, arm pronation/supination, and scarf sign)
Examination tended to be more predictive at 3 and 6 months
post-term, while maturational items, such as arm
A variety of standardized examination tools have protection, vertical suspension, and forward para-
been developed to estimate gestational age, detect chute, were highly predictive only after 9 months.
neurological abnormalities, and determine their Therefore these studies demonstrated that a stan-
course during the neonatal period and later on dardized neurological examination performed
during the first 2 years of life (Dubowitz et al. from 3 to 12 months can be used reliably in very
1998). Infants at high risk of brain damage may be preterm infants to predict motor outcome (Romeo
included in follow-up programs comprising serial et al. 2009).
neurological examinations in order to identify The predictive value of the HINE examination
early indicators of abnormal neurological devel- was also evaluated in infants with other
opment. A simple and scorable neurological neurodevelopmental risks, like infants with
examination for infants between 2 and 24 months hypoxic-ischemic encephalopathy (HIE) (see
of age was developed in the Paediatric Depart- ▶ Chap. 126, “Clinical Aspects and Treatment
ment of the Hammersmith Hospital in London of the Hypoxic-Ischemic Syndrome”).
(the Hammersmith Infant Neurological Examina- Follow-up studies have demonstrated that the
tion [HINE]) (Rosenbaum et al. 2005). The outcome cannot be always predicted by the sever-
assessment consists of different items assessing ity of HIE. Although HIE stage 1 is usually asso-
cranial nerve function, posture, movements, tone, ciated with a normal outcome and HIE stage
reflexes, the development of motor function, and 3 with severe neurodevelopmental abnormalities,
the state of behavior (Dubowitz et al. 1998). For the outcome in infants with HIE stage 2 can be
details, see ▶ Chap. 120, “Neurological Examina- quite variable, ranging from normal to CP and
tion of the Newborn Infant.” severe MR. Several studies have reported that
The prognostic power of the HINE optimality neurodevelopmental outcome is best predicted
score was explored in very preterm infants by the pattern of lesions observed on neonatal
between 9 and 18 months of age: 48% had sub- MRI (see ▶ Chap. 122, “Neuroimaging Studies”).
optimal scores; the scores were not associated The HINE was used in a group of infants with HIE
with the degree of prematurity and had a very at age 9–14 months to evaluate the correlation
high accuracy to predict walking at 2 years. The between the scores and early MRI findings and
scores were also not invariably associated with the whether the scores can be used to predict locomo-
pattern of ultrasonogram findings: cystic peri- tor function at 2 and 4 years. Approximately 40%
ventricular leukomalacia (PVL) was associated of the infants had suboptimal scores on neurolog-
with low scores, and other ultrasonogram abnor- ical examination, and the magnitude of the sub-
malities with both optimal and suboptimal scores. optimal scores was related to the pattern of the
This is not surprising because hemorrhages and MRI lesion. Severe BG lesions, diffuse brain
15 Early Markers of Poor Outcome in Neonatal Medicine 241
injuries, or both were associated with the most enough to allow for a reliable prognosis. Irritability,
severe outcome (Romeo et al. 2009). abnormal finger position, spontaneous Babinski
The use of the optimality score gave prognostic reflex, weakness of the lower limbs, transient
information on the severity of the functional abnormalities of tone, and delay in achieving
motor outcome. Although neonatal MRI can iden- motor milestones are some of the neurological
tify early infants who will have CP, the neurolog- signs that have been described in these high-risk
ical examination can provide information on the preterm infants. All of them may be encountered
severity of the functional motor impairment and before the onset of CP or during transient dystonia,
distinguish infants who will walk from those who dissociated motor development, and other transient
will only sit or not even acquire the sitting posture. neurological disturbances that vanish during the
It is interesting, however, that few children who first or second year of life.
were able to walk without restrictions at 4 years In the last two decades, a technique for
had an abnormal gait, associated with a mild assessing spontaneous motor activity has been
hemiplegia or with mild movement disorders, introduced and evaluated, namely, Prechtl’s
which suggested that mild neurological abnormal- assessment of general movements (GMs). This
ities can also occur in the absence of widespread approach, which involves observation of the
lesions or severe abnormalities. Further studies infant without direct physical examination, has
evaluating follow-up at school age are required proved a reliable and sensitive method in the
to evaluate whether these minor neurological neonatal period and early infancy for predicting
abnormalities are related to any difficulty in normal and abnormal motor outcome, particularly
everyday life (Ricci et al. 2006a). CP (Prechtl et al. 1997). It requires video record-
ing of a few minutes of spontaneous motility and
off-line observation of the quality of GMs. Serial
15.4 Early Markers of Cerebral Palsy: assessments of GMs from preterm birth until
The Role of General Movements 3–5 months post-term age define the developmen-
tal trajectory. Assessment based on developmen-
The types of brain injuries most frequently occur- tal trajectory predicts CP at a much earlier age
ring in term infants are hypoxic-ischemic injury to than other neurological assessment.
the BGT and parasagittal injury, and in preterm Recently, data evaluating the accuracy of mul-
infants PVL, intraventricular hemorrhages (IVH), tiple modalities used to predict a diagnosis of CP
and persistent flare. in high-risk patients showed how GMs present the
CP occurs in 8–10% of very preterm babies highest predictive accuracy. Moreover, there were
and approximately 40% of all children with CP evidences to support the use of MRI at term-
are born preterm. In preterm infants spastic diple- corrected age, neurological examination in the
gia prevails, followed by hemiplegia. In full-term older infant, and, to a lesser extent, ultrasound in
infants, tetraplegia and hemiplegia are by far the infants of preterm age (Bosanquet et al. 2013; Xie
most common forms; dyskinetic CP is more com- et al. 2015).
mon in full-term infants (Marlow et al. 2005).
The early prediction of CP will lead to the child
receiving neurological follow-up and earlier 15.4.1 Diplegia and Tetraplegia
enrolment in rehabilitation program. It is gener-
ally reported that CP cannot be diagnosed before Early specific markers for spastic cerebral palsy
several months after birth or even before the age are cramped-synchronized (CS) GMs and abnor-
of 2 years. A so-called silent period, lasting up to mal fidgety GMs. As far as CS GMs, the move-
few months, has also been described. ments of limbs and trunk appear rigid and lack
The neurological signs observed during the first normal smooth and fluent character. The limb and
months after birth in preterm infants who will trunk muscle contract and relax almost simulta-
develop CP are neither sensitive nor specific neously. All infants who show consistent and
242 F. Ferrari et al.
prolonged CS GMs later develop CP. The earlier independent digit movements is seen as early as
consistent CS GMs occur, the worse the later 12 weeks and predicts later HE. It is important to
motor impairment of preterm infants. If the CS note that only infants with concomitant ipsilateral
character is transient and followed by normal fidg- involvement of a cerebral hemisphere, BG, and
ety GMs, the infant may have a normal outcome the internal capsule on the MRI brain scan later
(Ferrari et al. 2002); if the CS character is still develop HE. Early recognition of subtle motor
present at 3 to 4 months of age, the infant will asymmetries is not easy with unaided eyes; it is
not develop fidgety movements (FMs) (Einspieler easier when video recording of spontaneous
et al. 2015). The second specific marker for CP is motor behavior is available (Guzzetta et al. 2003).
absent FMs. Almost all infants who never had A more recent and accurate multicenter study
FMs developed CP. The absence of FMs can be in infants who later developed hemiplegia,
preceded either by CS GMs or by poor repertoire conducted by the same research group but consid-
(PR) GMs. Both abnormal qualities of GMs, i.e., ering a new group of patients, confirmed the
CS GMs and absence of FMs, are seen within asymmetry and impoverishment of wrist segmen-
3–5 months post-term, thus much earlier than tal movements in the limb contralateral to the side
with other neurological assessment (Ferrari et al. of central focal lesion, but it also highlights new
2002). It was recently demonstrated by Einspieler findings: hemiplegia can be predicted by an early
et al. that infants with sporadic FMs and those with reduction in the frequency of independent upper
absent FMs (who developed CP) showed no dif- limb digit movements. In particular none of the
ference with respect to their GMFCS levels 3 to infants with abnormal outcome showed more than
5 years later. However, sporadic FMs were linked one digit movement per minute (with one excep-
to a slightly better (although not normal) concur- tion), whereas 10 out of the 13 infants with sym-
rent movement repertoire (Einspieler et al. 2015). metrical wrist movements had normal motor
development. It is important to note that the
degree of impoverishment or asymmetry was not
15.4.2 Hemiplegia correlated with the severity of later motor impair-
ment. All three of the infants with symmetrical
Hemiplegia (HE) is usually due to focal one-sided wrist movements who had abnormal neurological
lesions, either ischemic or hemorrhagic infarction, outcome developed a very mild form of hemiple-
more rarely to cystic lesions due to focal or uni- gia (Guzzetta et al. 2010).
lateral PVL. Brain US and MRI detect site and
severity of the focal lesions: the neurological
follow-up of these infants aims to detect 15.4.3 Dyskinetic CP
(or exclude) early signs of HE. Traditional neona-
tal neurological examination is of low predictive Dyskinetic CP has a frequency of only 10–15% of
value for such patients. all CP forms. The dyskinetic form of CP com-
The studies carried on with the GM method prises two subtypes: a syndrome of
have shown that all babies with a focal lesion have choreoathetosis (infants showing mainly massive,
an abnormal quality of GMs (PR or CS) from purposeless involuntary movements) and a dys-
term, and a silent window is not observed. Asym- tonic form, characterized by sudden shifts of mus-
metrical segmental movements can be recognized cle contraction and infantile reflex activity. This
from as early as 3 months post-term in preterm second subtype is more common. During the first
infants and from 3–6 weeks post-term in full-term 2 months, infants who will develop a dyskinetic
infants with neonatal cerebral infarction. Segmen- form display a PR of GMs, arm movements in
tal movements are distinct wrist movements, circles, and finger spreading. Abnormal arm and
occurring either in isolation or as a part of GMs. finger movements remain until at least 5 months
In term infants who later develop HE asymme- and are associated with lack of arm and leg move-
try in wrist movements, a lower frequency of ments toward the midline (particularly foot-foot
15 Early Markers of Poor Outcome in Neonatal Medicine 243
contact) and with lack of FMs. The abnormal I or II PVL) and size of the corpus callosum are
unilateral or bilateral circular arm movements also related to neuromotor function in school-age
are monotonous, slow forward rotations from the children without CP. New techniques such as
shoulder. The monotony in speed and amplitude is transmastoidal access have improved the repre-
the most characteristic quality of circular arm sentation of the cerebellum, a structure that can
movements. also be injured in very low birth weight (VLBW)
An early differential diagnosis of dyskinetic infants. Cerebellar injuries may contribute to
versus spastic later CP is not easy: later dyskinetic long-term neurocognitive disabilities, indepen-
infants share the absence of FMs and antigravity dent of associated supratentorial parenchymal
movements, i.e., leg lifting in infants with later lesions (Marlow et al. 2005).
spastic form. Moreover, circular arm movements Cerebral US is useful in the critically ill new-
can be mistaken for windmilling arm movements born who cannot be studied with MRI. During the
seen during the first year of life and with cycling first hours after asphyxia, US may give little infor-
movements described in infants with HIE. mation on the severity of lesions and prediction of
Choreoathetoid movements are easy to recognize, outcome. Arterial Doppler studies (measurement
but the sudden shifts of muscle contraction are of the pulsatility index) may better predict out-
difficult to differentiate from the abnormal muscle come, but in most cases it is still normal 6–12 h
tone of spastic forms. Dystonic and spastic fea- after the insult. The most frequent lesion observed
tures are quite commonly mixed in the same infant by US in asphyxia is BGT hyper-echogenicity,
(Einspieler et al. 2002). while parasagittal ischemia is more difficult to
detect, because the distance between brain lesions
and the acoustic window is high.
15.5 Neuroimaging Predictors
Besides neurological assessment of the infant 15.5.2 MRI Abnormalities
with neonatal brain injury or at risk for neurodeve- and Outcome
lopmental disturbances, neuroimaging can pro-
vide predictors of neurodevelopmental outcome. MRI of the preterm infant is best performed at
Two main imaging techniques have been used for term-equivalent age when the myelination of the
the prediction of neurodevelopmental outcome in posterior limb of the internal capsule (PLIC) may
the neonatal period: US and MRI (see ▶ Chap. be used as a predictor of motor outcome. MRI
122, “Neuroimaging Studies”). lesions in the full-term infant are best seen after
the first week.
In the preterm infant, MRI has been used to
15.5.1 Cerebral Ultrasound detect diffuse WM abnormalities and gray matter
changes. Gray matter abnormalities are also asso-
US is a simple bedside tool, and when used repeat- ciated with the same risks but to a lesser extent
edly, its sensitivity and specificity can be very than WM abnormalities. WM abnormalities can
high, especially in the preterm infant. US lesions be detected in more than 50% of VLBW children
can be detected in the majority of infants born and are predictive of CP and psychomotor delay
below 32 weeks of gestation who develop in early childhood and neurosensory impairment.
CP. IVH grades III and IV, PVL, and focal infarc- A significant relationship between WM abnor-
tions are major cerebral lesions detected by US in malities on MRI and absent FMs in infants born
the preterm population. Also infants with a grade at <30 weeks of gestation supports the idea that
I–II IVH are at an almost two times higher risk of abnormal GMs reflect white matter injury (Spittle
developing neurodevelopmental impairments at et al. 2008).
20 months compared with those without any hem- Recently it has been shown that HIE, typically
orrhage. The degree of milder US findings (grade described in full-term infants, can also be
244 F. Ferrari et al.
observed in preterm infants. These infants have a development during the preterm period, especially
high incidence of severe BGT and brainstem in the left hemisphere. Recent studies revealed
involvement, and the lesions are associated with impairment of cortical folding in extremely pre-
significant mortality and neurologic morbidity. term newborns relative to late preterm newborns,
Advanced MRI techniques such as volumetry demonstrating its potential to provide biomarkers
and morphometry, diffusion tensor imaging, and of prematurity-related developmental outcome
tractography have been used to better determine (Kim et al. 2016; Orasanu et al. 2016). However,
the full spectrum of brain injury. MRI at term age by itself cannot predict the func-
In infants born preterm and examined at term, tional outcome with 100% accuracy: neurodeve-
abnormalities in the cortex and deep nuclear struc- lopmental assessments, and in particular general
tures are related to the degree of immaturity at movements, have an important role as they can
birth and concomitant WM injury. Volumetric identify infants at risk for later neurological impair-
changes in the sensorimotor, premotor, mid- ment and may enhance the prognostic utility of
temporal, and parieto-occipital regions may be MRI if used in combination (Olsen et al. 2016).
related to intellectual performance at school age. Brain injury in neonates following hypoxic-
Brain volumes may be considered important ischemic encephalopathy (HIE) prior to the intro-
markers for neurodevelopmental deficits in mod- duction of neuroprotection with hypothermia was
erate and late preterm children. In fact, larger total generally described in MRI studies as either WM
brain tissue, WM, and cerebellar volumes at term- injury extending to the cortical areas or deep gray
equivalent age are seen to be associated with nuclei injury in the BGT or involvement in both
better neurodevelopment in moderate and late areas. In childhood, these areas of brain injury were
preterm children (Cheong et al. 2016). associated with cognitive delays and motor impair-
Recent findings indicate that the hippocampal ment (Rutherford et al. 2006). HIE and BGT are
volume may be reduced in preterm infants and that often associated with abnormal signal intensity in
it is associated with reduced working memory and the PLIC, brainstem, hippocampal region, and cor-
cognitive and motor performance at 2 years of age. tex, particularly around the central fissure and
Moreover, a small transcerebellar diameter and insula. Loss of the normal signal intensity from
short corpus callosal length on brain MRI at term- the PLIC is associated with adjacent BGT injury.
equivalent age are related to adverse neurodeve- The motor correlate is a spastic or dyskinetic
lopmental outcomes at a corrected age of 2 years CP. BGT lesions are the imaging signature of an
and could be a useful adjunctive tool for counseling acute and profound hypoxic-ischemic event. BGT
parents about future developmental outcomes. lesions associated with severe WM damage, con-
Biparietal width (BPW) and interhemispheric dis- versely, suggest a more prolonged hypoxic-
tance (ID) have recently been considered important ischemic insult. WM damage is proved by a loss
MRI findings for brain development of preterm of gray matter/WM differentiation, consistent with
infants at term-equivalent age. It was found that an overt infarction: in these infants a very poor
decreased BPW and increased ID were indepen- outcome can be expected. When the predominant
dently associated with delayed cognitive develop- lesion involves the WM and cortex but spares the
ment (Kidokoro et al. 2014). Cerebral cortical BG and PLIC, the pattern probably results from
folding becomes dramatically more complex in prolonged partial hypoxia-ischemia: the motor out-
the fetal brain during the third trimester of gesta- come is often good, but there may be cognitive and
tion; the process continues in a similar trend in behavioral impairments that are proportionate to
children who are born prematurely. To quantify the extent of WM and cortical injury. Severe BGT
this morphological development, it is necessary to lesions are associated with a high risk of develop-
extract the interface between gray matter and white ing CP and severe cognitive impairment regardless
matter, which is particularly challenging due to of the additional associated WM lesions (Ruther-
changing tissue contrast during brain maturation. ford et al. 1998). Hypothermia initiated within 6 h
The prefrontal and temporal lobes exhibit most of age at 33–34 C and continued for 72 h
15 Early Markers of Poor Outcome in Neonatal Medicine 245
decreases death or disability at 18–24 months of for neonatal HIE. The 6- to 7-year outcomes of trial
age or increases the number of normal survivors. participants in the NICHD trial and the Total Body
Rutherford et al. have reported MRI results of the Hypothermia for Neonatal Encephalopathy trial
“Total Body Hypothermia for Neonatal Encepha- have recently been reported showing decreased
lopathy Trial” demonstrating a reduction in lesions mortality and better neurodevelopmental outcome
in the BGT, WM, and abnormal PLIC among in childhood in the cooled group. Shankaran et al.
cooled infants. The accuracy of prediction by recently examined also the ability of MRI patterns
MRI of death or disability to 18 months of age of neonatal brain injury defined by NICHD to
was 84% in the cooled group and 81% in the predict death or IQ at 6–7 years of age following
non-cooled group. The site and severity of brain hypothermia for neonatal encephalopathy. MRI
lesions seen on MRI have been also correlated to pattern of neonatal brain injury resulted a marker
the quality of general movements in term infants of outcome at 6–7 years of age among neonates
with HIE to and the prognostic value of MRI, and undergoing whole-body hypothermia or normo-
general movements for motor outcome have been thermia for neonatal HIE. It was demonstrated
compared. MRI scores for the basal ganglia and that pattern of neonatal brain injury with involve-
thalami, posterior limb of the internal capsule, ment of either BGT, PLIC, or area of infarction and
white matter, and cortex and lesion patterns were additional cerebral lesions or cerebral hemispheric
correlated with 1-month and 3-month general devastation has high predictive indices for death or
movements and general movement trajectories; IQ <70 at 6–7 years of age, and a normal MRI was
central gray matter scores were correlated most also predictive of a normal outcome. Therefore, the
strongly with cramped-synchronized general neonatal MRI injury pattern may serve as a bio-
movements and abnormal motor outcome. MRI marker of brain injury and, along with follow-up,
scores were 100% sensitive and 72.2% specific may be useful to evaluate response to future
for motor outcome, and cramped-synchronized neuroprotective strategies (Shankaran et al. 2012;
general movements were 100% specific and Azzopardi et al. 2014; Shankaran et al. 2015).
68.7% sensitive for motor outcome. Therefore, in
term of infants with HIE, the site and severity of
brain lesions seen on early MRI resulted highly 15.5.3 Cognitive Evaluation
correlated with general movements. Central gray
matter damage leads to cramped-synchronized The most widely used standardized developmen-
general movements and poor motor outcome. tal scales to assess mental development in the first
Early MRI scans and general movements are com- two years after birth are the Bayley Scales of
plementary tools for predicting motor outcome Infant Development (BSID) and the Griffiths
(Ferrari et al. 2011). The National Institute of Mental Developmental Scales.
Child Health and Human Development (NICHD) The new Bayley Scales of Infant and Toddler
Neonatal Research Network (NRN) investigators Development, third edition, includes updated items
described a decrease in areas of infarction in the and modernized stimulus materials and manipula-
watershed (WS) area among infants in the hypo- tives and yields mental assessment results as sepa-
thermia group and described an MRI pattern of rate cognitive and language scores rather than as
brain injury that correlated with death or disability separate scores for cognitive, language, and motor
at 18 months of age. The “Infant Cooling Evalua- scales and separate scores for expressive and recep-
tion trial group” showed that WM injury decreased tive communication and for fine and gross motor
among cooled infants compared with the skills. The associated Adaptive-Behavior parent
non-cooled group, and PLIC and BGT injury questionnaire is an excellent addition to the new
were associated with death or disability at Bayley scales, giving functional information that
24 months of age. Thus, the neonatal MRI assess- can be used to support a tested significant mental
ment of brain injury appears to be a biomarker of delay. On the other hand, the Griffiths Mental
18- to 24-month outcome following hypothermia Development Scales for children from birth to
246 F. Ferrari et al.
24 months, reviewed in 1996, comprises items to infants with brain lesions even in the absence of
assess locomotor, personal-social, hearing and lan- ocular abnormalities (cortical blindness). Blind-
guage, eye and hand coordination, and performance ness affects early motor development, especially
domain. Domain raw scores are obtained and self-initiated postures and locomotion.
converted to standardized sub-quotients, percen- Term infants with HIE can show visual abnor-
tiles, and developmental age, the sum of which is malities (reduction in visual acuity, fixation shift,
the general quotient, a score for an overall develop- or visual fields) in the first years of life. Occipital
mental level. cortex and optic radiation injury have been found
The purpose of developmental standardized in infants with visual impairment, but cortical and
scales is to assess a child’s development at the WM lesions sparing the BG are not always asso-
time of observation, to determine developmental ciated with abnormal visual findings. Cortical and
delay or impairment, in order to implement early BG lesions are always associated with severe
habilitation interventions. Despite the wide use of abnormalities of visual function during the first
standardized scales to determine the extent of devel- year of life, confirming the role of BG in human
opmental delay or impairment, major concern visual development. Poor acuity, weak stereopsis,
remains about their accuracy in discriminating cog- and delayed visual maturation can occur in chil-
nitive function. To evaluate specific cognitive defi- dren with focal BG lesion (Mercuri et al. 1997).
cits, it is essential to use neuropsychological tests VLBW infants are at risk of visual,
and to continue cognitive follow-up at least visuocognitive, and visuomotor impairment.
until school age. Developmental scales are not Vision loss for preterm infants is given as visual
intelligence tests, and developmental quotients impairment with the best vision after correction of
(DQ) calculated in the first 2 years are not as reliable <20/60 or legal blindness with the best corrected
as the intelligence quotient (IQ) measurement, cal- vision of <20/200 (<6/60). Severe visual impair-
culated after the first 3 years of life, nor do they have ment occurs in 1–3% of ELBW and 2–6% in
as good a predictive value for later IQ. However, children with gestational ages below 27 weeks.
in preterm populations, a score of two standard Retinopathy of prematurity (ROP) is one of the
deviations (SD) below the normative mean has main causes of poor visual function and blindness;
been used as a cutoff to identify abnormalities. prevention is based on ophthalmic screening to
Currently, following a consensus statement, many identify cases requiring treatment. Less severe
authors suggest that a cutoff of three SD is more visual impairments include refractive errors,
appropriate and may be more predictive of later reduced visual acuity, strabismus, and nystagmus.
poor performance (Marlow et al. 2005). IVH and PVL are other causes of visual impair-
Recent studies on preterm infants demonstrated ment (Ricci et al. 2006b). Severity of visual
that abnormal GMs also reflect impairment of brain impairment is also related to the extent of basal
areas involved in cognitive development. A sys- ganglia, lateral geniculate nuclei, and optic radia-
tematic review by Einspieler et el. underlines that tion involvement. Fractional anisotropy of the
normal GMs associated with normal motor reper- optic radiation was related to visual assessment
toire during the first months after term are markers scores, independent of WM maturation.
for normal cognitive development until at least the Assessment of visual function at term-
age of 10 (Einspieler et al. 2016). corrected age includes ability to fix and follow a
target, preferential looking, attention at distance,
and color and stripe discrimination. Measures of
15.6 Visual Evaluation early visual cortical function are orientation rever-
sal visual event-related potentials (OR-VERP)
Subcortical visual pathways have a major role in and fixation shifts under competition. Both mea-
neonatal vision, while cortical visual modules sures correlate with the severity of brain abnor-
progressively emerge during the first months of malities and are sensitive predictors of
postnatal life. Abnormal visual function occurs in neurodevelopmental outcome at 2 years.
15 Early Markers of Poor Outcome in Neonatal Medicine 247
Post-discharge eye examinations until pre- Although as many as 6% of children with ges-
school are useful to monitor refractive errors and tational age below 26–27 weeks have severe to
to prevent amblyopia. profound hearing impairment, many function well
after the early placement of cochlear implants.
Children with undiagnosed HL can experience
15.7 Hearing Evaluation delays in the development of language, social, and
academic skills. Besides the degree of hearing loss
Hearing loss (HL) is one of the most common birth and age at onset of deafness, environmental fac-
defects (3/1000) and is associated with language tors (parental support and education methods)
and perception disorders. Genetic factors, prema- seem to play an important role in the cognitive
turity, low birth weight, hyperbilirubinemia, phar- development and academic success. As language
macologic ototoxicity, and noise exposure are the development begins within the first months of life,
main causes of HL. The introduction of universal it is important for parents to be aware of normal
screening resulted in a significant decrease of HL. language and communication developmental
Otoacoustic emissions (OAE) and auditory milestones beginning when their baby is very
brainstem response (ABR) are employed in new- young so that they can discuss development with
born hearing screening programs. The OAE mea- their child’s healthcare provider (Santiago-
sures the inner ear response to sound by placing a Rodriguez et al. 2005).
microphone in the ear canal. The ABR records the
brain’s response to sound by placing electrodes on
the head. 15.8 The International Classification
Auditory steady-state responses have been of Functioning
reported as a reliable and objective technique for
evaluating the hearing threshold. ABR and auditory The international classification of functioning
steady-state responses in infants with perinatal brain describes “functioning” as the dynamic interac-
injury show a high sensitivity of auditory steady- tion among three dimensions: body function/
state responses for detecting hearing impairment. structure, activity and participation, and environ-
In term infants, much hearing impairment is mental factors. Several authors have proposed
due to specific gene abnormalities, including the “neuromotor” or “neurobehavioral” assessments
connexin mutation. Some authors state that that evaluate the dynamic and developing systems
hypoxia-ischemia damages cochlear hair cells, in order to identify the “emerging functions” and
causing hearing impairment. Infants carrying the skill of adaptability to different stimuli. The
genetic mutations for hearing loss may coinciden- hypothesis is that this functional approach to
tally experience perinatal stress, but prevalence of neurodevelopmental evaluation may better relate
hearing impairment in children born with HIE is to later outcomes and focus on the consequences
not significantly increased. rather than on the disease itself. The role of
In preterm infants, sensorineural HL has been neurofunctional assessment has been emphasized
associated with prolonged ventilation, ligation of by authors involved in rehabilitative fields:
patent ductus, hypotension and ototoxicity, infec- neurodevelopmental treatment and bobathian
tions, craniofacial abnormalities, and family his- practice in the United Kingdom, education
tory. All extremely low birth weight (ELBW) therapeutique and evaluation factorielle by Tar-
infants are considered at high risk for HL, and in dieu in France, and pattern analysis and
most centers hearing testing is done prior to inten- neurorehabilitative semeiotics by Milani in Italy.
sive care discharge, either as OAE or full diag- Identification of infants at higher risk of later
nostic testing with ABR. Occasionally, this test negative developmental outcome remains a chal-
defines auditory neuropathy with abnormal audi- lenge for clinicians, especially in the preterm. This
tory brainstem function and a strong cochlear problem has been investigated mainly by using
microphonic with normal OAE. standard neurological assessments, which evaluate
248 F. Ferrari et al.
the relation between the nature and localization of of minor neuromotor dysfunctions at age 5 years in
brain lesions and related dysfunctions. prematurely born children: the EPIPAGE study. Arch
Pediatr Adolesc Med 161:1053–1061
However, new approaches to disability are Arpi E, Ferrari F (2013) Preterm birth and behaviour prob-
desirable considering the multidimensional nature lems in infants and preschool-age children: a review of
of the problem. Neurofunctional assessment and the recent literature. Dev Med Child Neurol 55:788–796
study of emerging functions in premature infants Azzopardi D, Strohm B, Marlow N, Brocklehurst P,
Deierl A, Eddama O et al (2014) Effects of hypother-
relate to prognosis better than standard neurolog- mia for perinatal asphyxia on childhood outcomes.
ical examination. N Engl J Med 371:140–149
Advances in obstetric and neonatal care have Bax M, Goldstein M, Rosenbaum P et al (2005) Proposed
dramatically improved the survival rate of very definition and classification of cerebral palsy. Dev Med
Child Neurol 47:571–576
low birth weight (VLBW; birth weight < 1500 g) Bosanquet M, Copeland L, Ware R, Boyd R (2013)
infants over the last decade. As a result, questions A systematic review of tests to predict cerebral palsy
arise about their long-term neurodevelopmental in young children. Dev Med Child Neurol 55:418–426
outcome. Cerebral palsy occurs in 10–15% of Cheong JL, Thompson DK, Spittle AJ, Potter CR, Walsh
JM, Burnett AC, Lee KJ, Chen J, Beare R, Matthews
the VLBW population, with higher rates in infants LG, Hunt RW, Anderson PJ, Doyle LW (2016) Brain
of lower birth weight and gestational age. An Volumes at Term-Equivalent Age Are Associated with
increased incidence of minor neurological dys- 2-Year Neurodevelopment in Moderate and Late Pre-
functions, such as learning disabilities, cognitive term Children. J Pediatr 174:91–97.e1
Dubowitz L, Mercuri E, Dubowitz V (1998) An optimality
defects, attention deficit/hyperactivity disorders, score for the neurologic examination of the term new-
and behavioral problems, has been reported, espe- born. J Pediatr 133:406–416
cially in school children of extremely low birth Einspieler C, Cioni G, Paolicelli PB et al (2002) The early
weight or gestational age. markers for later dyskinetic cerebral palsy are different
from those for spastic cerebral palsy. Neuropediatrics
Neurofunctional assessment is an additional 33:73–78
method for evaluating neurodevelopmental dis- Einspieler C, Yang H, Bartl-Pokorny KD, Chi X, Zang FF,
ability in infants at high risk; the functional Marschik PB, Guzzetta A, Ferrari F, Bos AF, Cioni G
approach to pediatric and neontological fields is (2015) Are sporadic fidgety movements as clinically
relevant as is their absence? Early Hum Dev 91:247–252
also recommended by the World Health Organi- Einspieler C, Bos AF, Libertus ME, Marschil PB (2016)
zation, as this approach allows early intervention The general movement assessment helps us to identify
and targeted follow-up, besides reassuring parents preterm infants at risk for cognitive dysfunction. Front
on integrity of function. In particular the Interna- Psychol 7:406
Ferrari F, Cioni G, Einspieler C et al (2002) Cramped
tional Classification of Functioning (ICF) for synchronized general movements in preterm infants as
Children and Youth was proposed as instrument an early marker for cerebral palsy. Arch Pediatr
of global assessment of the child, the Alberta Adolesc Med 156:460–467
Infant Motor Scale (AIMS) for the evaluation of Ferrari F, Todeschini A, Guidotti I, Martinez-Biarge M,
Roversi MF, Berardi A, Ranzi A, Cowan FM, Ruther-
motor functions during the first 18 months of age, ford MA (2011) General movements in full-term
the Gross Motor Function Classification System infants with perinatal asphyxia are related to basal
(GMFCS) specific for severe mental retardations ganglia and thalamic lesions. J Pediatr 158:904–911
and cerebral palsy, and VINELAND for adaptive Ferrari F, Gallo C, Pugliese M, Guidotti I, Gavioli S,
Coccolini E, Zagni P, Della Casa E, Rossi C, Lugli L,
functions (World Health Organization 2001; Todeschini A, Ori L, Bertoncelli N (2012) Preterm
Picciolini et al. 2006; Arpi and Ferrari 2013). birth and developmental problems in the preschool
age. Part I: minor motor problems. J Matern Fetal
Neonatal Med 25:2154–2159. https://doi.org/10.3109/
14767058.2012.696164
References Guzzetta A, Mercuri E, Rapisardi G et al (2003) General
movements detect early signs of hemiplegia in term
Arnaud C, Daubisse-Marliac L, White-Koning M, infants with neonatal cerebral infarction. Neuropediatrics
Pierrat V, Larroque B, Grandjean H, Alberge C, 34:61–66
Marret S, Burguet A, Ancel PY, Supernant K, Guzzetta A, Pizzardi A, Belmonti V, Boldrini A,
Kaminski M (2007) Prevalence and associated factors Carotenuto M, D’Acunto G, Ferrari F, Fiori S,
15 Early Markers of Poor Outcome in Neonatal Medicine 249
Gallo C, Ghirri P, Mercuri E, Romeo D, Roversi MF, Prechtl HF, Einspieler C, Cioni G et al (1997) An early
Cioni G (2010) Hand movements at 3 month predict marker for neurological deficits after perinatal brain
later hemiplegia in term infants with neonatal cerebral lesions. Lancet 349:1361–1363
infarction. Dev Med Child Neurol 52:767–772 Ricci D, Guzzetta A, Cowan F et al (2006a) Sequential
Johnson S, Strauss V, Gilmore C, Jaekel J, Marlow N, neurological examinations in infants with neonatal
Wolke D (2016) Learning disabilities among extremely encephalopathy and low apgar scores: relationship
preterm children without neurosensory impairment: with brain MRI. Neuropediatrics 37:148–153
comorbidity, neuropsychological profiles and scholas- Ricci D, Anker S, Cowan F et al (2006b) Thalamic atrophy
tic outcomes. Early Hum Dev 103:69–75 in infants with PVL and cerebral visual impairment.
Kidokoro H, Anderson PJ, Doyle LW, Woodward LJ, Neil Early Hum Dev 82:591–595
JJ, Inder TE (2014) Brain injury and altered brain Romeo DM, Cioni M, Scoto M et al (2009) Prognostic
growth in preterm infants: predictors and prognosis. value of a scorable neurological examination from 3 to
Pediatrics 134:e444–e453 12 months post-term age in very preterm infants: a
Kim H, Lepage C, Maheshwary R, Jeon S, Evans AC, Hess longitudinal study. Early Hum Dev 85:405–408
CP, Barkovich AJ, Xu D (2016) NEOCIVET: towards Rutherford MA, Pennock JM, Counsell SJ et al (1998)
accurate morphometry of neonatal gyrification and Abnormal magnetic resonance signal in the internal
clinical applications in preterm newborns. NeuroImage capsule predicts poor neurodevelopmental outcome in
138:28–42 infants with hypoxic-ischemic encephalopathy. Pediat-
Marlow N, Wolke D, Bracewell MA et al (2005) Neuro- rics 102:323–328
logic and developmental disability at six years of age Rutherford M, Srinivasan L, Dyet L, Ward P, Allsop J,
after extremely preterm birth. N Engl J Med 352:9–19 Counsell S et al (2006) Magnetic resonance imaging
Mercuri E, Atkinson J, Braddick O et al (1997) Basal in perinatal brain injury: clinical presentation, lesions
ganglia damage and impaired visual function in the and outcome. Pediatr Radiol 36:582–592
newborn infant. Arch Dis Child Fetal Neonatal Ed 77: Santiago-Rodriguez E, Harmony T, Bernardino M et al
F111–F114 (2005) Auditory steady-state responses in infants with
Olsen JE, Brown NC, Eeles AL, Einspieler C, Lee KJ, perinatal brain injury. Pediatr Neurol 32:236–240
Thompson DK, Anderson PJ, Cheong JL, Doyle LW, Shankaran S, Pappas A, McDonald SA, Vohr BR, Hintz
Spittle AJ (2016) Early general movements and brain SR, Yolton K et al (2012) Childhood outcomes after
magnetic resonance imaging at term-equivalent age in hypothermia for neonatal encephalopathy. N Engl J
infants born <30 weeks’ gestation. Early Hum Dev Med 366:2085–2092
101:63–68 Shankaran S, McDonald SA, Laptook AR, Hintz SR,
Orasanu E, Melbourne A, Cardoso MJ, Lomabert H, Ken- Barnes PD, Das A, Pappas A, Higgins RD, on behalf
dall GS, Robertson NJ, Marlow N, Ourselin S (2016) of the Eunice Kennedy Shriver National Institute of
Cortical folding of the preterm brain: a longitudinal Child Health and Human Development Neonatal
analysis of extremely preterm born neonates using Research Network (2015) Neonatal Magnetic Reso-
spectral matching. Brain Behav 6:e00488 nance Imaging Pattern of Brain Injury as a Biomarker
Palisano R, Rosenbaum P, Walter S et al (1997) Develop- of Childhood Outcomes following a Trial of Hypother-
ment and validation of a gross motor function classifi- mia for Neonatal Hypoxic-Ischemic Encephalopathy.
cation system for children with cerebral palsy. Dev Med J Pediatr 167:987–993
Child Neurol 39:214–223 Spittle AJ, Brown NC, Doyle LW, Boyd RN, Hunt RW,
Palisano RJ, Rosenbaum P, Bartlett D, Livingston MH Bear M, Inder TE (2008) Quality of general movements
(2008) Content validity of the expanded and revised is related to white matter pathology in very preterm
gross motor function classification system. Dev Med infants. Pediatrics 121:e1184–e1189
Child Neurol 50:744–750 World Health Organization (2001) International classifica-
Picciolini O, Gianni ML, Vegni C, Fumagalli M, Mosca F tion of functioning, disability and health. WHO, Geneva
(2006) Usefulness of an early neurofunctional assess- Xie K, Zheng H, Li H, Zhang C, Li H, Jin H, Ma B (2015)
ment in predicting neurodevelopmental outcome in The study of effect for general movements assessment
very low birthweight infants. Arch Dis Child Fetal in the diagnosis of neurological development disorders:
Neonatal 91:F111–F117 a meta-analysis. Clin Pediatr (Phila) 55:36–43
Quality of Neonatal Intensive
Care and Outcome for High-Risk 16
Newborn Infants
Liz McKechnie and Kathryn Johnson
Contents
16.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
16.2 What Is Quality in Neonatal Care? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
16.2.1 Assessing Quality in Neonatal Healthcare . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
16.2.2 Outcome Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
16.2.3 Audit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
16.2.4 Benchmarking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
16.2.5 Confidential Enquiries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
16.3 How Can Quality Be Improved in Neonatal Care? . . . . . . . . . . . . . . . . . . . . . . . . 255
16.3.1 National and International Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
16.3.2 Managed Clinical Networks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
16.3.3 Education and Knowledge Translation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
16.3.4 Quality Improvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
16.4 Short-Term and Long-Term Morbidity and Mortality in High-Risk
Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
16.4.1 Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
16.4.2 Morbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
16.4.3 Longer-Term Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Abstract assessment needs to be implemented in order
It is generally accepted that neonatal outcome to improve care such as audit, benchmarking,
is related to the quality of care an infant and confidential enquiries, which are discussed
receives, and therefore it should be closely below. Traditional measures of outcome such
monitored in order to improve outcome. Qual- as death, neurodevelopmental status, and
ity in neonatal care is a complex subject, but chronic lung disease are also discussed in
improving quality is a goal to which all neo- detail later in this chapter. Improving quality
natologists should aspire. Ongoing quality of care can additionally be achieved by
implementing modern, effective, evidence-
based methods of knowledge translation in
L. McKechnie (*) · K. Johnson
order to increase the use of evidence-based
Centre for Newborn Care, Leeds Teaching Hospitals Trust,
Leeds, UK healthcare.
e-mail: [email protected]; [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 251
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_165
252 L. McKechnie and K. Johnson
16.1 Salient Points Specific to neonatal care, quality is defined as
providing an appropriate level of care to well
• Neonatal outcome is closely related to quality newborn babies while providing a good quality
of care. of more specialized care to the few babies that
• Defining quality allows development of stan- need it. This should be done while obtaining the
dards of care or quality indicators. best medical neonatal outcome and satisfying par-
• Which aspects of care to assess for quality ents and families as well as providers. This should
depends on the audience it is aimed at. be delivered in the context of sound managerial
• Audit is widely used to measure adherence to and financial performance and while developing
quality indicators. perinatal services to further raise standards of care
• Benchmarking is popular with organizations (Acolet 2008).
such as the Vermont Oxford Network (VON). This definition clearly demonstrates the com-
• Quality improvement (QI) is enhanced by plexity of measuring quality in neonatal care; we
coordinated collaborative working. need to consider the structures supporting the care
• Improving quality of care should be the aspi- that the baby has received and the processes and
ration of every healthcare professional. outcomes of that care. We also should consider the
effect on the family, parents, and healthcare pro-
fessionals surrounding that baby. Compounding
16.2 What Is Quality in Neonatal these factors with the complexities of healthcare
Care? management and economics makes measurement
of quality very difficult.
The quality of the care that we provide to all Defining quality of care within a specific field
newborn babies has gained increasing promi- allows standards to be developed, i.e., quality
nence in the last decade or so. indicators. Systems to assess quality of care can
Quality in healthcare has been defined in many then be designed and where care does not reach
different ways and by many different authors. The the standard, improvements can be made.
American Institute of Medicine defines six
domains that should be assessed when looking to
improve quality of care (Institute of Medicine 16.2.1 Assessing Quality in Neonatal
(IOM) 2001): Healthcare
• Safety: avoiding harm to patients when The assessment of quality in neonatal care is
providing care. evolving, and the framework around which qual-
• Effectiveness: providing evidence-based care ity can be measured is that of clinical governance.
only to the patients that will benefit from it. This encompasses many different processes by
• Patient-centeredness: ensuring care is respect- which care can be measured.
ful of a patient’s (or families) beliefs and cul- Important to the choice of how to assess neo-
ture and that decision-making about clinical natal care is who the audience are: it may be for
care is done in partnership with them. clinicians, politicians, families, etc. and so the
• Timeliness: ensuring care is delivered when it choice of tool is important. The measurements
is needed. that are used – otherwise known as quality indi-
• Efficiency: ensuring care is not wasteful, e.g., cators – should be clearly defined, valid, reliable,
equipment, time, etc. sensitive and specific, relevant, actionable, and
• Equity: quality care is delivered regardless of evidence based (Mainz 2003).
differences, e.g., religion and race. When measuring quality it is important to rec-
ognize and differentiate the discrete aspects of
Many other institutions have developed their healthcare – the structure or organization of care
own definitions using similar domains. that is provided and the process of providing that
16 Quality of Neonatal Intensive Care and Outcome for High-Risk Newborn Infants 253
care and the outcome of the care that has been but whether perceived optimal care is actually
provided. These different aspects may be assessed provided.
individually to measure quality. In the UK, the National Neonatal Audit
In the past, outcome studies have been used for Programme (NNAP) uses the audit method to
reflecting the quality of care, but more recently capture information on current practice measured
other methods have become more commonplace against previously defined standards. The first
such as auditing, benchmarking, and confidential annual report highlighted many of the problems
enquiries. These may be done locally; nationally, encountered when auditing such a complex pro-
e.g., the National Neonatal Audit Project in the cess as healthcare (McIntosh and Youle 2008). In
UK; or internationally, e.g., the Vermont Oxford light of the results of the first period, changes were
Network. made to the questionnaire and also to data ascer-
tainment. The audit questions are adapted or
changed annually in order to ensure that the cor-
16.2.2 Outcome Studies rect data is being collected to answer a specific
question.
In the past much of the neonatal literature has The first report highlighted examples of diffi-
been focused on different aspects of care and culties in the analysis of data as a result of impre-
their effect on outcome for a baby. Outcome cise questions. One standard set by consensus of
can mean many different things, such as later the NNAP Board was “of those receiving surfac-
neurodevelopmental attainment and the presence tant, 90% should receive it within 1 hour of
or absence of chronic lung disease. These out- birth.” In answer to the audit question of whether
come measures can be used as a proxy for the this standard was achieved, there was data miss-
quality of care. ing from 173/647 babies. Of all eligible babies,
One of the problems with using studies 64% received surfactant in the first hour (87% of
reporting outcome as a marker for quality of babies with complete data) showing that the stan-
care is that there are frequently differences in dard was not achieved. However, the question
results between similarly designed studies. could not distinguish those babies who did not
These differences can be in part accounted for receive surfactant in the first hour because they
by differences in clinical practice or in the demo- were not intubated, following the increasingly
graphics of the study populations. However, it common occurrence of babies of this gestation
has been shown that these differences in clinical going directly onto nasal continuous positive
practice and in demographics are not enough to airway pressure (nCPAP) after birth. Similar
explain the variation in results. It has been issues were highlighted with the remaining ques-
suggested that the differences may therefore be tions. However, despite the problems encoun-
due to a difference in outcome in quality of care tered, the quality of early surfactant
(Horbar 1999). administration is clearly not up to the expected
standard, and so changes can be made to
improve this.
16.2.3 Audit Within Europe, the EuroNatal Study
(Richardus et al. 2003) investigated differences
Clinical audit is a process whereby care is mea- in perinatal mortality rate by looking at quality
sured against predefined standards. It aims to of care in a geographical region within ten indi-
improve patient care by logical review of care vidual countries. Differences were demonstrated
and subsequent implementation of change to between different healthcare systems. Suboptimal
improve quality of care. At this point audit can care factors occurred significantly less in Finnish
be repeated to measure the affect of the change and Swedish regions than in the remaining
made. It is a continuous circular process. There- participating regions (Spain, the Netherlands,
fore, audit does not define what optimal care is, Scotland, Belgium, Denmark, Norway, Greece,
254 L. McKechnie and K. Johnson
and England). An expert panel assessed 67% neonatal medicine was within the Vermont
of neonatal deaths 34 weeks to have had Oxford Network (VON) and now provides
suboptimal care factors that were likely or might benchmarking data for participating units
have contributed to the fatal outcome. Clearly, this internationally. The UK Managed Clinical
study showed that improvements in quality of care Networks (see below) can provide a group of
should be possible, but no reaudit has been carried similar units that can benchmark both inter-
out to date. nally and externally.
If, when auditing, the expected standard has
not been met, change should be implemented to
achieve that standard and improve quality. 16.2.5 Confidential Enquiries
Reaudit is then imperative in order to demonstrate
that change has been beneficial and the quality of Standard methods of measurement (e.g., audit)
care has improved. may not be sufficiently powerful to capture the
complexity of neonatal healthcare. A more
focused approach may sometimes be needed
16.2.4 Benchmarking such as that used in Project 27/28 (Confidential
Enquiry into Stillbirths and Deaths in Infancy
Benchmarking is a process whereby aspects of (CESDI) 2003), which was carried out in
healthcare practice are evaluated against known England, Wales, and Northern Ireland in the
best practice. It is a helpful way to compare 2-year period between September 1998 and
activity and performance in different areas with August 2000. The aim was to identify variations
other organizations and to provide an evidence in the standards of care that might have cont-
base for further review and action planning. ributed to the deaths of infants born at 27 and
Benchmarking is a commonly used technique 28 weeks gestation during this period.
across a wide range of different sectors and Anonymized medical records were scrutinized
industries to review and improve performance. by a panel of experts for deficiencies in the
It is one of the most widely applied management standards of care provided to the infants that
techniques used to improve organizational died. Having highlighted consistent deficiencies
performance. in the standards of care, the working party
A useful definition of benchmarking is published recommendations for changes to
provided by the NHS Benchmarking Club practice in order to improve the quality of care.
(Productive Time Delivery and Benchmarking Their main findings and recommendations were
Club 2006), who define the process as based upon early thermal, ventilatory, and
“Making evidence-based comparisons of prac- cardiovascular care.
tice, drawing conclusions and implementing Confidential enquiries (CE) have been an
improvements.” ongoing method of quality improvement in the
Benchmarking has many benefits. It is an UK since the first report was published in 1952
evidence-based quality improvement tool. It looking at maternal deaths. Over time the body
can provide the means to compare practice responsible for this has changed and is currently
with similar organizations and thereby identify carried out by Mothers and Babies: Reducing
outliers from the standard of care, i.e., good Risk Through Audits and Confidential Enquiries
and bad performers. It can assess whether Across the UK (MBRRACE-UK). They report
current performance achieves practice stan- into maternal and perinatal mortality as well as
dards and can provide the catalyst for organi- conducting CEs into specific conditions. In
zational change to improve quality of care. December 2014 a report into the CE of congenital
Sharing benchmarking data can share good diaphragmatic hernia was published (Field et al.
practice and motivate the need for change. 2014) with several recommendation for quality
The first large benchmarking collaboration in improvement.
16 Quality of Neonatal Intensive Care and Outcome for High-Risk Newborn Infants 255
16.3 How Can Quality Be Improved leading role in the development of education,
in Neonatal Care? audit, and guidelines (Marlow and Gill 2007).
The networks can also provide support and advice
16.3.1 National and International for individual units about both clinical and
Groups nonclinical matters. All these network roles
clearly can improve quality.
Different groups whose aim is to improve quality
within neonatal care have been set up. The largest
organization is the Vermont Oxford Network 16.3.3 Education and Knowledge
(VON). This is an international collaborative of Translation
neonatal units with the objective of integrating
research and clinical practice in order to improve It is well described that there are major gaps
the quality of neonatal care (Horbar 1995). Other between routine practice and what the evidence
organizations such as the Neonatal Survey shows is optimal practice (Institute of Medicine
(UK) and Australian and New Zealand Neonatal 2001). An example of this is nicely demonstrated
Network (ANZNN) collect data and use this to by the work done by Ligand in the early 1970s
provide information on outcome. Contributors to that showed the improvement in respiratory func-
these databases are then able to use the informa- tion of newborn premature lambs and later human
tion provided for developing and enhancing their preterm infants after antenatal maternal steroid
quality of care. administration. Although the benefit was clearly
demonstrated, it took until the late 1990s to reach
routine antenatal care.
16.3.2 Managed Clinical Networks Many barriers hamper translating audit and
research findings into best practice and
Managed Clinical Networks are a way of deliver- there are obstacles at all levels of care deliv-
ing high-quality care to a population across a large ery. This has been addressed in several studies
geographical area. A Managed Clinical Network that show that using active methods of infor-
has been defined as: mation dissemination (e.g., audit, feedback,
Linked groups of health professionals from multidimensional workshops, ongoing support)
primary, secondary, and tertiary care, working in knowledge translation can be far more effec-
a coordinated manner, are unconstrained by tive than traditional methods of learning such
existing professional and Trust/Health Authority as lectures and seminars (Horbar et al. 2004;
boundaries, to ensure equitable provision of high- Acolet et al. 2008).
quality and clinically effective services (Baker
and Lorimer 2000).
Managed Clinical Networks in the UK were set 16.3.4 Quality Improvement
up after a government initiative called “The NHS
Plan.” The aim was to create a more effective and Quality improvement (QI) has been defined as
efficient service. The network should ensure the combined and unceasing efforts of everyone,
appropriate access for patients to the right care healthcare professionals, patients and their
delivered in the most relevant setting. Access to families, researchers, payers, planners, and edu-
specialist knowledge and care should be stream- cators, to make the changes that will lead to
lined and quality of care should be consistent better patient outcomes (health), better system
(Cropper et al. 2002). performance (care), and better professional
The network can play a central role in the development (Batalden and Davidoff 2007).
maintenance of national standards for neonatal More succinctly, it is a formal approach to the
care but can also develop and implement local analysis of performance and systematic efforts to
quality improvement measures such as taking a improve it.
256 L. McKechnie and K. Johnson
It is a fashionable method of improving care Worldwide reported rates of preterm delivery
and can yield good results. There are several dif- (<37 weeks) are estimated at just less than 10%
ferent models of QI, e.g., PDSA, Six Sigma, etc. with 85% of the burden of preterm deliveries
The basis of QI is to embed a culture of quality occurring in the developing world; in 2010 an
improvement within the organization. This estimated 14.9 million babies were born preterm
requires strong leadership and empowerment of (Beck et al. 2010). The highest morbidity and
the workforce. The goals of the QI project should mortality not surprisingly are seen in the smallest,
be clear to all and have adequate resources to most premature infants (Slattery and Morrison
enable the work. The improvements made should 2002; El-Metwally et al. 2000; Fanaroff et al.
be measurable and feedback to motivate the team 2007; Hack and Fanaroff 2005; Alexander et al.
is essential. 2003; Markestad et al. 2005). Within the develop-
The largest neonatal organization using QI ing world, infants weighing less than 2000 g
methodology is the Vermont Oxford Network. (corresponding generally to <32 weeks gestation)
They have over 1000 neonatal units globally that have little chance of survival. In contrast, the
can participate in collaborative efforts toward survival rate of infants born at 32 weeks in devel-
quality improvement. They have had many publi- oped countries is similar to that of infants born at
cations demonstrating positive effects on out- term (Beck et al. 2010).
comes using this approach. Rates of premature delivery worldwide show
Although not a project with neonatal patients, a no evidence of declining; there are many reports
great example of the effectiveness of QI projects worldwide of increasing rates of preterm birth
was demonstrated by Pronovost in 2006 (Ananth and Vintzileos 2008; Slattery and Mor-
(Provonost et al. 2006). He reported a collabora- rison 2002; Stoelhurst et al. 2005; Smith et al.
tive cohort study that used five evidence-based 2007; Craig et al. 2002; Blencowe et al. 2012). A
interventions to reduce catheter-related blood- variety of factors have contributed to the increas-
stream infections (CRBSIs) in adult intensive ing preterm birth rate, including increased use of
care. They reduced CRBSIs by 66% and sustained assisted reproduction techniques and the associ-
that over the 18 months of the project. This clearly ated increase in multiple births (Ananth and
had significant benefits in morbidity, mortality, Vintzileos 2008; Slattery and Morrison 2002).
and cost. This QI project has been replicated in Increases have also been seen in the rates of
many places with significant improvements to singleton preterm birth particularly among med-
quality of care. ically induced preterm births rather than those
born following the spontaneous onset of labor
(Ananth and Vintzileos 2008). In addition single-
16.4 Short-Term and Long-Term tons born following assisted reproduction are
Morbidity and Mortality more likely to be preterm than the spontaneously
in High-Risk Infants conceived counterparts. Socioeconomic status is
well described to have a significant effect on
Infants born prematurely are at significant risk of preterm birth; however, this effect has been
both increased morbidity and mortality compared shown to be static over time (Smith et al. 2007).
with babies born at term and represent one of the Racial origin also impacts on rates of preterm
leading causes of perinatal morbidity and mortal- birth; changes in racial demographics over time
ity both in the developed and developing may therefore have influenced rates of preterm
world (Ananth and Vintzileos 2008; Slattery and birth (Alexander et al. 2003; Branum and
Morrison 2002; Hoyert et al. 2001). Of all early Schoendorf 2002; Demissie et al. 2001).
neonatal deaths (within 7 days) worldwide that are Reported rates of preterm birth may also have
not related to congenital malformation, 28% are been influenced by changing attitudes in delivery
due to preterm birth (Beck et al. 2010). units over time with more infants being classed
16 Quality of Neonatal Intensive Care and Outcome for High-Risk Newborn Infants 257
as live births or offered resuscitation (Peerzada Survival at limits of viability
et al. 2006; Hakansson et al. 2004); in one large
study, up to 22% of preterm infants born at Survival at Survival at Survival at
22 þ 0–22 þ 6 23 þ 0–23 þ 6 24 þ 0–24 þ 6
22 weeks were offered resuscitation (Rysavy weeks weeks weeks
et al. 2015). USA (To discharge) (To discharge) (To discharge)
(Rysavy 23.1% of infants 33.3% of infants 56.6% of infants
Interventions to reduce preterm delivery may et al. who received who received who received
vary according to location with simple interven- 2015) active treatment active treatment active treatment
UK (To discharge) (To discharge) (To discharge)
tions being potentially much more effective in (Costeloe 16% of admitted 30% of admitted 47% of admitted
lower-income settings than in the developed et al. infants infants infants
2012)
world (Chang et al. 2013). France (To discharge) (To discharge) (To discharge)
(Ancel 0% of live-born 1% of live-born 58% of live-born
et al. infants infants infants
2015)
16.4.1 Mortality
More recently into the twenty-first century,
Major advances in antenatal, delivery suite and large studies in Europe, especially the UK, and
neonatal management of preterm infants led to North America describe survival in preterm
major advances in survival up until the mid- to infants over time (Costeloe et al. 2012; Ancel
late 1990s when compared with the 1980s or et al. 2015; Stoll et al. 2010). UK data shows
earlier (Fanaroff et al. 2007; Stoelhurst et al. significantly more infants are surviving at
2005; The Victorian Infant Collaborative Study 24 and 25 weeks but not at 23 weeks as
Group 1997; de Kleine et al. 2007; Horbar et al. compared with their counterparts born 9 years
2002). Contributors to improved survival include previously (Costeloe et al. 2012), findings
the increasing and now widespread use of ante- supported by European data (Berger et al.
natal corticosteroids (Fanaroff et al. 2007; 2012).
Markestad et al. 2005; Stoelhurst et al. 2005;
Horbar et al. 2002), changes in attitude in deliv- 16.4.1.1 Multiple Births
ery units to the management of extremely pre- As a result of the well-described increase in
term infants, and widespread postnatal use of multiple birth rates over recent decades, con-
surfactant (Horbar et al. 2002; Costeloe et al. cerns have been raised regarding the potential
2000). There is now a wide range of international for increased mortality and morbidity in such
data from the mid- to late 1990s following wide- infants compared with their singleton counter-
spread introduction of antenatal corticosteroids parts. In a large retrospective study covering a
and postnatal surfactant reporting mortality for time period spanning 1995–2009 of twins born
the preterm infant for geographically based at less than 27 weeks, mortality was signifi-
studies. cantly higher in multiples versus singletons
Survival data at the limits of viability are although morbidity was comparable (Yeo et al.
shown in the table below; not surprising there 2015), these findings supported by other studies
are large improvements in survival between looking at mortality in extremely preterm twins
gestational ages of 22 and 24 weeks; even (Garg et al. 2010). At term multiples remain at
within a single-week gestational age bracket, high risk with increasing rates of cerebral palsy
improved survival is seen toward the end of with increasing chronicity; the higher rates are
the completed week rather than at the beginning explained, in the main, by increasing risks of
(Nguyen et al. 2012). Within the table major prematurity (Topp et al. 2004). The death of a
differences in survival will in part reflect both co-twin either prior to or shortly after birth has
differing attitudes in the delivery suite to infants been shown in a large population-based study to
born at the threshold of viability and the result in the highest risk of cerebral palsy in this
denominator used. group.
258 L. McKechnie and K. Johnson
16.4.1.2 Gender Effects morbidity although this was not seen below
Male infants born extremely preterm are 25 weeks (Ancel et al. 2015).
consistently shown to have a higher mortality When interpreting the wide range of studies
than their female counterparts (Fanaroff et al. examining morbidity in the preterm infant, one
2007; Costeloe et al. 2012), with some authors must be cautious with the interpretation of results,
reporting females showing generally a week’s as the denominator used clearly will affect the
additional maturity and a birth weight heavier results: the proportion of infants with a particular
by 100 g than their male counterparts (Taylor clinical condition may be a percentage of the total
et al. 2000). This negative effect of male sex is number of infants born, and the total number
pervasive into early childhood with higher admitted for intensive care and for longer-term
rates of neurological and developmental dis- morbidities may be a percentage of the total
ability when compared with females of the survivors.
same age (Moore et al. 2012; Wood et al. Morbidity in moderately preterm infants
2005). (30–36 weeks) is less than those born most pre-
term, but as these deliveries occur in much higher
16.4.1.3 Geographical Variations numbers than extremely preterm deliveries, abso-
There are notable intercountry and interregional lute numbers are much higher, and therefore such
variations in overall mortality of extremely pre- infants do impact significantly on neonatal inten-
term infants. Frequent comparisons are made sive care units. As infants then become more
between different regions/countries, but such mature toward term, morbidities gradually
comparisons can be misleading. Crude perinatal decrease (Boyle et al. 2015).
mortality rate used alone will be significantly
influenced by the rate of preterm birth which 16.4.2.1 Lung Disease
varies considerably between regions within Respiratory distress syndrome (RDS) is a frequent
Europe and worldwide (Draper et al. 2007; Zeitlin early marker of respiratory morbidity in preterm
et al. 2008). Denominators vary for all infants infants. This may then evolve into chronic respi-
including those terminated, to those admitted to ratory symptoms termed bronchopulmonary dys-
the neonatal unit for ongoing care following deliv- plasia (BPD) or chronic lung disease (CLD).
ery suite resuscitation. Definitions of BPD/CLD generally define this as
either oxygen dependence at 36 weeks’
postmenstrual age (PMA) or at 28 days after
16.4.2 Morbidity birth. More recently definitions of BPD have
been refined in order to provide more useful infor-
As with mortality the smallest most immature mation and have been subclassified into mild,
infants are at highest risk of adverse outcome moderate, and severe BPD (Jobe and Bancalari
(Hack and Fanaroff 2005; Stoll et al. 2010). 2001). Clear repeatable definitions of BPD/CLD
With the increased rate of survival seen in the are important; BPD/CLD at 36 weeks is fre-
1990s following extremely preterm birth, it was quently used as an outcome measure in studies
anticipated that a significant increase in survivors of interventions designed to improve outcomes in
with morbidity would be seen. Many authors have high-risk infants; it must therefore be comparable
shown morbidity in survivors to be static over from study to study.
time rather than increasing, but with the increase As with mortality and other morbidities the
in total numbers of survivors, the absolute num- highest rates of respiratory disease are seen in
bers of those with morbidity will undoubtedly the smallest most immature infants. The wide-
have increased (Fanaroff et al. 2007; Stoelhurst spread and routine use of antenatal steroids
et al. 2005; Costeloe et al. 2012). The EPIPAGE (ANS) has significantly reduced the risk of the
study along with increased survival showed need for respiratory support and respiratory dis-
increased rates of survival without major tress syndrome in the premature infant (Roberts
16 Quality of Neonatal Intensive Care and Outcome for High-Risk Newborn Infants 259
and Dalziel 2006). Postnatal surfactant therapy neurosensory impairment at 18 months if BPD is
also improves survival and reduces risk of pneu- present at 26 weeks corrected gestational age
mothorax (Horbar et al. 2002). Despite this, RDS (Schmidt et al. 2003).
rates over time are frequently reported as static
despite significant increase in the use of both 16.4.2.2 Brain Pathology
ANS and surfactant. RDS however has a wide Early neurodevelopmental morbidity can argu-
clinical phenotype, and it may be that cases over ably be monitored by rates of intraventricular
recent years following the widespread use of ANS hemorrhage (IVH) and/or cystic periventricular
and surfactant may be less severe. The use of leukomalacia (PVL) detected on cranial ultra-
European-wide consensus guidelines on the man- sound scan (CUSS). The incidence of CUSS
agement of RDS should result in consistent best abnormalities varies significantly between coun-
practice in management over a wide geographical tries and within regions of Europe (Zeitlin et al.
area (Sweet et al. 2013) and may improve 2008). In those infants with more severe IVH,
outcomes. intra-observer variability has been shown to be
Rates of BPD/CLD across Europe and world- less when compared with minor abnormalities
wide vary somewhat, with 40% of infants (Hintz et al. 2007). This intra-observer variability
<28 weeks in the USA having BPD and 26% in in the more minor abnormalities may explain
a European cohort (Ancel et al. 2015; Stoll et al. some of the increases in less severe IVH described
2010). Over two thirds of infants < 27 weeks in recently by some authors (Stoelhurst et al. 2005).
the UK EPICure II cohort had BPD. Modern equipment with higher resolution may
Recent focus in reducing the risks of BPD has also influence detection rates of minor IVH
been on the avoidance of intubation both via the detection.
use of CPAP in the delivery suite, the use of the Following improved perinatal care in recent
Intubate, Surfactant, Extubate (INSURE) tech- decades and specifically the widespread introduc-
nique, and the use of less invasive surfactant tion of antenatal steroids, a reduction in the rates
delivery techniques designed to avoid the need of IVH has been reported (Genzel-Boroviczeny
for intubation. et al. 2006; Linder et al. 2003). Comparisons of
In a multicenter trial of CPAP versus intubation individual data sets can be difficult as definitions
in infants <29 weeks, there was no difference in of abnormality and inclusion criteria vary. Data
BPD or death in the two groups (Morley et al. from the UK shows a 13% rate of severe abnor-
2008). The use of early CPAP rather than intuba- mality on last available CUSS in survivors born at
tion and surfactant in a separate study was associ- 26 weeks or less, which is unchanged from 1995
ated with less respiratory morbidity at toddler age (Costeloe et al. 2000; Costeloe et al. 2012)
(Stevens et al. 2014). A Cochrane review of the although rates of shunted hydrocephalus and sei-
INSURE technique showed a reduction in signif- zures decreased. Multicenter French data from
icant BPD (Stevens et al. 2007). The technique of 2011 shows a comparable rate of nearly 13% of
delivering surfactant is showing promise severe IVH (Grade 3 or 4) in the group 22–26
(Dargaville et al. 2011) which may translate into weeks with a rate of cystic PVL in the same
better long-term respiratory outcomes and less gestational age group of 2.4% (Ancel et al. 2015).
BPD (Kribs et al. 2015). Large multicenter trials In keeping with all morbidities associated with
on the technique are required to substantiate these extreme prematurity, rates of IVH/PVL increase
findings. with decreasing gestational age. Those at the
BPD is known to act as a predictor of poor limits of viability with the lowest birth weights
neurodevelopmental outcomes (Jobe 2011). At are most affected although absolute numbers are
2.5 years those infants with CLD have an odds small (Costeloe et al. 2012; Ancel et al. 2015;
ratio of >2 for cerebral palsy (Wood et al. 2005). Stoll et al. 2010).
These findings are supported by other studies The effect of early abnormalities seen on cranial
showing an odds ratio of 2.5 for death or ultrasound scan on long-term neurodevelopmental
260 L. McKechnie and K. Johnson
outcome is variable. A significantly abnormal final 16.4.3.1 Visual Disorders
cranial ultrasound scan independently increased the Retinopathy of prematurity (ROP) is frequently
risk of cerebral palsy (Wood et al. 2005). Follow-up used as a marker for morbidity in the high-risk
of the large multicenter French cohort showed that preterm infant. It can be challenging to report
25% of those with white matter damage on CUSS comparable figures as studies report different out-
had cerebral palsy at 2 years versus 4% of those comes including all ROP, severe ROP only, or
with a normal CUSS. Conversely it is reported one treatment for ROP. As infants become more
third of children with cerebral palsy had a normal mature, rates of ROP reduce gradually with
CUSS (Genzel-Boroviczeny et al. 2006). infants of higher gestations being very unlikely
to develop severe ROP and hence require treat-
ment (Ancel et al. 2015). Of infants born at less
16.4.3 Longer-Term Outcome than 26 weeks, approximately one fifth had sig-
nificant ROP (Grade 3 or above) with more than
Increasing neurological and developmental mor- three quarters of these requiring laser treatment
bidity data from discharge up into later childhood (Costeloe et al. 2012). Other studies report lower
and adulthood is now available from large multi- rates of severe ROP in similar gestational ages
center studies. The highest levels of poor long- (Ancel et al. 2015).
term outcome are seen in those high-risk infants Treatment for ROP in the two EPICure cohorts
born the most preterm. Rates up to 59% of severe (1995 versus 2006) showed a significant increase
neurodisability have been described on short-term from 13% to 21%, but it is likely that this increase
follow-up of some cohorts (Jarjour 2015), with represents a lower threshold for treatment rather
rates at their highest in those born 22–23 weeks. than a true increase in morbidity (Costeloe et al.
Challenges in complex cognition and learning 2000; Costeloe et al. 2012). When ROP is com-
are being increasingly recognized as the high- bined with two other morbidities, BPD and brain
risk survivors of extreme prematurity grow up injury, not surprisingly the three together were
into school age and adulthood. Mathematics dif- strongly predictive of death or neurosensory
ficulties appear to be a particular challenge impairment at 18 months (Schmidt et al. 2003).
(Wolke et al. 2015). In the follow-up of the UK
2006 cohort, as compared with 1995, rates of 16.4.3.2 Other Outcome Measures
cerebral palsy and severe disability remained Significant additional morbidity is seen in preterm
unchanged although rates of disability-free sur- infants influencing both their short- and long-term
vival increased (Berger et al. 2012). The original clinical course and outcome. Necrotizing entero-
1995 EPICure cohort is now being followed up colitis (NEC) continues to be a significant risk to
into early adulthood, at 11 years; within this the high-risk preterm infant; it is difficult to com-
cohort, 50% were rated as having below-average pare rates between cohorts as a variety of out-
attainment compared with 5% of classmates comes can be measured, all NEC, severe NEC,
(Johnson et al. 2009). or NEC requiring surgery. Generally rates are
High-risk infants born preterm may also have highest in the most preterm infants with 12% of
an increased risk of psychiatric disorders 23-week infants affected, as compared to 8% of
(Johnson and Marlow 2011). those born at 28 weeks in one large American
Any disability pervasive into childhood and cohort (Stoll et al. 2010). With recent data show-
adulthood as a result of a high-risk preterm birth ing less high-risk preterm infants dying of respi-
will have significant economic costs (Petrou et al. ratory disease, the proportion dying from NEC
2013). (and sepsis) is increasing (Costeloe et al. 2012;
Schools and providers of education need to be Berrington et al. 2012).
aware of these challenges in order to fully support Sepsis in the preterm also continues to be a
the increasing numbers of high-risk preterm significant source of morbidity and mortality.
infants surviving the neonatal period. 60% of infants in the large UK cohort
16 Quality of Neonatal Intensive Care and Outcome for High-Risk Newborn Infants 261
<27 weeks had a positive blood culture during Baker CD, Lorimer AR (2000) Cardiology: the develop-
their stay (Costeloe et al. 2012). Data from the ment of a managed clinical network. BMJ
321:1152–1153
USA for the most high-risk infants (born at Bassler D, Stoll BJ, Schmidt B et al (2009) Using a count of
28 weeks or less) shows an early-onset sepsis neonatal morbidities to predict poor outcome in
rate of 2%, with approximately one third of extremely low birth weight infants: added role of neo-
infants in the same group suffering from late- natal infection. Pediatrics 123(1):313–318. https://doi.
org/10.1542/peds.2008-0377
onset sepsis (Stoll et al. 2010). Again, as with Batalden PB, Davidoff F (2007) What is “quality improve-
all morbidities in the high-risk infant, rates were ment” and how can it transform healthcare? Qual Saf
at their highest in the most extremely preterm. Health Care 16:2–3
Rates of meningitis in the same cohort were 3%. Beck S, Wojdyla D, Say L et al (2010) The worldwide
incidence of preterm birth: a systematic review of
Sepsis, meningitis, and NEC have all been maternal mortality and morbidity. Bulletin of the
shown to then increase the risk not only of World Health Organization 88:31–38
death but also survival with neurosensory Berger TM, Steurer MA, Woerner A et al (2012) Trends
impairment (Bassler et al. 2009). and centre-to-centre variability in survival rates of very
preterm infants (<32 weeks) over a 10-year-period in
Given the increasing proportion of infants Switzerland. Arch Dis Child Fetal Neonatal Ed 97(5):
dying later in their neonatal stay from NEC F323–F328
and sepsis, much of the focus of research in Berrington JE, Hearn RI, Bythell M et al (2012) Deaths in
recent years has focused on their prevention. preterm infants: changing pathology over 2 decades. J
Pediatr 160(1):49–53
The use of probiotics for prevention of NEC is Blencowe H, Cousens S, Oestergaard MZ et al (2012)
controversial with the recent UK-wide multi- National, regional, and worldwide estimates of preterm
center trial showing no benefit (Costeloe et al. birth rates in the year 2010 with time trends since 1990
2016). The increasing use of breast milk and for selected countries: a systematic analysis and impli-
cations. Lancet 379(9832):2162–2172
donor breast milk may help to reduce NEC Boyle EM, Johnson S, Manketlow B et al (2015) Neonatal
rates along with strategies to reduce late-onset outcomes and delivery of care for infants born late
infection that may result in future years in preterm or moderately preterm: a prospective
reduced morbidity and better long-term out- population-based study. Arch Dis Child Fetal Neonatal
Ed 100(6):F479–F485
comes in high-risk preterm infants. Branum AM, Schoendorf KC (2002) Changing patterns of
low birthweight and preterm birth in the United States,
1981–98. Paediatr Perinat Epidemiol 16:8–15
Chang HH, Larson J, Blencowe H et al (2013) Preventing
preterm births: analysis of trends and potential reduc-
References tions with interventions in 39 countries with very high
human development index. Lancet 381(9862):223–234
Acolet D (2008) Quality of neonatal care and outcome. Confidential Enquiry into Stillbirths and Deaths in Infancy
Arch Dis Child Fetal Neonatal Ed 93:F69–F73 (CESDI) (2003) Project 27/28. An enquiry into quality
Acolet D, Allen E, Houston R, Elbourne D (2008) The of care and its effect on the survival of babies born at
Bliss Cluster randomised controlled trial of the effect 27–28 weeks. The Stationary Office, London
of “active dissemination of information” on the stan- Costeloe K, Hennessy E, Gibson A et al (2000) The EPI-
dards of care for premature babies in England Cure study: outcomes to discharge from hospital for
(BEADI). Perinatal Medicine Meeting, Harrogate, infants born at the threshold of viability. Pediatrics
UK, June 2008 106:659–671
Alexander GR, Kogan M, Bader D et al (2003) US birth Costeloe LK, Hennessy EM, Haider S et al (2012) Short
weight/gestational age-specific neonatal mortality: term outcomes after extreme preterm birth in England:
1995–1997 rates for whites, hispanics and blacks. Pedi- comparison of two birth cohorts in 1995 and 2006 (the
atrics 111:e61–e66 EPICure studies). BMJ 345, e7976
Ananth C, Vintzileos A (2008) Epidemiology of preterm Costeloe K, Hardy P, Juszczak E et al (2016)
birth and its clinical subtypes. J Matern Fetal Neonatal Bifidobacterium breve BBG-001 in very preterm
Med 21:289–295 infants: a randomised controlled phase 3 trial. Lancet
Ancel PY, Goffinet F, Kuhn P et al (2015) Survival and 387(10019):649–660
morbidity of preterm children born at 22 weeks through Craig ED, Thompson JMD, Mitchell EA et al (2002)
34 weeks’ gestation in France in 2011: results of the Socioeconomic status and preterm birth: New Zealand
EPIPAGE-2 cohort study. JAMA Pediatr Mar trends, 1980 to 1999. Arch Dis Child Fetal Neonatal Ed
169(3):230–238 86:F142–F146
262 L. McKechnie and K. Johnson
Cropper S, Hopper A, Spencer SA, Dodd K (2002) Man- Horbar JD, Badger GJ, Carpenter JH (2002) Trends in
aged clinical networks. Arch Dis Child 87:1–4 mortality and morbidity for very low birth weight
Dargaville PA, Aiyappan A, Cornelius A (2011) Prelimi- infants, 1991–1999. Pediatrics 110:143–150
nary evaluation of a new technique of minimally inva- Horbar JD, Carpenter JH, Buzas J et al (2004) Collabora-
sive surfactant therapy. Arch Dis Child Fetal Neonatal tive quality improvement to promote evidence based-
Ed 96:F243–F248 surfactant for preterm infants: a cluster randomised
de Kleine MJ, Lya den Ouden AL, Kollée LA et al (2007) trial. BMJ 329:1004
Lower mortality but higher neonatal morbidity over a Hoyert DL, Freedman MA, Strobino DM et al (2001)
decade in very preterm infants. Paediatr Perinat Annual summary of vital statistics: 2000. Pediatrics
Epidemiol 21:15–25 108:1241–1255
Demissie K, Rhoads GG, Ananth CV et al (2001) Trends in Institute of Medicine (2001) Crossing the quality chasm: a
preterm birth and neonatal mortality among blacks and new health system for the 21st century. National Acad-
whites in the United States from 1989 to 1997. Am J emy Press, Washington DC
Epidemiol 154:307–315 Institute of Medicine (IOM) (2001) Crossing the quality
Draper ES, Zeitlin J, Field DJ et al (2007) Mortality chasm: a new health system for the 21st century.
patterns among very preterm babies: a comparative National Academy Press, Washington, DC
analysis of two European regions in France and Jarjour IT (2015) Neurodevelopmental outcome after
England. Arch Dis Child Fetal Neonatal Ed 92: extreme prematurity: a review of the literature. Pediatr
356–360 Neurol 52(2):143–152
El-Metwally D, Vohr B, Tucker R (2000) Survival and Jobe AH (2011) The new bronchopulmonary dysplasia.
neonatal morbidity at the limits of viability in the mid Curr Opin Pediatr 23(2):167–172
1990s: 22 to 25 weeks. J Pediatr 137:616–622 Jobe AH, Bancalari E (2001) Bronchopulmonary dyspla-
Fanaroff AA, Stoll BJ, Wright LL et al (2007) Trends in sia. Am J Respir Crit Care Med 163:1723–1729
neonatal morbidity and mortality for very low Johnson S, Marlow N (2011) Preterm birth and childhood
birthweight infants. Am J Obstet Gynecol 196:147. psychiatric disorders. Pediatr Res 69:11R–18R
e1–e8 Johnson S, Hennessy E, Smith R et al (2009) Academic
Field D, Hyman-Taylor P, Bacon C, Draper ES on behalf of attainment and special educational needs in extremely
MBRRACE-UK (2014) Perinatal confidential enquiry preterm children at 11 years of age: the EPICure study.
– congenital diaphragmatic hernia. The Infant Mortal- Arch Dis Child Fetal Neonatal Ed 94(4):F283–F289
ity and Morbidity Group, Department of Health Sci- Kribs A, Roll C, Göpel W (2015) Nonintubated surfactant
ences, University of Leicester, Leicester application vs conventional therapy in extremely pre-
Garg P, Abdel-Latif ME, Bolisetty S et al (2010) Perinatal term infants: a randomized clinical trial. JAMA Pediatr
characteristics and outcome of preterm singleton, twin 169(8):723–730
and triplet infants in NSW and the ACT, Australia Linder N, Haskin O, Levit O et al (2003) Risk factors for
(1994–2005). Arch Dis Child Fetal Neonatal Ed intraventricular haemorrhage in very low birth weight
95(1):F20–F24 premature infants: a retrospective case control study.
Genzel-Boroviczeny O, Macwilliams S, Von Poblotzki M Pediatrics 111:e590–e595
et al (2006) Mortality and major morbidity in premature Mainz J (2003) Developing evidence-based clinical indi-
infants less than 31 weeks gestational age in the decade cators: a state of the art methods primer. Int J Qual
after introduction of surfactant. Acta Obstet Gynecol Health Care 15(1):i5–i11
Scand 85:68–73 Markestad T, Kaaresen PI, Ronnestad A et al (2005) Early
Hack M, Fanaroff AA (2005) Outcomes of children of death, morbidity and need of treatment among extremely
extremely low birthweight and gestational age in the premature infants. Pediatrics 115:1289–1298
1990s. Semin Neonatol 5:89–106 Marlow N, Gill AB (2007) Establishing neonatal networks:
Hakansson S, Farooqi A, Holmgren PA et al (2004) Pro- the reality. Arch Dis Child Fetal Neonatal Ed 92:
active management promotes outcome in extremely F137–F142
preterm infants: a population based comparison of McIntosh N, Youle L (2008) National Neonatal Audit
two perinatal management strategies. Pediatrics Project annual report. Royal College of Paediatrics
114:58–64 and Child Health
Hintz SR, Slovis T, Bulas D et al (2007) Interobserver Moore T, Hennessy EM, Myles J (2012) Neurological and
reliability and accuracy of cranial ultrasound scanning developmental outcome in extremely preterm children
interpretation in premature infants. J Pediatr born in England in 1995 and 2006: the EPICure studies.
150:592–596 BMJ 345, e7961
Horbar JD (1995) The Vermont-Oxford Neonatal Network: Morley CJ, Davis PG, Doyle L et al (2008) Nasal CPAP or
integrating research and clinical practice to improve the intubation at birth for very preterm infants. NEJM
quality of medical care. Semin Perinatol 19:124–131 358:700–708
Horbar JD (1999) The Vermont Oxford Network: Nguyen TP, Amon E, Al-Hosni M et al (2012) “Early”
evidence-based quality improvement for neonatology. versus “late” 23-week infant outcomes. Am J Obstet
Pediatrics 103:350–359 Gynecol 207(3):226.e1–6
16 Quality of Neonatal Intensive Care and Outcome for High-Risk Newborn Infants 263
Peerzada JM, Schollin J, Hakansson S (2006) Delivery oximetry randomized trial (SUPPORT). J Pediatr
room decision making for extremely preterm infants 165(2):240–249
in Sweden. Pediatrics 117:1988–1995 Stoelhurst GM, Rijken M, Martens SE et al (2005)
Petrou S, Johnson S, Wolke D et al (2013) The association Changes in neonatology: Comparison of two cohorts
between neurodevelopmental disability and economic of very preterm infants (gestational age <32 weeks):
outcomes during mid-childhood. Child Care Health the project on preterm and small for gestational age
Dev 39(3):345–347 infants 1983 and the Leiden follow up project on pre-
Productive Time Delivery Board and NHS Benchmarking maturity 1996–1997. Pediatrics 115:396–404
Club (2006) Delivering quality and value: focus on be Stoll BJ, Hansen NI, Bell EF et al (2010) Neonatal
nchmarking. http://www.dh.gov.uk/en/Publicationsand outcomes of extremely preterm infants from the
statistics/Publications/PublicationsPolicyAndGuidance/ NICHD neonatal research network. Pediatrics
DH_4139062 126(3):443–456
Provonost P, Needham D et al (2006) An intervention to Sweet DG, Carnielli V, Greisen G et al (2013) European
decrease catheter-related bloodstream infections in the consensus guidelines on the management of neonatal
ICU. N Engl J Med 355:2725–2732 respiratory distress syndrome in preterm infants – 2013
Richardus JH, Graafmans WC, Verloove-Vanhorick SP, update. Neonatology 103:353–368
Mackenbach JP (2003) Differences in perinatal mortal- Taylor HG, Klein N, Minich NM et al (2000) Middle-
ity and suboptimal care between 10 European regions: school-age outcomes in children with very low
results of an international audit. BJOG 110:97–105 birthweight. Child Dev 71:1495–1511
Roberts D, Dalziel SR (2006) Antenatal corticosteroids for The Victorian Infant Collaborative Study Group (1997)
accelerating fetal lung maturation for women at risk of Outcome at 2 years of children 23–27 weeks’ gestation
preterm birth. Cochrane Database Syst Rev born in Victoria in 1991–2. J Pediatr Child Health
3, CD004454 33:161–165
Rysavy MA, Li L, Bell EF et al (2015) Between-hospital Topp M, Huusom LD, Langhoff-Roos J et al (2004) Mul-
variation in treatment and outcomes in extremely pre- tiple birth and cerebral palsy in Europe: a multicenter
term infants. N Engl J Med 372(19):1801–1811 study. Acta Obstet Gynecol Scand 83(6):548–553
Schmidt B, Asztalos EV, Roberts RS et al (2003) Impact of Wolke D, Strauss VY, Johnson S et al (2015) Universal
bronchopulmonary dysplasia, brain injury, and severe gestational age effects on cognitive and basic mathe-
retinopathy on the outcome of extremely low-birth- matic processing: 2 cohorts in 2 countries. Pediatrics
weight infants at 18 months. JAMA 289:1124–1129 166(6):1410–1416
Slattery M, Morrison J (2002) Preterm delivery. Lancet Wood NS, Costeloe K, Gibson AT et al (2005) The EPI-
360:1489–1497 Cure study: associations and antecedents of neurolog-
Smith LK, Draper ES, Manktelow BN et al (2007) Socio- ical and developmental disability at 30 months of age
economic inequalities in very preterm birth rates. Arch following extremely preterm birth. Arch Dis Child
Dis Child Fetal Neonatal Ed 92:F11–F14 Fetal Neonatal Ed 90:F134–F140
Stevens TP, Harrington EW, Blennow M et al (2007) Early Yeo KT, Lee QY, Quek WS et al (2015) Trends in morbid-
surfactant administration with brief ventilation ity and mortality of extremely preterm multiple gesta-
vs. selective surfactant and continued mechanical ven- tion newborns. Pediatrics 136(2):263–271
tilation for preterm infants with or at risk for respiratory Zeitlin J, Draper ES, Kollee L et al (2008) Differences
distress syndrome. Cochrane Database Syst Rev in rates and short-term outcome of live births
4, CD003063 before 32 weeks of gestation in Europe in 2003:
Stevens TP, Finer NN, Carlo WA et al (2014) Respiratory results from the MOSAIC cohort. Pediatrics 121:
outcomes of the surfactant positive pressure and e936–e944
Cerebral Plasticity and Functional
Reorganization in Children with 17
Congenital Brain Lesions
Viviana Marchi, Andrea Guzzetta, and Giovanni Cioni
Contents
17.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
17.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
17.3 How Early Is Early . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
17.4 Cerebral Plasticity and the Different Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
17.4.1 Language . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
17.4.2 The Sensorimotor System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
17.4.3 The Visual System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
17.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
Abstract the processes of adaptive plasticity and limit
Mechanisms of cerebral plasticity are more the maladaptive ones. New techniques of
powerful during development. This however advanced brain mapping are providing a
does not necessarily lead to better outcomes unique opportunity to explore this matter in
in case of early brain injuries, as opposed to humans, both in the acute and post-acute
later ones, due to the complex interaction of phase, during the early stages of development,
brain plasticity, vulnerability, and maturation. and in the chronic phase, when the plastic
A deep understanding of the mechanisms reorganization has for a large part already
underlying the reorganization of brain func- occurred. We will review here the current
tions after early damage will give us the oppor- knowledge on the main mechanisms of plastic
tunity to target the intervention in terms of reorganization in subjects with congenital
timing, quality, and duration so to maximize lesions, with particular reference to the lan-
guage, sensorimotor, and visual systems. The
main differences with the effects of later inju-
V. Marchi (*) · A. Guzzetta · G. Cioni
ries will be underlined.
IRCCS Stella Maris, Department of Developmental
Neuroscience, Pisa, Italy
University of Pisa, Department of Clinical and
Experimental Neuroscience, Pisa, Italy
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 265
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_166
266 V. Marchi et al.
17.1 Salient Points The presence of more powerful mechanisms of
neuronal plasticity during early phases of devel-
• Damage during brain development affects opment should imply that recovery from brain
functional outcome differently from lesions of damage is more effective for early lesions com-
mature brains due to the complex interaction of pared to similar lesions occurred later in life. This
brain plasticity, vulnerability, and maturation. principle was first suggested by Paul Broca in
• Knowledge of the neurobiological and neuro- 1865 (Berker 1986) and then more systematically
physiological principles of plastic reorganiza- explored by Margaret Kennard in the late 1930s
tion after early brain damage allows for a (Finger 1988). Since then, most of the studies
therapeutic strategy to maximize the processes carried out in different species have not denied
of adaptive plasticity and limit the maladaptive this general principle although describing a more
processes by appropriate timing, nature, and complex picture, which takes into consideration
duration. several other aspects beyond the timing of the
• The recent application of advanced brain insult, including the location and extension of
imaging has provided answers to questions injury (e.g., focal versus diffuse), the clinical cor-
related to the mechanism of plasticity after relates (e.g., presence of seizures), or the genetic
early brain lesions, although a full knowledge susceptibility of the subject (Anderson et al. 2009;
of affects on the young brain is still far from Dennis et al. 2013).
being achieved. One of the most important predictors of the
efficacy of functional reorganization seems to be
the distribution, diffuse versus focal, of the dam-
17.2 Introduction age (Lidzba et al. 2009; Kolb and Gibb 2014;
Sweatt 2016). Most strikingly, children with
The substrates of developmental neuroplasticity early unilateral left hemisphere damage can
span across molecular alterations, cellular adapta- develop normal language abilities, while lesions
tions, cortical electrophysiological changes, and of similar site and extent in the adult brain would
structural and functional neuronal networks produce obvious patterns of aphasia. (Bates et al.
assembly and are expressed vigorously during 2001) Even if an entire hemisphere is removed at
time-sensitive periods of brain development an early stage of development (for instance, for
(Johnston et al. 2009). Mechanisms of cerebral the treatment of severe epilepsy), children can
plasticity are thought to be more powerful during develop normal language and cognitive function
development. For example, children are more (Liégeois et al. 2008; de Bode et al. 2015). Also,
fast-paced than adults in learning a new language children with unilateral ischemic stroke are able to
(Klein et al. 2014; Li et al. 2014) or in achieving develop normal cognitive functions and maintain
complex skills such as playing a musical instru- them over time (Ballantyne et al. 2008). In con-
ment (Barrett et al. 2013). In a classic experiment trast, evidence suggests that sustaining an early
on string players, the extent of the cortical repre- generalized cerebral insult (e.g., global hypoxia or
sentation of the left digits was found to be traumatic brain injury) is usually associated with
inversely correlated with the age at which the slower recovery and poorer outcome, compared to
person had begun to play, indicating a larger what is observed in adults with similar lesions
amount of cerebral plasticity in subjects with ear- (Anderson 2005; Anderson et al. 2011). The
lier exposition to training (Elbert et al. 1995; mechanism most often invoked for this higher
Vaquero et al. 2016). Similarly, children lacking vulnerability of early damage is that, at an early
proper environmental inputs early in life are more stage, cognitive development is highly dependent
prone to have an abnormal development of the on the integrity of diffuse neural networks, and so
functions related to those inputs (the concept of the transient disruption of the developing atten-
critical periods) (Lewis and Maurer 2005; tion, memory, and learning functions undermines
Mowery et al. 2016). the efficient acquisition of new abilities (Kolb and
17 Cerebral Plasticity and Functional Reorganization in Children with Congenital Brain Lesions 267
Gibb 2014). Conversely, at an older age, the gen- recently with computed tomography and mag-
eral, already acquired, cognitive abilities can be netic resonance imaging. These new methodolo-
spared, and the impairment is limited to functions gies, increasingly applied also in children, allow
directly related to the final area of damage. to perform in vivo investigations of cerebral
The aim of the present chapter will be to out- lesions, monitoring their evolution, and so pro-
line the major discoveries of the last years viding further insight on the relation between
concerning the mechanisms of functional reorga- lesion and function and on the different types of
nization typical of a young brain in different reorganization.
systems, in the light of future possible directions In broad terms, types of congenital brain dam-
of new non-pharmacological therapeutic age can be grouped according to timing (Fig. 1).
interventions. Lesions occurring during the first half of gestation
(and in particular the first trimester) give rise to
malformations of cortical development. These
17.3 How Early Is Early lesions are very complex in terms of their charac-
terization as they can be extremely variable in size,
The time boundaries of early brain damage have location, and distribution, resulting in completely
never been clearly defined. This is probably due different clinical pictures. The underlying mech-
not to the absence of effort but rather to the com- anisms of cerebral plasticity are likely to be sim-
plexity of the task. The changes of cerebral plastic- ilarly complex and variable. The second group of
ity, which influences the effects of brain damage, lesions is those occurring around the early third
are gradual during development, and the sensitive trimester of gestation (25–34 weeks of gesta-
periods are now known to be different for the tion). The most typical of this group are peri-
various functional subsystems (Lewis and Maurer ventricular leukomalacia and intraventricular
2005). Also, the types of brain insult are extremely hemorrhage. The first is an ischemic, bilateral,
variable during development and affect the nervous and diffuse lesion, while the second is a hemor-
system in ways that are directly dependent on the rhagic lesion, usually limited inside the ventri-
level of maturation at the moment they occur. For cles, but that sometimes complicates into a
these and other reasons, the boundaries between periventricular parenchymal infarction, usually
early and late lesions are necessarily blurry. As here unilateral. Finally, the third group includes
we are interested to explore how different can the lesions around term (typically lesions of the
young brain be in response to damage, we will term infant at around birth). The most relevant
focus on the lesions occurring before or around are the hypoxic-ischemic encephalopathy and
birth (also called congenital lesions), which are the focal cerebral stroke, of arterial origin. The
more frequent and have been more extensively first is an ischemic lesion, bilateral and diffuse,
studied, compared to later ones. while the second is a focal lesion, similar from
A relevant aspect of the pathophysiology of the neuropathological point of view to the stroke
congenital brain insult is the stage of cerebral observed in adults.
development at the moment of the insult, either As previously mentioned, the distribution of
prenatal or perinatal. Because of the complexity the lesion, namely, focal unilateral versus dif-
and speed of the maturational phenomena occur- fuse bilateral, is likely to be the single most
ring during gestation, the response to a harmful relevant factor to influence the efficacy of plas-
event varies significantly accordingly to gesta- tic reorganization of brain functions. In this
tional age and leads to different pictures both sense, congenital lesions provide an interesting
from the neuropathological and the clinical model for studying cerebral reorganization as
point of view. For the understanding of these they naturally encompass the different combi-
mechanisms, an essential contribution is pro- nations of distribution (focal, diffuse) and
vided by the noninvasive neuroimaging tech- timing (early gestation, late gestation, and
niques, first with ultrasonography and more term) of damage.
268 V. Marchi et al.
Fig. 1 Correlation between timing of insult and type of the central column, a case of periventricular white matter
brain injury. Three examples are shown of typical con- damage secondary to an intraventricular hemorrhagic
genital brain lesions on MRI, in which the correlation insult occurred at the beginning of the third trimester of
between timing and characteristics of the lesion is clear. gestation. In the right column, a case of ischemic infarction
In the left column, a case of schizencephaly, a malforma- of the territory of the middle cerebral artery occurred
tion of cortical development secondary to an insult, around birth in a term-born infant
occurred during the early phases of brain development. In
ability develops, what is its nature, and what hap-
17.4 Cerebral Plasticity
pens when the left hemisphere is damaged by a
and the Different Systems
cerebral lesion in early phases of development are
still matters of debate. Indeed, more than 30 years
The effects of a cerebral lesion are clearly
ago, invasive techniques such as the Wada test
connected with the site of the lesion. This implies
have demonstrated that, in patients with early
a different involvement of the various systems in
left-hemispheric brain lesions, the right hemi-
different subjects, with complex and heterogeneous
sphere is able to develop a specialization for lan-
functional correlates. Although it is common to
guage, in the absence of significant language
observe clinical pictures consisting of the impair-
disabilities (Rasmussen and Milner 1977). How
ment of multiple interconnected systems, espe-
this happens and what are the consequences for
cially in subjects with congenital cerebral damage,
brain function are starting to be clarified only
for the purpose of clarity, the principal systems will
more recently, thanks to the application of
be considered independently, focusing in particular
advanced functional neuroimaging techniques,
on the aspects of cerebral plasticity differentiating
such as positron emission tomography (PET)
the effects of an early and a late lesion.
and functional magnetic resonance imaging
(fMRI).
17.4.1 Language An important study of 2002 by Martin Staudt
and his coworkers with an fMRI language task
With few exceptions, the left hemisphere of the explored the topography of language organization
brain deals with language processing. It has been following early left brain injury (namely, unilat-
estimated that this specialization interests eral periventricular lesions) to discover where
between 95 and 98% of adults. How this special (and indirectly how) language function organizes
17 Cerebral Plasticity and Functional Reorganization in Children with Congenital Brain Lesions 269
in the right hemisphere. They revealed a remark- of seizures, suggesting a direct influence of timing
able similarity between the activation in normal on the pattern of reorganization suggesting, as for
controls (in the left hemisphere) and the activation other systems (see below), that the hemispheric
in brain-injured patients (in the right hemisphere), specialization of language develops as a result of a
with a perfectly specular distribution of the known competitive process between the two hemi-
cortical areas of the language circuit (Staudt spheres. When a left (non-epileptogenic) lesion
2002). occurs within the early third trimester of gestation,
These findings indicate that reorganization of when cerebral plasticity is highly effective, the
language in the right hemisphere occurs in areas affected hemisphere is more likely to maintain
that are perfectly homotopic to those normally its genetic advantage over the contralateral and
involved in normal conditions, strongly eventually develop control over language. When
suggesting a near equipotentiality of the two a left lesion occurs at term or during early devel-
hemispheres at birth as to the ability of developing opment, when the plastic potential is reducing, the
language control. non-affected hemisphere might prevail upon the
Similar findings had already been found in affected one and take over language control. This
patients with malformations of cortical develop- option becomes gradually less available during
ment (Hertz-Pannier et al. 1997; Müller et al. development, with later lesions invariably
1998). In those subjects, however, epileptic sei- resulting in an intra-hemispheric reorganization
zures, which are known to alter cerebral reorgani- of function and different degrees of language dis-
zation, were almost invariably present, thus turbance (i.e., the “right-hemisphere-take-over”
making it hard to explore whether shifting of theory) (Szaflarski et al. 2014).
language could happen also in the absence of Interestingly, other studies observed subtle dif-
seizures and/or in case of later damage (early ferences in language outcome in right versus left
third trimester). Those findings were then further congenital lesions, thus getting more complex
extended showing a similar pattern of contralat- idea of language plasticity and reinforcing the
eral homotopic reorganization even in patients idea of a specialization of the two hemispheres,
with arterial stroke occurred at term age (Fig. 2) in spite of their plastic potential (Guzzetta et al.
(Guzzetta et al. 2008). In that study, authors also 2008; Kolk et al. 2011). Convincing data support
showed that shifting of language function after a the hypothesis that a price for language function
stroke at term is even more common than for plasticity has to be paid by right-hemispheric
earlier lesions, when accounting for the variable functions, the so-called crowding effect. (Fiori
Fig. 2 Language
representation in patients
with left perinatal stroke
and right-hemispheric
reorganization of
language. fMRI shows the
activation of regions of the
right hemisphere which are
contralateral and homotopic
to the regions of the
language circuit activated in
normal controls (group
analysis performed on eight
patients and ten normal
controls; see (Bates et al.
2001))
270 V. Marchi et al.
and Guzzetta 2015) fMRI studies on language areas. The second mechanism is specific for
plasticity reveal that children with left-lesion- lesions occurring during the early phases of devel-
induced right-hemispheric language organization, opment. It is based on the existence, during the
despite the relatively well-preserved language first weeks of life, of bilateral motor projections
functions, show deficits in visuospatial abilities, originating in the primary motor areas, which
and the degree of visuospatial dysfunction is pro- connect each hemisphere with both sides of the
portional to the degree of right language represen- body. These fibers generally withdraw during
tation (Lidzba et al. 2006; Ilves et al. 2014). development, but they can persist in case of cere-
bral damage, giving rise to a contralesional reor-
ganization of motor function. This type of
17.4.2 The Sensorimotor System reorganization is specific for unilateral early
brain lesions, as it requires, at the time when
When a cerebral lesion, either cortical or subcor- damage occurs, the presence of a bilateral inner-
tical, involves the motor system, neuroplastic vation of motoneuronal pools and a developmen-
mechanisms should be able to drive recovery of tal increase in the number of both fast-conducting
voluntary movements, restoring an adequate cor- ipsilateral and contralateral corticospinal axons
tical impulse to the spinal motor neurons and from the intact hemisphere (Fig. 3).
interneurons. Two major mechanisms are avail- The application of fMRI can provide relevant
able to restore an efficient reconnection of the information on the type of reorganization occur-
motor cortex with the spinal cord circuitry in ring in each patient. Nevertheless it has to be
case of a cerebral lesion. The first one involves a integrated with techniques providing a high tem-
reorganization of the ipsilateral cortex, within the poral resolution such as transcranial magnetic
primary motor cortex or in non-primary motor stimulation (TMS), in order to document the
Fig. 3 Schematic representation of the main types of Contralesional reorganization of motor function and
reorganization of sensorimotor function following early ipsilesional reorganization of sensory function. Motor
brain damage. (a) Ipsilesional reorganization of motor and sensory function of the affected limb is processed by
and sensory function. Both functions are reorganized in different hemispheres. In this case, functional impairment
the affected hemisphere, in regions around the lesion. In is not only related to the extent of the damage of the
this case, functional impairment is mainly related to the sensorimotor system but also to the presence of the func-
extent of the damage of the sensorimotor system. (b) tional dissociation
17 Cerebral Plasticity and Functional Reorganization in Children with Congenital Brain Lesions 271
existence of cortical-spinal monosynaptic connec- (hypothesis of the “amblyopia of the corticospinal
tions. TMS can document that in many subjects system”) (Eyre et al. 2007).
with an early lesion of the motor cortex, a signif- Should this hypothesis be confirmed, the
icant corticospinal bilateral innervation of spinal importance of an early time window (first months
motoneuronal pools persists in the healthy hemi- of life) for therapeutic intervention would be
sphere. In these subjects activation of the intact greatly emphasized. This is especially true when
motor cortex elicits large responses in both the considering that children with contralesional reor-
ipsi- and the contralateral muscles, with similar ganization, i.e., with the unaffected hemisphere
latencies and thresholds. (Zsoter et al. 2012) directly controlling both hands, reach lower levels
Cerebral lesions interestingly the motor system of hand motor performance, making this pattern of
often involve the sensory system as well and may reorganization as potentially maladaptive (Staudt
lead to a functional deficit of different severity. et al. 2004; Guzzetta et al. 2007).
These functions can be studied in vivo with tech- The mechanisms underlying this phenomenon
niques like somatosensory evoked potentials, are not fully understood; however two elements
magnetoencephalography, and fMRI with senso- seem to be of special relevance. The first is the
rial tasks. lack of an anatomical substrate for contralesional
In contrast to primary motor function, the intra- reorganization, even in the early stages of devel-
hemispheric (ipsilesional) reorganization of pri- opment, at variance with what happens for the
mary sensory function is the principal compensa- motor system. The second is the possibility that
tory mechanism following damage to the sensory thalamocortical fibers, at least for some types of
system, even when it occurs during the very early early lesions, are still developing when the insult
stages of development (Zsoter et al. 2012; Staudt occurs and are thus able to bypass the lesion and
et al. 2004). Of critical interest is the fact that the reconnect with the sensory cortex within the dam-
different reorganizational potential of the sensory aged hemisphere (Staudt et al. 2006a; Papadelis
and the motor systems leads in many cases to an et al. 2012). This evidence comes from the com-
interhemispheric dissociation of these func- bined use of structural imaging methods, such as
tions, with the first being reorganized in the diffusion MRI-based tractography (Rose et al.
affected hemisphere and the second being 2011), which identify the likely trajectories of
shifted contralaterally (Fig. 3b). Some evidence thalamocortical white matter bundles, and func-
seems to support the hypothesis that such a tional imaging methods, such as MEG, which are
dissociation could determine some functional capable of reliably mapping the cortical location
deficits in tasks requiring a strong sensorimotor of primary sensory processing (Staudt et al.
integration (such as stereognosis). This is prob- 2006b).
ably due to the lack of anatomical substrates for Moreover, diffusion studies performed dur-
contralesional reorganization, even in the early ing the chronic phases of the disorder, i.e., in
stages of development. However, previous stud- adolescents and young adults with unilateral
ies indicated how this pattern of SM reorgani- cerebral palsy, showed that the asymmetry of
zation (contralesional reorganization) is already the corticospinal tract is less correlated with
determined during the first year of life and pos- sensory and motor function than the asymmetry
sibly even within the first few months (Eyre of other projections such as the thalamocortical
et al. 2007; Guzzetta et al. 2010). ones. Not surprisingly, the early structural
This appeared as not a mere consequence of the asymmetries of the corticospinal tract are not
size and site of the lesion, but is strongly always able to predict the presence and, most of
influenced by the experience following damage all, the severity of later hemiplegia. These data
(action-dependent reorganization), in the sense of suggest an essential role of higher-order com-
the complex interaction between residual motor pensatory mechanisms in shaping the long-term
output from the affected hemisphere and somato- functional outcome, and a growing body of
sensory feedback from the affected limb evidence supports the hypothesis that the
272 V. Marchi et al.
reorganization of motor function also heavily
involves subcortical structures such as the thal-
amus, brainstem or spinal cord, and cerebellum
(Dinomais et al. 2012). On the light of these
findings, the specific target of an early thera-
peutic intervention should be the activation of
the sensorimotor cortex of the affected hemi-
sphere, to enhance the competitive ability of a
damaged corticospinal system during develop-
ment and thus mitigate the consequences of the
lesion on motor outcome.
17.4.3 The Visual System
Among all the systems described, the reorganiza- Fig. 4 Schematic representation of the main types of
tion of the visual system after early lesions in reorganization of visual function following early brain
humans is maybe the less investigated. Con- damage. On the left, a possible type of reorganization
versely, more than any other system, visual func- following early damage of the optic radiations. The
thalamocortical connections are able to bypass the lesion
tion has been extensively studied in the animal and reach the final cortical target (primary visual cortex). A
model and especially the cat. The sparse scientific full recovery of conscious vision can be achieved. On the
evidence in humans on the specificity of reorga- right, the reorganization mechanisms following early dam-
nizational mechanisms after early damage is sum- age to the primary visual cortex. Circuits connecting the
retina with extrastriatal visual structures are expanded, in
marized below (Fig. 4). particular involving the superior colliculus and the
The correlation between damage to the optic pulvinar. A full recovery of conscious vision cannot be
radiations or the occipital cortex and the corre- achieved, but a high degree of functional compensation is
spondent visual field deficit is far less strong in obtained, consisting of near-normal exploratory visual
behavior and navigation. LGN lateral geniculate nucleus,
case of early lesion than of a lesion occurring SC superior colliculus, Pul pulvinar
later in life. This might be the direct expression
of more powerful cerebral plasticity mechanisms
in the young child that have at least in part similar networks are not fully understood. Some data
neurophysiological bases to what is observed for suggest that up to term age structural modifica-
the somatosensory system and in particular the tions of the geniculostriate pathway can support
possibility that thalamocortical fibers develop functional reorganization of the visual system.
after the lesion, bypassing it (Guzzetta et al. Some authors recently studied longitudinally an
2013). As our knowledge, along the typical infant with perinatal left arterial stroke, sparing
brain development, between the 22nd and 34th the primary visual cortex but involving the optic
week of gestation, when periventricular paren- radiations, using a combination of fMRI and
chymal lesions mostly occur, afferents ascending diffusion tensor tractography (Seghier et al.
from the thalamus make synaptic contact with 2004, 2005). When the infant was tested at
the maturing neurons in the subplate region, 3 months of age with visual fMRI, cortical acti-
which regulate the formation of the cortical vation could only be observed in the unaffected
plate. When focal periventricular brain damage side, and DTI was unable to show the presence of
occurs, geniculostriate fibers are expected to the optical radiations in the affected hemisphere
bypass the damaged tissue, reaching the visual (Seghier et al. 2004). At 20 months, the infant
cortex, with a full sparing of visual fields. The was tested again with the same protocol and
exact characteristics and limits of this specific surprisingly showed a clear fMRI activation,
type of plasticity involving thalamocortical indirect sign of functional reorganization, further
17 Cerebral Plasticity and Functional Reorganization in Children with Congenital Brain Lesions 273
supported by clear structural modifications on Previous findings have been also confirmed by
diffusion tractography (Seghier et al. 2004, a recent study of Ajina and colleagues who stud-
2005). Unfortunately, the assessment of visual ied human blindsight, the phenomenon described
fields was not performed due to the young age of as the ability to detect visual information within
the subject. However, regardless of the possible the blind region and functional brain connectiv-
presence of a functional impairment, the imag- ity in individuals with damage of primary visual
ing data seem to support the existence of a cortex acquired during adulthood. They con-
process of reorganization at the level of the cluded that blindsight after the adult brain lesion
thalamocortical pathway, able to restore, at is mainly mediated by persistence of an intact
least partially, the functional connection geniculo-extrastriate pathway, while this path-
between the lateral geniculate body and the way was significantly impaired or not measur-
occipital cortex. able in blindsight negative individuals (Ajina
Even when a visual field deficit is present, the et al. 2015).
subject with early damage seems to show fewer However, available data support a more effec-
difficulties in environmental navigation and tive mechanism of reorganization of visual func-
exploration. In accordance to previous studies, tion after early brain damage that may consist either
Tinelli and colleagues measured sensitivity to sev- in a reconnection with the targeted structures or in
eral visual tasks in a group of children with con- an enhanced use of compensating circuitries.
genital unilateral brain lesions involving optic In the study of Tinelli et al. (2013), they found
radiations compared to children with similar that congenitally lesioned subjects have strong
lesions, acquired in childhood. Children with con- activation of the contralesional calcarine cortex
genital (but not with acquired) postnatal brain for both stimuli in the contra- and ipsilateral visual
lesions show spared visual perception (although field, indicating a rewiring involving primary
unconscious) in the affected hemifield clear evi- visual processes and not limited to compensatory
dence for blindsight. In children with congenital circuits involving extrastriate cortices. One possi-
hemianopia, they also mapped the calcarine bility for explaining ipsilateral activity in the
BOLD activity for visual field quadrants stimula- spared V1 is that some of the retinal ipsilateral
tion with fMRI. They showed that the V1 region projections to lateral geniculate nucleus and supe-
of the intact hemisphere also responds to stimuli rior colliculus, observed during early develop-
in the ipsilateral “blind” hemifield (Tinelli et al. ment in young animals and possibly also in
2013). Their data perfectly agree with animal human infants (Arroyo and Feller 2016), did not
model findings, which detected clearly how the degenerate given the massive lesions to one hemi-
ablation of the whole primary visual cortex in the sphere at birth.
newborn animal does not affect its visual orienta- Interestingly, in a systematic review of
tion performances, that on the contrary are mas- Guzzetta and collaborators on visual functions
sively impaired after a similar lesion in the adult reorganization in preterm infants with peri-
animal (Fagiolini et al. 1994). Studies on the cat ventricular hemorrhagic infarction, they observed
model showed how this phenomenon is linked to a that the involvement of the optic radiations was
reorganization of the pathways connecting sub- often associated with normal visual fields; con-
cortical visual structures (lateral geniculate versely, the presence of basal ganglia/thalamus
nucleus, superior colliculus, and pulvinar) directly involvement apparently prevented such reorgani-
to the extrastriatal ipsi- and contralateral visual zation, resulting in unilateral field restriction
centers. Some evidence shows that this could (Guzzetta et al. 2013), These findings support
also apply to humans, at least to a certain degree, the existence of effective mechanisms of plastic
as shown, for example, by the increase in activa- reorganization that allow a rewiring of geniculo-
tion of extrastriatal structures on fMRI after the calcarine connections with restoration of full-field
stimulation of the affected hemifield (Leh et al. vision but which are hindered by the involvement
2006). of the basal ganglia and thalamus.
274 V. Marchi et al.
17.5 Conclusions Bates E et al (2001) Differential effects of unilateral lesions
on language production in children and adults. Brain
Lang 79:223–265
How can we summarize present knowledge on Berker EA (1986) Translation of Broca’s 1865 report. Arch
cerebral plasticity and reorganization following Neurol 43:1065
early brain damage? The concept that is clearly de Bode S, Smets L, Mathern GW, Dubinsky S (2015)
emerging, both from human and nonhuman stud- Complex syntax in the isolated right hemisphere:
receptive grammatical abilities after cerebral hemi-
ies, is that functional reorganization in children is spherectomy. Epilepsy Behav 51:33–39
neither better nor worse than in adults, but it is Dennis M et al (2013) Age, plasticity, and homeostasis in
simply different and gives rise to a really different childhood brain disorders. Neurosci Biobehav Rev
brain. Full knowledge of how different the young 37:2760–2773
Dinomais M, Groeschel S, Staudt M, Krägeloh-Mann I,
brain becomes (after damage), i.e., the specific Wilke M (2012) Relationship between functional con-
mechanisms of cerebral plasticity in infancy, is far nectivity and sensory impairment: red flag or red her-
from being achieved. The effort is however highly ring? Hum Brain Mapp 33:628–638
meritorious as this knowledge will be essential to Elbert T, Pantev C, Wienbruch C, Rockstroh B, Taub E
(1995) Increased cortical representation of the fingers
the definition and tuning of therapeutic programs of the left hand in string players. Science 270:305–307
based on solid neurobiological and neurophysio- Eyre JA et al (2007) Is hemiplegic cerebral palsy equiva-
logical principles. And with this is intended not lent to amblyopia of the corticospinal system? Ann
only the type of treatment but also its timing, its Neurol 62:493–503
Fagiolini M, Pizzorusso T, Berardi N, Domenici L, Maffei
dosage, and its means of administration. Brain L (1994) Functional postnatal development of the rat
mapping techniques and in particular fMRI devel- primary visual cortex and the role of visual experience:
oped over the last few years provided answers dark rearing and monocular deprivation. Vis Res
to many questions that had been at the center 34:709–720
Finger S (1988) The ‘Kennard effect’ before Kennard: the
of scientific debate for long periods. Next early history of age and brain lesions. Arch Neurol
implementations of these techniques, for example, 45:1136
the dissemination of ultrahigh-field MRI machines Fiori S, Guzzetta A (2015) Plasticity following early-life
integrated with functional approaches, will provide brain injury: insights from quantitative MRI. Semin
Perinatol 39:141–146
a new insight to the remaining questions. Guzzetta A et al (2007) Reorganisation of the somatosen-
sory system after early brain damage. Clin
Neurophysiol 118:1110–1121
Guzzetta A et al (2008) Language organisation in left
References perinatal stroke. Neuropediatrics 39:157–163
Guzzetta A et al (2010) Hand movements at 3 months
Ajina S, Pestilli F, Rokem A, Kennard C, Bridge H (2015) predict later hemiplegia in term infants with neonatal
Human blindsight is mediated by an intact geniculo- cerebral infarction. Dev Med Child Neurol 52:767–772
extrastriate pathway. Elife 4:e08935 Guzzetta A, Fiori S, Scelfo D, Conti E, Bancale A (2013)
Anderson V (2005) Functional plasticity or vulnerability Reorganization of visual fields after periventricular
after early brain injury? Pediatrics 116:1374–1382 haemorrhagic infarction: potentials and limitations.
Anderson V et al (2009) Childhood brain insult: can age at Developmental Medicine & Child Neurology 55:23–26
insult help us predict outcome? Brain 132:45–56 Hertz-Pannier L et al (1997) Noninvasive assessment of
Anderson V, Spencer-Smith M, Wood A (2011) Do chil- language dominance in children and adolescents with
dren really recover better? Neurobehavioural plasticity functional MRI: a preliminary study. Neurology
after early brain insult. Brain 134:2197–2221 48:1003–1012
Arroyo DA, Feller MB (2016) Spatiotemporal features of Ilves P et al (2014) Different plasticity patterns of language
retinal waves instruct the wiring of the visual circuitry. function in children with perinatal and childhood
Front Neural Circuits 10:54 stroke. J Child Neurol 29:756–764
Ballantyne AO, Spilkin AM, Hesselink J, Trauner DA Johnston MV et al (2009) Plasticity and injury in the
(2008) Plasticity in the developing brain: intellec- developing brain. Brain Dev 31:1–10
tual, language and academic functions in children Klein D, Mok K, Chen J-K, Watkins KE (2014) Age of
with ischaemic perinatal stroke. Brain 131: language learning shapes brain structure: a cortical
2975–2985 thickness study of bilingual and monolingual individ-
Barrett KC, Ashley R, Strait DL, Kraus N (2013) Art and uals. Brain Lang 131:20–24
science: how musical training shapes the brain. Front Kolb B, Gibb R (2014) Searching for the principles of brain
Psychol 4:713 plasticity and behavior. Cortex 58:251–260
17 Cerebral Plasticity and Functional Reorganization in Children with Congenital Brain Lesions 275
Kolk A, Ennok M, Laugesaar R, Kaldoja M-L, Talvik T Rose S, Guzzetta A, Pannek K, Boyd R (2011) MRI
(2011) Long-term cognitive outcomes after pediatric structural connectivity, disruption of primary sensori-
stroke. Pediatr Neurol 44:101–109 motor pathways, and hand function in cerebral palsy.
Leh SE, Johansen-Berg H, Ptito A (2006) Unconscious Brain Connect 1:309–316
vision: new insights into the neuronal correlate of Seghier ML et al (2004) Combination of event-related
blindsight using diffusion tractography. Brain 129: fMRI and diffusion tensor imaging in an infant with
1822–1832 perinatal stroke. NeuroImage 21:463–472
Lewis TL, Maurer D (2005) Multiple sensitive periods in Seghier ML et al (2005) Visual recovery after perinatal
human visual development: evidence from visually stroke evidenced by functional and diffusion MRI:
deprived children. Dev Psychobiol 46:163–183 case report. BMC Neurol 5:17
Li P, Legault J, Litcofsky KA (2014) Neuroplasticity as a Staudt M (2002) Right-hemispheric organization of lan-
function of second language learning: anatomical guage following early left-sided brain lesions: func-
changes in the human brain. Cortex 58:301–324 tional MRI topography. NeuroImage 16:954–967
Lidzba K, Staudt M, Wilke M, Krägeloh-Mann I (2006) Staudt M et al (2004) Reorganization in congenital
Visuospatial deficits in patients with early left- hemiparesis acquired at different gestational ages.
hemispheric lesions and functional reorganization of Ann Neurol 56:854–863
language: consequence of lesion or reorganization? Staudt M et al (2006a) Extensive peri-lesional connectivity
Neuropsychologia 44:1088–1094 in congenital hemiparesis. Neurology 66:771
Lidzba K, Wilke M, Staudt M, Krägeloh-Mann I (2009) Staudt M et al (2006b) Developing somatosensory pro-
Early plasticity versus early vulnerability: the problem jections bypass periventricular brain lesions. Neurol-
of heterogeneous lesion types. Brain 132:e128. author ogy 67:522–525
reply e129 Sweatt JD (2016) Neural plasticity and behavior – sixty
Liégeois F, Cross JH, Polkey C, Harkness W, Vargha- years of conceptual advances. J Neurochem 139
Khadem F (2008) Language after hemispherectomy in (Suppl 2):179–199
childhood: contributions from memory and intelli- Szaflarski JP et al (2014) Age at stroke determines post-
gence. Neuropsychologia 46:3101–3107 stroke language lateralization. Restor Neurol Neurosci
Mowery TM, Kotak VC, Sanes DH (2016) The onset of 32:733–742
visual experience gates auditory cortex critical periods. Tinelli F et al (2013) Blindsight in children with congenital
Nat Commun 7:10416 and acquired cerebral lesions. Cortex 49:1636–1647
Müller R-A et al (1998) Brain organization of language Vaquero L et al (2016) Structural neuroplasticity in expert
after early unilateral lesion: a PET study. Brain Lang pianists depends on the age of musical training onset.
62:422–451 NeuroImage 126:106–119
Papadelis C, Leonardelli E, Staudt M, Braun C (2012) Can Zsoter A, Pieper T, Kudernatsch M, Staudt M (2012)
magnetoencephalography track the afferent informa- Predicting hand function after hemispherotomy: TMS
tion flow along white matter thalamo-cortical fibers? versus fMRI in hemispheric polymicrogyria. Epilepsia
NeuroImage 60:1092–1105 53:e98–e101
Rasmussen T, Milner B (1977) The role of early left-brain
injury in determining lateralization of cerebral speech
functions. Ann N Y Acad Sci 299:355–369
Part II
Perinatal and Neonatal Care
Organization of Perinatal Care:
Training of Doctors and Nurses 18
Neil Marlow
Contents
18.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
18.2 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280
18.3 Models of Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
18.4 Care of High-Risk Newborn Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
18.4.1 Antenatal Counseling and Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
18.4.2 Delivery Room Care and Resuscitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
18.4.3 Screening and Acute Care Following “Normal” Births . . . . . . . . . . . . . . . . . . . . . . . 282
18.4.4 Care in the Neonatal Unit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
Abstract sickest children. In this chapter, the elements of
Medical and nursing care for the newborn is service organization are described.
organized differently in different health sys-
tems. Whereas general support in terms of
screening and routine care is provided for a 18.1 Salient Points
large number of babies in a maternity setting,
in comparison neonatal intensive care for sick • Sick newborn infants need to be treated in
and immature babies is a low throughput but specialist neonatal units.
high cost service. Increasing medical costs and • Neonatal care cannot take place in isolation
difficulty in staffing intensive care services from pediatric, obstetric, and fetal medicine
make it important to evaluate the organization services.
of neonatal care, and new data on the relation- • Outcomes are improved for babies born in
ship between throughput and outcome are driv- tertiary centers, particularly in terms of antena-
ing centralization of care for the smallest and tal and delivery room mortality.
• Neonatal staff are responsible for the organiza-
tion and training of all obstetric, midwifery,
and neonatal staff in neonatal stabilization
N. Marlow and resuscitation.
Institute for Women’s Health, University College London,
London, UK
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 279
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_167
280 N. Marlow
• With more enlightened views about the role of of neonatal intensive care has undoubtedly been
the parent in enhancing their baby’s progress one of the success stories of modern medicine. Its
during the neonatal period, parents are now rapid evolution since the early 1970s has led to
welcomed into the neonatal unit and encour- dramatic changes in mortality at low gestational
aged to participate in their child’s care. ages and a reduction in immediate and later
• The provision of recommended neonatal nurse morbidities.
staffing levels again will vary between health The extent to which different models of orga-
systems, depending on the roles that are under- nization of neonatal services have contributed to
taken by nurses and the availability of other this is hotly debated. Services evolve as the tech-
professionals, such as respiratory therapists. nical aspects of care change and are rarely planned
• The numbers of neonatologists required to staff on a geographic basis. However, there is a general
a neonatal service depend on the model of agreement that a sick newborn infant needs to be
health care provision. Mortality was increased treated in a specialist neonatal unit. Thus, a neo-
in areas of the USA with very low numbers of natal transport system must be a basic element for
neonatologists (<4.3 doctors per 10,000 any regional program that aims at reducing mor-
births). bidity and mortality (see ▶ Chap. 19, “Neonatal
• Clinical audit is key to the assessment of ser- Transport Services”).
vice quality and audit of structure and outcome Organization is very dependent on how the
can provide valuable information when bid- healthcare system is financed and managed and
ding for increased resources and redesigning on the regulatory framework of a particular coun-
services. It also helps to confirm that we are try. In this chapter, we describe the recent changes
achieving our aims in terms of outcomes and in organization within the United Kingdom
activity. healthcare system to illustrate the thinking and
• It is important to establish an external reference evidence base on which service changes may be
for the performance of a neonatal service, and planned and from which the reader may derive
there are important resources available to sup- concepts relevant to their own local health system.
port this, such as EuroNeoNet and the Vermont Briefly, in the UK, healthcare is organized inde-
Oxford Network, in addition to national or pendently in each of the four constituent countries.
local benchmarking systems. Within the UK, the majority of births occur in
• Target groups for follow-up programs are very hospital (approximately 600,000 out of 680,000
preterm or very low birth weight children, chil- annually), and healthcare is organized under the
dren who have been encephalopathic, and any auspices of the National Health Service. The NHS
others considered to be at risk. Combined with is regionalized into 10 Regional Hubs that are
mortality data, this information is useful in responsible for “purchasing” health services for
terms of monitoring outcomes and providing their population from Hospital and Primary Care
center-based information for parents. Trusts (the “providers”). However, low volume ser-
vices, such as neonatal intensive care, are “commis-
sioned” (purchased or contracted) centrally.
18.2 Overview Neonatal care is delivered in maternity hospital
settings within the UK, except for highly specialist
Medical and nursing care for the newborn is orga- areas, for example such as cardiac surgery. Since
nized differently in different health systems. 2000, hospitals have become increasingly focused
Whereas general support in terms of screening on the areas of neonatal care they undertake based
and routine care is provided for a large number around a three tier model, where some units pro-
of babies in a maternity setting, neonatal intensive vide only basic noninvasive care, some more inva-
care for sick and immature babies is a low sive care (usually including short periods of
throughput high cost service. The development intensive care), and other hospitals provide a full
18 Organization of Perinatal Care: Training of Doctors and Nurses 281
neonatal intensive care service; more specialist ser- as linked groups of health professionals and orga-
vices – surgery, extracorporeal membrane oxygen- nizations from primary, secondary, and tertiary
ation, cardiac surgery – are provided in only a few care working in a coordinated manner to ensure
centers around England to optimize efficiency and equitable provision of high-quality clinically
maximize quality outcomes. effective services, unconstrained by existing pro-
fessional and Health Board boundaries. Further
description of the roles and responsibilities of
18.3 Models of Care Managed Neonatal Networks is available
(Marlow and Gill 2007), but in essence all hospi-
Neonatal care cannot take place in isolation from tals serving a population agree to work together to
other services. In particular pediatric, obstetric, deliver the whole range of care. Where possible
and fetal medicine services are interdependent, this is carried out as close to the mother’s area of
so it makes sense that these are colocated. In residence but where specialist care (i.e., intensive
many non-UK systems, however, neonatal inten- care) is required then the mother and baby are
sive care takes place within a children’s hospital transferred to the appropriate center. This way
setting, which has implications for family integ- hospitals that provide different levels of care act
rity and support but may provide optimal support together to make sure that the baby and family are
for some of the highly technical aspects of care appropriately supported. Service standards and
and management. In contrast, there are increasing descriptors are available (Department of Health
moves in some countries to enhance the concept 2009; Neonatal Critical Care Clinical Reference
of family-centered care by colocating maternal Group 2015).
and neonatal care for mother and child in the As part of EPICure2 an analysis of variation
same area. This model does allow for some sepa- by place of birth was undertaken which demon-
ration for the periods of necessary intensive care strated improved outcomes for babies born in
but optimizes the family experience and is tertiary centers, particularly in terms of antenatal
designed to minimize parental and infant psycho- and delivery room mortality (Marlow et al.
logical morbidity. Neonatal care should be orga- 2014), which was subsequently confirmed for
nized in a manner appropriate to the societal neonatal unit admissions (Watson et al. 2014).
setting and resources available. In addition, there is the intriguing suggestion
The issue of centralized versus dispersed ser- that higher throughput units have better survival
vices has been the subject of much debate. Apart at extremely low gestational ages, which does
from research carried out in the UK (Field and require confirmation.
Draper 1999), studies in other health systems have
seen advantages in terms of mortality and morbid-
ity where services are centralized to provide care 18.4 Care of High-Risk Newborn
for the sickest and smallest infants in large “ter- Infants
tiary” units (Marlow and Gill 2007; Lasswell et al.
2010). It has been suggested that the reason that Within a neonatal service a range of areas require
this has not been shown in England relates to planning and monitoring:
under-capacity within the large neonatal services
(Tucker et al. 1999; BLISS the premature baby Antenatal counseling and support
charity 2005), as there is evidence that mortality is Delivery room care and resuscitation
related to the number of nurses available each Screening and acute care following “normal”
shift (Tucker et al. 2002). births
To address this problem we have developed a Care in the neonatal unit
series of “managed clinical networks” of neonatal Discharge care and support
care. A managed clinical network may be defined Follow-up of at-risk children
282 N. Marlow
18.4.1 Antenatal Counseling 18.4.3 Screening and Acute Care
and Support Following “Normal” Births
Central to good perinatal care is the availability of Within our health system the neonatologist is
neonatal staff to discuss forthcoming deliveries responsible for carrying out a screening examina-
with women and their partners. This is a key role tion for the newborn baby and troubleshooting
for the neonatologist and the neonatal nurse. Dis- where the midwife has identified potential post-
cussions may simply include information about natal problems. This involves identifying babies
the process of birth for an at-risk child and a who are at high risk of particular conditions
predelivery visit to the neonatal unit. In other such as neonatal infection, hip dysplasia, and con-
situations, the neonatologist must be involved in genital heart disease. Screening for metabolic dis-
discussions of prognosis where delivery is antici- ease is also undertaken in most countries.
pated very prematurely or where fetal anomaly most hospitals the screening examination is
has been detected and on occasions must be part delegated to trainees or to specifically trained mid-
of the decision-making process as to where a baby wifery staff, although in some settings it may be
is best delivered to receive optimal care. Most undertaken by the family pediatrician. A single
fetal medicine services now involve the relevant neonatal examination is usually sufficient to iden-
pediatric specialist, where a fetal problem has tify major anomalies, although problems that
been identified to help develop a delivery plan, become apparent later in the neonatal period such
but of equal importance is the neonatal team who as duct or pressure dependent congenital heart dis-
will often have a different perspective on the early ease and jaundice may need separate assessments
management of the baby, which may alter the (Perlman et al. 2015b). Screening with saturation
initial proposal. monitors for heart disease may enhance the detec-
tion rate of screening examinations (Moss et al.
1991). Hospitals need to ensure that they have a
18.4.2 Delivery Room Care range of protocols for treating babies at risk of
and Resuscitation infection (Mahle et al. 2009) and babies who
develop new problems after birth (Royal College
Neonatal staff are usually responsible for the orga- of Obstetricians and Gynaecologists 2003).
nization and training of all obstetric, midwifery,
and neonatal staff in neonatal stabilization and
resuscitation. In most countries, formalized train- 18.4.4 Care in the Neonatal Unit
ing is available through nationally accredited neo-
natal life support courses, and all staff that are 18.4.4.1 Designation of Neonatal Care
likely to be involved in neonatal stabilization and Services
should be properly accredited (Resuscitation Neonatal units have a range of service available to
Council (UK) 2015; Perlman et al. 2015a). Clear them that differ from hospital to hospital. Often
written arrangements for checking that resuscita- the quanta of care that is provided depend upon
tion apparatus is always available and for calling staffing levels and colocated facilities. In many
appropriate staff when necessary should be countries, a three level system operates formally
agreed. Management plans where comfort or pal- or informally with a fourth level designating those
liative care is anticipated need to be agreed and, hospitals which provide “super-specialist” care
given the ethical difficulties that surround, in par- such as cardiac surgery, neonatal surgery, etc.
ticular, birth at extremely low gestations each The detail will vary from one health system to
neonatal unit should agree with their obstetric another. The British Association of Perinatal
and midwifery colleagues a policy for communi- Medicine (BAPM) grading (Royal College of
cating risk to prospective parents facing such Obstetricians and Gynaecologists et al. 2007) is
deliveries. shown in Table 1.
18 Organization of Perinatal Care: Training of Doctors and Nurses 283
Table 1 Designation of neonatal services within a neona- the greater proportion of total unit costs this
tal network allows reimbursement to be made for care on a
Level 1 or Special Care Units – provide special care but bed day basis.
do not aim to provide any continuing high dependency or
intensive care; this includes units with or without resident
medical staff 18.4.4.2 Family-Centered Neonatal Care
Level 2 or Local Neonatal Units – provide high Traditionally, parents were observers while med-
dependency care and some short-term intensive care as ical and nursing experts assumed responsibility
agreed within the network; medical staffing at middle for care. Indeed many units were designed with
grade and consultant level is shared with a general viewing galleries or corridors to prevent contact.
pediatric service
With the advent of more enlightened views of the
Level 3 or Neonatal Intensive Care Units – provide the
whole range of medical neonatal care but not necessarily role of the parent in enhancing the baby’s progress
all specialist services such as neonatal surgery; medical through the neonatal period, parents are now wel-
staffing at all grades is dedicated to the neonatal service comed into the neonatal unit and encouraged to
Adapted from Royal College of Obstetricians and participate in their child’s care. The advantages of
Gynaecologists et al. (2007) this in engendering better psychological support
for parents are clear, and there is evidence that
Within these designations it is important that skin-to-skin contact is of great importance in pro-
we define what activity occurs within each ser- moting infant stability and well-being. Encourag-
vice. Again these definitions will vary widely ing close parental involvement in their child’s care
between health systems. The BAPM definitions demands organizational changes in the way neo-
of normal, special, high dependency, and inten- natal services are run, the facilities available for
sive care are shown in Table 2. One of the key parents such as sitting rooms and overnight bed-
features about the use of definitions such as rooms, and for privacy when they are with their
these is that they reflect the level of support child (The Neonatal Taskforce 2009). Some units
required by the baby and that this is independent have developed the concept of single room care to
of the setting in which the care is delivered. For accommodate this more appropriately, but
example, if a baby required intensive care while staffing, space, and cost constraints make this an
awaiting transfer to a neonatal unit, the referring expensive, if desirable, option and is not suitable
hospital should be able to provide the equipment for all families. Caring for a child in a single room
and manpower immediately available to cope without family present may reduce stimulation
with the baby’s needs. This may cause problems and opportunity for the baby to interact, poten-
in that if the staff are needed for an emergency tially increasing parental stress (British Associa-
elsewhere in the hospital; other staff members tion of Perinatal Medicine 2001).
should be available to deal with that leaving Within a neonatal service it is possible to draw
experienced staff to care for the baby who up a range of standards for family-friendly care to
needs intensive care. Similarly, often babies ensure that a baby and his family are afforded due
who fall into the category “special care” are respect and that communication and involvement
cared for alongside their mothers. This requires occur. An example of one such set of standards is
enhanced nursing support but may occur outside included in Table 3. Importantly, these should be
the confines of a neonatal unit. Sometimes, this auditable so that the neonatal service should be
is known as “transitional care.” Neonatal units able to demonstrate its commitment to this impor-
have used transitional care as a means of enhanc- tant area.
ing the care they give (promoting mother-baby Further organizational issues center around the
contact) and also of enhancing the capacity of discharge of the baby home at the completion of
their neonatal unit but need extra resources the episode of perinatal care. The process of
to do it properly. In our system, the nursing taking a baby home is highly stressful for par-
requirements also follow the care category as ents. Units need to develop expertise and clear
indicated in Table 2. Because staff costs are arrangements for preparing families for home
284 N. Marlow
Table 2 Definitions of categories of neonatal care (see http://bapm.org/publications/)
Intensive care
These babies have the most complex problems. They need 1:1 care by a nurse with a neonatal qualification. The
possibility of acute deterioration is such that there should be the constant availability of a competent doctor
1. Receiving any respiratory support via a tracheal tube and in the first 24 h after its withdrawal
2. Both noninvasive respiratory support and parenteral nutrition
3. The day of surgery (including laser therapy for retinopathy)
4. The day of death
5. A day during which any of the following occur:
Presence of an umbilical arterial line
Presence of an umbilical venous line
Presence of a peripheral arterial line
Insulin infusion
Presence of a chest drain
Exchange transfusion
Therapeutic hypothermia
Prostaglandin infusion
Presence of replogle tube
Presence of epidural catheter
Presence of silo for gastroschisis
Presence of external ventricular drain
Dialysis (any type)
High dependency care
A nurse should not be responsible for the care of more than two babies in this category
1. Any day where a baby receives any form of noninvasive respiratory support (e.g., nasal CPAP, SIPAP, BIPAP,
HHFNC)
2. Any day receiving any of the following:
Parenteral nutrition
Continuous infusion of drugs (except prostaglandin and/or insulin)
Presence of a central venous or long line (PICC)
Presence of a tracheostomy
Presence of a urethral or suprapubic catheter
Presence of trans-anastomotic tube following esophageal atresia repair
Presence of NP airway/nasal stent
Observation of seizures/CF monitoring
Barrier nursing
Ventricular tap
Special care
A nurse should not be responsible for the care of more than four babies receiving Special or Normal Care
Any day where a baby does not fulfill the criteria for intensive or high dependency care and requires any of the
following:
Oxygen by nasal cannula
Feeding by nasogastric, jejunal tube, or gastrostomy
Continuous physiological monitoring (excluding apnoea monitors only)
Care of a stoma
Presence of IV cannula
Baby receiving phototherapy
Special observation of physiological variables at least 4 hourly
Routine care
• Is provided for babies who themselves have no medical indication to be in hospital
and if possible supporting them in the transition. 18.4.4.3 Nurse Staffing
Information packs, training in resuscitation tech- The provision of recommended neonatal nurse
niques, and supportive outpatient follow-up are staffing levels again will vary between health sys-
important steps in the discharge process. tems, depending on the roles that are undertaken
18 Organization of Perinatal Care: Training of Doctors and Nurses 285
Table 3 Examples of family-friendly standards for NICU
1. Where admission to a neonatal unit is predicted, a prenatal opportunity to visit the neonatal unit and meet key
personnel should be offered to the family
2. All parents should be introduced to facilities, routines, staff, and equipment on admission to a neonatal unit
3. Every parent should have unrestricted access to his or her baby, unless individual restrictions can be justified in the
baby’s best interest
4. Parents should be encouraged and supported to participate in decision-making about the care and treatment of their
baby. Written and regularly updated care plans should be shared with parents. Clinical care decisions, including end-of-
life decisions, should be made by experienced staff in partnership with the parents and discussions held in an appropriate
setting
5. Parents are encouraged and supported to participate in their baby’s care at the earliest opportunity, including:
Regular skin-to-skin care
Providing comforting touch, comfort holding, particularly during painful procedures
Feeding
Day-to-day care, such as nappy changing
6. Every baby should be treated with dignity and respect:
Appropriate positioning is promoted and encouraged
Clinical interventions are managed to minimize stress, avoid pain, and conserve energy
Noise and light levels are managed to minimize stress
Appropriate clothing is used at all times, taking into account parents’ choice
Privacy is respected and promoted as appropriate to the baby’s condition
7. Every parent will have the opportunity to discuss their baby’s diagnoses and care with a senior clinician within 24 h
following admission or a significant change in condition
8. Written information should be available (in languages and formats appropriate to the local community) to all users of
the service on medical and surgical treatments, to permit early and effective communication with parents covering at
least:
Condition/diagnosis
Treatment options available
Likely outcomes/benefits of treatment
Possible complications/risks
Possible tests and investigations
Who to contact with queries or for advice
Where to go for further information, including useful websites
Circumstances requiring consent (written and verbal)
9. Maternity and neonatal services should encourage breastfeeding and the expression of milk through the provision of
information and dedicated support, including:
Whenever possible, initiation of breast feeding as soon as possible after birth
When necessary, support to start expression as soon after delivery as the mother’s condition allows to maximize the
benefit of colostrum
The availability of a comfortable, dedicated, and discrete area
The facility to express discretely at the cotside
The availability of breast pumps and associated equipment for every mother who requires them
Supporting breastfeeding as part of the discharge process
Promotion of safe and hygienic handling and storage of breast milk
Possible availability of donor breast milk
Adapted from The Neonatal Taskforce (2009)
by nurses and the availability of other profes- that adequacy of nurse staffing is a key issue
sionals, such as respiratory therapists. Within the within neonatal units in relation to mortality (Wat-
UK system there have been few studies of nursing son et al. 2016). Further research is needed to
input on which to base the recommendations set support recommendations in this area.
out in Table 2, although recent evidence suggests In systems where nurses take on more techni-
that one-to-one nursing provision may be associ- cal roles (cannulation, intubation, ventilator man-
ated with lower mortality (BLISS the premature agement), enhanced nursing support is required.
baby charity 2009). Nonetheless, it is apparent With appropriate training many units have
286 N. Marlow
developed the role of Advanced Nurse Practi- The clinical audit process
tioner; such individuals form an intermediate tier The use of standards, guidelines, and perinatal
between junior and senior resident doctors and audit tools
assume many of the roles previously taken on by Benchmarking and the application of evidence-
medical staff (at least in the UK) and may con- based care
tribute to on call rosters (Hamilton et al. 2007). In
some settings, they may act without medical staff Although all three are interwoven they merit
in supporting low risk deliveries, whereas in other consideration separately.
settings they provide intensive care activity. Both
these and other roles require different and bespoke Clinical Audit
training. The key to the process or cycle of audit is the
setting of standards, the appraisal of your service
18.4.4.4 Medical Staffing against the standard, and the revision of your stan-
Medical staffing is equally dependent upon the dard consequent upon the audit to be followed by a
health service model. In the UK, medical trainees reaudit to make sure it is appropriate. The areas that
and Advanced Neonatal Nurse Practitioners are amenable to audit cover the range of activities
support neonatal intensive care services at a tech- of a neonatal service and include the structure of
nical grade (junior resident) and as experienced the service (people/facilities available); the process
senior resident support. The number of staff neo- of care (are we consistently doing what we think
natologists in this system is relatively few and we are?); and the outcome of care (Is our prophy-
they have more of an executive and managerial lactic indomethacin effective?; Is our mortality rate
role. Changes to working hours (for example, the appropriate for our population?).
European Working Time Directive) and avail- Clinical audit is a key part of assessing the
ability of resident staff to work in these high service we are giving and audit of structure and
intensity settings mean that such systems are outcome can provide valuable information
under threat. In many other settings, staff when bidding for resources and redesigning
neonatologists (nationally qualified doctors) services. It also helps to confirm that we are
provide medical care. achieving what we aim to achieve in terms of
Research into the numbers of neonatologists outcomes and activity. More information on the
required to staff a neonatal service is unusual. use of clinical audit in neonatal care is to be
One epidemiologic approach determined that found elsewhere.
mortality rose in areas of the USA where
there was a very low supply of neonatologists Standards and Guidelines
(<4.3 doctors per 10,000 births) but that Part of the way in which we develop our service is
increasing the number did not result in further to provide a range of policy that is based around
reductions (Hall and Wilkinson 2005). In the the best evidence we have. In the USA, the Fetus
UK, the number of consultants was not related and Newborn Committee of the American Acad-
to mortality or nosocomial infection rates emy of Pediatrics produces regular guidance
(Goodman et al. 2002). based on best evidence. In the UK, guidance on
aspects of clinical care is sometimes available
18.4.4.5 Clinical Governance from professional organizations and may be spec-
Within any neonatal service a strong clinical gov- ified as part of the process of resourcing the ser-
ernance framework is required in order to maxi- vice. The series of Green-top guidelines produced
mize safety and efficiency. Clinical governance by the Royal College of Obstetricians and
comprises a range of organizational structures Gynaecologists, for example, contain much of
which we use as professionals in order to quality relevance to neonatal care and guide practice
assure the care we provide, the most useful of widely in the UK. The Royal College of Paediat-
which are: rics and Child Health publishes a range of
18 Organization of Perinatal Care: Training of Doctors and Nurses 287
documents, which although not primarily aimed conclusions (see ▶ Chap. 133, “Epidemiology of
at neonatal care are of great importance in neona- Adverse Cerebral Outcome of Newborns”).
tal practice, for example, Withholding or With- However, it is important to establish an exter-
drawing Life Sustaining Treatment in Children: A nal reference for the performance of a neonatal
Framework for Practice (2004), which guides service and there are important resources avail-
practice around end-of-life decisions. The British able to support this – such as EuroNeoNet (https://
Association of Perinatal Medicine (BAPM) www.euroneostat.org) and the Vermont Oxford
also produces a range of practical guidance, for Network (https://www.vtoxford.org), in addition
example: to national or local benchmarking systems.
Whereas the exact ranking in such datasets is not
Management of extremely preterm babies (2008) really helpful, progress against the reference pop-
Use of Central Venous Catheters in Neonates – a ulation and the identification of areas where a
Framework for Practice (2015) service is an outlier are invaluable pieces of infor-
Newborn Early Warning Trigger & Track mation. The most valuable benchmarking process
(NEWTT) – a Framework for Practice in the UK is the MBRRACE-UK: Mothers and
(2015) Babies: Reducing Risk through Audits and Con-
Practical guidance for the management of pallia- fidential Enquiries across the UK (www.npeu.oc.
tive care on neonatal units (2014) ac.uk/mbrrace-uk), whereby there is national
Position Statement on Therapeutic Cooling for monitoring of perinatal and maternal mortality
Neonatal Encephalopathy (2010) with focused confidential enquiries and other
Guideline for the Screening and Treatment of audit projects.
Retinopathy of Prematurity (2008) Alongside the benchmarking process, the Ver-
mont Oxford Network offers a range of quality
Further guidance is published on an ad hoc improvement programs, which serve to help a
basis, for example, the recent European Guidance service deliver state-of-the-art care and minimize
on the Management of Respiratory Distress Syn- morbidity, in areas such as nosocomial infection,
drome (Tucker et al. 2002). chronic lung disease, and intraventricular hemor-
Most neonatal intensive care units are busy rhage through a process of audit.
places, and it is helpful to have a range of guidance
easily assessable to staff. It is also helpful to work to Data Collection
protocols so that audit of care is more meaningful. The key to all aspects of clinical governance is the
Key aspects of guidelines are that they should: collection of robust and accurate information
about the unit and the babies it looks after. There
Be evidence based is a range of datasets available but all require close
Explain in principle why a treatment/process is attention to details to ensure that what is collected
preferred is accurate and useful. BAPM initially produced a
Be auditable to ensure they are working UK national dataset to support the writing of
annual reports that could then be compared
Within the UK neonatal networks, guidelines (Sweet et al. 2013) and the international
are usually shared for key areas of practice: refer- benchmarking groups require similar datasets.
ral, transfer, and early care for very preterm The UK Neonatal Collaborative has more recently
babies, for example, and shared between units codified a national dataset which is collected uni-
via their websites. versally for all neonatal unit admissions (British
Association of Perinatal Medicine 1997).
Benchmarking
Comparing the performance of one unit with 18.4.4.6 Follow-up After Discharge
another is fraught with difficulty. Population Most neonatal services now provide follow-up for
risks are different and can lead to erroneous groups who are at high risk of disability. In the
288 N. Marlow
Table 4 Recommended format for reporting perinatal outcomes at 2 years (BAPM 2008)
Gestational age at birth 22 w 23 w ... 31 w
Number of births (exclude terminations of pregnancy)a
Number of live births
Number of babies offered active care
Number of admissions for intensive care
Number of survivors discharged home
No. of deaths between discharge and 2y
No. of survivors evaluated at 2y
No. with cerebral palsy
No. with motor impairment GMFCS 2b
No. with motor impairment GMFCS 3–5c
No. with cognitive score < 2 SDb
No. with cognitive score < 3 SDc
No. with hearing aids but not severe hearing impairmentb
No. with severe hearing impairmentc
No. with speech and language impairmentb
No. with severe speech and language disabilityc
No. with visual impairment but not severe visual impairmentb
No. with severe visual impairmentc
Total with neurodevelopmental impairment (moderate or severe)b
No. with moderate disability
No. with severe neurodevelopmental disability (SND)c
Moderate impairment % survivors evaluated
% admissions for NIC
% birthsb
Death or moderate impairment % admissions for NIC
% birthsb
Severe impairment % survivors evaluated
% admissions for NIC
% birthsb
Death or severe impairment % admissions for NIC
% birthsb
No. with other disability
Describe
GMFCS gross motor function classification system
a
“Births” may be total births or particular groups (e.g., gestational age) in a defined population – this could be hospital
based, network based, or population based depending upon the need
b
Components of moderate disability – a child with an impairment in any category (but none in the severe category) is
classified as having moderate disability
c
Components of severe disability – a child with any one severe disability or impairment in any category is classified as
having severe impairment
UK, a recent working party has revisited the Health and Human Development (NICHD) Neo-
criteria for defining health status as an outcome natal Network in North America. Target groups
measure for perinatal care, recommending a for- for follow-up are very preterm or very low birth
mal assessment and recording of data at 2 years of weight children, children who have been enceph-
age (The UK National Neonatal Dataset). These alopathic, and any that are identified by other
are similar to those used within the The Eunice routes to be at risk. Combined with mortality
Kennedy Shriver National Institute of Child data, this powerful information is useful in terms
18 Organization of Perinatal Care: Training of Doctors and Nurses 289
of monitoring outcomes and providing center- https://www.england.nhs.uk/commissioning/spec-ser
based information for parents. An example of vices/npc-crg/group-e/e08/
Perlman JM, Wyllie J et al (2015a) Part 7: Neonatal Resus-
the output from such a service is shown in Table 4. citation: 2015 International consensus on cardiopulmo-
nary resuscitation and emergency cardiovascular care
science with treatment recommendations. Circulation
132:S204–S241
References Perlman JM, Wyllie J, Kattwinkel J et al (2015b) Part 7:
Neonatal Resuscitation: 2015 international consensus
BLISS the premature baby charity (2005) Special care for on cardiopulmonary resuscitation and emergency car-
sick babies-choice or chance? BLISS, London diovascular care science with treatment recommenda-
BLISS the premature baby charity (2009) The Bliss baby tions. Pediatrics 136(Suppl 2):S120–S166
charter standards. BLISS, London Resuscitation Council (UK) (2015) Resuscitation and sup-
British Association of Perinatal Medicine (1997) The port of transition of babies at birth. https://www.resus.
BAPM neonatal dataset for the annual reporting of org.uk/resuscitation-guidelines/resuscitation-and-sup
data by neonatal intensive care units. BAPM, London port-of-transition-of-babies-at-birth
British Association of Perinatal Medicine (2001) Standards Royal College of Obstetricians and Gynaecologists (2003)
for hospitals providing intensive and high dependency Prevention of early onset neonatal Group B streptococ-
care. BAPM, London cal disease (Greentop Guideline no. 36). RCOG,
British Association of Perinatal Medicine (2008) Report of London
a BAPM/RCPCH working group: health status at two Royal College of Obstetricians and Gynaecologists, Royal
years as a perinatal outcome. BAPM, London College of Anaesthetitsts, Royal College of Paediatrics
Department of Health (2009) Toolkit for high quality neo- and Child Health (2007) Safer childbirth: minimal stan-
natal services. Department of Health, London dards for the organisation, delivery of care in labour.
Field D, Draper ES (1999) Survival and place of delivery RCOG, London
following preterm birth: 1994–96. Arch Dis Child Fetal Sweet DG, Carnielli V, Greisen G et al (2013) European
Neonatal Ed 80:F111–F114 consensus guidelines on the management of neonatal
Goodman DC, Fisher ES, Little GA et al (2002) The relation respiratory distress syndrome in preterm infants–2013
between the availability of neonatal intensive care and update. Neonatology 103(4):353–368
neonatal mortality. N Engl J Med 346:1538–1544 The Neonatal Taskforce (2009) A framework for commis-
Hall D, Wilkinson AR (2005) Quality of care by neonatal sioning neonatal services. Department of Health, London
nurse practitioners: a review of the Ashington experi- The UK National Neonatal Dataset. Available from: https://
ment. Arch Dis Child Fetal Neonatal Ed 90:F195–F200 www1.imperial.ac.uk/neonataldataanalysis/data/data/
Hamilton KE, Redshaw ME, Tarnow-Mordi W et al (2007) Tucker J, UK Neonatal Staffing Study Group (2002)
Nurse staffing in relation to risk-adjusted mortality in Patient volume, staffing, and workload in relation to
neonatal care. Arch Dis Child Fetal Neonatal Ed 92: risk-adjusted outcomes in a random stratified sample of
F99–F103 UK neonatal intensive care units: a prospective evalu-
Lasswell SM, Barfield WD, Rochat RW et al (2010) Perinatal ation. Lancet 359:99–107
regionalization for very low-birth-weight and very pre- Tucker J, Tarnow-Mordi W, Gould C et al (1999) UK
term infants: a meta-analysis. JAMA 304(9):992–1000 neonatal intensive care services in 1996. On behalf of
Mahle WT, Newburger JW, Matherne GP et al (2009) Role the UK Neonatal Staffing Study Collaborative Group.
of pulse oximetry in examining newborns for congen- Arch Dis Child Fetal Neonatal Ed 80:F233–F234
ital heart disease: a scientific statement from the Amer- Tucker J, McCabe C, McCabe C et al (2002) Patient
ican Heart Association and American Academy of volume, staffing, and workload in relation to risk-
Pediatrics. Circulation 120:447–458 adjusted outcomes in a random stratified sample of
Marlow N, Bryan Gill A (2007) Establishing neonatal UK neonatal intensive care units: a prospective evalu-
networks: the reality. Arch Dis Child Fetal Neonatal ation. Lancet 359:99–107
Ed 92:F137–F142 Watson SI, Arulampalam W, Petrou S et al (2014) The
Marlow N, Bennett C, Draper ES et al (2014) Perinatal effects of designation and volume of neonatal care on
outcomes for extremely preterm babies in relation to mortality and morbidity outcomes of very preterm
place of birth in England: the EPICure 2 study. Arch infants in England: retrospective population-based
Dis Child Fetal Neonatal Ed 99(3):F181–F188 cohort study. BMJ Open 4(7), e004856
Moss GD, Cartlidge PH, Speidel BD, Chambers TL (1991) Watson SI, Arulampalam W, Petrou S et al (2016) The
Routine examination in the neonatal period. BMJ effects of a one to one nurse to patient ratio on the
302:878–879 mortality rate in neonatal intensive care: a retrospec-
Neonatal Critical Care Clinical Reference Group (2015) tive, longitudinal, population-based study. Arch Dis
Neonatal Service Specification 2015 Available from: Child Fetal Neonatal Ed 101(3):F195–F200
Neonatal Transport Services
19
Rocco Agostino, Roberto Aufieri, and Maurizio Gente
Contents
19.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
19.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
19.3 NETS: A Mission Statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
19.4 Organization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
19.5 NETS Coordinating Center . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
19.6 Types of Transfers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
19.7 Transport Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
19.7.1 Triage and Cot Search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
19.7.2 Patient Stabilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
19.7.3 Personnel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
19.7.4 Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
19.7.5 Road and Vehicles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
19.8 Challenging Situations During Neonatal
Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
19.8.1 Surgical Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
19.8.2 Duct-Dependent Congenital Heart Disease
(CHD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
19.8.3 Persistent Pulmonary Hypertension of the Newborn (PPHN) . . . . . . . . . . . . . . . . 298
R. Agostino (*)
Ethics Committee, Pediatric Hospital Bambino Gesù,
Rome, Italy
e-mail: [email protected]
R. Aufieri
Division of Neonatology and Neonatal Intensive Care,
Casilino General Hospital, Rome, Italy
M. Gente
Department of Pediatrics and Infant Neuropsychiatry,
Neonatal Emergency Transport Service, Sapienza
University of Rome, Rome, Italy
# Springer International Publishing AG, part of Springer Nature 2018 291
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_168
292 R. Agostino et al.
19.8.4 Neonates with Hypoxic-Ischemic Encephalopathy
(HIE) Requiring Hypothermia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
19.8.5 Severe Hyperbilirubinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
19.9 Family-Centered Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
19.10 Quality Evaluation and Costs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
19.11 Training and Outreach Education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
19.12 Future Perspectives of NETS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
Abstract • The organization of NETS should be appropri-
Neonatal transfer is necessary when a newborn ate to the needs and characteristics of the
baby needs care that cannot be provided in the region covered. Each regional network should
referral center. Since it represents an additional ideally have a NETS coordinating center.
risk factor for a critically ill neonate, it should be • Transfer requests should be appropriately
performed, when possible, by a well-organized assessed and a transport plan formulated to
neonatal transport service. In a network, aimed at determine level and characteristics of admitting
the regionalization of perinatal care, high-risk hospital, road, vehicles, and personnel required.
pregnancies should be transferred “in utero” in • Referring centers should be able to perform basic
order to minimize risks for both mother and resuscitation and stabilization before the arrival
neonate. However, there will always be a number of the transport team: Insufficient performances
of neonates who need to be transferred for may result in clinical deterioration during the
unpredicted or unpredictable reasons. Every transfer.
maternity unit should therefore be able to provide • Good communication between transport team,
effective neonatal resuscitation in the delivery referring staff, and neonate’s family is manda-
room, be able to maintain a sick baby in a stable tory, along with audit for evaluation and
condition in the short term, and have access to a improvement of the service. Efficiency and
neonatal emergency transport service (NETS) for effectiveness measures should be assessed
the provision of neonatal intensive care when after each transport.
appropriate. Thus, NETS provides a bridge
between birth centers and neonatal intensive
care units (NICUs).
Organization of NETS, quality evaluation, 19.2 Introduction
transport process, family-centered care, and
challenging situations that can be encountered Neonatal transfer is necessary when a newborn
during neonatal transport are some of the baby needs care that cannot be provided in the
topics treated in this chapter. referral center. Since it represents an additional
risk factor for a critically ill neonate (Arora
et al. 2014; Lim and Ratnavel 2008), it should be
performed, when possible, by a well-organized
19.1 Salient Points neonatal transport service.
In a network, aimed at the regionalization of
• Newborn babies requiring care that cannot be perinatal care, high-risk pregnancies should be
provided in the referral center should be trans- transferred “in utero” in order to minimize risks
ferred by a neonatal emergency transport ser- for both mother and neonate (Arora et al. 2014;
vice (NETS) that can guarantee a safe transport Kollèe et al. 1992). However, there will always be
with minimization of risk. a number of neonates who need to be transferred
19 Neonatal Transport Services 293
for unpredicted or unpredictable reasons – Available economic resources, personnel,
(Finnstrom et al. 1997). Every maternity unit vehicles, and equipment
should therefore be able to provide effective neo- – Regular clinical audits
natal resuscitation in the delivery room, be able to
maintain a sick baby in a stable condition in the There are different models of perinatal net-
short term, and have access to a neonatal emer- works for the provision of the most appropriate
gency transport service (NETS) for the provision service. The choice between the two models in
of neonatal intensive care when appropriate. terms of cost-benefit ratio depends mainly on
Thus, NETS provides a bridge between birth cen- the number of transports per year and on the
ters and neonatal intensive care units (NICUs). referral area (Agostino et al. 1998, 1999), as
follows:
19.3 NETS: A Mission Statement • Dedicated service: all transports carried out by
a team devoted full time to this service. The
NETS should aim to guarantee: optimal number of transports per year is
400–600. Fewer than 400 increase costs and
– Optimal care for every neonate in the most more than 600 decrease efficiency.
appropriate location • On-call service: in this organizational model,
– Safe and quick transport with minimization of transports integrated into the overall activity of
risk an individual NICU and carried out by “in-
– Good communication between transport team, house” personnel. The optimal number of
parents, and centers involved transports per year to minimize costs and max-
– Rational resource use with optimized cost- imize efficiency is 150–200.
benefit ratio
– An outreach education program relating to The characteristics of each model are summa-
resuscitation and pre-transport stabilization rized in Table 1. In Europe, the most usual models
– Guidelines for referral centers and transport for regional networks are dedicated or on-call
personnel NETS.
The NTI is an expression of the number of
The establishment of a NETS therefore neonates transferred per 100 live births. This
requires planning and organization. There should index can be used to compare the flow of new-
be regular auditing to monitor its efficiency and borns between facilities in each area. A low NTI
effectiveness (see ▶ Chap. 18, “Organization of
Perinatal Care: Training of Doctors and Nurses”). Table 1 Characteristics of the two NETS models
Dedicated On-call
Activation Usually shorter Usually longer
19.4 Organization times
Availability Around the clock Available on-call
The organization of a NETS should be appropriate Distances Longer Shorter
to the needs and characteristics of the region cov- covered
ered and resources available. Account should be Area covered Usually larger Usually smaller
taken of: Receiving All NICUs Only NICU
center (interfacility where NETS is
transports) based
– Demography (birth rate and distribution)
Individual- More, because Less, because
– Place, number, and levels of perinatal units specific mainly appointed temporarily
– Number of transports per year and patient flow transport to transport service detached from
between centers expertise NICU
– Neonatal transport index (NTI; see below) Costs More expensive Less expensive
294 R. Agostino et al.
(around 1%) indicates a good distribution of – Return transfers: for diagnostic investiga-
perinatal facilities and well-organized maternal- tions (e.g., MRI) or procedures (laser treat-
neonatal transport services. Programs of regional- ment for ROP)
ization of high-risk perinatal care, in the past
years, have been effective in reducing NTI in
most of European countries (Kempley 19.7 Transport Process
et al. 2007; Zeitlin et al. 2004; Neto 2006).
To account for regional diversity, it is also The transport process (Table 2) starts with a
possible to organize a network with more than request for transfer by the referring center. Each
one type of NETS. transport should be coordinated by the coordinat-
ing center or by a senior neonatologist at the
admitting center.
19.5 NETS Coordinating Center
Each regional network should ideally have a
19.7.1 Triage and Cot Search
NETS coordinating center. Its role is to:
When the coordinating center (or the transport
– Triage requests for transfers.
team) receives the transfer request from the refer-
– Monitor cot availability and find
ral center, severity and requirements of infant
appropriate cots.
conditions should be appropriately assessed and
– Activate the appropriate transport team and
an initial transport plan formulated. Level and
coordinate the transfer.
characteristics of admitting hospital, road, vehi-
– Prioritize simultaneous requests.
cles, and personnel needed should be identified.
– Give advice to referring clinicians and to the
Prioritization of simultaneous transfer requests
transport team.
has to be performed adopting validated scoring
– Supervise staff, plan audits, and education.
systems. The Mortality Index for Neonatal
– Ensure the provision of appropriate resources.
Table 2 Transport process
19.6 Types of Transfers Events Operative approach
Request for transfer Discussion, triage, advice and
support for referring center,
Transfers can be classified on the basis of the
plan of action
degree of emergency and destination: Cot search Finding the most appropriate
cot and activation of the
• Acute: transport team
– Primary transfers: to a NICU or a higher Transport team Continuing advice and support
level center, depending on the require- departs from base for the referring center, which
hospital is responsible for pre-transport
ment for intensive or high dependency stabilization
care Transport team at the Assessment and further
– Intertertiary: between NICUs, if there is a referring hospital stabilization prior to transport
lack of cots or the need for surgical or spe- Transfer of the baby to Monitoring, continuous
cialized care admitting hospital assessment, specific treatment
if needed
• Elective:
Transport team at the Final assessment, hand over to
– Back transports: usually from a NICU to the admitting hospital admitting team
local hospital, when a neonate is stable, to Transport team returns Check and replacement of
maintain the availability NICU cots and to base hospital used equipment and medical
minimize costs and discomfort for families gases, communicate new
(Argus et al. 2009) availability
19 Neonatal Transport Services 295
Table 3 Mortality Index for Neonatal Transportation stabilization before the arrival of the transport
(MINT) score. (Modified from Broughton et al. 2004) team. It has been shown how birth and stabiliza-
MINT score tion in a tertiary center can improve outcomes
Parameter Value points (Gente et al. 2015). An epidemiological analysis
pH <6.9 10 of 1,495 infants transported in Lazio region
6.91–7.1 4 (Italy) showed that factors that significantly
>7.1 0
increased stabilization time were the lower ges-
Age 0–1 h 4
tational age, the lower level of care of the refer-
>1 h 0
ring hospital, the medical reason for transport
Apgar score at 0 8
1 min (compared to surgical), and the location of the
1 5
2 2
referring hospital outside the main city area
3 2 (Di Lallo et al. 2010).
>3 0 The baby’s clinical condition should be
Birth weight <750 g 5 carefully evaluated to establish the initial diag-
751–1,000 g 2 nosis and a therapeutic plan. Stabilization
1,001–1,500 g 1 involves basic physiological support and is
>1,500 g 0 defined as the treatment or correction of those
PaO2 3 kPa 2 processes which, if not addressed, may lead to
(22,56 mmHg) deterioration in the baby’s condition. After sta-
>3 kPa 0 bilization, preparations for transfer are started.
(>22,56 mmHg)
These include ensuring that physiological
Congenital Yes 5
abnormality parameters are satisfactory, that airway and
No 0
Intubated at time Yes 6
vascular access are secure, and that appropriate
of call No 0 monitoring is in place. Insufficient attention to
resuscitation and stabilization may result in
clinical deterioration during the transfer, and
Transportation (MINT) score (Table 3) is a vali- the environment during transport (limited
dated, easy-to-use mortality prediction score for space, vibration, noise, etc.) is not conducive
retrieved neonates, which can be used to deter- to optimal patient care (Arora et al. 2014; Lim
mine priority of request and resource allocations and Ratnavel 2008; Bouchut et al. 2011;
(Broughton et al. 2004). All of the data used in the Karlsson et al. 2012).
MINT score can be collected at the time of the
telephone call requesting transfer. Particular atten-
tion should be given to the evaluation of requests 19.7.3 Personnel
of transfer for patients with unconfirmed diagno-
sis or need for specialized care and treatments The choice of personnel for a transport team varies
(i.e., in the suspect of hypoxic-ischemic encepha- widely between NETS, depending on organiza-
lopathy (HIE), congenital heart disease (CHD), or tional preferences, budgets, and availability of pro-
surgical conditions). fessional groups (Agostino et al. 1998; Lupton and
Systems ensuring the online monitoring of Pendray 2004). The traditional view that a neona-
NICU and surgical cots available in the area cov- tologist and a nurse should constitute a neonatal
ered can help to reduce activation times. transport team is no longer generally accepted.
Retrieval teams with different professional back-
grounds do not appear to affect the outcome of
19.7.2 Patient Stabilization transports (Leslie and Stephenson 2003; Morrison
and Cheema 2007). The nature of the professional
It is important that staff at the referring hospital background of transport team members is less
should be able to perform basic resuscitation and important than training in transport practice with
296 R. Agostino et al.
specific core competencies (Fenton and Leslie working conditions and mechanical stresses,
2009). Poor transport experience reduces quality caused by vibrations and sudden forceful impact,
of NETS (Macnab 1991). Time devoted to stabili- mean that equipment should be checked and
zation of the neonate prior to transport increases tested regularly. Staff should be trained in their
with operator experience (James 1993). There use and should be aware of the more frequent
should be regular rotation of personnel between minor causes of malfunctioning so they are able
NICU and the transport service to prevent burnout to fix them.
and allow for professional updating.
19.7.5 Road and Vehicles
19.7.4 Equipment The choice of road and vehicle should aim to
guarantee the quickest, safest, and most comfort-
Equipment taken on transfer needs to be suitable able transport for the baby, taking account of
for a variety of babies, from the extremely low birth clinical conditions, regional geography, and
weight to term, and for the range of medical or weather, road, and traffic conditions (Sedin
surgical problems that require different therapies in et al. 1999). Different scenarios should be con-
transit. The transport itself requires a transport sidered and guidelines prepared to determine the
incubator system with a mechanical ventilator, choice of vehicle and appropriate response to
infusion pumps, suction pump, and monitors emergency situations. Vehicles that can be used
(Fig. 1). A neonatal resuscitation kit, including by NETS are ambulance, helicopter, and fixed
drugs, should be carried in a separate bag. wing aircraft. Ambulances are most commonly
Equipment should be dedicated exclusively for used because of lower costs, universal availabil-
neonatal transport, to ensure its ready availability ity, short activation times, and the possibility of
and that the battery is fully charged. Some recom- reaching hospitals directly. Dedicated vehicles
mendations have been provided by the European guarantee shorter activation times and better
Committee for Standardization (European Com- compatibility between equipment. Air transport,
mittee for Standardization 2003a, b). Difficult including by helicopter, is indicated for longer
Fig. 1 Transport incubator
system
19 Neonatal Transport Services 297
distances and for regions with poor weather con- support of multiple experts. Continuous advice
ditions during winter or peculiar geographic from the coordinating center and the pediatric
characteristics (e.g., mountain regions). Account surgeons of the receiving center should be
should also be taken of the possible need for an guaranteed. Few basic considerations about the
additional ambulance journey, depending on most common surgical conditions are summa-
whether there are facilities for landing at the rized in Table 3 (Puri and Doodnath 2011). For
hospital. Air transport is characterized by the further indications, please refer to the chapters
presence of high noise and vibration levels and in the books dedicated to the mentioned surgical
changes in gas pressures, temperatures, humid- condition.
ity, and gravitational forces that may affect care
and possibly worsen the condition of the criti-
cally ill neonate and, for these reasons, should 19.8.2 Duct-Dependent Congenital
only be performed by specifically trained person- Heart Disease (CHD)
nel (Bouchut et al. 2011; Karlsson et al. 2012;
Jackson and Skeoch 2009). Global positioning Differential diagnosis and treatment plan in case
systems (GPS) on vehicles allow the coordinat- of a suspected duct-dependent CHD represent
ing center to monitor and localize their positions one of the most challenging dilemmas to solve
and eventually redirect the team to a different for the NETS team and the coordinating center.
destination in case of emergencies or change of For infants born in centers without the availabil-
priorities. ity of a pediatric cardiologist consultation, a first
telephone triage should be performed, using the
available tools as the Simplified Congenital
19.8 Challenging Situations During heart disease-Oriented for Urgencies and emer-
Neonatal Transport gencies Triage (SCOUT) system (Warren
et al. 2001).
Critically ill infants with special requirements that Transport team at the referring center has to
until a few years ago were to be considered as distinguish a duct-dependent CHD from other
“untransportable,” or should have discontinued conditions (i.e., persistent pulmonary hyperten-
special treatments during transport, nowadays, sion of the newborn (PPHN), non-duct-depen-
can be safely transported with a similar level of dent CHD, severe sepsis) and take the decision
care provided in a NICU. A few of these situa- to start or not to start treatment with prostaglan-
tions, along with some of the most challenging din E1, relying often only on a clinical basis.
scenarios to be faced by a NETS team, are Accuracy of clinical diagnosis in identifying
depicted below. CHD by NETS team varies from 77% to 88%
depending on authors (Shivananda et al. 2010;
Gupta et al. 2014). A recent study, who retro-
19.8.1 Surgical Conditions spectively analyzed 144 newborns with
suspected CHD, showed how combined clinical
Ideally, pregnant women with antenatally diag- findings, chest X-rays, SpO2 and blood gases
nosed congenital surgical conditions should may assist in the diagnosis of duct-dependent
deliver in a tertiary level center with the availabil- CHD. Labile saturation and mean blood arterial
ity of a pediatric surgery. However, for sometime pressure at referral <40 mmHg were the only
unpredictable reasons (i.e., undiagnosed condi- significant predictors of non-duct-dependent
tions, preterm labor), births of infants with surgi- CHD at the multivariate analysis; meanwhile
cal conditions in non-tertiary centers continue to none of the clinical factors considered were
occur. significantly associated with duct-dependent
Management of the surgical neonates CHD on multivariate analysis. The authors con-
requires a multidisciplinary approach with clude that in the absence of a reliable single
298 R. Agostino et al.
clinical discriminator, prostaglandin E1 should 19.8.4 Neonates with Hypoxic-
be used when duct-dependent CHD is suspected Ischemic Encephalopathy (HIE)
(Gupta et al. 2014). For detailed information Requiring Hypothermia
about diagnosis, stabilization, and preoperative
management of infants with CHD, PGE1 indi- Randomized controlled trials involving term and
cations, and adverse effects, please refer to near-term infants with evidence of perinatal
▶ Chaps. 67, “Cardiovascular Physiology, asphyxia showed how moderate hypothermia
Pathology, and Clinical Investigation in Neona- (33–34 C), if started within 6 h after delivery,
tal Medicine,” and ▶ 68, “Early Diagnosis of reduced the risk of death and disabilities at
Congenital Heart Disease: When and How to 18–24 months of age and improved
Treat” of this book. neurocognitive outcome in middle childhood
(Jacobs et al. 2013; Azzopardi et al. 2014).
Therefore, cooling should be initiated for neo-
19.8.3 Persistent Pulmonary nates with GA 35 weeks with evidence of peri-
Hypertension of the Newborn natal asphyxia and moderate or severe HIE that
(PPHN) meet the eligibility criteria for therapeutic hypo-
thermia (as specifically defined and adapted by
Infants with clinical suspect or diagnosis of per- each center or network) and they should be trans-
sistent pulmonary hypertension of the newborn ferred to referral specialized centers for hypother-
(PPHN) can be treated and transported following mia as soon as possible (within 6 h after birth).
current evidences and recommendations (Dhillon Referring centers, after confirming with the
2012; Steinhorn 2010). Infants should be NETS coordinating center infant’s eligibility
intubated, ventilated (HFOV can be beneficial), criteria, should immediately start passive cooling,
and sedated. A central line should be positioned at turning the warmer off, undressing, and monitoring
the referring center. Oxygen therapy should be infant’s temperature, aiming at a target temperature
targeted to maintain pre-ductal SpO2 94%. If of 35 C, meanwhile waiting for the NETS team.
necessary, consider inotropes to maintain mean The coordinating center and NETS team
blood pressure about 55–60 mmHg and fluids to should provide advice to the referring center and
increase preload. give priority to transports of HIE neonates, trans-
Inhaled nitric oxide (iNO) therapy should be ferring them to the referral center within the
started if severe hypoxia is present. The use of shortest time possible.
iNO therapy during transport has been described NETS team at the referring center should pro-
by several authors (Lowe and Trautwein 2007; vide further metabolic (correct acidosis and defi-
Lutman and Petros 2008; Gaddam Bhoomaiah cits), cardiocirculatory (guarantee a venous
et al. 2014). The use of intravenous vasodilators access, fluid restriction, monitor blood pressure
as PGE1 has been also described during transport and diuresis), and respiratory (avoid hypocapnia)
of infants with PPHN (Gupta et al. 2013). Trans- stabilization, if needed. Treatment for seizures
portation of infants on extracorporeal membrane should be avoided, unless strictly necessary, for
oxygenation (ECMO) can be performed by spe- its possible interference with the EEG evaluation
cialized ECMO teams, when critical hypoxemic at the referral center. Fentanest and Midazolam
infants are not responsive to treatment (Broman can be used, if required. Eligibility criteria should
et al. 2015; Rambaud et al. 2016). Refer to be rechecked, and parental informed consent to
▶ Chaps. 60, “Persistent Pulmonary Hyperten- therapeutic hypothermia should be collected.
sion of the Newborn,” ▶ 61, “Pulmonary Hyper- During transport a target rectal temperature of
tension in Congenital Diaphragmatic Hernia,” and 35 C should be maintained, using passive or
▶ 64, “Extracorporeal Membrane Oxygenation active cooling (applying cold packs in the incuba-
for Neonates” for further information about tor or using servo-controlled cooling systems).
PPHN and iNO therapy. Continuous ECG and temperature monitoring by
19 Neonatal Transport Services 299
a rectal probe are mandatory to avoid severe hypo- every effort should be performed to admit all
thermia (32–33 C) and bradycardia (heart rate siblings in the same hospital. This would reduce
<80 bpm). parental stress, avoiding frequent trips between
Both processes of active and passive cooling hospitals, in an already difficult situation. When-
have been used and described during neonatal ever this would not be possible, siblings should be
transport (Kendall et al. 2010; Chaudhary reunited in the same center as soon as their con-
et al. 2013; Akula et al. 2015). dition will be stable enough (Mosher 2013).
Please refer to the dedicated chapters in the
book for more information about stabilization of
infants with HIE and treatment with hypothermia. 19.10 Quality Evaluation and Costs
Audit is essential for the evaluation and improve-
19.8.5 Severe Hyperbilirubinemia ment of the service (Leslie and Stephenson 1997,
1994). Data collection should include demo-
Whenever possible, it should be avoided to sus- graphics, staffing, pre- and intra-transport times,
pend phototherapy during neonatal transport, for as well as clinical parameters (Table 4).
neonates with severe unconjugated hyperbilir- NETS availability and time required can
ubinemia at risk of developing bilirubin encepha- be considered as indicators of efficiency
lopathy. The adoption of a portable phototherapy (Ramnarayan 2009). Time investment includes:
unit during transport has been showed to be safe
and effective and may result in a decreased 1. The response time (period between call for
requirement for exchange transfusion (Waterham transport and departure for referring hospital)
et al. 2016). 2. The waiting time (time between call for trans-
port and arrival at referring hospital)
3. The stabilization time (time required to assist
19.9 Family-Centered Care neonate at referring hospital)
4. “On-the-road” time (time with baby in trans-
Good communication among team members and port between departure from referring unit to
transport team, referring staff, and neonate’s fam- admission at receiving hospital)
ily is mandatory. Transferring a neonate in a center 5. The total transfer time (from departure, to
different from the birthplace means a disruption of referring hospital, to the availability of the
the familiar unity and of the ongoing mother/ team for another transfer)
father-baby bonding. Parents should be encour-
aged to see the baby before transportation and Measures of effectiveness can be based on
during stabilization and to visit the receiving hos- changes in the infant’s core temperature during
pital as soon as it will be possible, considering transfer, validated transport scores (Hermansen
also maternal conditions. et al. 1998; Zupancic et al. 2007; Lee et al. 2001),
Informed signed parental consent to transpor- and monitoring complications during transport.
tation and emergency procedure foreseen to be The Transport Risk Index of Physiologic Stability
performed should be requested (i.e., blood trans- (TRIPS) score is a validated and reliable tool used
fusion, emergency surgical procedures). to assess effectiveness of transport services, pro-
Baby’s pictures in the receiving center should tocols, and policies (Lee et al. 2001) (Table 5).
be taken and showed to the mother. She should be The annual budget for running a NETS
also encouraged to express her milk with breast includes fixed and variable costs. Fixed costs are
pump to promote lactation and to include her in independent of the number of the transports and
the caring process of the neonate. include equipment amortization, insurance cover,
In case of a multiple birth, especially if neo- training and education, organization, and commu-
nates are at risks of prolonged hospitalizations, nication. Variable costs depend on the number of
300 R. Agostino et al.
Table 4 Stabilization and management of neonates with surgical conditions prior to and during transport to a referral
center (Puri and Doodnath 2011)
Surgical condition Stabilization and management prior to and during transport
Gastroschisis Keep baby warm and monitor incubator’s temperature (higher risk for
hypothermia). Assess and treat respiratory distress. Intravenous fluids and correct
deficits. To minimize heat loss and trauma, exposed viscera should be placed in
clear plastic bag or silo. If not available, localize loops in the center of the abdomen
and use cling film to encircle the exposed intestine and wrap film around infant.
Nasogastric tube, antibiotics, vitamin K
Omphalocele Assess and treat respiratory distress. Stabilize the sac in the middle of the
abdomen, and cover it with a sterile, dry, nonadherent dressing to prevent trauma,
heat loss, and vessels kinking. If the sac is a ruptured sac, treat as it for
gastroschisis. Nasogastric tube, intravenous fluids, antibiotics, vitamin K
Pierre Robin syndrome Place infant in prone position and insert an oropharyngeal airway to prevent
tongue swallowing and asphyxiation
Choanal atresia Secure in place an oral airway (appropriately sized, with the end or teeth cut off to
keep the mouth open) to prevent intermittent hypoxia
Myelomeningocele Place infant in prone position to prevent trauma and pressure on the spinal area.
Place a warm, sterile, saline-soaked dressing over the lesion and cling film
wrapped around the baby to prevent drying and dehiscence. If the sac is ruptured
and CSF leaking, or if myelomeningocele is open, cover with Betadine-soaked
gauze and start intravenous antibiotics. Prevent fecal contamination in sacral
lesions. Evaluate and document neurological function, including sensorimotor
level and degree of hydrocephalus
Bladder exstrophy Remove umbilical clamp and ligate umbilical cord close to the abdominal wall to
prevent mechanical damage. Cover the defect with cling film wrapped around the
baby to avoid the mucosa from sticking to clothes. Wash the surface of the bladder
with warm saline at each diaper change, and apply a clean cling film layer.
Prophylactic antibiotics
Esophageal atresia with Intubation and ventilation if required (tip of the ET tube should be placed proximal
tracheoesophageal fistula to the carina but distal to the fistula). Handle with care and avoid crying to reduce
risk of aspiration and abdominal distension. Provide oxygen if necessary. Place
infant with head slightly elevated, prone, or in a right lateral position. The upper
esophageal pouch should be kept empty positioning a Replogle sump catheter
connected to low-intermittent or low-continuous suction (irrigate to prevent
blockage by mucus). Intravenous fluids and electrolytes to compensate esophageal
secretion losses. Antibiotics, vitamin K
Congenital diaphragmatic hernia Avoid mask ventilation. Perform intubation and initiate gentle ventilation (risk of
barotraumas due to hypoplastic lungs). Sedation and HFOV (if available) can help
to reduce barotrauma. Prevent pulmonary hypertension (hyperventilate, low
pressures, high oxygen, correct acidosis, prevent thermal and metabolic stress).
Insert a nasogastric tube to prevent lung compression. Administer intravenous
fluids to maintain adequate peripheral perfusion (consider inotropes, if necessary),
maintain warm environment, check arterial pre-ductal blood gases, and administer
antibiotics and vitamin K. Exclude pneumothorax in case of acute deterioration
Intestinal obstruction Same principles of care, irrespective of level and cause of obstruction: decompress
bowel and prevent aspiration, correct fluid losses, and prevent heath loss. Insert a
nasogastric tube, and suction every 15–30 min. Correct electrolyte, acid-base, and
volume deficits. Prophylactic antibiotics
Necrotizing enterocolitis Ensure appropriate infant’s stabilization. IPPV is often required. Correct shock and
acidosis if present, monitor blood pressure and blood glucose, nasogastric tube,
antibiotics
19 Neonatal Transport Services 301
transports and include supplies, equipment main- Table 5 Transport Risk Index of Physiologic Stability
tenance, and ambulance expenses. Personnel sal- (TRIPS) score. (Modified from Lee et al. 2001)
aries depend on the type of NETS: in the TRIPS
“dedicated” model, this is a fixed cost, whereas score
Parameter Value points
in the “on-call” model, it affects both fixed costs
Temperature ( C) <36.1 or >37.6 8
(depending on availability) and variable costs
36.1–36.5 or 1
(actual hours). The total cost of the NETS and 37.2–37.6
the average cost of each transport depend on the 36.6–37.1 0
fixed and variable costs, which in turn depend on Respiratory Severe (apnea, 14
the organizational model adopted and the load of status gasping, intubated)
scheduled jobs (Agostino et al. 1998). Moderate (RR >60/min 5
and/or SpO2 <85 %)
None (RR <60/min 0
and SpO2 >85 %)
19.11 Training and Outreach Systolic blood <20 26
Education pressure (mmHg) 20–40 16
>40 0
Continued improvement of perinatal outcomes Response to None, seizure, muscle 17
depends on all health professionals recognizing painful stimuli relaxant
their responsibility to keep up to date with recent Lethargic response, no 6
advances in perinatal care, by updating their cry
knowledge and clinical skills. Transport personnel Withdraws vigorously, 0
cries
must receive appropriate training and supervision.
RR respiratory rate, SpO2 pulse oximetry
Core competencies include clinical, procedural,
communication, and teamwork skills and the abil-
ity to work in the transport environment (Fenton
and Leslie 2009). Continuing education in neonatal indicated. As already seen for certain branches,
transport involves training and supervision of all programs of outreach medical and surgical spe-
members of the transport team. It relates not only to cialized care should be planned and implemented
clinical care but also to safety and communication, (Maka et al. 2015; Huang et al. 2008).
as well as to administrative and other relevant Personnel should be trained to face with the
topics. Extending continuing education throughout worst scenarios. High-fidelity simulation, even if
the referral region (outreach education) is also different from the “live setting,” can help to train
important for the health-care professionals respon- less-experienced personnel to deal with clinical
sible for referring and stabilizing infants for trans- and environmental difficult situations.
port (Agostino et al. 1998). Clinical computerized notes, containing images
and videos of patient and exams, that can be shared,
updated, and seen on smartphones or tablets “on
19.12 Future Perspectives of NETS the road” could represent the future of neonatal
transport in higher-resource settings.
Neonatal transport equipment has been massively
improving over the years, and nowadays dedi-
cated ambulances can be considered as proper References
mobile NICUs (Whyte et al. 2015).
Agostino R, Chabernaud JL, Di Renzo GC (1998) Neona-
The goal is a further reduction of number and
tal transport service, types, cost/benefit ratio, indicators
rates of infants transported and promoting “in of efficiency and effectiveness. Dev Physiopathol Clin
utero” transfer of high-risk pregnancies, when 8:113–115
302 R. Agostino et al.
Agostino R, Fenton AC, Kollée LAA et al (1999) Organi- Gente M, Di Lallo D, Franco F et al (2015) Stabilization of
zation of neonatal transport in Europe. Prenat Neonatal the critically ill neonate awaiting transport. Ital J Pediatr
Med 4:20–34 41(Suppl1):A15
Akula VP, Joe P, Thusu K et al (2015) A randomized Gupta N, Kamlin CO, Cheung M et al (2013) Prosta-
clinical trial of therapeutic hypothermia mode during glandin E1 use during neonatal transfer: potential
transport for neonatal encephalopathy. J Pediatr beneficial role in persistent pulmonary hypertension
166:856–861 of the newborn. Arch Dis Child Fetal Neonatal Ed
Argus BM, Dawson JA, Wong C et al (2009) Financial 98:F186
costs for parents with a baby in a neonatal nursery. J Gupta N, Kamlin CO, Cheung M et al (2014) Improving
Paediatr Child Health 45:514–517 diagnostic accuracy in the transport of infants with
Arora P, Bajaj M, Natarajan G et al (2014) Impact of suspected duct-dependent congenital heart disease. J
interhospital transport on the physiologic status of Paediatr Child Health 50:64–70
very low-birth-weight infants. Am J Perinatol Hermansen MC, Hasan S, Hoppin J et al (1998) A valida-
31:237–244 tion of a scoring system to evaluate the condition of
Azzopardi D, Strohm B, Marlow N et al (2014) Effects of transported very low birth weight neonates. Am J
hypothermia for perinatal asphyxia on childhood out- Perinatol 5:74–78
comes. N Engl J Med 371:140–149 Huang T, Moon-Grady AJ, Traugott C et al (2008) The
Bouchut JC, Van Lancker E, Chritin Vet al (2011) Physical availability of telecardiology consultations and transfer
stressors during neonatal transport: helicopter com- patterns from a remote neonatal intensive care unit. J
pared with ground ambulance. Air Med J 30:134–139 Telemed Telecare 14:244–248
Broman LM, Holzgraefe B, Palmér K et al (2015) The Jackson L, Skeoch CH (2009) Setting up a neonatal trans-
Stockholm experience: interhospital transports on port service: air transport. Early Hum Dev 85:477–481
extracorporeal membrane oxygenation. Crit Care Jacobs SE, Berg M, Hunt R et al (2013) Cooling for
19:278 newborns with hypoxic ischaemic encephalopathy.
Broughton SJ, Berry A, Jacobe S et al (2004) The mortality Cochrane Database Syst Rev 1:CD003311
index for neonatal transportation score: a new mortality James AG (1993) Resuscitation, stabilization, and trans-
prediction model for retrieved neonates. Pediatrics 114: port in perinatology. Curr Opin Pediatr 5:150–155
e424–e428 Karlsson BM, Lindkvist M, Lindkvist M et al (2012)
Chaudhary R, Farrer K, Broster S et al (2013) Active Sound and vibration: effects on infants’ heart rate and
versus passive cooling during neonatal transport. Pedi- heart rate variability during neonatal transport. Acta
atrics 132:841–846 Paediatr 101:148–154
Dhillon R (2012) The management of neonatal pulmonary Kempley ST, Baki Y, Hayter G et al (2007) Effect of a
hypertension. Arch Dis Child Fetal Neonatal Ed 97: centralized transfer service on characteristics of inter-
F223–F228 hospital neonatal transfers. Arch Dis Child Fetal Neo-
Di Lallo D, Franco F, Farchi S et al (2010) Pre-transport natal Ed 92:F185–F188
stabilization time and characteristics of the referring Kendall GS, Kapetanakis A, Ratnavel N et al (2010)
hospital: an epidemiological study on neonatal trans- Cooling on Retrieval Study Group: passive cooling
port in Lazio. Eur J Public Health 20:118 for initiation of therapeutic hypothermia in neonatal
European Committee for Standardization (2003a) EN encephalopathy. Arch Dis Child Fetal Neonatal Ed
13976-1:2003 rescue systems – transportation of incu- 95:F408–F412
bators – part 1: interface conditions (harmonised stan- Kollèe LA, Brand R, Schreuder A et al (1992) Five-year
dard under the Directive 93/42/EEC) outcome of preterm and very low birth weight infants: a
European Committee for Standardization (2003b) EN comparison between maternal and neonatal transport.
13976-2:2003 rescue systems – transportation of incu- Obstet Gynecol 80:635–638
bators – part 2: system requirements (harmonised stan- Lee SK, Zupancic JA, Pendray M et al (2001) Transport
dard under the Directive 93/42/EEC) risk index of physiologic stability: a practical system
Fenton AC, Leslie A (2009) Who should staff neonatal for assessing infant transport care. J Pediatr
transport teams? Early Hum Dev 85:487–490 139:220–226
Finnstrom O, Otterblad Olausson P, Sedin G et al (1997) Leslie AJ, Stephenson TJ (1994) Audit of neonatal inten-
The Swedish national prospective study on extremely sive care transport. Arch Dis Child 71:F61–F66
low birth weight (ELBW) infants. Incidence, mortality, Leslie AJ, Stephenson TJ (1997) Audit of neonatal inten-
and survival in relation to level of care. Acta Paediatr sive care transport – closing the loop. Acta Paediatr
86:503–511 86:1253–1256
Gaddam Bhoomaiah S, Chandra P, Leslie A (2014) Inhaled Leslie A, Stephenson T (2003) Neonatal transfers by
nitric oxide therapy during transport of neonates – advanced neonatal nurse practitioners and paediatric
experience of CenTre transport service. Arch Dis registrars. Arch Dis Child Fetal Neonatal Ed 88:
Child Fetal Neonatal Ed 99:A44 F509–F512
19 Neonatal Transport Services 303
Lim MT, Ratnavel N (2008) A prospective review of paediatric mobile ECMO team in the north of France.
adverse events during interhospital transfers of neo- Intensive Care Med 42:940–941
nates by a dedicated neonatal transfer service. Pediatr Ramnarayan P (2009) Measuring the performance of an
Crit Care Med 9:289–293 inter-hospital transport service. Arch Dis Child
Lowe CG, Trautwein JG (2007) Inhaled nitric oxide ther- 94:414–416
apy during the transport of neonates with persistent Sedin G, Agostino R, Chabernaud JL et al (1999) Techni-
pulmonary hypertension or severe hypoxic respiratory cal aspects of neonatal transport in Europe. Prenat
failure. Eur J Pediatr 166:1025–1031 Neonatal Med 4:35–45
Lupton BA, Pendray MR (2004) Regionalized neonatal Shivananda S, Kirsh J, Whyte HE et al (2010) Accuracy of
emergency transport. Semin Neonatol 9:125–133 clinical diagnosis and decision to commence intrave-
Lutman D, Petros A (2008) Inhaled nitric oxide in neonatal nous prostaglandin E1 in neonates presenting with
and paediatric transport. Early Hum Dev 84:725–729 hypoxemia in a transport setting. J Crit Care 25(174):
Macnab A (1991) Optimal escort for interhospital transport e1–e9
of pediatric emergencies. J Trauma 31:205–209 Steinhorn RH (2010) Neonatal pulmonary hypertension.
Maka E, Imre L, Somogyvári Z et al (2015) Laser treatment Pediatr Crit Care Med 11:S79–S84
for retinopathy of prematurity in neonatal intensive care Warren D, Jarvis A, Leblanc L et al (2001) Canadian
units. Premature Eye Rescue Program. Orv Hetil paediatric triage and acuity scale: implementation
156:192–196 guidelines for emergency departments. CJEM 3:
Morrison J, Cheema I (2007) Neonatal transfers by S1–S27
advanced neonatal nurse practitioners: is it time to Waterham M, Bhatia R, Donath S et al (2016) Photother-
end the debate? Early Hum Dev 83:134 apy in transport for neonates with unconjugated
Mosher SL (2013) The art of supporting families faced with hyperbilirubinaemia. J Paediatr Child Health 52:67–71
neonatal transport. Nurs Womens Health 17:198–209 Whyte HEA, Jefferies AL, Canadian Paediatric Society,
Neto MT (2006) Perinatal care in Portugal: effects of Fetus and Newborn Committee (2015) The interfacility
15 years of a regionalized system. Acta Paediatr transport of critically ill newborns. Paediatr Child
95:1349–1352 Health 20:265–275
Puri P, Doodnath R (2011) Transport of the surgical neo- Zeitlin J, Papiernik E, Bréart G et al (2004) Regionalization
nate in “Newborn Surgery 3E” Prem Puri. CRC Press, of perinatal care in Europe. Semin Neonatol 9:99–110
Boca Raton, pp 83–90 Zupancic JA, Richardson DK, Horbar JD et al (2007)
Rambaud J, Léger PL, Larroquet M et al (2016) Transpor- Revalidation of the score for neonatal acute physiology
tation of children on extracorporeal membrane oxygen- in the Vermont Oxford network. Pediatrics 119:
ation: one-year experience of the first neonatal and e156–e163
Risk Management of Newborns
20
Isabelle Ligi and Sophie Tardieu
Contents
20.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
20.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
20.3 Epidemiology of Iatrogenesis in Neonatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
20.3.1 Definitions of Patient Safety Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
20.3.2 General Epidemiology of Iatrogenesis: Frequency, Severity, Preventability,
and Type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
20.4 Learning from Iatrogenic Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
20.4.1 Factors Contributing to Iatrogenic Event
Occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
20.4.2 Barriers Contributing to Iatrogenic Event
Limitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
20.4.3 Tools to Assess Risk: Corrective Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
20.4.4 Tools to Assess Risk: Preventive (Proactive)
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
20.5 Strategies to Reduce the Risk: Components of Risk Management . . . . . . . 311
20.5.1 Leadership and Safety Culture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
20.5.2 Communication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
20.5.3 Training, Induction, and Competence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
20.5.4 Guidelines, Protocols, and Checklist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
20.5.5 Five Steps for Implementation of a Safety Program . . . . . . . . . . . . . . . . . . . . . . . . . . 312
20.5.6 Prevention of MEs: An Example of Risk
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
Abstract
Neonates are highly vulnerable to iatrogenesis
owing to their immaturity and an important
I. Ligi (*)
Division of Neonatology, La Conception Hospital, exposure to invasive therapies. Recent studies
Marseille, France highlight the problem in terms of financial,
e-mail: [email protected] medicolegal, and particularly human costs.
S. Tardieu The concept of clinical risk management
Medical Evaluation Department, Public Health evolved from industry to assess and reduce
Department, La Conception Hospital, Marseille, France
# Springer International Publishing AG, part of Springer Nature 2018 305
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_170
306 I. Ligi and S. Tardieu
the risk and finally to improve patient safety. In arising from any aspect of health-care manage-
complex and multifaceted systems like neona- ment (Thomas et al. 2000). The report To Err Is
tal intensive care units, incident occurrence is Human by the Institute of Medicine revealed the
often multifactorial and reveals system failures importance of medical errors in terms of patient
rather than individual error. The identification harm, death, and cost in the USA (Kohn
of incidents by voluntary, anonymous, and et al. 1999). Despite newborn infants constituting
nonpunitive reporting system followed by a a high-risk population, data are still scarce. Inci-
causation analysis is a major step to risk assess- dence of iatrogenesis varies strongly between
ment and prevention. But risk management is studies according to the methods of data collection
first of all a behavior based on culture safety and the definition used, but recent prospective
and leadership. studies have reported high incidences of
0.4–0.74 iatrogenic events (IEs) per patient (Ligi
List of Abbreviations et al. 2008; Sharek et al. 2006; Kugelman
CPOE Computerized provider order entry et al. 2008; Frey et al. 2000). Many iatrogenic
FMEA Failure mode and effects analysis events result in permanent harm and more than a
IE Iatrogenic event third is considered to be preventable (Ligi
ME Medication error et al. 2008; Sharek et al. 2006; Kugelman
NICU Neonatal intensive care unit et al. 2008). They have huge financial, human,
and medicolegal costs for the patient, their fami-
lies, and the staff (Kohn et al. 1999; Donn 2005).
20.1 Salient Points In response to improve patient safety, the
concepts and practice of risk management
• Neonatology is a high-risk speciality for evolved during the last decade. Clinical risk
iatrogenesis. management can be defined as organizational
• Risk management is a structured process that systems or processes that aim to improve the
can improve quality of health. quality of health care and maintain safe systems
• Nosocomial infections and unplanned of care (Scholefield 2005). It is based on a sys-
extubations are severe iatrogenic events; med- tem approach, rather than an individual approach
ication errors and cutaneous injuries are com- to error, taking account that human beings are
mon but usually trivial. fallible and that IE occurrence is a consequence
• Many tools have been developed to assess risk. of a successive lost of protective defenses, bar-
• Incident reporting systems and causation anal- riers, and safeguards (Reason 2000). That is why
ysis are key components of risk management. risk management is an ongoing process based on
• Leadership is critical to promote patient safety attitude (awareness of potential risk and liabil-
and create a safety culture. ity), the knowledge, and understanding of haz-
ards, skills, and commitment.
20.2 Introduction
20.3 Epidemiology of Iatrogenesis
Rapid advances in neonatal medicine have caused a in Neonatology
substantial reduction in neonatal mortality, espe-
cially in low birth weight babies. However, caring 20.3.1 Definitions of Patient Safety
for newborn infants in the neonatal intensive care Terms
unit (NICU) exposes them to invasive therapies and
therefore to iatrogenic damage. Moreover, NICU is Many definitions are commonly used in the
a complex system with an environment of contin- patient safety literature. Using precise definitions
uous and emergency care prone to error. Iatrogen- helps interpreting the findings in the studies as
esis is defined as an unintended harm or suffering there is no standardized nomenclature.
20 Risk Management of Newborns 307
Error: a failure of a planned action to be com- neonates (Brennan et al. 1991; Kanter
pleted as intended or use of a wrong plan to et al. 2004). Actually, recent studies highlight
achieve an aim (Kohn et al. 1999). the importance of iatrogenesis among neonates,
Serious medical error: a medical error that as expected, in terms of frequency and severity.
could harm or injure a vulnerable patient if it These studies (most of them based on a prospec-
reached the patient uninterrupted (Morriss 2008). tive, anonymous, voluntary, and nonpunitive sys-
Adverse (medical) event: an injury caused by tem) reported high incidences of 0.4–1.25 events
medical management rather than the underlying per patient (Ligi et al. 2008; Sharek et al. 2006;
condition of the patient (Kohn et al. 1999). Kugelman et al. 2008; Frey et al. 2000; Snijders
IE: any event that compromised the safety of et al. 2009). Two studies reported rates of 20–25
the patient in the presence or the absence of harm. IEs ‰ patient-days (Ligi et al. 2008; Kugelman
It may or may not have been preventable and may et al. 2008). As 30–50% of the incidents were
or may not have involved an error by the health- judged to be severe and harmful, the impact on
care team (Ligi et al. 2008). patient morbidity is considerable (Ligi et al. 2008;
Critical incident: any event which could have Sharek et al. 2006; Kugelman et al. 2008; Frey
reduced, or did reduce, the safety margin for the et al. 2000). Preventability is often high from 35%
patient (Frey et al. 2000). to 83% of events (Ligi et al. 2008; Sharek
Severe IE: any unintended injury or complica- et al. 2006; Kugelman et al. 2008).
tion that resulted in disability, death, or extended Frequency of incident by category is heteroge-
hospital stay and which was caused by health-care neous, varying with local environments and pat-
management. terns of problems. Nosocomial infections and
Preventable IE: any avoidable iatrogenic event respiratory events are reported to be common and
based on available knowledge and accepted prac- often severe events. Particularly, unplanned
tices (Woods et al. 2005). extubations are a frequent (0.14–6.6 per 100 venti-
Near-miss event: an event that could have lation days), severe, but largely preventable inci-
resulted in an injury, fatality, or property damage dent (Sadowski et al. 2006; Merkel et al. 2014).
if it had not been prevented. MEs and cutaneous injuries (Fig. 1) occur fre-
Adverse drug event: any injury resulting from quently in NICU but are often minor. ME rates
medical intervention related to a drug. vary widely between studies, partly due to differ-
Medication error (ME): any preventable event ences in the definitions of an error and the method-
that occurs in the process of ordering, transcribing, ology used to their identification. Kaushal and
dispensing, administering, or monitoring a drug, coworkers found an incidence as high as 5.7 MEs
irrespective of whether an injury occurred or the per 100 NICU prescriptions (91 MEs per
potential for injury was present (Kaushal et al. 2001). 100 admissions) but including near miss (Kaushal
et al. 2001). Near miss excluded, Raju and col-
leagues reported a rate of 15 ME per 100 admissions
20.3.2 General Epidemiology (Raju et al. 1989). Dose error, occurring during the
of Iatrogenesis: Frequency, prescribing and particularly the administration
Severity, Preventability, stage, is reported to be the most common type of
and Type ME (Chedoe et al. 2007). Tenfold MEs are com-
mon and mainly related to errors in programming
Data on epidemiology of iatrogenesis in neona- of flow rates of electric infusion pumps. Lastly,
tology are scarce and heterogeneous depending of cutaneous injuries were found to be a frequent
definitions and methodology used. Table 1 shows incident. Although skin necrosis was rare, scars
data of eight studies reviewed. Undoubtedly, ret- constituted a severe and significant event with aes-
rospective chart reviews underestimate broadly thetic and sometimes functional troubles.
rates of iatrogenesis estimating that medical errors As expected, the major risk factors of iatrogen-
affect between 1.2% and 1.5% of admitted esis are low birth weight and use of invasive
Table 1 Epidemiology of iatrogenesis in neonatal intensive care
308
Results
Incidence/
Reference Study design Population Characteristics of reporting Definition n reports Severe Preventable
Frey 2000 (Frey Prospective 467 Comprehensive, anonymous, nonpunitive Critical incident 0.45 CI per 30 % Not
et al. 2000) 1 year admissions admission described
Switzerland (56 %
neonates)
Suresh 2004 (Suresh Prospective 54 NICU Nonpunitive, anonymous, voluntary, externally, Medical errors, near- 1,230 27 % Not
et al. 2004) USA Period 1: Internet based, free text (period 1), or structured form miss, adverse events reports described
17 months (period 2)
Period 2:
10 months
Kanter 2004 (Kanter Retrospective 66,146 Discharge records Medical error 1.2 % Not Not
et al. 2004) USA 1 year premature premature described described
neonates
Sharek 2006 (Sharek Cross- 749 charts, Trigger tool Adverse event 0.74 AE 40 % 56 %
et al. 2006) USA sectional, 15 NICU per patient
retrospective
Ligi 2008 (Ligi Prospective 388 neonates Anonymous, nonpunitive, voluntary Iatrogenic event 25.6 IE ‰ 29 % 34 %
et al. 2008) France patient-
days
8 months 0.69 IE per
patient
Kugelman 2008 Prospective 4 NICU Anonymous, daily report by a iatrogenesis advocate. Iatrogenic event, 20.2 IE ‰ 48.5 % 83 %
(Kugelman Medical staff aware of the study in period 2 medical errors, near- patient-
et al. 2008) Israel miss event days
Period 1: 697 neonates 0.4 IE per
3 months patient
Period 2:
3 months
Snijders 2008 Prospective 8 NICU, Anonymous, voluntary, nonpunitive Critical incident 1.25 CI per 1.4 % Not
(Snijders et al. 2008) 12 months 1 PICU admission described
Netherlands 3,859
neonates
De Franco 2014 Cross- 1 NICU, Anonymous, voluntary Errors 0.43 error Not Not
(De Franco sectional, 1 subintensive per patient described described
et al. 2014) Italy 2 months 166 neonates
I. Ligi and S. Tardieu
20 Risk Management of Newborns 309
awareness, fatigue) and team (communication,
supervision) conditions, institutional (financial
resources, safety culture) and environmental
(staffing levels, equipment) factors, task conditions
(workload, protocols), and patient attributes (age,
language, personality, general health, social
conditions).
20.4.2 Barriers Contributing
to Iatrogenic Event Limitation
Fig. 1 Skin necrosis related to extravasation of fluids from
peripheral venous catheter A safety system is composed by three different
types of barriers.
procedure (central venous line and mechanical
ventilation). Moreover, iatrogenesis is indepen- 20.4.2.1 Prevention Barriers
dently associated with an increased length of Such barriers prevent error or iatrogenic event
stay (Ligi et al. 2008; Sharek et al. 2006; occurrence.
Kugelman et al. 2008).
20.4.2.2 Recovering Barriers
Error is made but recovered prior to generating an
20.4 Learning from Iatrogenic iatrogenic event (also called a near-miss event).
Events
20.4.2.3 Reducing Barriers
Four steps are fundamental in developing risk Incident occurred but barriers limited their conse-
management policy: identification, analyze, quences and effects.
assessment and graduation, and control of the risk.
20.4.3 Tools to Assess Risk: Corrective
20.4.1 Factors Contributing Methods
to Iatrogenic Event Occurrence
20.4.3.1 Incident Reporting Systems
Multiple factors are invariably involved in the (Ahluwalia and Marriott 2005)
sequence of events that results in iatrogenesis
occurrence. As described by James Reason in the Methodologies
“Swiss cheese” model of iatrogenic event occur- Incident reporting systems refer to structured
rence, a set of circumstances coincide both in time reporting, collation, and analysis of iatrogenic
and space to cause an event (Reason 2000). Human events. Reporting systems are a key strategy for
errors can contribute or cause an event in an active learning from errors. Mandatory reporting sys-
or a latent way. Active failures comprise the tems, on the basis of retrospective chart reviews,
unintentional lapses or slips (misinterpretation, focus on errors associated with serious injuries or
error of attention or memory, or selection) and the death. But errors resulting in serious harm are only
intentional mistakes (rule or knowledge based) or part of the problem, and iatrogenesis is certainly
procedural violations. Active failures are immedi- underestimated by these systems. However,
ate causes of an iatrogenic event. Latent failures are Sharek and colleagues recently described a trigger
local and organizational conditions that facilitate tool chart review that retrospectively and effi-
event occurrence by providing a point of weakness. ciently identifies adverse events in NICU (Sharek
Factors include individual (training, health, et al. 2006). Trigger tool methodology is a rapid
310 I. Ligi and S. Tardieu
tool to screen for adverse events using a epidemiologist, and referent nurses on the basis
predetermined list of specified “word signals” of published work, professional expert devices,
that are associated with adverse events (Resar and a pilot study in 2003. The form consisted of
et al. 2003). By contrast, voluntary reporting sys- three sections: administrative data (neonatal unit,
tems focus on incidents that often result in slight patient identification, date of birth, discharge date,
injury, no harm, or even intercepted (so-called hospital length of stay, or death), patient charac-
near miss). The intent is to identify and remedy teristics (birth weight, gestational age, sex,
vulnerabilities in systems to improve patient’s mechanical and/or continuous positive pressure
safety. Leape and coworkers emphasize the support, central venous line), and narrative sec-
importance of a nonpunitive, anonymous, and tions about incidents (date, age and weight,
timely reporting system to effectively monitor description, causative mechanisms). At the back
adverse events. This approach has been shown to of the form, a trigger list of 53 potential incidents
be effective in improving the report (Frey was established to help in reporting. Before the
et al. 2000; Leape 2002; Suresh et al. 2004). introduction of the form, several tutorial sessions
Reporting can be facilitated by adding a trigger and group discussions were held to familiarize
list of key incidents that reflect the nature of local nursing and medical staff with the incident report.
clinical practice and areas of concern. Moreover, The form was placed in the baby’s chart from the
prospective methods of data collection demon- time of admission until the discharge or death.
strate their superiority to cross-sectional or retro- Every month, two pediatricians independently
spective method (Michel et al. 2004). Indeed, they reviewed the reported incident to confirm the
seem more appropriate to identify preventable diagnosis and to rate severity and preventability
events, to assess the impact of error-prevention of each event. A monthly meeting is organized by
strategies, to study organizational and human fac- the work group to discuss rates and to enact pre-
tors, and to assess the consequences of incidents. ventive measures. A monthly bulletin composed
Furthermore, prospective incident report can be of general data (number of admissions, activity
used as an educational process to convince clini- level), of a summary of IE reports and nosocomial
cal teams that errors contribute significantly to infections, and of clinical lessons or guidelines is
adverse events. WHO established guidelines for posted in units for feedback. Every 4 months, a
adverse event reporting and learning systems staff meeting is organized with the nursing and
(WHO 2005). medical team to discuss the rates and measures
(Ligi et al. 2008).
Limitations of Incident Reporting Systems
The prospective incident reporting systems are
time-consuming in reporting and investigating 20.4.3.2 Investigation and Causation
incidents. Moreover, voluntary reporting can Analysis of Incident
be inadvertently perceived as a means to blame Investigations are needed for serious incidents or
and can paradoxically encourage defensive clini- for recurrent ones. Root cause analysis (standard-
cal practices. Another bias important to bear ized debriefing) is a key process to understand
in mind is the underestimation of incidents by incident genesis and to learn from the incident to
underreporting or undetecting. improve patient safety. Debriefing process has to
be confidential, nonthreatening, structured, and
Our Local Experience of Iatrogenic Event timely. It is a collaborative process used to dissect
Reporting events. The objectives are to determine what hap-
Since 2005, we use an anonymous, nonpunitive, pened, to identify why it happened (underlying
and voluntary incident reporting system. The causative human and system factors), and to pin-
reporting form had been composed by a work point lessons learned to make recommendations
group that consisted of neonatologists, one for improvement in a blame-free way. The lessons
20 Risk Management of Newborns 311
learned need to be fed back timely to the staff via method for evaluating a process to identify
meeting and/or a monthly bulletin. where and how it might fail and to assess the
relative impact of different failures, failures
modes or “what could go wrong?”, failure causes
20.4.3.3 Morbidity and Mortality
or “why would the failure happen?”, and failure
Committee
effects or “what would be the consequences of
Mortality and morbidity clinical review meeting is
each failure?”, in order to identify the parts of
a regular, structured, multidisciplinary (medical
the process that are most in need of change.
and nursing staff) process that analyzes critically
Even if it is time-consuming, the proactive analy-
the circumstances surrounding outcomes of care
sis facilitates assessment of potential risk prior to
(death, serious morbidity, and significant aspect of
its implementation.
regular clinical practice). Such process focuses on
systems dysfunction and failures in ways to
20.4.4.3 Quality Indicators
develop recommendations, change systems, and
and Benchmarking
improve care.
Neonatal-specific quality indicators (like breast
milk nutrition, central catheter-related infections,
etc.) exist and can be used to compare patient
20.4.4 Tools to Assess Risk: Preventive
outcomes between different national and interna-
(Proactive) Methods
tional NICU. Benchmarking is a strong tool
to measure performance and improve care and
Assessment and graduation of medical risk in
neonatal outcomes.
terms of probability of occurrence and harm
potential is important for organizations in health
care. Many proactive approaches have been
developed: comparison with standards, analysis
20.5 Strategies to Reduce the Risk:
of processes, and of quality indicators.
Components of Risk
Management
20.4.4.1 Audits and Patient Safety Walk
Rounds The goal of safety is not to remove all errors but is
Independent assessment of care and risk can be to manage errors in ways to reduce serious inci-
useful to implement preventive measures and to dents or recurrent ones and identify and recover
assess their effect during reaudit. Performance is (near-miss incidents) errors (Fig. 2). Local safety
reviewed to ensure that what should be done is program can be developed to improve quality
being done through a systematic review of care of care and is based on leadership, communica-
(structure, processes, and outcomes) against tion, training, quality tools, and standards of care
explicit criteria. Patient safety walk rounds are (Ligi 2010).
regular rounds of seniors’ leaders for the purpose
of discussing safety with staff. This method has
been shown to improve the safety culture of 20.5.1 Leadership and Safety Culture
hospitals.
They are critical to convince that hazard and risk
20.4.4.2 Failure Mode and Effects are not inevitable and can be managed to
Analysis (FMEA) Tools improve patient safety. Leaders must sensitize
The reliability and potential failures of any new and encourage the entire staff in a collaborative
system, process, equipment, or service are sys- and nonhierarchical process. The objectives are
tematically evaluated prior to exposure of patient to convince that patient safety is a primary goal,
and staff. FMEA is a systematic, proactive that the system can be improved, and that
312 I. Ligi and S. Tardieu
S
T INCIDENT REPORTING SYSTEM
A
F WARNING SYSTEM
F Serious/recurrent IE
Debriefing
Feedback
CAUSATION ANALYSIS SAFETY CULTURE PREVENTION STRATEGIES
L
E
A
D
E
R
S
H
I
P
Fig. 2 Organization of risk management
the risk can be reduced. Leaders emphasize 20.5.4 Guidelines, Protocols,
the importance of a blame-free incident moni- and Checklist
toring as a positive mean to improve quality,
empower changes, and allow development of Standards developed from evidence-based medi-
targeted interventions. Leaders organize feed- cine are useful to assist professionals in decision
back, communication, and promotion of patient in every steps of the care.
safety.
20.5.5 Five Steps for Implementation
20.5.2 Communication of a Safety Program
Communication with the parents is a major issue The Plan-Do-Act-Study method can be applied to
to limit claims and complaints. Parent consent and develop safety program using quality tools to
information are key areas. Transparency is capital identify risk, forces, and weaknesses of local sys-
in case of iatrogenic event occurrence. Communi- tems and processes (Table 2).
cation between professionals is also essential to
reduce risk and hazards.
20.5.6 Prevention of MEs: An Example
of Risk Management
20.5.3 Training, Induction,
and Competence MEs occur frequently in NICU with a real
potential for harm. Prescription and adminis-
As inexperience and unfamiliarity are key factors tration, in particular smart pump programming,
in error occurrence, continuous training is needed. are two high-risk stages. Inexperience and
Moreover, turnover is high in NICU and new staff intensity of workload are the major risk factors
is usual. All new staff must be aware of guide- for occurrence. Even if medication manage-
lines, policies, and procedure. ment is a complex and multifaceted system,
20 Risk Management of Newborns 313
Table 2 Risk management tools and the five steps for implementation of a safety program
Analysis of Assessment
Selection of situation situation and and Following and
with safety risk and safety identification of prioritization Risk results longevity
Tools program organization safety risk of risk treatment and sustainability
Trigger tools +
Continuous + + +
prospective
incident
reporting
Clinical audits + +
Safety walk + +
rounds
Quality + +
indicators
Root cause +
analysis
Mortality and + + +
morbidity
review
FMEA +
Checklist +
Guidelines +
Protocols +
studies show that risk can be efficiently these drugs separately from ward stock, strict
reduced and MEs prevented. First, the involve- identification of syringes, and handoff verifi-
ment of a NICU-based pharmacist significantly cation check. These measures demonstrated
reduces dosing errors (Simpson et al. 2004). their efficiency in reducing MEs.
Strategies to reduce error at the prescribing
stage include clinical staff education (indica-
tion documentation, formulation, and dose reg- References
imen information), improving environment
conditions at the time of prescription, imple- Ahluwalia J, Marriott L (2005) Critical incident reporting
mentation of standardized dosing references, systems. Semin Fetal Neonatal Med 10:31–37
Brennan TA et al (1991) Incidence of adverse events and
and perhaps use of computerized provider
negligence in hospitalized patients. N Engl J Med
order entry (CPOE). CPOE could prevent 324:370–376
66% of MEs. However, CPOE may contribute Chedoe I et al (2007) Incidence and nature of medication
to new types of errors and more studies are errors in neonatal intensive care with strategies to
improve safety. Drug Saf 30(6):503–513
needed to assess the impact of such technology
De Franco S et al (2014) The error in neonatal intensive
on MEs so CPOE are expensive systems care: a multicenter prospective study. Minerva Pediatr
(Chedoe et al. 2007). Strategies to reduce 66(1):1–6
errors at the administration stage include use Donn S (2005) Medical liability, risk management, and the
quality of health care. Semin Fetal Neonatal Med
of standard concentrations for infusion, restric- 10:3–9
tion of verbal orders to emergency situations, Frey B et al (2000) Comprehensive critical incident mon-
limitation of handwritten orders, requirement itoring in a neonatal-pediatric intensive care unit: expe-
of double-checking at each step of the medi- rience with the system approach. Intensive Care Med
26:69–74
cation process specially for high-alert drugs
Kanter D, Turenne W, Slonim A (2004) Hospital-reported
(opiates, sedatives, insulin, anticoagulants, medical errors in premature neonates. Pediatr Crit Care
concentrated electrolyte solutions), storage of Med 5(2):119–123
314 I. Ligi and S. Tardieu
Kaushal R et al (2001) Medication errors and adverse Sadowski R et al (2006) Continuous quality improvement:
drug events in pediatric inpatients. JAMA 285(16): reducing unplanned extubations in a pediatrics inten-
2114–2120 sive care unit. Pediatrics 114(3):628–632
Kohn L, Corrigan J, Donaldson M (1999) In: I.o. Medicine Scholefield H (2005) Risk management in obstetrics. Curr
(ed) To Err is human: building a safer health system. Obstet Gynaecol 15:237–243
National Academy Press, Washington, DC Sharek PJ et al (2006) Adverse events in the
Kugelman A et al (2008) Iatrogenesis in neonatal intensive neonatal intensive care unit: development, testing,
care units: observational and interventional, prospec- and findings of an NICU-focused trigger tool to
tive, multicenter study. Pediatrics 122:550–555 identify harm in north american NICUs. Pediatrics
Leape LL (2002) Reporting of adverse events. N Engl J 118(4):1332–1340
Med 347(20):1633–1638 Simpson J, Lynch R, Alroomi L (2004) Reducing medica-
Ligi I (2010) Iatrogenic events in neonates: beneficial tion errors in the neonatal intensive care unit. Arch Dis
effects of prevention strategies and continuous moni- Child Fetal Neonatal Ed 89:F480–F482
toring. Pediatrics 126(6):1461–1468 Snijders C et al (2009) Specialty-based, voluntary incident
Ligi I et al (2008) Iatrogenic events in admitted neonates: a reporting in neonatal intensive care: description of
prospective cohort study. Lancet 371:404–410 4846 incident reports. Arch Dis Child Fetal Neonatal
Merkel L et al (2014) Reducing unplanned extubations in Ed. 94(3):F210–F215
the NICU. Pediatrics 133(5):1367–1372 Suresh G et al (2004) Voluntary anonymous reporting of
Michel P et al (2004) Comparison of three methods for medical errors for neonatal intensive care. Pediatrics
estimating rates of adverse events and rates of prevent- 113(6):1609–1618
able adverse events in acute care hospitals. BMJ 328:1–5 Thomas E et al (2000) A comparison of iatrogenic injury
Morriss F (2008) Adverse medical events in the NICU: studies in Australia and the USA. I: context,
epidemiology and prevention. Neoreviews 9:e8–e23 methods, casemix, population, patient and
Raju T et al (1989) Medication errors in neonatal and hospital characteristics. Int J Qual Health Care
paediatric intensive-care units. Lancet 12(2):374–376 12:371–378
Reason J (2000) Human error: models and management. WHO (2005) Who draft guidelines for adverse event
BMJ 320(7237):768–770 reporting and learning systems. From information to
Resar RK et al (2003) Methodology and rationale for the action. WHO Press, Geneva
measurement of harm with trigger tools. Qual Saf Woods D et al (2005) Adverse events and preventable
Health Care 12(Suppl 2):39–45 adverse events in children. Pediatrics 115:155–160
Guidelines and Protocols for
Newborns 21
Rinaldo Zanini and Roberto Bellù
Contents
21.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
21.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
21.3 The Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
21.4 Clinical Pathways (CPs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
Abstract clinical guidelines. From an evaluation point of
The principal aim of the guidelines is to offer view, according to an approach to systemati-
recommendations to assist in clinical decisions. cally develop guidelines, the AGREE II
In neonatology systematic evaluation of scien- approach reached an elevated degree of validity
tific evidence is even more important than in and feasibility also for busy clinician and
other fields because of variability between the healthcare operator. Based on evidence-based
methodology of clinical studies and the diffi- guidelines, clinical pathways emerged as
culty to perform studies in the neonatal popula- an important way to implement guidelines
tion. Guidelines are “statements that include at the local level, looking at the specific
recommendations, intended to optimize patient processes of a given patient. Evidence-
care, that are informed by a systematic review of based guidelines can be effective in improv-
evidence and an assessment of the benefits and ing patient care; the focus is increasingly
harms of alternative care options.” In this frame- shifting toward how to encourage the use
work they can help clinicians and healthcare of guidelines throughout clinical practice.
providers in taking best decisions in specific CP framework is one of the most promising
conditions and setting. Methodology issues are approaches to reach this goal.
of paramount importance in developing and
evaluating guidelines. The GRADE approach
is actually the standard framework to develop 21.1 Salient Points
• Guidelines are statements that include recom-
R. Zanini (*) · R. Bellù mendations, intended to optimize patient care,
NICU, Ospedale Manzoni, Lecco, Italy
that are informed by a systematic review of
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 315
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_171
316 R. Zanini and R. Bellù
evidence and an assessment of the benefits and for the newborn population. However, this has
harms of alternative care options. also imposed new behavioral and organizational
• They can help clinicians and healthcare pro- models to physicians and healthcare workers to
viders in taking optimal decisions in specific ensure that all these opportunities result in
conditions and settings. improved and consistent clinical outcomes for
• In neonatology, systematic evaluation of scien- patients.
tific evidence is very important because of the Organizational processes to promote team-
variability between the methodology of clini- work are needed to facilitate the support and man-
cal studies and difficulty in performing studies agement of a healthcare process that is no longer
in the neonatal population. in the hands of a single physician. The costs of
• Guidelines are systematic, repeatable, shared, healthcare have increased enormously because of
and transparent and may also be considered as advancing technology, the complexity of inter-
tools for reducing the gap between current ventions, and a continuing demand for better out-
practice and alternative practices. comes. These increased costs affect the healthcare
• Guidelines must be regularly updated. systems of all industrialized countries, and there is
• The GRADE approach is actually the standard a risk that they will stunt medical progress in the
framework to develop clinical guidelines. future years. Increased costs have tended to
• AGREE II approach reached an elevated reduce the fairness of the healthcare system, mak-
degree of validity and feasibility for busy cli- ing access less easy and decreasing its availability
nician and healthcare operator. to users.
• Clinical pathways are common components of Because guidelines (GLs) are systematic,
guideline implementation mainly used for spe- repeatable, shared, and transparent, their use
cific and homogeneous group of patients shar- can contribute to a response to both control
ing similar conditions. of costs and ease of access (Kurtin and Stucky
2009).
Complexity and cost are linked by the
21.2 Introduction increasingly pressing need to provide high-
quality treatment with six fundamental attri-
The principal aim of the guidelines is to offer butes: safety, appropriateness, efficacy, effi-
recommendations to assist in clinical decisions, ciency, fairness, and centrality for the user
based on relevant and updated scientific evidence. and his/her family.
In neonatology systematic evaluation of such
scientific evidence, the evaluation of the quality
and relevance of the information, as well as their 21.3 The Guidelines
subsequent adaptability to local circumstances to
allow its implementation acquire even more A definition of GL has been agreed by the Institute
importance than in other fields. The variability of Medicine, USA: Guidelines are “statements
between the methodology of clinical studies; the that include recommendations, intended to opti-
difficulty to study the neonatal population, often mize patient care, that are informed by a system-
with expert opinions; and adapting age neonatal atic review of evidence and an assessment of the
scientific results related to later ages or even to benefits and harms of alternative care options”
adults underlines the urgent need for neonatal (Consensus Report, Institute of Medicine 2011).
evidence-based guidelines. Rather than being an imposition, GLs are an
The complexity of modern medical proce- aid to obtaining the most appropriate healthcare
dures, joining different branches of medicine results, through clearly defined criteria of scien-
(obstetrics and neonatoIogy to make perinatol- tific validity, which take into account the view-
ogy), increased knowledge, and available technol- points of different stakeholders and which must
ogy, has contributed to the actual good outcomes therefore balance the interests of patients (clinical
21 Guidelines and Protocols for Newborns 317
outcomes), physicians, and healthcare providers evaluation of adherence of a specific GL to the
(availability of resources). reference methodology, which is considered a
The increasing use of GL has highlighted sev- guarantee of achieving the desired results.
eral problems, mainly related to the non-unicity of GLs may also be considered as tools for
definitions and to not observing essential method- reducing the gap between current practice
ological prerequisites. The spread of low-quality and alternative practices. They are therefore
GL and GLs that give contradictory recommen- supporting tools to help make decisions for indi-
dations is of growing concern (Grilli et al. 2000; vidual patients and for organizations by spelling
Shaneyfelt et al. 1999). out the benefits, risks, and costs of different
GLs require validity, which can be defined as healthcare choices.
the capacity to obtain an improvement in health. Based on these assumptions, the following
Validity in this sense is measurable. It is analo- methodological criteria have been identified:
gous to the efficacy of a drug, which can be
evaluated for specific, determinable interventions, 1. The development of a GL and its evaluation
for example, by way of randomized clinical trials, must be oriented toward the results of the
or of a diagnostic procedure, which can be char- healthcare: the start of the process of forming
acterized in terms of sensitivity, specificity, pre- (or using) a GL must always start from a
dictive value, and probability ratio. The validity of precise healthcare context which is seen (or,
the diffusion and implementation of a GL may even better, evaluated) as problematic and
then be evaluated in terms of the outcomes it pro- therefore targeted for improvement.
duces (Bellù and Zanini 2001). 2. The GL must be based on the best evidence
Systematic reviews of these studies showed available. This should also take into account
that in some contexts GL can change the behavior the paucity of clinical studies in several clin-
of healthcare practitioners and in some cases they ical areas, typically diagnosis.
can lead to significant improvements in clinical 3. The method used to summarize the available
outcomes for patients (Shaneyfelt et al. 1999; evidence must be rigorous and follow a series
Bellù and Zanini 2001; NHS Centre for Reviews of agreed steps: definition of the topic, forma-
and Dissemination and Nuffield Institute for tion of the writing group, definition of the
Health 1994). These systematic reviews showed method of bibliographical research and eval-
how a greater chance of obtaining positive results uation of the studies, dissemination, and
was associated with certain characteristics of GL. implementation.
These include simplicity, local adaptability, and 4. The GL must contain an explicit classification
the involvement of relevant professionals in their of the strength of the recommendation: this is
development. crucial and requires the need to give a
An important problem highlighted by system- “strength” to the various recommendations,
atic reviews was the identification of methodolog- based on criteria arising directly from the
ical weakness of the available studies. This quality of the studies which support the dif-
limited the ability to draw definitive conclusions ferent recommendations of a GL. At this
about the validity of some treatments (NHS Cen- regard, recent work produced a more compre-
tre for Reviews and Dissemination and Nuffield hensive way for classifying the strength of the
Institute for Health 1994). recommendations, based not only on the
Assessment of the validity of a set of GL quality of the evidence (type and quality of
should be based on the positive changes its imple- the primary studies) but also on the relevance
mentation induces on a specific pathological pro- of the clinical outcomes (Neumann et al.
cess. Such an assessment is made difficult by 2016; Mustafa et al. 2013; Atkins et al.
numerous confusing elements and by the com- 2004; Guyatt et al. 2008). This is known as
plexity of the studies required. The concept of the “GRADE approach” or framework. In this
the validity of a GL has therefore shifted toward way more strength recommendations are
318 R. Zanini and R. Bellù
given for more relevant clinical outcome assumes knowledge of epidemiology and
(such as mortality or disability). the methodology of research. The table of
5. The process of developing a GL must be evidence should state the strength of evi-
multidisciplinary and involve users and dence on which the GL is based, using an
patients. Experts in a discipline must not be approach such as the GRADE (Neumann
the only ones to deal with a certain topic, and et al. 2016; Mustafa et al. 2013; Atkins
others, who are in some way involved with et al. 2004; Guyatt et al. 2008) (Table 1).
the clinical management, including the • Formulation of recommendations. On the
patients, must also be included. basis of identified studies, recommenda-
6. A GL must be adapted to the specific local tions for best practice can be made. These
circumstances. At this regard one should con- are then graded, according to the GRADE
sider to develop specific, local documents, criteria listed in Table 2.
such as clinical pathways, for example, 4. Dissemination and implementation. These
based on more general guidelines. steps are an integral part of creating a set of
7. A GL must take into consideration the avail- GL. This section covers the identification of
able resources. This bridges the gap between problems that may arise during the application
experimental situations and the actual clinical of the GL and approaches for their resolution
context in which the individual practitioners (e.g., incentivizing initiatives, structural and
work. Again, locally developed clinical path- organizational changes, the use of specific
ways are tools very used to deploy general tools such as reminders (paper or electronic),
recommendations. etc.) which can reach the site where the clini-
8. Once produced, GL must be disseminated cian actually makes the healthcare decisions
and implemented in an appropriate man- (US Agency for Health Care Policy and
ner. The simple act of publishing a set of Research (AHCPR) 1993). By conducting an
GL in journals or congresses is not an
effective way of promulgating their use in
clinical practice. Table 1 Criteria for grading of evidence (according to
GRADE)
9. The implementation of GL must be carefully
monitored. 1. Type of evidence
Randomized clinical trial = high
10. A GL must be regularly updated.
Observational study = low
Any other evidence = very low
The main steps required for the formulation of
2. Decrease grade if:
GL are:
Serious (1) or very serious (2) limitation to study
quality
1. Formation of the work group. Important inconsistency (1)
2. An evaluation of the literature, aimed at Some (1) or major (2) uncertainty about directness
establishing the best available research-based Imprecise or sparse data (1)
evidence for practice and researching GL High probability of reporting bias (1)
already in existence. 3. Increase grade if:
3. Drafting the GL: Strong evidence of association – significant relative risk
• Systematic search of the literature. of >2 (<0.5) based on consistent evidence from at least
two observational studies with no plausible confounders
• Evaluation of the methodology of the (þ1)
studies. Very strong evidence of association – significant risk of
• Evaluation of the quality of the studies. >5 (<0.2) based on direct evidence with no major threats
• Production of a table of evidence, setting to validity (þ2)
out the results of each study in terms of its Evidence of a dose-response gradient (þ1)
conclusions and level of evidence. This step All plausible confounders would have reduce the
effect (þ1)
is the most difficult methodologically, as it
21 Guidelines and Protocols for Newborns 319
Table 2 Strength of recommendation (according to GRADE)
Strong Conditional (weak) Only in Conditional (weak) Strong
recommendation recommendation against a research recommendation for a recommendation
against a given action given action given action for a given action
analysis of 431 sets of GL produced by inter- tools are accessible at www.agreetrust.org. The
national scientific societies between 1988 and AGREE evaluation tool focuses attention on the
1998, evaluating them on the basis of essential methodological and formal aspects described
criteria, such as their multidisciplinary appli- above, structuring the analysis and the evaluation
cability, completeness of the systematic review of them in a format that is easily understood and
of the literature, and gradation of the evidence, usable. In particular, the AGREE focuses on six
Grilli et al. (2000) demonstrated that 67% did major domains with 23 items and an overall
not provide information on the staff involved, assessment:
88% did not provide information on the biblio-
graphic search strategies, and 82% did not 1. Scope and purpose (3 items)
grade the evidence. Only 5% of GL reviewed 2. Stakeholder involvement(3 items)
satisfied all the criteria. However, there was an 3. Rigor of development(8 items)
improvement with time, especially in respect 4. Clarity of presentation(3 items)
of the search strategy (from 2% to 18%) and 5. Applicability(4 items)
grading of the evidence (from 6% to 27%). 6. Editorial independence(2 items)
Similar studies revealed the same problems,
meaning that tracking down good-quality GL In this way it is possible to evaluate a set of GL,
cannot be taken for granted. adhere to a good development process, and, there-
fore, by inference, achieve the desired health
If it is possible to find GL with good validity, effect. Actually, the tool is based on theoretical
what strategies can be used to identify valid GL? It assumptions and on empirical evidence, which it
might be possible to adopt GLs that have already is now accumulating with the wide diffusion of
produced positive results in terms of health out- the instrument in the last years (Brouwers et al.
comes. However, such experiences are relatively 2012).
scarce and cannot be reproduced in different con-
texts. Account needs to be taken therefore of the
Iocal situation, ensuring the relevance of GL, 21.4 Clinical Pathways (CPs)
which may Iead to recommendations that are dif-
ferent to the originals. CPs are a common component of guideline imple-
An alternative strategy is to adopt stringent, mentation. More specifically that in GL, they aim
validated methodological criteria to assess the to organize and standardize care processes, thus
available GL or to construct evaluation “grids,” trying to maximize patient outcomes (Rotter et al.
which can be used by clinicians and by the final 2010). Originating in the USA, CPs have been
users. A recent systematic review analyzed avail- used since the 1980s. Their goal is to improve
able studies on this topic. It came to the conclu- patient outcomes, such as mortality rate and
sion that more than one of the tools had others, while containing costs and, possibly,
characteristics of such validity as to be of practical improving quality (Kinsman et al. 2010). They
use, the one developed within the context of the are also a means of improving systematic collec-
European project AGREE (AGREE Collabora- tion and abstraction of clinical data for audit and
tion 2003; Brouwers et al. 2010), being one of of promoting change in practice. Different terms,
the most widespread and useful. The AGREE II including care maps, critical pathways, local
320 R. Zanini and R. Bellù
protocols, or algorithms, are used to describe the 7. Identify key areas for service development for
construct of CPs. that clinical condition and express appropri-
CPs are mainly used for specific and homoge- ate goals for the service.
neous groups of patients sharing similar condi- 8. Develop a care pathway which specifies ele-
tions. The implementation of CPs may be driven ments of care detailed in local protocol, the
by a variation in the quality of care and outcomes sequence of events, and expected patient pro-
for patients with similar health conditions; in neo- gress over time.
natology they have been used since many years. 9. Prepare documentation for the CP.
Usually, the aim of the implementation is to 10. Educate staff in the use of the CP.
reduce a pre-identified variation in patient out- 11. Pilot then implement the integrated CP.
comes and costs and, more recently, to keep 12. Regularly analyze variances from the inte-
patients and families informed about their course grated care pathway. Investigation of the rea-
of treatment or care. sons why current practice is different from
Recently, an operational definition for CPs was that recommended in the CP can be used to
developed, including four major criteria for devel- identify common variations from agreed best
oping and evaluating CPs (Lawal et al. 2016): practice, alert staff to patients who are failing
to progress as expected, update the CP by
1. CP is a structured multidisciplinary care plan. incorporating agreed changes, and identify
2. Is it used to direct the translation of guidelines research issues.
or evidence into local structures. 13. Discuss variations from the CP and identify
3. CPs detail the steps of care in a plan, pathway, avoidable and unavoidable variations; then
algorithm, guideline, protocol, or other “inven- identify and implement solutions to avoidable
tory of actions” (i.e., the intervention had time variations.
frames or criteria-based progression).
4. CPs aim to standardize care for a specific clin- Integration of CP into clinical record is an
ical problem, procedure, or episode of care in a essential issue, characterizing this instrument.
specific population. The CP should be placed in the patient’s clinical
record. It records essential clinical information in
Given the above definition, Campbell (Campbell way that is easy to complete and to extract data
et al. 1998) proposed the following steps to for audit; for example, checklists of all necessary
develop CPs: activities to tick and boxes for specific results to
be recorded. This can result in more legible and
1. Select an important area of practice. Selection complete clinical records and contains a mini-
criteria could include common or costly clin- mum essential data set for auditing and
ical conditions, those where there is a high reviewing. Separate sheets should be used to
level of interest among local staff or those record all variations from the CP so that it can
where variations in practice occur and affect be easily extracted for audit purposes. Integra-
patient outcome. tion of CP into electronic medical record (EMR)
2. Gather support for the project. should improve ease of use and implementation
3. Form a multidisciplinary group to compare of CP.
current practice with established clinical In conclusion, evidence-based guidelines can
guidelines. be effective in improving patient care; the focus
4. Identify established guidelines. is increasingly shifting toward how to encourage
5. Review practice, both current and past. the use of guidelines throughout clinical practice.
6. Involve local staff from all disciplines provid- CP framework is one of the most promising
ing care for the condition. approaches to reach this goal.
21 Guidelines and Protocols for Newborns 321
References Kinsman L, Rotter T, James E, Snow P, Willis J (2010)
What is a clinical pathway? Development of a defini-
AGREE Collaboration (2003) Development and validation tion to inform the debate. BMC Med 8:31
of an international appraisal instrument for assessing Kurtin P, Stucky E (2009) Standardize to excellence:
the quality of clinical practice guidelines: the AGREE improving the quality and safety of care with clinical
project. Qual Safety Health Care 12:18–23 pathway. Pediatr Clin N Am 56:893–900
Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Lawal AK, Rotter T, Kinsman L, Machotta A,
Flottorp S, Guyatt GH, Harbour RT, Haugh MC, Ronellenfitsch U, Scott SD, Goodridge D, Plishka C,
Henry D, Hill S, Jaeschke R, Leng G, Liberati A, Groot G (2016) What is a clinical pathway? Refinement
Magrini N, Mason J, Middleton P, Mrukowicz J, of an operational definition to identify clinical pathway
O’Connell D, Oxman AD, Phillips B, Schünemann studies for a Cochrane systematic review. BMC Med
HJ, Edejer T, Varonen H, Vist GE, Williams JW Jr, 14:35
Zaza S, GRADE Working Group (2004) Grading qual- Mustafa RA, Santesso N, Brozek J, Akl EA, Walter SD,
ity of evidence and strength of recommendations. BMJ Norman G, Kulasegaram M, Christensen R, Guyatt
328:1490 GH, Falck-Ytter Y, Chang S, Murad MH, Vist GE,
Bellù R, Zanini R (2001) Sono valide le Linee Guida che Lasserson T, Gartlehner G, Shukla V, Sun X,
utilizziamo in reparto? Riv Ital Pediatr 27:645–650 Whittington C, Post PN, Lang E, Thaler K, Kunnamo
Brouwers MC, Kho ME, Browman GP, Burgers JS, I, Alenius H, Meerpohl JJ, Alba AC, Nevis IF, Gentles
Cluzeau F, Feder G, Fervers B, Graham ID, S, Ethier MC, Carrasco-Labra A, Khatib R, Nesrallah
Grimshaw J, Hanna SE, Littlejohns P, Makarski J, G, Kroft J, Selk A, Brignardello-Petersen R,
Zitzelsberger L, AGREE Next Steps Consortium Schünemann HJ (2013) The GRADE approach is
(2010) AGREE II: advancing guideline develop- reproducible in assessing the quality of evidence of
ment, reporting and evaluation in health care. J Clin quantitative evidence syntheses. J Clin Epidemiol
Epidemiol. 63:1308–1311 66:736–742
Brouwers MC, Kho ME, Browman GP, Burgers JS, Neumann I, Santesso N, Akl EA, Rind DM, Vandvik PO,
Cluzeau F, Feder G, Fervers B, Graham ID, Grimshaw Alonso-Coello P, Agoritsas T, Mustafa RA, Alexander
J, Hanna SE, Littlejohns P, Makarski J, Zitzelsberger L, PE, Schünemann H, Guyatt GH (2016) A guide for
AGREE Next Steps Consortium (2012) The Global health professionals to interpret and use recommenda-
Rating Scale complements the AGREE II in advancing tions in guidelines developed with the GRADE
the quality of practice guidelines. J Clin Epidemiol approach. J Clin Epidemiol 72:45–55
65:526–534 NHS Centre for Reviews and Dissemination and Nuffield
Campbell H, Hotchkiss R, Bradshaw N, Porteous M (1998) Institute for Health (1994) Implementing clinical
Integrated care pathways. BMJ 316:133–137 guidelines. Can guidelines be used to improve clinical
Consensus Report, Institute of Medicine (2011) Clinical practice? Effective Health Care 1:1–12
practice guidelines we can trust. http://nationala Rotter T, Kinsman L, James E, Machotta A, Gothe H,
cademies.org/hmd/~/media/Files/Report%20Files/2011/ Willis J (2010) Clinicalpathways: effects on profes-
Clinical-Practice-Guidelines-We-Can-Trust/Clinical% sional practice, patient outcomes, length of stayand
20Practice%20Guidelines%202011%20Report%20Brief. hospital costs. Cochrane Database Syst Rev 3:
pdf. Accessed on 23 Oct 2016 CD006632
Grilli R, Magrini N, Penna A et al (2000) Practice guide- Shaneyfelt TM, Mayo-Smith MF, Rothwangl J (1999) Are
lines developed by specialty societies: the need for a guidelines following guidelines? The methodological
critical appraisal. Lancet 355:103–106 quality of clinical practice guidelines in the peer-
Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, reviewed medical literature. JAMA 281:1900–1905
Alonso-Coello P, Schünemann HJ, GRADE Working US Agency for Health Care Policy and Research (AHCPR)
Group (2008) GRADE: an emerging consensus on (1993) Program note: clinical practice guidelines devel-
rating quality of evidence and strength of recommen- opment. AHCPR publication no. 93-0023. US Depart-
dations. BMJ 336:924–926 ment of Health and Human Services
Physical Environment for Newborns:
The Thermal Environment 22
Daniele Trevisanuto and Gunnar Sedin
Contents
22.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
22.2 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
22.3 Thermal Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
22.3.1 Routes of Heat Exchange . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
22.4 Water and Heat Exchange Between the Infant’s
Body Surface and the Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
22.4.1 Determination of Water Loss from the Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
22.4.2 Calculation of Heat Exchange Between the Infant and the Environment . . . 326
22.5 Heat Exchange in Incubators, Under Radiant
Heaters and Heated Beds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
22.5.1 Incubators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
22.5.2 Radiant Heaters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
22.5.3 Heated Beds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
22.6 Water and Heat Exchange Between the Skin and Environment . . . . . . . . 329
22.6.1 Heat Exchange During the First Hours
After Birth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
22.6.2 Transepidermal Water Loss During the First
4 Postnatal Weeks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
22.6.3 Heat Exchange During the First Day
After Birth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
22.6.4 Heat Exchange at Different Ambient Humidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
22.6.5 Heat Exchange During the First Weeks After Birth . . . . . . . . . . . . . . . . . . . . . . . . . 331
22.6.6 Heat Exchange Between Infant’s Skin and the Environment
During Care Under Radiant Heaters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
D. Trevisanuto (*)
Department of Women’s and Children’s Health, Azienda
Ospedaliere di Padova, University of Padua, Padua, Italy
e-mail: [email protected]
G. Sedin
Department of Women’s and Children’s Health, University
Children’s Hospital, Uppsala, Sweden
# Springer International Publishing AG, part of Springer Nature 2018 323
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_172
324 D. Trevisanuto and G. Sedin
22.6.7 Ambient Humidity Influence on the Rate of Skin
Barrier Maturation in Extremely Preterm
Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334
22.6.8 Heat Exchange Between the Infant’s Skin and the Environment During
Phototherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334
22.6.9 Heat Exchange Between the Infant’s Skin and the Environment During
Care on a Heated Bed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334
22.6.10 Heat Exchange Between the Infant’s Skin and the Environment
During Skin-to-Skin Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
22.6.11 Keeping the Very Preterm Infant Warm Early After
Birth: The Effect of Thin Clothing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
22.7 Water and Heat Exchange Between the
Respiratory Tract and Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
22.7.1 Respiratory Water and Evaporative Heat Exchange
Before and After Intubation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
22.7.2 Respiratory Water and Evaporative Heat Loss in
Relation to GA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
22.7.3 Respiratory Water and Evaporative Heat Exchange
During Phototherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
22.7.4 Respiratory Water and Heat Exchange During
Mechanical Ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
22.8 Clinical Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
22.8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
22.8.2 Thermal Delivery Room Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
Abstract thermal losses in very preterm infants. In this
The exchange of heat between the infant’s skin chapter, we report the mechanisms of thermal
and the environment is influenced by insula- homeostasis in the newborn infant and
tion provided by the skin, the permeability of describe the clinical management of the neo-
the skin, and the environmental factors such as nates, especially very preterm infants, to pre-
the ambient temperature and humidity, airflow vent heat losses at birth.
velocity, and characteristics of surfaces where
the infant is positioned. High incidence of
postnatal hypothermia has been reported in 22.1 Salient Points
high- as well as low-resource countries, and it
is an independent predictor of neonatal mor- • Physiological mechanisms involved in the
bidity and mortality. All efforts should be put maintenance of temperature include convec-
in place to prevent heat losses at birth, espe- tion, radiation, conduction, and evaporation.
cially in very preterm infants. Interventions • The high evaporative losses of heat from the
include delivery room temperature >25 C, infant’s skin, especially in preterm infants, will
use of infant warmers, exothermic mattress, gradually decrease with increasing postnatal age.
woolen caps, plastic wraps, and humidified • In very preterm infants, hypothermia at NICU
and heated gases. Skin-to-skin contact has be admission is significantly associated with
considered, especially in low-resource set- adverse neonatal outcomes such as mortality,
tings. In addition to specific interventions, intracranial hemorrhage, necrotizing enteroco-
quality improvement initiatives, including the litis, and late-onset sepsis.
use of checklists and continuous feedbacks • Maintaining delivery room temperature
with the staff involved in the management of >25 C, use of infant warmers, exothermic
the neonate, contribute to reduce postnatal mattress, woolen caps, plastic wraps, and
22 Physical Environment for Newborns: The Thermal Environment 325
humidified and heated gas are effective in pre- with cotton fabrics to lower the loss of heat
venting postnatal thermal losses in preterm through evaporation and to cover the infant with
infants. a warm, dry towel or blanket, or both, to lessen the
• More than the single intervention, their sum exposure of the infant’s skin to the environment
associated to the use of checklists and contin- (Hammarlund et al. 1980, 1986). This interven-
uous feedbacks to the staff is the “secret” to tion is recommended for infants with gestational
prevent delivery room thermal losses in pre- age higher than 32 weeks. The infant born at term
term infants. or moderately preterm can be covered with a
• Skin-to-skin contact has be considered, espe- blanket and then placed on the mother’s chest
cially in low-resource settings. (Bauer et al. 1997, 1998; Whitelaw et al. 1988),
but extremely preterm infants usually need other
types of measures to maintain their body temper-
22.2 Overview ature, usually placement in an incubator or under a
radiant heater (Hammarlund and Sedin 1982,
During intrauterine life, heat production by the 1979; Hammarlund et al. 1986; Kjartansson
fetus results in a fetal temperature that is about et al. 1995; Marks et al. 1980; Sjörs et al. 1992a)
0.5 C higher than the maternal temperature and, if necessary, mechanical ventilation with
(Bruck 1978). After birth, the newborn infant is warm and humidified gas (Hammarlund et al.
exposed to air and surfaces, which have a much 1988; Riesenfeld et al. 1994, 1995; Sedin 1996a).
lower temperature than that previously experi- This chapter is divided into parts: the first part
enced in utero. The skin surface at birth is covered includes the mechanisms of thermal homeostasis
with amniotic fluid, causing heat loss through in the newborn infant; in the second part, we will
evaporation in an environment with a low vapor describe the clinical management of the neonates,
pressure (Hammarlund et al. 1980). As a result, especially very preterm infants, to prevent heat
the body temperature of the infant is lowered, and losses at birth.
the rate of this reduction is influenced by the
temperature of the environmental air in the deliv-
ery room and the delivery of its flow. This gives 22.3 Thermal Homeostasis
rise to thermogenic responses that increase basal
heat production (Bruck 1978; Dahm and James 22.3.1 Routes of Heat Exchange
1972), and the skin circulation may decrease to
lower the heat losses (Sjors et al. 1994). Heat exchange between the infant and its environ-
Heat balance in the newborn infants depends ment occurs through the skin and through the
on the heat transfer between the infant and the respiratory tract. About 30 years ago, the intro-
environment (Hammarlund and Sedin 1982; duction of new techniques to measure the evapo-
Hammarlund et al. 1986, 1988; Sedin 1995). ration rate from the skin (Hammarlund et al. 1985,
This transfer is related to the temperature and the 1986; Kjartansson et al. 1995; Nilsson 1977) and
humidity of environmental air (the vapor pres- from the respiratory tract (Hammarlund et al.
sure), the flow velocity of that air (which causes 1988, 1985; Kjartansson et al. 1992a) has permit-
a sense of cooling of the skin), the temperature of ted to determine the heat loss through evaporation
the surfaces facing the infant (ceiling, walls of the (Hammarlund et al. 1986). It is also possible to
room or incubator, or bedding material), and the calculate the heat losses through other modes of
temperature of the surfaces in direct contact with heat exchange, such as radiation, convection (air
the infant (Hammarlund and Sedin 1982; movements), and conduction (in direct contact
Hammarlund et al. 1986; Sedin 1995, 2004). with a piece of material or skin), and to determine
After birth, the immediate interventions the heat loss per unit surface area and from the
required to avoid body cooling are to carefully total body surface area (Riesenfeld et al. 1995)
wipe off the amniotic fluid from the skin surface and also to take into consideration the proportions
326 D. Trevisanuto and G. Sedin
of the surface area of the body participating in the TEWL ¼ 0:92 ERða, b, cÞ þ 1, 32
different modes of heat exchange (Hammarlund
and Sedin 1982; Hammarlund et al. 1986). In where ER(a,b,c) is the arithmetic mean of ER mea-
addition, the modes of heat exchange between sured from the chest, an interscapular area, and a
the infant’s respiratory tract and the environment buttock (Sedin 1995, 2004; Hammarlund et al.
can be determined. 1985; Kjartansson et al. 1992a).
The gradient method (Evaporimeter, Servomed
AB, 511 21 Varberg, Sweden) allows quick mea-
22.4 Water and Heat Exchange surements of free evaporation without disturbing
Between the Infant’s Body the infant (Nilsson 1977; Kjartansson et al. 1992a).
Surface and the Environment
Heat exchange through evaporation, radiation, 22.4.2 Calculation of Heat Exchange
convection, and conduction can be calculated Between the Infant
with knowledge of the transepidermal water loss and the Environment
(loss of water through the skin), the temperature of
the infant’s skin (Tskin), the temperature of the 22.4.2.1 Exchange at the Surface
ambient air (Tamb), the temperature of the material Heat exchange through evaporation (Hevapor) can
on which the infant is placed (Tbed), and the char- be calculated if TEWL is known (Sedin 1995,
acteristics of the material in the infant’s environ- 2004; Nilsson 1977; Hammarlund et al. 1985;
ment (Hammarlund et al. 1980; Hammarlund and Kjartansson et al. 1992a) according to the equation:
Sedin 1982).
1
Hevapor ¼ k1 TEWL 3:6 103 W=m2
22.4.1 Determination of Water Loss
from the Skin where K1 is the latent heat of evaporation
(2.4 103 J/g) and 3.6 103 is the correction
In the absence of forced convection (air move- factor for time (s).
ments), and if the effect of thermal diffusion is Heat exchange through radiation (Hrad) can be
disregarded, the process of water exchange determined if the mean temperature of the skin
through a stationary water-permeable surface can (T1; K) and the mean temperature of the surround-
be expressed in terms of the vapor pressure gradi- ing walls (T2; K) are known:
ent immediately adjacent to the surface (Nilsson
1977). ðHrad Þ ¼ S0 e1 e2 T1 4 T2 4 W=m2
The evaporation rate (ER; g/m2 h) from the
infant’s skin can thus be determined by a method where S0 is Stefan-Boltzmann’s constant
based on calculation of the water vapor pressure in (5.7 108 W/m2 K4), e1 is the emissivity of
the layer of air immediately adjacent to the vapor the skin, and e2 is the emissivity of the surround-
pressure and the distance from the evaporating ing walls (0.97).
surface (Nilsson 1977). In this zone, the relation- Heat exchange through convection (Hconv) can
ship between the vapor pressure and the distance be calculated if the mean temperature of the skin
from the evaporating surface is linear (Nilsson (T1; K ) and the mean temperature of the ambient
1977). If the gradient in this layer is known, the air (T3; K ) are known:
amount of water evaporated per unit time (trans-
epidermal water loss, TEWL; g/m2 h, which is a H con ¼ K 2 ðT 1 T 3 Þ W=m2
mean value of cutaneous water loss) can be cal-
culated (Nilsson 1977) according to the following where K2 is the convection coefficient (2.7 W/m2
equation: K). The coefficient for convection given above and
22 Physical Environment for Newborns: The Thermal Environment 327
used in many studies referred to this chapter has the body, passes along the mucosa of the infant
usually been determined in measurements in adult during inspiration, it gains heat by convection and
human skin (Okken et al. 1982). A convection gains water vapor by evaporation from the
coefficient suggested as being more valid for new- mucosa. On reaching the alveoli, the air is at
borns infants (Wheldon 1982) can alternatively be thermal equilibrium with the central body temper-
used, and Hconv will then be 48% higher. ature and is saturated with water. During expira-
Heat exchange through conduction (Hcond) can tion, the expired air may become a little cooled
be determined if the temperature of the skin (Tskin; than the body temperature before it leaves the
K) and the temperature of the bed (Tbed; K) are infant (Hammarlund et al. 1985, 1988).
known:
22.4.2.3 Determination of Water Loss
H cond ¼ K 0 ðT skin T bed Þ W=m2 from the Airway
Respiratory water loss (RWL) is usually included
In this equation, K0 is a conductive heat transfer in measurements of total insensible water loss
coefficient. With the thermal conductivity charac- when these are performed with ventilated cham-
teristics of most regular mattresses, the heat loss bers, but it can be estimated separately (Hey and
through conduction is very low. Katz 1969; Sulyok et al. 1973). Hey and Katz
The extent of heat exchange between the body (1969) and Sulyok and colleagues (Sulyok et al.
surface area and the environment thus depends on 1973) found that the respiratory water loss was
the type of heat exchange, on the position and higher at a low ambient humidity than at a high
geometry of the body (Hammarlund et al. 1986; humidity. In other studies, data on respiratory
Sedin 1995), and on the magnitude and frequency water loss, oxygen consumption, and carbon
of body movements. As different modes of heat dioxide production were provided (Hammarlund
exchange are unequally influenced by changes in et al. 1985, 1988; Riesenfeld et al. 1994, 1995,
the body position, the relative contribution of 1987a, b, 1988, 1990; Sjörs et al. 1992b).
different modes of heat exchange might vary
with time. Heat exchange is often presented per
area of body surface exposed to the ambient air or 22.4.2.4 Calculation of Heat Exchange
facing the walls of the incubator. Between the Infant’s
Respiratory Tract
and the Environment
22.4.2.2 Heat Exchange Between The exchange of heat through convection in the
the Infant’s Respiratory Tract respiratory tract, Hconv-r, is calculated from the air
and the Environment volume ventilated per unit time (V = ventilation
The expired air is usually more humid than the volume) and from the temperature difference
inspired air and has a higher water vapor pressure. between expired and inspired air (Te–Tl)
This implies that evaporative loss of water and according to the following relationship:
heat takes place from the respiratory tract. Con-
vective heat transfer, usually of low degree, also Hconvr ¼ V r c ðT e T l Þm1 ðW=KgÞ
occurs in the respiratory tract. In research, these
two processes are considered together (Houdas where V is ventilation volume per unit time, r is
and Ring 1982). In the newborn, heat can also the density (1 g = 0.880 L), c is the specific heat
be gained through the respiratory tract if the infant (1 J g-1 C1), and m is the body weight
inspires very warm air with a high humidity. (kg) (Sedin 1995).
Because of the alternating displacement of air Because of the alternating inspiratory warming
during the respiratory cycle, convective and evap- and expiratory cooling of the air, the convective heat
orative heat transfer in the respiratory tract is exchange in the respiratory tract depends mainly on
complex. When ambient air, which is cooler than the temperature of the inspired air. In human infants
328 D. Trevisanuto and G. Sedin
nursed in an incubator, there is a very small differ- the air temperature, and the vapor pressure gradi-
ence between the temperatures of the inspired and ent close to the skin surface will be maintained,
expired air, and convective losses are small. avoiding an increased evaporative rate due to
Evaporative heat exchange from the airway, increased airflow velocity (Sedin 1995; Okken
Hevap-r, depends on the difference in water content et al. 1982; Wheldon 1982)
between the expired and inspired air. This is the An evaluation of environmental and climate con-
respiratory water loss (Riesenfeld et al. 1994; Sedin trol in incubators has shown that the airflow veloc-
1996a; Hey 1969). As the formation of water vapor ities and capacity for humidification vary markedly
in the respiratory tract requires thermal energy, the between the different types of incubators. Also, the
amount of heat exchange by evaporation per unit wall temperature varies considerably between dif-
time is expressed by the following equation: ferent incubators (Sjörs et al. 1992b), and it is there-
fore necessary to determine the airflow velocities,
1 humidity, and wall temperatures carefully before
H evapr ¼ K 1 RWL 3:6 103 ðW=KgÞ
calculating heat exchange. With airflows higher
where k1 is the latent heat of evaporation of water than 0.2 m/s, there will be a forced convection.
((2.4 103 J/kg), RWL is the respiratory water
loss (mg/kg min), and (3.6 103)1 is the cor-
rection factor for time. 22.5.2 Radiant Heaters
A radiant warmer placed over an open bed platform
provides good accessibility and visibility for the
22.5 Heat Exchange in Incubators, care of the newborn infant and has therefore
Under Radiant Heaters become widely used in neonatal intensive care.
and Heated Beds Infants nursed under a radiant heater gain heat,
but they may also have extensive heat losses
When it was realized that a good thermal environ- through evaporation and convection, and also,
ment increases the chances of survival of the from surfaces, through radiation (Kjartansson
newborn infants, attempts were made to provide et al. 1992b, 1995; Marks et al. 1980; Baumgart
them with a warm environment. The ambient tem- 1982; Sjörs et al. 1997; Sosulski et al. 1983), mak-
perature influences the survival rate and oxygen ing it difficult to estimate the relative contributions
consumption in newborn infants (Dahm and of different modes of heat exchange. Because of
James 1972; Hey and Katz 1969; Hey 1969), the free movements of air above the infant’s body
and a body temperature of around 37 C is appro- surface, both evaporative and convective heat loss
priate for newborn infants at rest (Riesenfeld et al. may increase as a result of a high air velocity.
1990). At a high ambient temperature, full-term
infants start to sweat, and if they are fed cold
glucose through a gastric tube, sweating is 22.5.3 Heated Beds
inhibited (Stromberg et al. 1983).
In the 1990s, Sarman and co-workers found that
infants weighting 1,000 g or more can be kept
22.5.1 Incubators warm by placing them on a heated water-filled mat-
tress early after birth (Sarman et al. 1989). By cov-
In a convectively heated incubator, the warm air ering most parts of the body except the face, direct
supplied should be directed so that both the air heat exchange between the infant’s skin and the
temperature of the incubator and the incubator environment trough other modes can be almost
walls are kept warm. If the airflow velocity is eliminated in a large proportions of the body surface.
lower than 0.1 m/s, the convective heat transfer Preterm and term infants can maintain a normal
will depend on the gradient between the skin and body temperature during skin-to-skin care, if they
22 Physical Environment for Newborns: The Thermal Environment 329
are placed lying naked except for a diaper on the radiation is high if the infant’s skin is facing the
mother’s or father’s chest and are covered with the walls of the delivery room and is much lower if it
mother’s clothing or a blanket (Bauer et al. 1997, is facing the inner walls of the incubator
1998; Whitelaw et al. 1988). Only parts of the (Hammarlund et al. 1980), (Fig. 1, middle dia-
head are exposed to the environmental air and grams). The heat loss through convection is lower
will exchange heat with the environment (Bauer than through radiation but is much higher when the
et al. 1997, 1998; Whitelaw et al. 1988). infant is nursed in room air (Fig. 1, lower left dia-
gram) than when nursed in the incubator (Fig. 1,
lower right diagram).
22.6 Water and Heat Exchange
Between the Skin
and Environment 22.6.2 Transepidermal Water Loss
During the First 4 Postnatal
In a series of studies, water evaporation from the Weeks
skin surface of infants nursed in incubators has
been determined by the use of the gradient method The transepidermal water loss from the skin surface
(the ServoMed Evaporimeter), and trans- of the newborn infant depends primarily on the
epidermal water loss (TEWL) (Hammarlund and gestational age (GA) at birth (Hammarlund and
Sedin 1979; Hammarlund et al. 1983, 1985; Sedin 1979), but it is also influenced by the postnatal
Kjartansson et al. 1992a) and heat exchange age (Hammarlund et al. 1983). The transepidermal
have been calculated (Hammarlund et al. 1980, water loss in newborn infants is also lower in small
1986; Hammarlund and Sedin 1982). In these for gestational age (SGA (Hammarlund et al. 1985)
studies, the body temperature has been maintained than in appropriate for gestational age (AGA)
at 36–37 C, except when the effect of warming (Hammarlund and Sedin 1979; Hammarlund et al.
has been investigated, and the ambient humidity 1983, 1985) infants. There is an exponential rela-
has been kept at 50% except when the effects of tionship between TEWL and gestational age in
different humidities have been analyzed. Evapo- AGA infants when measurements are made during
rative heat loss is usually insensible but might the first day after birth (Hammarlund and Sedin
become sensible when term infants are nursed in 1979). This relationship prevails over the first
a warm environment and start to sweat (Stromberg 4 weeks after birth, even though the difference in
et al. 1983). Some infants born at term and nursed TEWL between the most preterm and full-term
in a warm environment do not begin to sweat AGA infant gradually diminishes with increasing
(Stromberg et al. 1983), and if they do, the sweat- age. The evaporation rate and TEWL both depend
ing is preceded by an increase in skin blood flow. on the ambient relative humidity or ambient
In preterm infants, the sweat glands are non- vapor pressure (Hammarlund and Sedin 1979;
functional (Hey and Katz 1969). Hammarlund et al. 1985). This relationship seems
to be valid for all gestational ages and is also valid
for all postnatal ages studied (Hammarlund and
22.6.1 Heat Exchange During the First Sedin 1979; Hammarlund et al. 1983, 1985; Sedin
Hours After Birth 1996b).
Immediately after birth, when the infant’s skin is
covered with amniotic fluid, there is an enormous 22.6.3 Heat Exchange During the First
evaporative heat loss from the skin surface. This Day After Birth
evaporative heat loss decreases gradually during
the first hours, whether the infant is nursed in the The evaporative heat exchange is directly propor-
delivery room or in an incubator (Hammarlund et al. tional to the amount of water that evaporates from
1980; Fig. 1, top two diagrams). Heat loss through the infant’s skin and shows the same type of
330 D. Trevisanuto and G. Sedin
W/m2 W/m2
Evaporative heat loss 80 80
60 60
40 40
20 20
0 0
0 0.5 1.0 h 0 1 2 3 4 h
Age Age
W/m2 W/m2
80 80
Radiant heat loss
60 60
40 40
20 20
0 0
0 0.5 1.0 h 0 1 2 3 4 h
Age Age
W/m2 W/m2
Convective heat loss
60 60
40 40
20 20
0 0
0.5 1.0 h 1 2 3 4 h
–20 Age –20 Age
Fig. 1 Heat exchange between the skin of full-term in a cot. After the measurements made at 1 and 5 min after
infants and the environment immediately after birth and birth, the infants were covered with a towel between the
during the first 1–4 h postnatally. The infants were not measurements. Data in the right-hand diagrams are based
washed or wiped. Data presented in the left-hand scatter on measurements in infants who were covered with a towel
diagrams are based on measurements in infants initially after birth and until they were placed in an incubator
placed at the delivery bed or at the mother’s chest and later (Hammarlund et al. 1980)
relationship to GA as TEWL (Hammarlund and 50 W/m2 of the body surface area in the most
Sedin 1982; Hammarlund et al. 1985). When preterm infants (Hammarlund and Sedin 1982),
infants are nursed in an ambient humidity of whereas in term infants, it is close to 5 W/m2
50%, the evaporative heat exchange may reach (Fig. 2). The high evaporative heat loss in very
22 Physical Environment for Newborns: The Thermal Environment 331
Fig. 2 Heat exchange
through evaporation at
50
ambient humidity of 50 %
in relation to gestational
Evaporative heat exchange (W/m2)
age. Measurements were
40
made during the first 24 h
after birth in preterm infants
and during the first 30 h in 30
term infants (Hammarlund
and Sedin 1982)
20
10
0
25 30 35
–10
Gestational age (weeks)
preterm infants makes it necessary to have a very ambient temperature can be sufficient to maintain
high ambient temperature in the incubator to a normal body temperature (Hammarlund and
maintain a normal body temperature of Sedin 1982).
36.0–37.0 C in these infants.
The servocontrol system of the incubator that
controls the skin temperature regulates the tem- 22.6.4 Heat Exchange at Different
perature of the air, which also lead to changes in Ambient Humidities
temperature of the incubator walls and thereby
influences the heat exchange through convection Evaporative heat exchange between the skin of
and radiation. very preterm infants and the environment is
The most preterm infants can even gain heat highest at a low humidity (Hammarlund and
through these modes of heat exchange. Preterm Sedin 1982) and lower at higher ambient humid-
infants were nursed in an incubator with a relative ity. In fact, heat exchange through evaporation in
humidity of 50%, at a higher ambient vapor pres- the most preterm infants is twice as high at 20%
sure than the more mature infants need as at 60% ambient humidity. Other modes of heat
(Hammarlund et al. 1983, 1985). This means exchange are all influenced by the ambient
that the heat exchange between the very preterm humidity (Fig. 4). The sum of the different
infants and their environment could have been modes of heat exchange in the different GA
ever greater, if comparisons had been made at groups is almost the same, but the total heat
equal ambient vapor pressures instead of at equal loss cannot be calculated in this way, as the pro-
ambient humidities. portions of the body surface area exchanging
In studies on the effects of different ambient heat in different ways are not known.
humidities, it was found that infants born at a GA
of less than 28 weeks need a Tamb of around 40 C
to maintain a normal body temperature at an ambi- 22.6.5 Heat Exchange During the First
ent humidity of 20%, whereas full-term infants Weeks After Birth
need a Tamb of around 34 C at this ambient
humidity (Fig. 3). Nursing very preterm infants The high evaporative losses of heat from the
at a higher ambient humidity means that a lower infant’s skin that are seen in the most preterm
332 D. Trevisanuto and G. Sedin
Fig. 3 The relationship
20% 40% 60%
between gestational age and
the ambient temperature
needed to maintain a normal 42
body temperature at three ± SD
different humidities of
20 %, 40 %, and 60 %. 40
Measurements were made
Tamb (°C)
during the first 24 h after
birth in preterm infants and 38
during the first 30 h in term
infants (Hammarlund and
Sedin 1982) 36
34
25– 31– 37– 28– 34– 25– 31– 37–
27 33 39 30 36 27 33 39
Gestational age (weeks)
Fig. 4 Heat exchange 20 % 40% 60%
through evaporation in (4)
relation to gestational age at
relative ambient humidities 50
of 20 %, 40 %, and 60 %.
SD, standard deviation
(Hammarlund and Sedin
1982) 40 ± SD
Evaporative heat exchange (W/m2)
30
(0)
20
(6) (4)
10
(19)
–10
25– 31– 37– 28– 34– 25– 31– 37–
27 33 39 30 36 27 33 39
Gestational age (weeks)
22 Physical Environment for Newborns: The Thermal Environment 333
infants during the first days after birth will gradu- radiative heat exchange is the most important
ally decrease with increasing postnatal age mode of heat loss (Hammarlund et al. 1986).
(Hammarlund et al. 1986). Heat loss through radi- The total heat exchange between the infant’s
ation is low early after birth in the most preterm skin and the environment can be calculated if the
infants born at 25–27 weeks of gestation. Heat body surface area of the infant and the fractions of
loss from radiation will, however, be the most this area that participate in the different modes of
important mode of heat exchange after the first heat exchange are known (Hammarlund et al.
postnatal week. In infants born at a GA of 28 or 1985, 1986; Hey and Katz 1969). This is very
more weeks, the radiative heat exchange is the difficult with available methods, especially if esti-
most important mode of heat exchange from mations are to be made over a longer period of time
birth, and it gradually increases with age. The (Hammarlund et al. 1986). The total heat exchange
heat exchange through convection is low in is basically dependent on the metabolic rate.
infants nursed in incubators. Initially there is a
gain of heat through convection in the most pre-
term infants early after birth. 22.6.6 Heat Exchange Between
During the first weeks after birth, the relative Infant’s Skin and the
magnitude of the different modes of heat Environment During Care
exchange markedly depends on the ambient Under Radiant Heaters
humidity (Fig. 5). In infants born at
25–27 weeks of gestation and nursed in a dry Several authors have considered that a lower
environment, evaporative heat exchange will be vapor pressure in the ambient air (Bell et al.
the most important mode of heat exchange for 1980) and more convective air currents under
more than 10 days after birth. At an ambient the radiant heater (Baumgart 1982) cause an
humidity of 60%, this mode of exchange is the increase in evaporative water loss and heat
highest only during the first 5 days. Thereafter, the exchange. More recent determination of the
W/m2 RH = 20% RH = 40% RH = 60%
40
Heat exchange (W/m2)
30
20 HRad
10
HEvap
0
HConv
–10
0 3 6 9 0 3 6 9 0 3 6 9
Postnatal age (days)
Fig. 5 Heat exchange between the infant and the environment in relation to postnatal age at relative ambient humidities
(RH) of 20 %, 40 %, and 60 % in infants born at 25–27 weeks of gestation (Hammarlund et al. 1986)
334 D. Trevisanuto and G. Sedin
evaporation rate from the skin of term, moder- at a lower RH. The findings have an impact for
ately preterm, and very preterm infants nursed promoting skin barrier integrity in extremely
in incubators with 50% ambient humidity and preterm infants (Fig. 6; Agren et al. 2006).
under a radiant heater has shown that the evap- The individual decrease in TEWL50 was con-
oration rate from the skin surface of full-term sistently more pronounced in the RH50 than in
infants is significantly higher under a radiant the RH75 group. There were no differences in
heater than in an incubator (Kjartansson et al. body temperature, skin temperature, or ambient
1995). In moderately preterm infants born at temperatures (Tamb and Twall) between the two
30–34 weeks of gestation, the evaporation rate study groups. The total fluid intake and serum
from the skin is significantly higher at an envi- sodium levels during the period 0–14 days of
ronmental humidity of 30% than at 50%, and in PNA are presented in Fig. 6.
very preterm infants with GA of less than Table 1 further documents that there are no
30 weeks, the evaporation rate is higher under significant differences between the group of
a radiant heater than in an incubator at an envi- infants that were nursed at an RH of 75% and
ronmental humidity of 50%. A transparent heat those nursed at an RH of 50% (Table 1).
shield positioned over the infant can lower the
heat exchange (occurring through both convec-
tion and evaporation) between the infant and its 22.6.8 Heat Exchange Between
environment, decrease convective air currents, the Infant’s Skin
increase humidification (Baumgart 1982), and and the Environment During
diminish the water loss (Bell et al. 1980; Phototherapy
Fanaroff et al. 1972; Flenady and Woodgate
2003). It has been suggested that a bed platform Phototherapy has been reported to increase insen-
that can be used with a radiant heater or with a sible water loss in newborn infants (Baumgart
hood might make it easier to adapt to the mode 1982; Bell et al. 1980). This loss of water and
of care that such an infant needs (Greenspan heat might be caused by altered barrier properties
et al. 2001). in the skin or by increased respiratory water loss.
However, other studies have indicated that in
thermally stable term and preterm infants
22.6.7 Ambient Humidity Influence (Kjartansson et al. 1992b), there is no increase in
on the Rate of Skin Barrier the evaporation rate from the skin surface during
Maturation in Extremely phototherapy.
Preterm Infants
In infants born at 24–25 completed weeks of 22.6.9 Heat Exchange Between
gestation and nursed in incubators at 50% ambient the Infant’s Skin and the
humidity, water loss was higher than that previ- Environment During Care
ously found in infants born at 25–27 weeks of on a Heated Bed
gestation (Agren et al. 1998).
To investigate if the level of radiant heaters An infant on a heated bed gains heat through
(RH) in which the preterm infants are nursed conduction. Some losses of water and heat from
might influence their postnatal skin maturation, the airway will take place, depending on the vapor
TEWL was determined in twenty preterm pressure of the room air. Sarman and colleagues
infants (GA 23–27 weeks) nursed at postnatal showed that infants weighting 1,000 g could be
ages (PNA) of 0, 3, 7, 14, and 28 days (Agren kept warm when nursed on a heated water-filled
et al. 2006). The results indicate that the level mattress (Sarman et al. 1989). In a 2-week trial
of RH influences skin barrier development, with with infants whose birthweights were between
more rapid barrier formation in infants nursed 1,300 and 1,500 g, Gray and Flenady found that
22 Physical Environment for Newborns: The Thermal Environment 335
Fig. 6 Daily total fluid a 180
intake (a) and serum
sodium levels (b) at
postnatal ages (PNA) of 160
0–14 days in infants nursed
mL/kg birthweight
at RH75 or RH50 from PMA 140
7 days (indicated by dotted
lines). There are no
120
statistically significant RH75
differences between study
RH50
groups (Agren et al. 1998) 100
80
60
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Postnatal age (days)
b 145
RH75
140
RH50
mmol/L
135
130
125
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Postnatal age (days)
Table 1 Effect of activity levels on insensible water loss 22.6.10 Heat Exchange Between
and oxygen consumption the Infant’s Skin and
Activity level IWLS IWLR IWLT VO2 the Environment During Skin-
0 6 6 12 8 to-Skin Care
1 8 9
2 9 10 After the introduction of skin-to-skin care for
3 10 11 newborn infants (Whitelaw et al. 1988), Bauer
4 12 12 and colleagues showed that preterm infants less
5 7 16 23 13 than 1 week of age and with a birthweight of less
Insensible water loss from the skin (IVLs) and from the than 1,500 g were not exposed to cold stress
respiratory tract (IWLR) and their sum (IWT) in g/kg/24 h, during 60-min skin-to-skin care in stable preterm
and oxygen consumption (VO2; L/kg/24 h), in full-term
appropriate for gestational age infants at different levels of infants (Bauer et al. 1997). Similarly, preterm
activity (From Riesenfeld et al. (1987b)) infants born at 28–30 weeks of gestation and
studied during the first and second week after
weight gain was lower and body temperature birth increased their body temperature during 1 h
higher in those who were cot-nursed with of skin-to-skin contact with no significant change
warming than in those who were nursed in an in oxygen consumption (Bauer et al. 1998). More
incubator (Gray and Flenady 2003). immature infants, born at 25–27 weeks of
336 D. Trevisanuto and G. Sedin
gestation, showed no increase in oxygen con- loss depends on the humidity of the inspired air,
sumption but a decrease in rectal temperature with lower losses occurring at a high humidity (Hey
during the same duration of skin-to-skin contact and Katz 1969; Sosulski et al. 1983). The respira-
during the first week after birth. tory water loss (mg/kg min) can be determined
During the second postnatal week, the body using a flow-through system with a mass spectrom-
temperature did not change in infants born at eter for measurement of gas concentrations
25–27 weeks of gestation during skin-to-skin (Hammarlund et al. 1988; Sedin 1995, 2004;
care (Bauer et al. 1998). It has been suggested Riesenfeld et al. 1987a, b, 1988, 1994, 1995; Sjörs
that infants born at 25–27 weeks of gestation et al. 1992b). In an environment with an ambient
might have a very high evaporative heat loss humidity of 50%, the evaporative heat loss from the
during the first week after birth, causing cold airway will be moderate (Riesenfeld et al. 1987a), i.
stress (Hammarlund et al. 1986; Hammarlund e., in term AGA infants, the insensible water loss
and Sedin 1979). from the respiratory tract (IWLR) and that from the
skin (IWLs) will be of equal magnitude (Riesenfeld
et al. 1987a). The evaporative heat loss from the
22.6.11 Keeping the Very Preterm respiratory tract (Hevap-r) and the evaporative heat
Infant Warm Early After Birth: loss (Hevap-s) from the skin will also be of equal
The Effect of Thin Clothing magnitude under these conditions.
The evaporative loss of water and heat from the
Newborn infants are at risk of losing heat soon airways depends on the ambient humidity both in
after birth. It is therefore of great importance to lambs (Hammarlund et al. 1988) and infants
wipe off amniotic fluid from the skin surface, (Riesenfeld et al. 1987a), with lower losses at a
remove wet linen, and wrap the infant in high than at a low humidity. Whereas IWLs
pre-warmed blankets or, alternatively, place decreased from 9 to 2 g/Kg/24 h in term infants
the infant skin to skin on the mother’s chest to when the ambient humidity was increased from
use her body as a heat source (Whitelaw et al. 20% to 80%, the corresponding change in IWLR
1988). was much smaller, i.e., from 9 to 5 g/Kg/24 h
When an infant is placed in an environment (Riesenfeld et al. 1987a). In infant placed in a
where the temperature and humidity are low, the calorimeter, Solyok et al. (1973) found that the
evaporative heat and water exchange will be high, respiratory heat loss was between 0.07 and
and air movements in the environment may fur- 0.22 W/Kg or 3–10% of the total heat production
ther increase the loss of heat through evaporation, from metabolism and about 40% of the insensible
conduction, convection, and radiation. It is there- heat loss. In term infants, RWL and Hevap-r may
fore of outmost importance to keep the infant increase during activity by up to 140% of the
warm. In a laboratory setting, we present data on values at rest (Riesenfeld et al. 1987b).
the evaporation rate from a semipermeable mem- In Table 2, data are presented on IWLs and
brane positioned above a membrane IWLR. During moderate heat stress, both lambs
(Hammarlund et al. 1980; Hammarlund and and infants can increase their RWL and Hevap-r
Sedin 1979, 1982; Adamson et al. 1965). without increasing their oxygen consumption and
CO2 production (Riesenfeld et al. 1988, 1994).
Exposure to radiant heat can alter the respiratory
22.7 Water and Heat Exchange water loss in a lamb while leaving the oxygen
Between the Respiratory Tract consumption and CO2 production unchanged.
and Environment RWL is directly proportional to the rate of breath-
ing (Riesenfeld et al. 1988, 1990, 1994), which
Water and heat exchange from the respiratory tract means that lambs and infants will lose more water
takes place with each expiration. Using indirect and heat when they have a high rate of breathing
methods, it has been shown that respiratory water (Fig. 7). The oxygen consumption will increase if
22 Physical Environment for Newborns: The Thermal Environment 337
Table 2 Effect of phototherapy on respiratory value in neonates
n RWL (mg/kg/min) VO2 (mL/kg/min) VCO2 (mL/kg/min) RR (breath/min)
Before 11 4.4 0.7 5.9 0.9 4.0 0.7 48 7
12 min 11 4.4 0.6 5.9 1.0 3.9 0.6
24 min 10 4.1 0.8 5.5 1.1 3.8 0.7
36 min 9 4.2 1.0 5.4 1.0 3.6 0.6
48 min 11 4.4 0.7 5.9 1.1 3.9 0.7 51 11
60 min 9 4.6 0.9 5.9 1.1 4.1 0.8
After 9 4.8 0.8 6.1 0.9 4.1 0.4
Respiratory water loss (RWL), oxygen consumption (VO2), carbon dioxide production (VCO2; mean SD), and
respiratory rate (RR) in full-term infants before, during, and after 60 min of phototherapy (From Kjartansson et al. (1992a))
Fig. 7 Respiratory water 40
loss (RWL), body
temperature (Tbody), oxygen A B
consumption (VO2), and
CO2 production (VCO2) in
6-day-old lamb before (a) 30
°C
and during (b) heat stress
VO2 VCO2 (mL/kg min)
RWL (mg/kg min)
(Riesenfeld et al. 1988) 41
Tbody
40
20
39
•
38
•
10 RWL
Tbody
•
VO2
•
VCO 2
0
0 10 0 20 40 60
Time (min)
the heat stress induces bodily movements with rate of breathing from 46 to 125 breaths/min. In
higher levels of activity (Riesenfeld et al. 1987b). intubated lambs, both the oxygen consumption
and CO2 production increased significantly
(Hammarlund et al. 1985).
22.7.1 Respiratory Water
and Evaporative Heat Exchange
Before and After Intubation 22.7.2 Respiratory Water
and Evaporative Heat Loss
In non-intubated lambs, exposed to a radiant heat in Relation to GA
source, RWL increased from 10.5 to 33.4 mg/kg/
min, while the respiratory rate increased from 54 to RWL was found to be highest in the most preterm
161 breaths/min, and the oxygen consumption and infants and lower in more mature infants; they
CO2 production were unaltered (Hammarlund were usually asleep during the measurements
et al. 1985). During exposure to the same heat (Riesenfeld et al. 1995). Studies were performed
source, intubated lambs increased their respiratory in incubators with 50% ambient relative humidity
water loss from 8.1 to 18.7 mg/kg/min and their and an ambient temperature that allowed the
338 D. Trevisanuto and G. Sedin
infant to maintain a normal and stable body tem- of the balance between heat production and net
perature. RWL per breath (mg/kg) was almost the heat loss, a normal body temperature should be
same at all gestational ages, and the higher RWL not confused with “normal” metabolic rate
values found in the most preterm infants as com- (Adamson et al. 1965).
pared to the more mature ones were thus due to the A cold-stressed infant depends primarily on
higher rate of breathing (Agren et al. 1998). mechanisms that cause chemical thermogenesis.
When an infant is stimulated by cold, norepineph-
rine is released (Stern et al. 1965), inducing lipol-
22.7.3 Respiratory Water ysis in brown fat stores principally found in the
and Evaporative Heat Exchange interscapular, paraspinal, and perirenal areas.
During Phototherapy Because of the protein thermogenin, brown fat
can decouple oxidative phosphorylation and
When term and preterm infants were exposed to break down fats to produce heat, without the inhib-
phototherapy in the absence of heat stress, there itory feedback loop of adenosine triphosphate
were no significant changes in RWL, oxygen con- (ATP) production. Triglycerides in the fat are bro-
sumption, CO2 production, or rate of breathing ken down to fatty acids and glycerol. The fatty
(Kjartansson et al. 1992a; Table 2). acids enter thermogenic metabolic paths that end
in the common pool of metabolic acid. Brown fat is
turned on in response to skin thermoreceptors prior
22.7.4 Respiratory Water and Heat to a decrease in core temperature, and shivering is
Exchange During Mechanical initiated by a decrease in core temperature.
Ventilation Glycolysis may also be stimulated during
stress when epinephrine released from the adre-
In clinical neonatal care with warm and humid nals activates glycogen stores, which may result in
environment or with warm and humidified gas transient hyperglycemia (Pribylova and
supplied from a respirator, heat exchange through Znamenacek 1966). Lowered blood sugars in
evaporation and convection between the respira- cold-stressed infants also have been reported
tory tract and the environment is low (Cornblath and Schwrtz 1966), possibly caused
(Hammarlund et al. 1988; Sulyok et al. 1973; by inhibition of glycolysis, by lipolysis, or by
Riesenfeld et al. 1987a). Infants who inspire cold exhaustion of glycogen stores.
air with low water vapor pressure will have high
evaporative loss from the respiratory tract and will
also lose heat through convection. These losses 22.8 Clinical Management
may become clinically significant, for example,
during transport in a cold climate (Sedin 1996a). 22.8.1 Introduction
The concept of an optimum thermal environ-
ment for newborn infants evolved during the In very low-birth-weight infants, hypothermia
1960s (Adamson et al. 1965). This idealized set- (temperature <36 C) at NICU admission is sig-
ting, called the neutral thermal environment, is nificantly associated with adverse neonatal out-
characterized as the range of an environmental comes such as mortality, intracranial hemorrhage,
temperature within which the metabolic rate is at necrotizing enterocolitis, and late-onset sepsis
minimum and within which temperature regula- (Miller et al. 2011; Laptook et al. 2007).
tion is achieved by non-evaporative physical pro- A recent observational study assessed the asso-
cesses alone. There is no reason to believe that ciation between admission temperature and neo-
normal temperature of infants is different from natal outcomes and estimated the admission
that of adults. An infant’s internal temperature temperature associated with lowest rates of
within the range of 36.5–37.5 C (with a diurnal adverse outcomes in 9,833 preterm infants born
variation of 0.5 C) is probably normal. Because at fewer than 33 weeks’ gestation (Lyu et al.
22 Physical Environment for Newborns: The Thermal Environment 339
2015). The results show that the lowest rates of Similarly, the World Health Organization
adverse outcomes were associated with admission (WHO) also advocates maintaining the temper-
temperatures between 36.5 C and 37.2 C. Fur- ature in the delivery room at 25 C (WHO
thermore, the study showed that the relationship Library Cataloguing-in-Publication Data.
between admission temperature and adverse neo- World Health Organization 2003). This goal,
natal outcomes was U-shaped. These data suggest however, is rarely achieved in clinical practice.
that hypothermia and hyperthermia at NICU A recent study including 39 Vermont Oxford
admission negatively influence neonatal Network centers showed that 86% of the
outcomes. 801 infants with gestational age between
Therefore, all efforts should be focused on 24 and 27 weeks received their initial resusci-
preventing hypothermia and hyperthermia during tation in a room with a temperature <25 C
the first minutes of life. (Reilly et al. 2015).
Previous observational studies with historical
controls showed increasing the environmental
22.8.2 Thermal Delivery Room temperature in the operating theater improved
Management admission temperature (Kent and Williams 2008;
Knobel et al. 2005). In a randomized controlled
The physiological mechanisms involved in the trial, admission rectal temperatures of newborns
maintenance of temperature are convection, radi- <32 weeks’ gestation delivered in rooms with
ation, conduction, and evaporation (http://www. temperature set at 24–26 C were compared with
slideshare.net/drdilipbharodiya/nursing-care-of- those of similar newborns delivered in rooms with
elbw-and-lbw-babies-41344677) (Fig. 8). temperature set at 20–23 C. Premature newborns
Of these, evaporation plays the most important delivered in rooms with mean temperature
role in extremely preterm infants. 25.1 0.6 C (n. 43), compared with those deliv-
In relation to the pathophysiological mecha- ered in rooms with mean temperature
nisms, clinicians have to consider four major 22.5 0.6 C (n. 48), had a lower incidence
interventions for preventing heat losses in preterm (34.9% vs. 68.8%, p < 0.01) of admission rectal
infants (Fig. 9). temperature <36 C and higher admission rectal
temperatures (36.0 0.9 C vs. 35.5 0.8 C,
22.8.2.1 Delivery Room Temperature p < 0.01) (Jia et al. 2013).
Increasing the delivery room temperature for an
anticipated preterm delivery is recommended by 22.8.2.2 Infant Warmer
the American Heart Association and European Newborn infants, in particular those needing
Guidelines for Neonatal Resuscitation (Wyckoff resuscitation maneuvers at birth, must be readily
et al. 2015; Wyllie et al. 2015). positioned under a radiant infant warmer (RIW)
Fig. 8 Mechanisms of heat
loss (http://www.slideshare.
net/drdilipbharodiya/ Convection
nursing-care-of-elbw-and- Evaporation
lbw-babies-41344677)
Radiation
Conduction
340 D. Trevisanuto and G. Sedin
Fig. 9 Interventions to prevent heat loss in preterm infants
turned on, but further details, such as temperature studies show that the use of the exothermic mat-
of exposure and/or level of RIW power to set up, tresses in preterm infants managed in a plastic
are not specified (Wyckoff et al. 2015; Wyllie bag/wrap under a radiant warmer from delivery
et al. 2015). In a bench study, Trevisanuto et al. room to NICU improves temperature at NICU
assessed the exposure temperature generated by admission (Chawla et al. 2011; Ibrahim and
three different RIWs (Trevisanuto et al. 2011). Yoxall 2010; McCarthy and O’Donnell 2011;
One of them did not reach the target temperature Singh et al. 2010). In a RCT, McCarthy et al.
(37 C) in all studied settings; in contrast, the randomized infants <31 weeks to treatment with
other two were always above this target when set or without an exothermic mattress before birth
in full-power manual mode. This study shows that (McCarthy et al. 2013). All infants were placed
patient’s exposure temperature under RIW (turned in a polyethylene bag and under radiant heat
on preselected power outputs) significantly varies immediately after birth and brought to NICU in
among commercially available devices, a transport incubator. Infants randomly assigned
suggesting that neonates can be easily put in con- to exothermic mattress were placed on a mattress
ditions of hypo- or hyperthermia. immediately after delivery and remained on it
until admission. Fewer infants in exothermic mat-
22.8.2.3 Exothermic Mattress tress group had temperatures within the target
The use of exothermic mattresses is mentioned as range (41% vs. 77%, p = 0.002) and more had
a thermoregulatory strategy for preterm infants in temperatures >37.5 C (46% vs. 17%,
2010 ILCOR guidelines (Kattwinkel et al. 2010). p = 0.009). The data safety monitoring commit-
Gel-filled mattresses used in published studies tee recommended stopping the study for efficacy
reach 38–42 C in 1–3 min; the price is about after analyzing data from half the planned sample.
€35 [$46.50] each. Results from observational This study shows that placing polyethylene-
22 Physical Environment for Newborns: The Thermal Environment 341
wrapped very preterm infants on exothermic mat- protruding from the bag, minimizes heat loss
tresses in the delivery room results in more infants from the trunk, but not heat losses from the
with abnormal temperature and more hyperther- head. The brain of the newborn infant has high
mia on admission to the NICU. As hyperthermia oxygen consumption and generates a significant
could be harmful, a word of caution on the use of amount of the total heat produced. The surface
the exothermic mattress is needed. area of the head represents 20.8% of the total
body surface area (Klein and Scammon 1930).
22.8.2.4 Plastic Bag/Wrap Therefore, if the head were to be insulated by
In very preterm infants, a diminished capacity for provision of a cap, heat loss should be reduced.
metabolic heat production coupled with a high Doglioni et al. evaluated whether a polyethylene
surface area-to-volume ratio and an immature epi- total body wrapping (covering both the body and
dermal barrier leads to extraordinarily high evap- head) was more effective than conventional treat-
orative heat losses. In view of this, the use of ment (covering up to the shoulders) in reducing
polyethylene bags to reduce evaporative heat perinatal thermal losses in very preterm infants
loss while permitting radiant warming has been (Doglioni et al. 2014). They found that axillary
evaluated by several studies (Knobel et al. 2005; temperature on NICU admission was similar in
Cordaro et al. 2012; Vohra et al. 1999, 2004). Two the two groups (36.5 0.6 C total body vs. 36.4
systematic reviews concluded that infants 0.8 C controls; P = 0.53), but the rate of
wrapped immediately after birth had significantly moderate hypothermia (temperature <36 C)
greater admission temperatures compared with was slightly lower in the total body group (12%)
non-wrapped infants and that wrapping signifi- than in the control group (20%).
cantly reduced the incidence of hypothermia Only a few studies have examined the effect of
(McCall et al. 2010; Cramer et al. 2005). A recent head insulation on neonatal heat loss after deliv-
RCT assessed whether the application of occlu- ery (Chaput de Saintonge et al. 1979; Rowe et al.
sive wrap applied immediately after birth reduced 1983; Stothers 1981; Lang et al. 2004). These
mortality in very preterm infants (Reilly et al. studies, conducted in healthy full-term infants,
2015). Eight hundred one infants were enrolled. show that neonatal heat loss following delivery
Wrap infants had statistically significant greater may be reduced or prevented by the application of
baseline temperatures (36.3 C wrap vs. 35.7 C simple woolen hats.
no wrap, p < 0.0001) and post-stabilization tem-
peratures (36.6 C vs. 36.2 C, p < 0.001) than 22.8.2.6 Humidified and Heated Gas
non-wrap infants. However, there were no signif- The use of humidified and heated gas is the stan-
icant differences in mortality rate (OR 1.0, 95% CI dard of care for preterm infants who need respira-
0.7–1.5) between the two groups. tory support in the NICU, but international
resuscitation guidelines do not stipulate the use
22.8.2.5 Cap/Hat of this therapy during stabilization at birth
Despite the relative success of wrapping infants (Kattwinkel et al. 2010).
in food or hospital standard polythene bags, some One observational study with two historical
infants still develop hypothermia. In the Heat cohorts (Pas et al. 2010) and one RCT (Meyer
Loss Prevention study of infants <28 weeks’ et al. 2015) from the same group assessed the
gestational age, the infants wrapped in polythene impact of the use of the heated gases in preterm
bags had a mean SD rectal admission temper- infants <32 weeks’ gestation needing respiratory
ature of 36.5 0.8 C (Vohra et al. 2004). In this support (CPAP or intubation) at birth. The results
study, the polyethylene occlusive skin wrap cov- show that the use of humidified and heated gases
ered the body up to the shoulders, but the infants’ from birth added to the other measures to prevent
head was dried and left uncovered. The method hypothermia (i.e., use of a radiant heater in deliv-
consisting of putting the infant inside a polyeth- ery room, suitable ambient temperature, body
ylene or polyurethane bag, with the head wrap, and head covering) may be of benefit for
342 D. Trevisanuto and G. Sedin
preterm infants <32 weeks and particularly for the back, prone on the mother’s bare chest. A
those <28 weeks. recent Cochrane review assessed the effects of
early SSC on breastfeeding, physiological adap-
22.8.2.7 Combination of Interventions tation, and behavior in healthy mother-newborn
More than a single intervention, the sum of inter- dyads (Moore et al. 2012). For the outcome
ventions is the “secret” to prevent delivery room “infant thermoregulation,” only three studies
thermal losses in preterm infants. In addition, a were reported including a total of 168 dyads
quality improvement intervention involving all (mother and neonate). Two studies showed a pos-
the staff seems to be fruitful to reach this goal. itive effect of SSC on temperature control during
For example, the introduction of checklists for the first 90 postnatal minutes (RR 0.40, 95% CI
preparation of material and the opportunity to 0.19–0.61, and RR 0.50, 95% CI 0.17–0.83
give continuous feedbacks to the team were respectively), whereas in one study temperatures
other important organizational aspects (Wyckoff were on average slightly higher for the control
et al. 2015; Wyllie et al. 2015). group at this time point (RR 0.10, 95% 0.24
A recent meta-analysis including four Ameri- to 0.04). A further study, conducted in a
can studies shows that this strategy is effective to low-resource setting, assessed the impact of
reduce hypothermia at NICU admission in pre- early SSC provided for the first 24 h on incidence
term infants (Trevisanuto D, De Almeida MF, of hypothermia in stable newborns weighing
unpublished data) (Fig. 10). 1,800 g or more during the first 48 h of life
2015 international guidelines for neonatal (Nimbalkar et al. 2014). In the intervention
resuscitation recommend that the application of group, mothers followed the SSC procedure. In
all these measures associated with checklists and the control group, after providing routine care
frequent feedbacks on the team are able to opti- under radiant warmer, newborns were kept
mize the thermal management of preterm infants clothed (including head cap) and covered with
(Wyckoff et al. 2015; Wyllie et al. 2015). Follow- blanket with their mother (bedding in) for the
ing this practice, the frequency of hypothermia in first 48 h. The results showed that mean tempera-
extremely low-birth-weight infants at NICU ture in the SSC group was higher compared with
admission significantly declined over time at our the control group at all stages of reading during
institution (Rech Morassutti F et al. 2015; the first 48 h of life.
Fig. 11). Temperature of newborns in SSC groups
progressively increased after birth, whereas in
22.8.2.8 Skin-to-Skin Contact the control group, there was reduction in tem-
Early skin-to-skin contact (SSC) begins ideally at perature at 1 h of birth and never matched with
birth and involves placing the naked baby, head the SSC group for the first 48 h. This study also
covered with a dry cap and a warm blanket across showed that early SSC for the first 24 h can
Intervention Control Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H,Fixed, 95%CI M-H,Fixed, 95%CI
DeMauro SB, 2013 1 80 11 80 1.5% 0.08 [0.01, 0.63]
Lee HC, 2014 328 4132 633 4179 80.6% 0.48 [0.42, 0.56]
Pinheiro JMB, 2o14 20 440 56 164 10.8% 0.09 [0.05, 0.16]
Russo A, 2014 12 193 36 66 7.0% 0.06 [0.03, 0.12]
Total (95% Cl) 4845 4489 100.0% 0.40 [0.35, 0.46]
Total events 361 736
Heterogeneity:Chi2 = 62.53, df = 3 (P < 0.00001); I2 = 95%
0.01 0.1 1 10 100
Test for overall effect: Z = 13.38 (P < 0.00001)
Favours [Intervention] Favours [Control]
Fig. 10 Effect of an approach based on the combination preterm infants (Trevisanuto D, De Almeida MF,
of interventions associated with the use of checklists and unpublished data)
feedback on reducing hypothermia at NICU admission in
22 Physical Environment for Newborns: The Thermal Environment 343
100%
90%
80%
70%
60%
Percentages
≥ 36.5 °C
50% 36-36.4 °C
< 36 °C
40%
30%
20%
10%
0%
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
(n=74) (n=58) (n=60) (n=75) (n=71) (n=71) (n=87) (n=63) (n=61) (n=61) (n=63)
Fig. 11 Distribution of temperature at NICU admission over time at the Department of Women’s and Children’s Health,
Azienda Ospedaliera di Padova, University of Padua (Rech Morassutti F et al. 2015)
Fig. 12 Mean temperature during the first 48 postnatal hours in SSC and control group (Nimbalkar et al. 2014)
reduce the risk of hypothermia at 48 h of life independent predictor of neonatal morbidity and
(Fig. 12). mortality. Effective interventions to prevent heat
The results of these studies suggest that early losses at birth, especially in very preterm infants,
SSC is effective, and it should be promoted to comprise increase of environmental temperature,
prevent hypothermia in term and late-preterm use of infant warmers, exothermic mattress,
newborns, especially in low-resource settings. woolen caps, plastic wraps, and humidified and
In conclusion, hypothermia at NICU admis- heated gas. Skin-to-skin contact has been consid-
sion is a worldwide problem and is an ered, especially in low-resource settings.
344 D. Trevisanuto and G. Sedin
References newborn infants. Cochrane Database Syst Rev
2, CD000435
Adamson SK Jr, Gandy GM, James LS (1965) The influ- Gray PH, Flenady V (2003) Cot-nursing versus incubator
ence of thermal factors on oxygen consumption of care in preterm infants. Cochrane Database Syst Rev
newborn human infants. J Pediatr 66:495–508 1, CD003062
Agren J, Sjors G, Sedin G (1998) Transepidermal water Greenspan JS, Cullen AB, Touch SM et al (2001) Thermal
loss in infants born at 24 and 25 weeks of gestation. stability and transition studies with a hybrid warming
Acta Paediatr 87:1185–1190 device for neonates. J Perinatol 21:167–173
Agren J, Sjors G, Sedin G (2006) Ambient humidity influ- Hammarlund K, Sedin G (1979) Transepidermal water loss
ences the rate of skin barrier maturation in extremely in newborn infants. III. Relation to gestational age.
preterm infants. J Pediatr 148:613–617 Acta Paediatr Scand 68:795–801
Bauer K, Uhrig C, Sperling P et al (1997) Body tempera- Hammarlund K, Sedin G (1982) Transepidermal water loss
ture and oxygen consumption during skin-to-skin (kan- in newborn infants. VI. Heat exchange with the envi-
garoo) care in stable preterm infants weighting less than ronment in relation to gestational age. Acta Paediatr
1500 grams. J Pediatr 130:240–244 Scand 71:191–196
Bauer K, Pyper A, Sperling P et al (1998) Effects of Hammarlund K, Nilsson GE, Oberg PA et al (1980)
gestational and postnatal age on body temperature, Transepidermal water loss in newborn infants.
oxygen consumption, and activity during early skin- V. Evaporation from the skin and heat exchange dur-
to-skin contact between preterm infants of 25–30 ing the first Hours of life. Acta Paediatr Scand
week gestation and their mothers. Pediatr Res 69:385–392
44:247–251 Hammarlund K, Sedin G, Stromberg B (1983) Trans-
Baumgart S (1982) Radiant energy and insensible water epidermal water loss in newborn infants. VIII. Relation
loss in the premature newborn infant nursed under a to gestational age and post-natal age in appropriate and
radiant warmer. Clin Perinatol 9:483–503 small for gestational age infants. Acta Paediatr Scand
Bell EF, Weinstein MR, Oh W (1980) Heat balance in 72:721–728
premature infants: comparative effects of convectively Hammarlund K, Norsted T, Riesenfeld T et al (1985)
heated incubator and radiant warmer, with and without Endotracheal intubation influences respiratory water
plastic heat shield. J Pediatr 96:460–465 loss during heat stress in young lambs. J Appl Physiol
Bruck (1978) Heat production and temperature regulation. 79:801–804
In: Stave U, Weech A (eds) Perinatal physiology. Ple- Hammarlund K, Sromberg B, Sedin G (1986) Heat loss
num Medical Book Company, New York from the skin of preterm and fullterm newborn infants
Chaput de Saintonge DM, Cross KW, Hathorn MKS et al during the first weeks after birth. Biol Neonat 50:1–10
(1979) Hats for the newborn infant. BMJ 2:570–571 Hammarlund K, Reisenfield T, Sedin G (1988) Measure-
Chawla S, Amaram A, Gopal SP et al (2011) Safety and ments of respiratory water loss in newborn lambs. Acta
efficacy of Trans-warmer mattress for preterm neonates: Physiol Scand 127:61–65
results of a randomized controlled trial. J Perinatol Hey EN (1969) The relation between environmental tem-
31:780–784 perature and oxygen consumption in newborn baby.
Cordaro T, Gibbons Phalen A et al (2012) Hypothermia J Physiol 200:589–603
and occlusive skin wrap in the low birthweight prema- Hey EN, Katz G (1969) Evaporative water loss in newborn
ture infant: an evidentiary review. Newborn Infant Nurs baby. J Physiol 200:605–619
Rev 12:78–85 Houdas Y, Ring EFJ (1982) Human body temperature. Its
Cornblath M, Schwrtz R (1966) Disorders of carbohy- measurement and regulation. Plenum Press, New York
drate metabolism in infancy. WB Saunders, Ibrahim CPH, Yoxall CW (2010) Use of self-heating gel
Philadelphia mattresses eliminates admission hypothermia in infants
Cramer K, Wiebe N, Hartling L et al (2005) Heat loss born below 28 weeks gestation. Eur J Pediatr
prevention: a systematic review of occlusive skin 169:795–799
wrap for premature neonates. J Perinatol 25:763–769 Jia YS, Lin ZL, Lv H et al (2013) Effect of delivery room
Dahm LS, James LS (1972) Newborn temperature and temperature on the admission temperature of premature
calculated heat loss in delivery room. Pediatrics infants: a randomized controlled trial. J Perinatol
49:504–513 33:264–267
Doglioni N, Cavallin F, Mardegan V et al (2014) Total Kattwinkel J, Perlman JM, Aziz K et al (2010) Part 15:
body polyethylene wraps for preventing hypothermia neonatal resuscitation: 2010 American Heart Associa-
in preterm infants: a randomized trial. J Pediatr tion Guidelines for Cardiopulmonary Resuscitation and
165:261–266.e1 Emergency Cardiovascular Care. Circulation 122:
Fanaroff AA, Wald M, Gruber HS et al (1972) Insensible S909–S919
water low in low birth weight infants. Pediatrics Kent AL, Williams J (2008) Increasing ambient operating
50:236–245 theatre temperature and wrapping in polyethylene
Flenady VJ, Woodgate PG (2003) Radiant warmers ver- improves admission temperature in premature infants.
sus incubators for regulating body temperature in J Paediatr Child Health 44:325–331
22 Physical Environment for Newborns: The Thermal Environment 345
Kjartansson S, Hammarlund K, Riesenfeld T et al (1992a) incidence of hypothermia in neonates more than 1800
Respiratory water loss and oxygen consumption in g: randomized control trial. J Perinatol 34:364–368
newborn infants during phototherapy. Acta Paediatr Okken A, Blijham C, Franz W et al (1982) Effects of forced
81:769–773 convection of heated air on insensible water loss and
Kjartansson S, Hammarlund K, Sedin G (1992b) Insen- heat loss in preterm infants in incubators. J Pediatr
sible water loss from the skin during phototherapy 101:108–112
in term and preterm infants. Acta Paediatr Pribylova H, Znamenacek K (1966) The effect of body
81:764–768 temperature on the level of carbohydrate metabolites
Kjartansson S, Arsan S, Hammarlund K et al (1995) Water and oxygen consumption in the newborn. Pediatrics
loss from the skin of term and preterm infants nursed 37:743–749
under a radiant heater. Pediatr Res 37:233–238 Rech Morassutti F, Cavallin F, Zaramella P (2015) Asso-
Klein AD, Scammon RE (1930) The regional growth of the ciation of rewarming rate on neonatal outcomes in
surface area of the human body in prenatal life. Proc extremely low birth weight infants with hypothermia.
Soc Exp Med Biol 27:463–466 J Pediatr 167:557–561.e1-2
Knobel RB, Wimmer JE Jr, Holbert D (2005) Heat loss Reilly MC, Vohra S, Rac VE et al (2015) Randomized trial
prevention for preterm infants in the delivery room. of occlusive wrap for heat loss prevention in preterm
J Perinatol 25:304–308 infants. J Pediatr 166:262–268.e2
Lang N, Bromiker R, Arad I (2004) The effect of wool Riesenfeld T, Hammarlund K, Sedin G (1987a) Respira-
vs. cotton head covering and length of stay with the tory water loss in fullterm infants on their first day after
mother following delivery on infant temperature. Int J birth. Acta Paediatr Scand 76:647–653
Nurs Stud 41:843–846 Riesenfeld T, Hammarlund K, Sedin G (1987b) Respira-
Laptook AR, Salhab W, Bhaskar B et al (2007) Neonatal tory water loss in relation to activity in fullterm infants
Research Network. Admission temperature of low birth an their first day after birth. Acta Paediatr Scand
weight infants: predictors and associated morbidities. 76:889–893
Pediatrics 119:e643–e649 Riesenfeld T, Hammarlund K, Sedin G (1988) Influence of
Lyu Y, Shah PS, Ye XY et al (2015) Association between radiant heat stress on respiratory water loss in newborn
admission temperature and mortality and major mor- lambs. Biol Neonate 53:290–294
bidity in preterm infants born at fewer than 33 weeks’ Riesenfeld T, Hammarlund K, Sedin G (1990) The effect of
gestation. JAMA Pediatr 169, e150277 a warm environment on respiratory water loss in
Marks KH, Gunther RC, Rossi JA et al (1980) Oxygen fullterm newborn infants on their first day after birth.
consumption and insensible water loss in premature Acta Paediatr Scand 79:893–898
infants under radiant heaters. Pediatrics 66:228–232 Riesenfeld T, Hammarlund K, Norsted T et al (1994) The
McCall EM, Alderdice F, Halliday HL et al (2010) Inter- temperature of inspired air influences respiratory water
ventions to prevent hypothermia at birth in preterm loss in young lambs. Biol Neonate 65:326–330
and/or low birthweight infants. Cochrane Database Riesenfeld T, Hammarlund K, Sedin G (1995) Respiratory
Syst Rev 17(3), CD004210 water loss in relation to gestational age in infants on
McCarthy LK, O’Donnell CP (2011) Warming preterm their first day after birth. Acta Paediatr 84:1056–1059
infants in the delivery room: polyethylene bags, exo- Rowe MI, Weinberg G, Andrews W (1983) Reduction of
thermic mattresses or both? Acta Paediatr neonatal heat loss by an insulated head cover. J Pediatr
100:1534–1537 Surg 18:909–913
McCarthy LK, Molloy EJ, Twomey AR et al (2013) A Sarman I, Can G, Tunell R (1989) Rewarming preterm
randomized trial of exothermic mattresses for preterm infant on a heated, water filled mattress. Arch Dis
newborns in polyethylene bags. Pediatrics 132: Child 64:687–692
e135–e141 Sedin G (1995) Physics of neonatal heat transfer, routes of
Meyer MP, Hou D, Ishrar NN et al (2015) Initial respiratory heat loss and heat gain. In: Okken A, Kock J (eds)
support with cold, dry gas versus heated humidified gas Thermoregulation of sick and low birth weight neo-
and admission temperature of preterm infants. J Pediatr nates. Springer, Berlin, p 21
166:245–250 Sedin G (1996a) Fluid management in the extremely pre-
Miller SS, Lee HC, Gould JB et al (2011) Hypothermia in term infant. In: Hansen TN, McIntosh N (eds) Current
very low birth weight infants: distribution, risk factors topics in neonatology. WB Saunders Company,
and outcomes. J Perinatol 31(Suppl 1):S49–S56 London, pp 50–66
Moore ER, Anderson GC, Bergman N et al (2012) Early Sedin G (1996b) Heat loss from the respiratory tract of
skin-to-skin contact for mothers and their healthy new- newborn infants ventilated during transport. In: The
born infants. Cochrane Database Syst Rev 16(5), proceeding of the XV European Congress on Perinatal
CD003519 Medicine. Glasgow, p 511
Nilsson GE (1977) Measurement of water exchange Sedin G (2004) Physics and physiology of human neona-
through skin. Med Biol Eng Comput 15:209–218 tal incubator. In: Polin R, Fox W (eds) Fetal and
Nimbalkar SM, Patel VK, Patel DV et al (2014) Effect of neonatal physiology. Saunders Company, Philadel-
early skin-to-skin contact following normal delivery on phia, p 570
346 D. Trevisanuto and G. Sedin
Singh A, Duckett J, Newton T et al (2010) M. Improving te Pas AB, Lopriore E, Dito I et al (2010) Humidified and
neonatal unit admission temperatures in preterm heated air during stabilization at birth improves tem-
babies: exothermic mattresses, polythene bags or a perature in preterm infants. Pediatrics 125:
traditional approach? J Perinatol 30:45–49 e1427–e1432
Sjörs G, Hammarlund K, Sedin G (1992a) Thermal balance Trevisanuto D, Coretti I, Doglioni N et al (2011) Effective
in term and preterm newborn infants nursed in an temperature under radiant infant warmer: does the
incubator equipped with a radiant heat source. Pediatr device make a difference? Resuscitation 82:720–723
Res 32:631 Vohra S, Frent G, Campbell V et al (1999) Effect of poly-
Sjörs G, Hammarlund K, Oberg PA et al (1992b) An ethylene occlusive skin wrapping on heat loss in very
evaluation of environment and climate control in low birth weight infants at delivery: a randomized trial.
seven infant incubators. Biomed Instrum Technol J Pediatr 134:547–551
26:294–301 Vohra S, Roberts RS, Zhang B et al (2004) Heat loss
Sjors G, Hammarlund K, Kjartasson S et al (1994) Respi- prevention (HeLP) in the delivery room: a random-
ratory water loss and oxygen consumption in fullterm ized controlled trial of polyethylene occlusive skin
infants exposed to cold air on the first day after birth. wrapping in very preterm infants. J Pediatr 145:
Acta Paediatr 83:802–807 750–753
Sjörs G, Hammarlund K, Sedin G (1997) Thermal balance Wheldon AE (1982) Energy balance in the newborn baby:
in term and preterm infants nursed in an incubator with use of a manikin to estimate radiant and convective heat
a radiant heat source. Acta Paediatr 86:403–409 loss. Phys Med Biol 27:285–296
Sosulski R, Polin R, Baumgart S (1983) Respiratory water Whitelaw A, Heisterkamp G, Steatlh K et al (1988) Skin to
loss and heat balance in intubated infants receiving skin contact for very low birth weight infants and their
humidified air. J Pediatr 103:307–310 mothers. Arch Dis Child 63:1377–1381
Stern L, Lees MH, Leduc J (1965) Environmental temper- WHO Library Cataloguing-in-Publication Data. World
ature on the level of carbohydrate and catecholamine Health Organization (2003) Managing newborn prob-
excretion in newborn infants. Pediatrics 36:367–373 lems: a guide for doctors, nurses, and midwives. World
Stothers JK (1981) Head insulation and heat loss in the Health Organization pp. F30–F31
newborn. Arch Dis Child 56:530–534 Wyckoff MH, Aziz K, Escobedo MB et al (2015) Part 13:
Stromberg B, Oberg PA, Sedin G (1983) Transepidermal neonatal resuscitation: 2015 American Heart Associa-
water loss in newborn infants. X Effects of central cold- tion guidelines update for cardiopulmonary resuscita-
stimulation on evaporation rate and skin blood flow. tion and emergency cardiovascular care. Circulation
Acta Paediatr Scand 71:735–739 132:S543–S560
Sulyok E, Jequier E, Prod’hom LS (1973) Respiratory Wyllie J, Bruinenberg J, Roehr CC et al (2015) European
contribution to the thermal balance of the newborn resuscitation council guidelines for resuscitation 2015:
infant under various ambient conditions. Pediatrics section 7. Resuscitation and support of transition of
51:641–650 babies at birth. Resuscitation 95:249–263
Neonatology and the Law
23
Vittorio Fineschi, Francesca Maglietta, and Emanuela Turillazzi
Contents
23.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
23.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
23.3 Neonatal Resuscitation Practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
23.3.1 Presuppositions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
23.3.2 Some Critical Assumptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
23.3.3 The Crux of the Matter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
23.4 Cerebral Palsy and Perinatal Hypoxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
23.4.1 Presuppositions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
23.4.2 The Timing of Perinatal Hypoxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
23.5 Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
23.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
Abstract extensive debate about some issues reflects
Neonatology is one of the areas of medicine both the technical and scientific progresses
that in recent years has received much atten- that have been made in the neonatological
tion. This interest primarily concerns the con- field. On the other hand, tightly argued issues
stant progress in this field and the inherent such as medical malpractice litigation have
ethical and medico legal problems. The reached crisis proportions in the neo-
natological and pediatric field. Moreover, pedi-
atric claims are very expensive because the
V. Fineschi (*) damages cover the life of the child and the
Department of Anatomical, Histological, Forensic juries tend to be very sympathetic toward chil-
Medicine and Orthopaedic Sciences, “Sapienza” dren and their families. Care at the limits of
University of Rome, Rome, Italy viability and cerebral palsy are some of the
e-mail: vittorio.fi[email protected]
more contentious areas of legal medicine on
F. Maglietta · E. Turillazzi the neonatological field. Since recognizing
Department of Legal Medicine, University of Foggia,
Foggia, Italy “red flags” can lessen chances of malpractice
e-mail: [email protected]; claims against neonatologists, this chapter
[email protected]
# Springer International Publishing AG, part of Springer Nature 2018 347
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_173
348 V. Fineschi et al.
focuses on some issues which have a high issues reflects both the technical and scientific
vulnerability to claims of medical negligence progresses that have been made in the neo-
and on high-risk situations. The principles are natological field. On the other hand, tightly argued
primarily the same for any doctor working in issues such as medical malpractice litigation have
any country under any clinical circumstances; reached crisis proportions in the neonatological
of course, subtle differences in the law can and pediatric field. In general, children are more
appertain to an individual case depending on vulnerable when treated in any healthcare envi-
where it arose and the jurisdiction that applies. ronment, but especially in the acute care setting,
thus neonatologic and pediatric care carry unique
factors that increase the risk of litigation (Greve
23.1 Salient Points 2011). Malpractice suits in neonatology most
commonly arise from delivery room care, poor
• Malpractice suits in neonatology mostly arise neurologic outcome (cerebral palsy/hypoxic-
from delivery room care, poor neurologic out- ischemic encephalopathy), line complications
come, infusion line complications, and delay in (thrombus and vascular accidents related to cen-
diagnosis/treatment. tral lines), and delay in diagnosis/treatment – aci-
• Medical decisions regarding care at the limits dosis, hypotension, antibiotics, developmental
of viability (between 22 and 25 weeks) should dysplasia of the hip, and congenital heart disease.
be based on the individual circumstances of Pediatric claims are very expensive because the
each newborn rather than on inflexible guide- damages cover the life of the child and the juries
lines, especially if these are based only on tend to be very sympathetic toward children and
gestational age. their families (Donn 2005). Very few data are
• Neurologic damage in newborns frequently available on neonatal malpractice claims. Italian
leads to allegations of peripartum mis- data reported that among over 190 claims, the
management; thus, new markers providing majority regards events in delivery room and
more accurate information about the timing of nursery (almost 40% each) while a lower percent-
perinatal hypoxia would be of paramount age in NICU (about 20%) and a minimum number
importance to medical and legal professionals. of cases in the transport system (almost 1%)
• The most prevalent cause of malpractice suits (Fanos et al. 2012). The NICHD workshop on
against pediatricians involves errors in diagno- patient safety in 2011 pointed out some specific
sis; for this reason, many physicians have issues of patient safety in neonatology. In partic-
resorted to defensive medicine, ordering ular, the substantial sources of errors were:
unnecessary additional tests or diagnostic
procedures. (a) Medication and total parenteral nutrition
• Malpractice claims are often caused by inade- (b) Resuscitation and respiratory care
quate informed consent.Good communication, (c) Invasive procedures
using layman’s terms and avoiding medical (d) Nosocomial infections
jargon, is critical in reducing malpractice (e) Patient identification
lawsuits. (f) Diagnostics
Factors that could increase the injury risk are
23.2 Introduction likely to be related to size, prematurity, vulnera-
bility, and underlying disease conditions of new-
Neonatology is one of the areas of medicine that born patients, but also to multidisciplinary teams
in recent years has received much attention. This involved in the care of sick newborn infants,
interest primarily concerns the constant progress working conditions providing fatigue, a large
in this field and the inherent ethical and medico variety of treatment, and investigative modalities
legal problems. The extensive debate about some needed in the care of high-risk newborn infants
23 Neonatology and the Law 349
(e.g., ventilator, central catheter, medications, viability. At the same time there has been an
bed-side tests) (Raju et al. 2011). In developed increasingly insistent request for juridical regula-
countries, the insurance costs due to malpractice tion of neonatal resuscitation practices as well as
claims in conjunction with childbirth are steadily for clarification of the role of parents in decisions
increasing, and today, they amount to 25% of all regarding this kind of assistance.
health insurance costs, primarily due to lifelong The practice approach to the resuscitation of
compensation for severe disabilities caused by extremely low birth weight (ELBW) infants varies
asphyxia (Berglund and Norman 2012). greatly between the countries and, in the same
Neonatologists’ concerns about a potential com- country, between different centers, reflecting a
plaint, inquiry, or lawsuit influence their practice of paucity of evidence and consequent uncertainty
medicine in potentially positive ways such as devel- among clinicians. Different and increasing possi-
oping audit procedures, maintaining better commu- bilities to intervene in ELBW infants’ care neces-
nication with parents and families, ensuring timely sarily require special attention, reflecting both the
documentation of procedures, and communication of need to ensure that the mother and the newborn
complications, but also negatively such as increased are offered adequate assistance and spare them
prescribing of drugs, referrals, and diagnostic testing, useless, painful, and ineffective therapies.
and avoiding treatment of certain conditions. The central issue regards the “of uncertain
Since recognizing “red flags” can lessen vitality” infants born between 22 and 25 weeks
chances of malpractice claims against neonatolo- of gestational age whose treatment at birth is one
gists (Donn et al. 2003), this chapter focuses on of the most challenging concerns for neonatolo-
some issues which have a high vulnerability to gists (Pignotti and Donzelli 2008). Advances in
claims of medical negligence and on high-risk medical technology enable doctors to save the
situations. The principles are primarily the same lives of newborn infants who would have previ-
for any doctor working in any country under any ously died. Some of these infants have a low
clinical circumstances; of course, subtle differ- chance of survival with treatment or may survive
ences in the law can appertain to an individual with significant morbidity and shortened life
case depending on where it arose and the jurisdic- expectancy. Even with full resuscitation efforts,
tion that applies (Cowan 2005). two of three newborns delivered at 23 weeks of
gestation die, and approximately 90% of survi-
vors have moderate to serious disability.
23.3 Neonatal Resuscitation When we are confronting with extremely low
Practices gestational age 22 weeks’ gestational age
(154–160 days’ intrauterine life), a quite general
23.3.1 Presuppositions agreement seems to exist that decisions regarding
the treatment of the mother must be based on her
In recent decades, a lively debate has developed health conditions, cesarean section must be
concerning the decision to interrupt or not to performed only when indicated by the mother’s
initiate resuscitation procedures on low gesta- clinical conditions, and the newborn should be
tional age newborns (Chiswick 2008; Pinter provided with comfort therapies. On the other
2008; Sklansky 2001). In many countries, all hand, with the growth of gestational age if the
over the world the flourishing of rulings by multi- newborn shows capacity to survive, the new-
disciplinary study groups is evidence of the born’s vitality must be carefully assessed at birth
importance of this debate, with neonatologists, and resuscitation must be performed. On the basis
pediatricians, obstetricians, and bioethicists work- of favorable objective clinical criteria (presence of
ing together in the attempt to support decisions attempts at respiration, valid cardiac frequency,
regarding whether to resuscitate “at risk” new- recovery of skin color) which suggest proceeding
borns or not (Brunkhorst et al. 2014; Arora et al. with extraordinary therapies, intensive treatment
2016; Liu et al. 2016) mostly at the gray zone of of the newborn can become more advisable. It is
350 V. Fineschi et al.
widely believed that when gestational age is at difficult in defining the proper management for
25 weeks, cesarean section may be performed newborns in this gray zone (Haward et al. 2011;
for fetal reasons; newborns must be resuscitated Nadroo 2011; April and Parker 2007; Savulescu
and subjected to intensive, extraordinary thera- and Kahane 2009).
pies, except those cases presenting severely Furthermore, no other area of medicine has
compromised clinical conditions suggesting the been as focused upon such policies or as specific
impossibility of survival. in delineating treatment limitations. Instead, in
In this scenario and after years of discussion other areas, guidelines are broad and general,
across this troubled terrain, some crucial issues with much room for individual clinical judgment
are intensely debate and still remain to be solved. and professional discretion. What some authors
find, in fact, is that policies for newborns appear
very different from those for other patient
23.3.2 Some Critical Assumptions populations (Janvier et al. 2007). In fact, even in
critical situations burdened by high mortality or
First is the assumption that gestational age could be morbidity (e.g., adult patients with cardiac arrest
taken as a reference parameter for medical deci- after trauma; cardiac arrest in children following
sions. In fact, there is a fair margin of error in the severe trauma; adult patients with a primary hem-
estimation of gestational age, so that in dubious orrhagic stroke), the low percentages of survival
cases, clinical evaluation of the newborn is of fun- or even the prevision of long term significant and
damental importance. Neonatologists should take disabling sequelae certainly do not lead to absten-
into account particularly the newborn’s conditions tion from the resuscitation procedures laid down
at birth, obstetric history, and response to resusci- in rigorous protocols or guidelines (Savulescu and
tation procedures. A subtle decisional distinction Kahane 2009; Janvier et al. 2007; Janvier et al.
exists in that gray zone in which even a temporal 2008).
oscillation of a few days may lead to abstention Finally, a point of fundamental importance is
from neonatal resuscitation procedures or, con- the centrality of parents in the decision-making
versely, the initiation of resuscitation therapies. process regarding the therapies administered to
On the other hand, neonatal prognosis is condi- their premature newborns. It being understood
tioned by many independent predictive factors that resuscitation treatment requires immediate
(birth weight, use of steroids before birth, multi- decisions and prompt and timely actions, the par-
plicity of pregnancy) (Patel 2016). ents should be provided with understandable and
In general, the literature has established as the exhaustive information about the newborns’ con-
limit of viability the interval between 22 and ditions and their life expectancy, offering them
25 weeks of gestational age. Below this limit it understanding and all possible psychological sup-
is considered that the degree of developmental port. In the event of a conflict between the parents’
immaturity is a limiting factor to life and the requests and the physician’s decision, a shared
benefit of treatment is not challenged (Seri and solution should be sought, taking into consider-
Evans 2008; Blackmon 2003). However, the chro- ation the safeguard of the fetus and newborn’s life
nological criterion of gestational age alone might and health.
lead to a dangerous simplification in evaluating
decisional paths, giving an excessive value to one
single parameter. It is well known that the prog- 23.3.3 The Crux of the Matter
nosis for very preterm children varies with the
place of birth (level III perinatal center or not), Not only guidelines differ but also international,
the attitude of both obstetricians and pediatricians national, and local variations in actual practice do
toward care and hence the interventions they use, exist and recent data suggest there may be a gap
gestational age, postnatal age, and then later between policy recommendations calling for
comorbidities (Patel 2016). Thus, there is a great shared decision making and actual clinical
23 Neonatology and the Law 351
practice in resuscitation decision for periviable Advances in science and technology have allo-
births (Tucker Edmonds et al. 2016). wed researchers to gain a better understanding of
The crux of the matter is whether strict guide- the pathophysiology leading to long-term neuro-
lines, reference standards based on the gestational logic damage in newborns. Intrapartum events are
age parameter, and authority rules are necessary. We now known to be an infrequent cause of adverse
personally believe that the right answer to this ques- neurologic outcome. New insights into the origins
tion is “no”. In a decisional sphere burdened by such of cerebral palsy have recently transformed the old
limited prognostic certainties, an individual concept that most cases of cerebral palsy begin in
approach is infinitely more acceptable than a statis- labor. Many factors can damage the “developing”
tical approach: any decision ought to be based upon fetal brain including prepartum, intrapartum and
the individual circumstances of each newborn rather postpartum ischemia/hypoxemia, developmental
than on reference to guidelines, especially if these abnormalities, genetic factors, metabolic disease,
are based on gestational age (Turillazzi and Fineschi infections, autoimmune and coagulation disor-
2009). Physicians do not need rigid rules based on ders, and maternal and fetal drug use (MacLennan
inflexible gestational age and birthweight guidelines 1999). Clinical signs of brain damage are often
but guidance to address the difficult and trying considered to result from intrapartum asphyxia
issues associated with infants born at the margins and a marker of perinatal obstetric and/or neo-
of viability with a realistic assessment of the infant’s natologic mismanagement leading to medico-
clinical condition (Fanaroff 2008). We firmly think legal problems. Contrary to previous beliefs and
that as the principles regarding treatment of low or assumptions, clinical epidemiological studies
very low gestational age newborn should be the indicate that in most cases the events leading to
same of those followed for other patients, there is cerebral palsy occur in the fetus before the onset of
no need for specific policy statement. Generally, the labor, or in the newborn after delivery. Actually it
purposes of guidelines have to improve knowledge is suggested that 70–80% of cases of CP are due to
regarding neonatal outcomes, to provide consis- prenatal factors and that birth asphyxia plays a
tency in periviability counseling, and relatively minor role. Intrapartum asphyxia is
to promote informed, supportive, responsible believed to account for around 10% of CP in
choices. Flexible guidelines are well accepted term and near-term infants (Graham et al. 2008).
and can be used by all neonatologists, obstetri- Notwithstanding many advances in research into
cians, and nurses who provide care to pregnant the causation of cerebral palsy, defining a causal
women and infants at extremely early gestational relation between acute intrapartum events and
ages, but resuscitation decisions for extremely cerebral palsy still remains very difficult.
preterm infants should be approached in the Since the event of a brain damaged newborn
same way as for other patients. They should be frequently led to allegations of peripartum mis-
individualized with objective and the most accu- management, understanding the time of onset of
rate individual prognostication, taking into the brain lesion is of paramount importance to
account all the relevant clinical characteristics. medical and legal professionals. In Courts, in
fact, much of the debate focuses on whether or
not there is evidence of acute intrapartum hypoxia
23.4 Cerebral Palsy and Perinatal and if so, whether the care provided was timely
Hypoxia and adequate (Greenwood et al. 2003; Freeman
2008).
23.4.1 Presuppositions
Despite the recognition that cerebral palsy (CP) is 23.4.2 The Timing of Perinatal Hypoxia
rarely related to medical malpractice, there are
many instances where clinicians face litigation The timing of perinatal hypoxia is complex and
when a child is diagnosed with cerebral palsy. incompletely understood. It is traditionally based
352 V. Fineschi et al.
on clinical, laboratory and instrumental criteria (PVL, lesions of the basal ganglia, cerebral edema,
which are nonspecific markers of a difficult birth ischemic infarcts). Cranial CT may depict ischemic
(Paneth 2001; Blair and Stanley 1997). These or hemorrhagic lesions, generalized or focal
nonspecific intrapartum markers provide poor edema, and diffuse cerebral atrophy with ex
information on the timing and duration of an vacuo ventricular dilatation due to severe hypox-
asphyxiating insult (Nielsen et al. 2008). Autopsy, emic insult. On CT, PVL can be well visualized
placental and cord examination, laboratory tests, appearing as a region of decreased attenuation,
and genetic studies may explain both the cause of occasionally intermixed with areas of increased
death and the time of onset of the neuropathology. attenuation due to secondary hemorrhage. How-
Brain histological examination can provide useful ever, MRI is the imaging modality of choice in
information on the timing of an hypoxic-ischemic the assessment of cerebral hypoxic lesion.
lesion; the patterns of perinatal brain injury In cases of neonatal death, it is essential that the
depend on the etiology and the stage of develop- contribution of autoptic examination is
ment of the fetal nervous system, since the vul- complemented by toxicological, microbiological,
nerabilities of gray and white matter differ and genetic investigations (Squier and Cowan
depending on postconceptional age and on neuro- 2004). The histological study of the brain with
anatomic site (Folkerth 2007; Squier 2002). New traditional histochemical techniques can provide
insights into the mechanisms involved in neonatal relevant data since it is well known that depending
hypoxic-ischemic brain injury have recently on mechanism, severity, and timing of the insult,
transformed the old concept that most cases are the distribution and the histological pattern of
the results of an acute hypoxia during labor and lesions in the brain changes dramatically. The
delivery. international scientific panorama is actually rich
Since October 1999, the International Cerebral of studies aiming to the research of histological,
Palsy Task Force published a consensus statement histochemical, and immunohistochemical
for defining a causal relationship between acute markers which can provide more and more accu-
intrapartum events and cerebral palsy in the aim to rate information about the time of onset of hyp-
attempt “to define an objective template of evi- oxic-ischemic brain damage. However, data
dence to better identify cases of cerebral palsy reported by literature appear fragmentary and con-
where the neuropathology began or became tradictory, often concerning experimental studies
established around labour and birth.” Three performed only on animals. Moreover, it should
“essential criteria,” which should be met before be underlined that most reports concern experi-
attributing cerebral palsy to an intrapartum hyp- mental studies which have used markers with late
oxic event and a number of “criteria that together expression (>24 h) which, therefore, are scarcely
suggest an intrapartum timing, but are non- spe- reliable in cases of perinatal hypoxic-ischemic
cific” were established (Greenwood et al. 2003). brain damage due to intrapartum asphyxia (Squier
Laboratory studies, that is, acid-base distur- 2002). These neurobiological insights into the
bance assessed by means of umbilical-artery pH mechanisms of the cellular responses implicated
measurement, serum concentration of brain-spe- in perinatal brain damages, and the characteriza-
cific creatine kinase isoenzyme BB (CK-BB), tion of the various mechanisms involved might
other serum factors (blood lactate, hypoxanthine, open new horizons for understanding the time of
aspartate-aminotransferase, erythropoietin beta- onset of a brain hypoxic-ischemic lesion and for
endorphin), factors measured in the CSF (lactate, effective therapeutic strategies (Kadhim et al.
neuron-specific enolase, lactate dehydrogenase, 2005). By means of immunohistochemical tech-
hydroxybutyrate dehydrogenase, fibrinogen degra- niques applied in studies both on animals and
dation products, ascorbic acid) may have an utility humans, it has been possible to identify in the
in defining the timing of an hypoxic event. Imaging brain tissue some markers of hypoxic-ischemic
studies such as head ultrasonography may be very damage with reliable and reproducible results.
useful for the detection of typical injuries’ patterns The immunohistochemical picture obtained
23 Neonatology and the Law 353
using a panel of selected antibodies (chaperonins certain treatment that are to be explained? Which
HSPs, ORP-150, COX2) can help to identify a predictable sequelae are to be concealed to the
rather precise chronology of expression of the newborn’s parents?
different markers of hypoxic-ischemic brain The purpose of information and communica-
damage in newborns, which is correlated to the tion is to enable parents to make informed choices
duration of the same insult and is to be ascribed, about health care of their newborns. However, in
essentially, to a different stimulation of the dif- this perspective one crucial matter is the fact that
ferent cellular types and also to a different we must distinguish the rights of the newborn and
response by the same cells to the ischemic insult. the capacity to make autonomous choices. A great
Some immunohistochemical markers seem to be caution is necessary when we are dealing with this
more reliable than others in the evaluation of the issue; our attention must be focused on what is to
timing of the neonatal hypoxic-ischemic damage be done with the newborn or the infant who have
(Riezzo et al. 2010). The results of histologic and never had the capacity to make autonomous
immunohistochemical investigation would sug- choices. Moreover, the dimension of informed
gest a message to the clinicians to extend the consent has become more difficult to manage not
differential diagnosis of a too large neonatal hyp- only because technologies, widening the sphere of
oxic-ischemic insult chronological category to intervention and the possibilities of diagnosis and
delineate a more accurate judgment (Kadhim cure, have paradoxically sharpened the question
et al. 2005). but also because this question is more frequently
transferred in judicial suits.
When we are dealing with the issue of
23.5 Informed Consent informed consent in the neonatological and pedi-
atric field, there are some unique challenges that
Inadequate informed consent represents a very differ somewhat from adult medicine.
frequent basis alleged for medical malpractice One of the crucial questions which has major
also in the neonatological field where some issues ethical importance is that of parents’ role in the
are absolutely unique since consent is not decision-making process. Many elements related
obtained from the patient but from the family to the newborn’s parents, that is, to the recipient of
and, often, during a very emotionally stressful the informative message are to be taken in account
period. In the neonatological scenario, inadequate by the physician: their real desire of knowledge;
communication (between the obstetrician and their desire to participate to the therapeutic
pediatrician/neonatologist, the nurse and physi- choices; their psychological condition; their level
cian, or the healthcare team and the family) often of knowledge. The risk is that information became
led to malpractice claims (Donn 2005). only a moment of learned, specialistic, and
In the relation between physician and patient’s iperspecialistic disquisitions to which parents
parents and families, the problem of language and remain completely stranger; a special burden is
of the quality and the amount of the information placed on the neonatologist to ensure that the
becomes central: on one side there is the news, newborn or infant’s parents comprehended the
like mere description of a situation, and on the explanation and information given.
other side there is the information, as relationship Since malpractice claims are filed by parents
with the person who receives the news. The two whose newborns are died or have suffered poor
dimensions are not equivalent: to provide news outcomes, the value of the informed consent pro-
and to provide information are not the same thing. cess in reducing malpractice losses may be
In this regard, a fundamental issue is that of truth undermined by the tendency to approach
and of the amount of information which is to be informed consent as a means to “protect” the
provided to the newborns’ family. How and how physician rather than to communicate with the
much is to be told about the newborn’s disease, parents and to share clinical decisions, often very
outcome, and prognosis? Which are the risks of a challenging, with them.
354 V. Fineschi et al.
Open communication with parents and fami- Facilitating parents’ informed consent is substantial,
lies should represent the gold standard of the but it could be not straightforward.
physician- parents’ patients relationship in which The complexity of what can be revealed with
the physician and the parents, each with his/her genetic testing and the parents’ right to obtain a
background of competences and specificities, complete information before agreeing to genomic
technical and scientific to those of the physician, testing are key issues in the approach to genomic
human, of pain, perception, and quality of life to newborn testing (Cohen et al. 2013).
those of the parents, cooperate to the achievement Genetic testing may reveal very troubling
of the aim health of the newborn. Parents are information, including potential, secondary inci-
active participant in a dialogue that is important dental findings, so that clinicians and parents have
to the shared decision-making process; the physi- to be prepared for the implications of the results
cian has the burden to ensure that comprehension (Lucassen 2012). As well as medical geneticists
is achieved and that the parents themselves are and genetic counselors, neonatologists may help
acting in the best interests of the child. families understand testing options and potential
Finally, the focus is on genomics testing in the implications and can address the wide range of
neonatological context. Genomic testing could be associated medical, psychosocial, and ethical
used at multiple different time points, for example, issues that may arise before and after results are
preconception, preimplantation, antenatally or post- known. Given the background of uncertainty and
natally, and will play a role in neonatal treatment future implications surrounding genomic testing
decisions. Neonatal intensive care units are espe- in newborn, it is important for parents and families
cially suitable for early adoption of genetic testing understanding the real meaning and scope of such
because many of the 3528 monogenic diseases of a test. It is essential that parents have appropriate
known cause are present during the first 28 days of expectations and limitations of genetic testing for
life (Online Mendelian Inheritance in Man 2012). their newborn; neonatologists may play a substan-
Genomic testing may be used for diagnosis and tial role in the decision-making process to enable
prognostically for critically ill infants. Aims of parents to understand the testing being offered and
genetic testing may be summarized in: treatment make informed choices (Frati et al. 2017).
modification to identify potential treatments;
anticipation or information, providing parents
with advance knowledge of potential future prob- 23.6 Conclusion
lems as well as the risk of recurrence in future
offspring; treatment limitation, either because it is During the last years, a host of issues have
relevant to the best interests of the infant, to emerged from the explosive growth of neo-
parental preferences for treatment or to resource natological science. In fact, neonatology is one
allocation (Wilkinson et al. 2016). of the areas of medicine that, in recent years, has
Deep ethical challenges arise from these different received much attention, both in the scientific
use of genomic testing in neonatal care (Goldenberg literature and in the ethical and juridical debate.
and Sharp 2012; Stark et al. 2013). Traditional This interest primarily concerns the constant pro-
targeted diagnostic testing (such as those used for gress in resuscitation of extremely preterm new-
infants with a suspected not be diagnosed by con- borns and the inherent ethical problems which is a
ventional biochemical screening) is obviously the still debated question. Prior to the new technolo-
least problematic from an ethical point of view. gies, we accepted the death of extremely preterm
When targeted prognostic testing is proposed, the newborns as a natural and inevitable event. The
balance between potential benefits and burdens of new technologies may represent wonderful means
the test is substantial. Is prognostic information to save life of viable newborns; however, the
potentially actionable? Is the information unhelpful? problem emerges when it becomes evident that
Do the best interest of newborn (and future adoles- the strategies deployed could achieve desirable
cent) coincide or conflict with that of parents? outcomes. Is it appropriate to continue therapies
23 Neonatology and the Law 355
on an extremely preterm newborn when their only Cowan PJ (2005) Litigation. Semin Fetal Neonatal Med
effect is to preserve life or to postpone death, 10:11–21
Donn SM (2005) Medical liability, risk management, and
irrespective of any question on the quality of life the quality of health care. Semin Fetal Neonatal Med
of that newborn? Are the rights and whishes of the 10:3–9
parents to be considered when it is evident that the Donn SM, Chiswick ML, Whittell P, Anderson S (2003)
continuance of therapies is medically futile? Are Medico-legal implications of hypoxic ischemic brain
injury. In: Donn SM, Sinha SK, Chiswick ML (eds)
guidelines and law regulations appropriate places Birth asphyxia and the brain: basic science and clinical
for these determinations? Or, on the contrary, implications. Futura Publishing, Armonk, pp 379–401
should these be made at the bedside by physicians Fanaroff AA (2008) Extremely low birthweight infants –
and parents together? the interplay between outcomes and ethics. Acta
Paediatr 97:144–145
Furthermore, we stressed on the fact that a real- Fanos V, Tagliabue P, Greco L, Agostiniani R, Carbone
ity of the current practice of medicine is that phy- MT, D’Agostino P, Correra A (2012) Neonatal mal-
sicians will likely be faced with a malpractice claim practice claims in Italy: how big is the problem
at some point in their career. Neonatologists and and which are the causes? J Matern Fetal Neonatal
Med 25(5):493–497
pediatrics are not immune from this reality. Issues Folkerth RD (2007) The neuropathology of acquired pre-
involved in documentation and communication are and perinatal brain injuries. Semin Diagn Pathol
substantial also in neonatologists’ practice. Conse- 24:48–57
quently, neonatologists are encouraged to explore Frati P, Fineschi V, Di Sanzo M, La Russa R, Scopetti M,
Severi FM, Turillazzi E (2017) Preimplantation and
parents’ lived experiences and expectations and prenatal diagnosis, wrongful birth and wrongful life: a
engage in trusting empowering relationships. global view of bioethical and legal controversies. Hum
Finally, it calls on neonatologists to the need for Reprod Update 23(3):338–357
thorough and accurate documentation in practice. Freeman RK (2008) Medical and legal implications for
necessary requirements to diagnose damaging hyp-
oxic-ischemic encephalopathy leading to later cerebral
palsy. Am J Obstet Gynecol 199:585–586
Goldenberg AJ, Sharp RR (2012) The ethical hazards and
References programmatic challenges of genomic newborn screening.
JAMA 1:307(5). https://doi.org/10.1001/jama.2012.68
April C, Parker M (2007) End of life decision-making in Graham EM, Ruis KA, Hartman AL et al (2008) A sys-
neonatal care. J Med Ethics 33:126–127 tematic review of the role of intrapartum hypoxia –
Arora C, Savulescu J, Maslen H, Selgelid M, Wilkinson D ischemia in the causation of neonatal encephalopathy.
(2016) The intensive care lifeboat: a survey of lay Am J Obstet Gynecol 199:587–595
attitudes to rationing dilemmas in neonatal intensive Greenwood C, Newman S, Impey L et al (2003) Cerebral
care. BMC Med Ethics 17(1):69 palsy and clinical negligence litigation: a cohort study.
Berglund S, Norman M (2012) Neonatal resuscitation BJOG 110:6–11
assessment: documentation and early paging must be Greve P (2011) Pediatrics: a unique and volatile risk.
improved! Arch Dis Child Fetal Neonatal Ed 97(3): J Healthc Risk Manag 31(2):19–29
F204–F208 Haward MF, Kirshenbaum NW, Campbell DE (2011) Care
Blackmon LR (2003) Biologic limits of viability: implica- at the edge of viability: medical and ethical issues. Clin
tions for clinical decision-making. NeoReviews 4: Perinatol 38:471–492
e140–e146 Janvier A, Bauer KL, Lantos JD (2007) Are newborns
Blair E, Stanley FJ (1997) Issues in the classification and morally different from older children? Theor Med
epidemiology of cerebral palsy. Ment Retard Dev Bioeth 28:413–425
Disabil Res Rev 3:184–193 Janvier A, Leblanc I, Barrington KJ (2008) The best-inter-
Brunkhorst J, Weiner J, Lantos J (2014) Infants of border- est standard is not applied for neonatal resuscitation
line viability: the ethics of delivery room care. Semin decisions. Pediatrics 121:963–969
Fetal Neonatal Med 19(5):290–295 Kadhim H, Evrard P, Kahn A et al (2005) Insights into
Chiswick M (2008) Infants of borderline viability: ethical etiopathogenic mechanisms involved in perinatal cere-
and clinical considerations. Semin Fetal Neonatal Med bral injury: implications for neuroprotection. In: Fong
13:8–15 HD (ed) Focus on cerebral palsy research. Nova
Cohen J, Hoon A, Wilms Floet AM (2013) Providing Science Publishers, Hauppauge, pp 1–26
family guidance in rapidly shifting sand: informed Liu J, Chen XX, Wang XL (2016) Ethical issues in neona-
consent for genetic testing. Dev Med Child Neurol tal intensive care units. J Matern Fetal Neonatal Med
55(8):766–768 29(14):2322–2326
356 V. Fineschi et al.
Lucassen A (2012) Ethical implications of new genetic HSPs, ORP-150 and COX2 are reliable markers to
technologies. Dev Med Child Neurol 54:196 classify acute, perinatal events. Diagn Pathol 5:49.
MacLennan A (1999) A template for defining a causal doi:10.1186/1746-1596-5-49
relation between acute intrapartum events and cerebral Savulescu J, Kahane G (2009) The moral obligation to
palsy: international consensus statement. BMJ create children with the best chance of the best life.
319:1054–1059 Bioethics 23:274–290
Nadroo AM (2011) Ethical dilemmas in decision making at Seri I, Evans J (2008) Limits of viability: definition of the
limits of neonatal viability. J IMA 43:188–192 gray zone. J Perinatol 28:S4–S8
Nielsen LF, Schendel D, Grove J et al (2008) Asphyxia- Sklansky M (2001) Neonatal euthanasia: moral consider-
related risk factors and their timing in spastic cerebral ations and criminal liability. J Med Ethics 27:5–11
palsy. BJOG 115:1518–1528 Squier W (2002) Pathology of fetal and neonatal brain
Online Mendelian Inheritance in Man. McKusick-Nathans damage: identifying the timing. In: Squier W (ed)
Institute of Genetic Medicine, Johns Hopkins Univer- Aquired damage to the developing brain, timing and
sity; Baltimore. Accessed 13 July 2012. Available at causation. Arnold, London, pp 110–127
www.omim.org/statistics Squier W, Cowan FM (2004) The value of autopsy in
Paneth N (2001) Cerebral palsy in term infants–birth or determining the cause of failure to respond to resusci-
before birth? J Pediatr 138:791–792 tation at birth. Semin Neonatol 9:331–345
Patel RM (2016) Short- and long-term outcomes Stark Z, Gillam L, Walker SP, McGillivray G (2013)
for extremely preterm infants. Am J Perinatol Ethical controversies in prenatal microarray. Curr
33(3):318–328 Opin Obstet Gynecol 25(2):133–137
Pignotti MS, Donzelli G (2008) Perinatal care at the thresh- Tucker Edmonds B, McKenzie F, Panoch JE, White DB,
old of viability: an international comparison of practical Barnato AE (2016) A pilot study of neonatologists’
guidelines for the treatment of extremely preterm decision-making roles in delivery room resuscitation
births. Pediatrics 121:e193–e198 counseling for periviable births. AJOB Empir Bioeth
Pinter AB (2008) End-of-life decision before and after 7(3):175–182
birth: changing ethical considerations. J Pediatr Surg Turillazzi E, Fineschi V (2009) How old are you? Newborn
43:430–436 gestational age discriminates neonatal resuscitation
Raju TNK, Suresh G, Higgins RD (2011) Patient safety in practices in the Italian debate. BMC Med Ethics
the context of neonatal intensive care: research and 12:10–19
educational opportunities. Pediatr Res 70(1):109–115 Wilkinson DJC, Barnett C, Savulescu J, Newson AJ (2016)
Riezzo I, Neri M, De Stefano F, Fulcheri E, Ventura F, Genomic intensive care: should we perform genome
Pomara C, Turillazzi E, Fineschi V (2010) The timing testing in critically ill newborns? Arch Dis Child Fetal
of perinatal hypoxia/ischemia events in term neonates: Neonatal Ed 101(2):F94–F98
Environment and Early
Developmental Care for Newborns 24
Dominique Haumont
Contents
24.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358
24.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358
24.3 The NICU Environment, the Early
Developmental Care, and the Neonatal Individualized
Developmental Care and Assessment
Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358
24.4 Couplet Care or Restoring the Mother-Infant
Dyad: The New Challenge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
24.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
Abstract preterm infant behavior, strategies to reduce
Preterm infants are exposed in the neonatal stress, and a NICU design adapted to provide
intensive care unit (NICU) to an environment this type of care.
of important and often chaotic neurosensory Among the different strategies of EDC,
stimulation. There is substantial scientific evi- restoring the mother-infant dyad (couplet care)
dence to support the negative effects of pain and the Neonatal Individualized Developmental
and stress, prolonged periods of intense light Care and Assessment Program (NIDCAP) are
and noise, sleep disturbances, and difficulties the most complex and holistic interventions.
of parenting. It is against this background that
early developmental care (EDC) has been
proposed. The important elements of early Abbreviations
developmental care are parental physical and AS Active sleep
emotional closeness, fine-tuning of care EDC Early developmental care
according to appropriate assessment of the KMC Kangaroo mother care
Nicu Neonatal intensive care unit
NIDCAP Neonatal individualized develop-
D. Haumont (*)
mental care and assessment
Department of Neonatology, Saint – Pierre University
Hospital, Brussels, Belgium program
e-mail: [email protected] OS Oxidative stress
# Springer International Publishing AG, part of Springer Nature 2018 357
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_174
358 D. Haumont
QS Quiet sleep to what they would experience in utero. At this
REM Rapid eye movement young age, brain growth and development are
VLBW Very low birth weight particularly critical and are in an extremely active
process. It is well known that very low gestational
age and birth weight, gender, perinatal infection
24.1 Salient Points and inflammation, intracranial hemorrhage,
periventricular white matter disease, postnatal
• EDC reduces pain and stress. use of steroids, nutritional imbalances, or unfa-
• EDC include restoring parents in their role as vorable socioeconomical situation impact brain
primary caregiver. development or later outcome. Which underlying
• NIDCAP is the most holistic teaching tool. mechanisms are responsible for these develop-
• Couplet care (mother-infant dyad) from birth mental difficulties is very complex and not totally
to discharge is the aim. understood. Interactions between genetic back-
• Architectural adaptations are recommended. ground, epigenetic effects, vulnerability to oxida-
tive stress, and other metabolic disturbances will
result in individual consequences for each baby.
24.2 Introduction The existing evidence of interaction between
environment and brain development has been
The spectacular development of neonatal intensive extensively reviewed and better practices encour-
care since the 1960s allowed a drop in neonatal aged (Liu et al. 2007; White et al. 2013). Outcome
mortality of very-low-birth-weight (VLBW) will further depend on the family environment of
infants from 50% to less than 15% in the last the infants. The importance of neurodevelop-
decades (Horbar et al. 2002). In Europe, there is mentally supportive care, the NICU environment,
an important variation among countries, regions, and parental closeness is the new challenge for
and even units which is not completely understood changing practices (Haumont 2014).
(Zeitlin et al. 2015). In the gray zone of
22–24 weeks of gestation, survival increased dra-
matically in the recent years, but interestingly the 24.3 The NICU Environment,
decision to resuscitate according to birth weight or the Early Developmental Care,
gestational age has not changed over the last and the Neonatal
20 years (Condie et al. 2012). Despite better care, Individualized Developmental
15–25% of the VLBW infants will present Care and Assessment Program
neurodevelopment impairment in the following
fields: motor function, vision, auditory function, Babies in the NICU are overwhelmed by sensory
cognition, behavior, attention deficit and hyperac- inputs. They perceive noise, vestibular, olfactory,
tivity disorders, visual-motor integration, and lan- visual stimuli, pain, thermal changes, and move-
guage (Marlow et al. 2007). Compared to their term ments. Social interactions with parents are not
pairs, there is substantial scientific evidence of natural. Moving away from the traditional way
altered early brain development. These differences of care in the NICU toward patient- and family-
are now well documented in brain magnetic reso- centered care and adapting the environment
nance imaging, including diffusion tensor imaging, accordingly are now sustained by scientific
resting state functional connectivity, and magnetic evidence.
resonance spectroscopy (Lubsen et al. 2011; Kwon Noise. Against noisy open wards, the focus has
et al. 2014). Some of these differences persist at evolved to very silent NICUs with single rooms.
later age (Constable et al. 2008). These have been shown to reduce infections and
Preterm infants spend weeks and sometimes favor parental presence and breastfeeding
months in the neonatal intensive care unit (Nicu) (Domanico et al. 2011). However, in a recent
which is a quite different environment compared study, adverse outcome was attributed to silence
24 Environment and Early Developmental Care for Newborns 359
of single rooms (Pineda et al. 2013). It might be of long-term exposure to narcotics on brain devel-
indeed inadequate to keep preterm infants too opment and not recognizing pain and stress symp-
much in silence. But what is appropriate auditory toms results in inappropriate pain relief in
stimulation? Another paper demonstrated that the newborns. Non-pharmacological interventions
exposure to parental talk was a significantly stron- like oral sucrose, nonnutritive sucking, swaddling,
ger predictor of infant vocalizations at 32 weeks and facilitated tucking have been proven efficient
and conversational turns at 32 and 36 weeks than against pain (Cignacco et al. 2007). In a study of
language from other adults (Caskey et al. 2014). infants born at <30 weeks gestation, the Neonatal
Single rooms should be seen as an incentive to Infant Stressor Scale scores were correlated with
favor parental presence which is the most impor- magnetic resonance imaging (brain metrics, diffu-
tant priority when implementing EDC. sion, and functional magnetic resonance imaging)
Light. The development of the visual system and neurobehavioral examinations at term equiva-
has been fairly extensively investigated (Haumont lent postmenstrual age. Exposure to stressors in the
and Hansen 2005). Neonatal Intensive Care Unit was associated with
During gestation, the synchronous ganglion regional alterations in brain structure and function.
cell waves are targeting the different neurons to The most stressed infants showed decreased parie-
allow appropriate transmission toward the visual tal and frontal cerebral width, altered diffusion
cortex. The protection of rapid eye movement measures, and functional connectivity in the tem-
(REM) sleep is in this regard essential for normal poral lobes and abnormalities in motor behavior on
development of ocular dominance columns neurobehavioral examination (Smith et al. 2011).
(Graven 2004; Penn and Shatz 2002). Some units will claim an aggressive pain man-
The preterm neonatal eye shows specific char- agement with very liberal use of medication for
acteristics. The pupillary light reflex appears only medical procedures. However, the first step in
after 30 weeks of gestation, and mydriasis is medical care is “do no harm,” and therefore,
physiological until 32 weeks. Light acts also as a each procedure should be questioned. It is very
stimulus for the production of free radicals in likely that many routine interventions are histori-
retinal membrane lipids. It has been suggested cal and suppressible. Positioning and handling
that the immature antioxidant status of the preterm these babies matters. Even routine care like a
infant might play a role on their susceptibility to diaper change induces significant variations in
retinal damage. Preterm infants should be cerebral hemodynamics (Limperopoulos
protected from direct bright light in the eyes. et al. 2008). Swaddling has been practiced for a
Input pathways entrained by light are relayed to long time and is associated with better sleep and
the SCN which will express output signals. These diminished pain and stress response (van Sleuwen
include temperature, cortisol, melatonin, sleep- et al. 2007). Babies with respiratory problems do
wake cycle, behavior, and cardiovascular func- often better in prone position (Bauer 2005). The
tion. In utero, the fetus has a biological clock strong neck extensor muscles have to be
responding to maternal entraining signals. If the counterbalanced to support later motor develop-
baby is born preterm, he will be deprived of this ment (Amiel – Tison 1995). Healthy preterm
circadian rhythm and submitted to an often cha- infants have been shown to benefit from position-
otic NICU environment. Preterm infants have ing in nests with flexed posture favoring more
ultradian rhythms (period lengths much less than elegant movements and reducing frozen postures
24 h), which parallels the maturation of sleep (Ferrari et al. 2007).
pattern (Rivkees and Hao 2000). There is some Protection of sleep. The term newborn has
clinical evidence that babies in cycled lighting sleeps around 70% of the time with about half of
grow and sleep better (Liu et al. 2007). the time in well recognizable active sleep (AS or
Pain and stress. It is well known that newborn REM sleep) and quiet sleep (QS) patterns. Before
infants in the NICU undergo many painful proce- 27 weeks, it is not possible to identify a sleep
dures (Carbajal et al. 2008). The fear of side effects pattern comprising AS and QS in the same cycle
360 D. Haumont
(Dreyfus – Brisac 1968). REM sleep is considered care procedures like intubation, chest drainage,
in the ontogeny theory as a very intense cerebral or intratracheal suctioning are well known to
activity playing an important role in brain matu- destabilize the baby. But even routine procedures
ration. The ultradian cycles of the preterm infant like chest X-ray, changing electrodes, physiother-
will progressively mature toward a circadian apy, excessive noise, weighing, or even diaper
model of sleep-wake cycles. Maturation of sleep change are accompanied by an acute decrease in
will be characterized by progressive change in the transcutaneous oxygen tension (Limperopoulos
proportion of REM sleep toward a predominance et al. 2008). EDC is also avoiding any hypoxic
of quiet sleep after term. The endogenous synaptic event or unnecessary care.
proliferation during REM sleep will prepare the Early developmental care (EDC) has emerged
brain for further refinement with exogenous against all potential harmful effects of the NICU
stimulation. environment with pain, stress, and neglected
There is growing evidence in animal and parental role. The term EDC is confusing because
human research that supports the importance of it ranges from very simple interventions like light
sleep during early brain development. Animal and noise control, positioning, or nonnutritive
studies on sleep deprivation showed structural sucking to the very complex Neonatal Individual-
and functional deterioration in several models. ized Developmental Care and Assessment Pro-
The need of endogenous synchronous waves gram (NIDCAP). The NIDCAP model is an
during REM sleep has been well established for early intervention program based on the observa-
the development of synaptogenesis in the visual tion of the preterm infant’s behavior (Als
system (Frank and Stryker 2003). Routine et al. 1994). The theory behind developed by Als
unnecessary care interrupting sleep should be is designated as “synactive theory.” The concept
avoided. derives from the interdependency, differentiation,
Kangaroo Mother Care (KMC). KMC was modulation, and regulation of five behavioral sub-
started in 1978 in Columbia to support low- systems: autonomic, motor, state organizational
birth-weight infants in a low-cost way (Charpak (maturation of well-defined sleep and wake
et al. 2005). The proven effectiveness and safety states), attentional/ interactional, and self-
have since enlarged this practice in countries with regulatory system. The assessment tool in
no limited resources. The benefits attributed to NIDCAP is a formal and repeated observation of
KMC are decreased morbidity, improved weight the infant behavior before, during, and after a care.
gain, breastfeeding, neurobehavioral assessment, These observations describe the reactions of the
and more mature sleep patterns. KMC is benefi- baby toward the sensory inputs and his capacity of
cial for the mother because it favors attachment self-regulation. The developmental goals for each
and diminishes stress. Although less research infant will be defined according to his own skills
about KMC in industrialized countries has been and weaknesses. Individual caregiving plans and
undertaken, it is now a recommended practice environmental adaptations will be recommended.
(Boundy et al. 2016). As the NIDCAP implementation evolves in the
Oxidative stress (OS). OS is one of the main unit, the caregivers become more and more aware
causes of injury in preterm infants (Saugstad of the signs shown by the baby, and handling is
2005). Many clinical situations will produce adjusted accordingly. The families are
excessive free radical production: ischemia reper- empowered in the caregiving and put in a central
fusion injury, hypoxia and hyperoxia, inflamma- position. NIDCAP is an extensive and complex
tory diseases, phototherapy, and intravenous teaching program. The competence of the
nutrition with long-chain polyunsaturated fatty NIDCAP observer has to be validated by certified
acids. Their immature antioxidant defenses will NIDCAP trainers. The level of developmental
put them at increased risk for OS. care in the NICU can be evaluated by the
Any intervention in the NICU, which causes NIDCAP Nursery Certification. In this evalua-
hypoxia, is potentially source of OS. Intensive tion, all aspects of developmental care are
24 Environment and Early Developmental Care for Newborns 361
analyzed: from the architecture of the unit to the and white matter connectivity at diffusion tension
behavioral assessment of the baby, the collabora- brain imaging (DTI) compared to controls
tion with the parents, and the skills of the staff (Milgrom et al. 2010). In animal studies, varia-
(NIDCAP Nursery Assessment and Certification). tions in early life maternal stimulation can alter
The awareness of caregivers has dramatically offspring gene expression via epigenetic mecha-
increased over the last decades. In Europe, the nism receptor genes (Curley et al. 2011).
first NIDCAP training center opened in Stock- Human milk is widely recommended as the best
holm in 1999. Now 11 training centers are nutrient for term and preterm infants (American
established and more are on the way. There is an Academy of Pediatrics 2012). It reduces the risk
important demand for teaching developmental of infection, necrotizing enterocolitis, and is asso-
care, and it is likely that new approaches will ciated with better cognitive development. The
emerge to respond to this growing need. Parents unique components of colostrum, an immune
are also increasingly involved in the care of baby. juice, are especially important in VLBW infants.
They want and deserve to fulfill their role as Closeness of the mother and skin to skin contact are
primary caregiver of their infant (EFCNI Rights mandatory to reach successful breastfeeding.
of Parents and Newborns). Some places in Sweden have a long-lasting
experience in caring for infants with permanent
parental presence and fully restored mother-infant
24.4 Couplet Care or Restoring dyad. In those “couplet care” settings, parents and
the Mother-Infant Dyad: The infants live together from the very first minutes
New Challenge after birth until discharge. This option resulted in a
significant reduction of the length of stay
Despite the fact that the importance of early (Örtenstrand et al. 2010).
mother-infant relations is well known since a
long time, parental access to the unit has been
very often limited (Fanaroff et al. 1972). Today 24.5 Conclusion
the parents have theoretically permanent access,
but local resistance toward this rule still exists. In Neonatal units are facing a period of important
northern Europe, it is less often the case (Greisen conceptual changes, a real paradigm shift. The
et al. 2009). traditional unit appeared to be inadequate, with
Neonatal care units and maternity wards are harmful effects on brain development during this
generally run by a different nursing and medical particularly vulnerable period. New strategies in
team. Moreover, they are geographically not caring for the baby in a holistic way and integrating
always contiguous, and in most units when babies his level of development and his reactions toward
need special care after birth, it is difficult to have the different treatments have been elaborated.
the mother next to her baby. Restoring the physi- Moving away from traditional units toward
cal closeness between mothers and babies from family-centered developmentally supportive
birth to discharge is a concrete challenge for mod- units is the challenge of modern neonatology.
ern neonatology: introducing couplet care. The important elements of early developmental
Emotional and physical closeness are linked. care are parental physical and emotional close-
The mother who is separated from her newborn ness, fine-tuning of care according to appropriate
child will show anxiety and stress and is at risk for assessment of the preterm infant behavior, strate-
depression (Davis et al. 2003). It is not only a gies to reduce stress, and a NICU design adapted
question of a humane attitude, but there is growing to provide this type of care.
evidence of the importance of parent-infant close- Keeping mothers and babies in absolute prox-
ness (Flacking et al. 2012). A group of babies born imity from birth to discharge is the driving trend
from mothers who had benefit from an early sen- of the couplet care. In order to achieve these
sitivity training program showed better maturation changes, reference strategies have to be used and
362 D. Haumont
the transitional period is still ongoing. At the effects during development. Psychoneuroendocrinology
moment, NIDCAP is the most complete tool to 36(3):352–371
Davis L, Edwards H, Mohay H et al (2003) The impact of
achieve these changes, but concepts are evolving. very premature birth on the psychological health of
They will have to adapt according to further mothers. Earl Hum Dev 73(1–2):61–70
research, changes in caregiving, and local strate- Domanico R, Davis DK, Coleman F et al (2011)
gies. EDC is the first step to help parents in under- Documenting the NICU design dilemma: comparative
patient progress in open-ward and single family rooms
standing their baby, a task which does not stop at units. J Perinatol 31(4):281–288
discharge from the unit. Dreyfus – Brisac C (1968) Sleep ontogenesis in early
human prematurity from 24 to 27 weeks of conceptual
age. Dev Psychobiol 1:162–169
EFCNI rights of parents and newborns. www.efcni.org
References Fanaroff AA, Kennell JH, Klaus MH (1972) Follow – up of
low birth weight infants – the predictive value of mater-
Als H, Lawhon G, Duffy FH et al (1994) Individualized nal visiting patterns. Pediatrics 49(2):287–290
developmental care for the very low – birth – weight Ferrari F, Bertoncelli N, Gallo C et al (2007) Posture and
preterm infant. Medical and neurofunctional effects. movement in healthy preterm infants in supine position
JAMA 272:853–858 in and outside the nest. Arch Dis Child Fetal Neonatal
American Academy of Pediatrics (2012) Breastfeeding and Ed 92:F386–F390
the use of human milk. Pediatrics 129:e827–e841 Flacking R, Lehtonen L, Thomson G et al (2012) Close-
Amiel – Tison C (1995) Clinical assessment of the infant ness and separation in neonatal intensive care. Acta
nervous system. In: Levene MI, Lilford RJ (eds) Fetal Paediatr 101(10):1032–1037
and neonatal neurology and neurosurgery. Churchill Frank M, Stryker M (2003) The role of sleep in the devel-
Livingstone, Edinburgh, pp 83–104 opment of central visual pathways. In: Maquet P,
Bauer K (2005) Effect of positioning and handling on Smith C, Stickgold R (eds) Sleep and brain plasticity.
preterm infants in the neonatal intensive care unit. In: Oxford University Press, New York, pp 190–206
Sizun J, Browne JV (eds) Research on early develop- Graven SN (2004) Early neurosensory visual development
mental care for preterm neonates. John Libbey, Paris, of the fetus and newborn. Clin Perinatol 31:199–216
pp 39–44 Greisen G, Mirante N, Haumont D et al (2009) Parents,
Boundy EO, Dastjerdi R, Spiegelman D et al (2016) Kan- siblings and grandparents in the Neonatal Intensive
garoo mother care and neonatal outcome: a meta- Care Unit a survey of policies in eight European coun-
analysis. Pediatrics 137(1):1–16 tries. Acta Paediatr 98:1744–1750
Carbajal R, Rousset A, Danan C et al (2008) Epidemiology Haumont D (2014) NIDCAP and developmental care. J
and treatment of painful procedures in neonates in Pediatr Neonatal Individ Med 3(2):e030240
intensive care units. JAMA 300:60–70 Haumont D, Hansen V (2005) Neonatal development:
Caskey M, Stephens B, Tucker R et al (2014) Adult talk in effects of light. In: Sizun J, Browne JV (eds) Research
the NICU with preterm infants and developmental out- on early developmental care for preterm neonates. John
comes. Pediatrics 133(3):e578–e584. https://doi.org/ Libbey, Paris, pp 33–37
10.1542/peds.2013-0104 Horbar JD, Badger GJ, Carpenter JH et al (2002) Trends in
Charpak N, Ruiz JG, Zupan J et al (2005) Kangaroo mother mortality and morbidity for very low birth weight
care: 25 years after. Acta Paediatr 94:514–522 infants, 1991–1999. Pediatrics 110:143–151
Cignacco E, Hamers JP, Stoffel L et al (2007) The Kwon S, Vasung L, Ment L, H€ uppi P (2014) The role of
efficacy of non – pharmacological interventions in the neuroimaging in predicting neurodevelopmental out-
management of procedural pain in preterm and term comes of preterm neonates. Clin Perinatol 41:257–283
neonates. A systematic literature review. Eur J Pain Limperopoulos C, Gauvreau KK, O’Leary H et al (2008)
11:139–152 Cerebral hemodynamic changes during intensive care
Condie J, Caldarelli L, Tarr L et al (2012) Have the bound- of preterm infants. Pediatrics 122:e1006–e1013
aries of the “grey zone” of perinatal resuscitation Liu WF, Laudert S, Perkins B et al (2007) The development
changed for extremely preterm infants over 20 years? of potentially better practices to support the
Acta Paediatr. https://doi.org/10.1111/apa.12119 neurodevelopment of infants in the NICU. J Perinatol
Constable RT, Ment LR, Vohr BR et al (2008) Prematurely 27:S48–S74
born children demonstrate white matter Lubsen J, Vohr B, Myers E, Hampson M et al (2011)
miscrostructural differences at 12 years of age, relative Microstructural and functional connectivity in the
to term control subjects: an investigation of group and developing preterm brain. Semin Perinatol 35:34–43
gender effect. Pediatrics 121:e306–e316 Marlow N, Hennessy E, Bracewell M et al (2007) Motor
Curley JP, Jensen CL, Mashoodh R et al (2011) Social and executive function at 6 years of age after extremely
influences on neurobiology and behavior: epigenetic preterm birth. Pediatrics 120:793–804
24 Environment and Early Developmental Care for Newborns 363
Milgrom J, Newnham C, Anderson PJ et al (2010) Early Rivkees SA, Hao H (2000) Developing circadian rhyth-
sensitivity training for parents of preterm infants: impact micity. Semin Perinatol 24:232–242
on the developing brain. Pediatr Res 67(3):e330–e335 Saugstad OD (2005) Oxidative stress in the newborn-a
NIDCAP nursery assessment and certification. www. 30 year perspective. Biol Neonate 88:228–236
NIDCAP.org Smith GC, Gutovich J, Smyser C et al (2011) Neonatal
Örtenstrand A, Westrup B, Berggren Broström E Intensive Care Unit stress is associated with brain
et al (2010) The Stockholm Neonatal Family Centered development in preterm infants. Ann Neurol 70:
Care Study: effects on length of stay and infant mor- e541–e549
bidity. Pediatrics 125(2):e278–e285 van Sleuwen BE, Engelberts AC, Boere – Boonekamp
Penn AA, Shatz CJ (2002) Principles of endogenous and MM et al (2007) Swaddling: a systematic review. Pedi-
sensory activity – dependent brain development. The atrics 120:e1097–e1106
visual system. In: Lagercrantz H, Hanson M, Evrard P White R, Smith J, Shepley M et al (2013) Recommended
(eds) The newborn brain: neuroscience and clinical standards for newborn ICU design. J Perinatol 33
applications. Cambridge University Press, New York, (Suppl 1):S2–S16
pp 204–225 Zeitlin J, Mortensen L, Cuttini M et al (2015) Declines in
Pineda RG, Neil J, Dierker D et al (2013) Alterations in stillbirth and neonatal mortality rates in Europe
brain structure and neurodevelopmental outcome in between 2004 and 2010: results from the Euro-Peristat
preterm infants hospitalized in different NICU environ- project. J Epidemiol Community Health. https://doi.
ments. J Pediatr 164(1):52–60.e2 org/10.1136/jech.207013
Neonatal Pain: Neurophysiology,
Recognition, Prevention, and 25
Management with
Nonpharmacological Interventions
Carlo V. Bellieni, Celeste Johnston,
Marsha Campbell-Yeo, Britney Benoit, and Timothy Disher
Contents
25.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366
25.2 Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366
25.3 Development of Connections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366
25.4 Subplate Zone and Cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
25.5 Stress Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
25.5.1 Hemodynamic and Neuroendocrine Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
25.6 Overcoming Procedural Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
25.6.1 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
25.6.2 Recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
25.7 Overcoming Parents’ Pain/Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370
C. V. Bellieni
Neonatal Intensive Care Unit, Siena University Hospital,
Siena, Italy
e-mail: [email protected]
C. Johnston (*)
School of Nursing, McGill University, Montreal, Canada
e-mail: [email protected]
M. Campbell-Yeo (*)
Departments of Pediatrics, Psychology and Neuroscience,
Dalhousie University School of Nursing, Halifax, Canada
e-mail: [email protected]
B. Benoit (*)
School of Nursing, Centre for Pediatric Pain Research,
Maternal-Newborn Program, Dalhousie University, IWK
Health Centre , Halifax, Canada
e-mail: [email protected]
T. Disher (*)
Centre for Pediatric Pain Research, Dalhousie University
School of Nursing and IWK Health Centre, Halifax,
Canada
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 365
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_175
366 C. V. Bellieni et al.
25.8 Overcoming Healthcare Professionals’ Pain/Anxiety . . . . . . . . . . . . . . . . . . . . . . 370
25.9 A Therapeutic Tripod . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
25.10 Procedural Pain Management with Non-pharmacological
Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
25.11 Oral Sweet Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
25.12 Breastfeeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
25.13 Skin-to-Skin Care or Kangaroo Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
25.14 Nonnutritive Sucking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
25.15 Containment/Facilitated Tucking and Swaddling . . . . . . . . . . . . . . . . . . . . . . . . . 375
25.16 Rocking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
25.17 Auditory Recognition/Music . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
25.18 Olfactory/Aromatherapy Recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
25.19 Sensorial Saturation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
25.20 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
Abstract • Decreasing the number of painful procedures
Evidence indicates that the experience of pain is an obvious means of decreasing pain exposure.
begins in the second trimester of pregnancy, • Multiple non-pharmacological interventions,
well before the third and last trimester of preg- many usable by parents, have strong support-
nancy human gestation: thus preterm babies can ive evidence to decrease pain response to
perceive pain. When babies are born preterm, procedures.
they undergo painful experiences that should be
avoided. These experiences can result in impor-
tant short-term stress responses as well as long- 25.2 Anatomy
term effects on development. Pharmacological
agents should be used to alleviate extensive pain To feel pain, it is necessary for stimuli to involve
from surgery, but most pain is from daily pro- neural connections between the peripheral receptors
cedures. Decreasing the number of procedures and the spinal cord and upward transmission via the
or clustering the procedures is the first step to spinal cord to the thalamus and from there to the
overcome it. Also several non-pharmacological outer cerebral layers. The development of the
interventions supported by strong evidence, human nervous system is a progressive and ascend-
such as sensorial saturation, can be used by ing process, with the cerebral cortex being the last
nursing staff and, more importantly, by parents. region to develop. Thus, to experience pain, an
intact system of pain transmission must be available.
25.1 Salient Points
25.3 Development of Connections
• The anatomy and physiology of the fetus are
sufficiently developed in the second trimester Peripheral receptors develop from the seventh
to experience nociception. gestational week (Vanhatalo and Van
• Babies in the neonatal intensive care unit Nieuwenhuizen 2000). Connections from the
(NICU) experience painful procedures that periphery to the spinal cord are formed early, at
have long-term effects. about 8 weeks (Okado 1981). C fibers begin to
25 Neonatal Pain: Neurophysiology, Recognition, Prevention, and Management with. . . 367
grow into the spinal cord at about 10 weeks. Early transient laminar compartment of the cerebral
in gestation, after the tenth week of gestation, wall of the human fetus. The importance of the
substance P and enkephalin-positive fibers subplate as the main synaptic zone of the human
appear (Yew et al. 2001). From 13 weeks’ gesta- fetal cortex is based on the rich input of “waiting”
tion, the afferent system located in the substantia afferents from the thalamus and cortex during the
gelatinosa of the dorsal horn of the spinal cord crucial phase of cortical target area selection.
develops (Okado 1981; Bijlani et al. 1988; Yew Recent neurobiological evidence shows that the
et al. 2001). Spinothalamic connections start to subplate is an important site of spontaneous
develop from 14 weeks and are complete at endogenous activity, building a framework for
20 weeks’ gestation, and thalamocortical connec- the development of cortical columnar organiza-
tions are present from 17 weeks and completely tion (Kostović and Jovanov-Milosevic 2008). The
developed at 26–30 weeks’ gestation (Kostovic conscious perception of pain requires peripheral
and Goldman-Rakic 1983). From 15 weeks, there pain receptors, connections to the spinal cord
is a subplate zone which lies beneath the cortex. through an afferent system, fibers that connect
This is a layer of neurons below the cortex that is the spine and the thalami, and, most importantly,
specific to the fetus (see later). The thalamus connections between the thalamus and the
plays a pivotal role in regulating the spinal- subplate zone or cerebral cortex. It is also impor-
brainstem-spinal loops that mediate context- tant to know that pain impulses may be processed
dependent descending facilitation or inhibition, in other subcortical structures, including the hypo-
coordinated through the key mechanisms under- thalamic pituitary system and amygdala (impor-
lying consciousness. In contrast to direct tant for the emotional modulation of pain)
thalamocortical fibers, which are not visible (Lowery et al. 2007). The subplate zone expands
until almost the third trimester, thalamic afferents considerably between 17 and 20 weeks and
begin to reach the somatosensory subplate at recedes after 30 weeks’ developmental age
20 weeks’ gestation (Kostović and Rakic 1990) (Kostoví and Judaš 2002); from about 17 weeks,
and the visual subplate at 20–22 weeks’ gestation there is a shifting population of connections from
(Hevner 2000). Thalamic fibers penetrate the the thalamus to this region. Neurons in the
cortical plate from 24 to 28 weeks’ gestation. subplate zone initiate excitatory amino acid or
From 20 weeks’ gestation, peripheral receptors peptide neurotransmission in the cortex, influenc-
are present on the whole body (Valman and Pear- ing the development of fetal cortical circuits
son 1980; Bijlani et al. 1988). Recent studies (Kostović et al. 1991; Clancy et al. 2001), while
have noted robust activation of the somatosen- the cortical plate matures into the six layers of the
sory cortex in preterm neonates exposed to tactile cerebral cortex (Mrzljak et al. 1988). Differentia-
or painful stimuli, modulated by gestational tion of subplate neurons at 17–25 weeks’ gesta-
maturity, postnatal age, sex, laterality, and tion produces five cellular subtypes whose distinct
sleep-wake states (Bartocci et al. 2006; Slater et dendritic and axonal patterns correspond to differ-
al. 2006). Cortical development starts only at ent functional roles in development (Kostović et
about 17 weeks’ gestation, but continues until al. 2002; Perkins et al. 2005). From 16 weeks’
long after birth. Synapses appear within the cor- gestation, pain transmission from a peripheral
tical plate from mid-gestation. receptor to the cortex is possible and is certainly
completely developed from 26 weeks’ gestation.
Assuming that activity in the cerebral cortex or
25.4 Subplate Zone and Cortex subplate zone is necessary for consciousness, then
for the fetus to be conscious of an external expe-
The role of the cerebral cortex is crucial for pain rience, these regions need to be connected with
sensitivity, but we should not ignore the role of the incoming nervous activity. This starts to happen at
subplate in the development of sentience and con- about 16 weeks and puts an early limit on the time
sciousness. The subplate zone is a prominent, point at which it is likely the fetus might feel what
368 C. V. Bellieni et al.
is going on in its body or elsewhere (Van de Velde postconceptional weeks 28 through 32 in a
et al. 2006). Serotonin-releasing inhibitory NICU are less mature in their pain response to
descending pain fibers only develop after birth, heel prick than newborn premature infants of
and it is therefore possible that preterm babies and 32 weeks’ postconceptual age (PCA) (Johnston
fetuses feel more pain than small infants. and Stevens 1996). Differences in these response
patterns were strongly correlated with the number
of invasive procedures experienced since birth,
rather than other clinical factors (e.g., age, sever-
25.5 Stress Responses ity of illness, Apgar score, birth weight). These
data suggest that repetitive pain and stress might
25.5.1 Hemodynamic and alter the neurological response to pain, leading to
Neuroendocrine Responses altered neurobehavioral reactions to subsequent
painful events (Van de Velde et al. 2006).
Neonatal responses to painful stimuli have been According to Anand et al., repetitive pain in neo-
evaluated using a variety of measures within three natal rat pups may lead to an altered development
classes of responses (biochemical, physiological, of the pain system associated with decreased pain
and behavioral). Plasma catecholamine assays thresholds during development (Anand et al.
may provide the most valid and reliable measures 1999). Increased plasticity of the neonatal brain
of the biochemical responses of neonates to pain- may allow these and other changes in brain devel-
ful stimuli (Franck and Miaskowski 1997). As opment to increase the vulnerability of these ani-
early as 16 weeks’ gestational age, the human mals to stress disorders and anxiety-mediated
fetus mounts a cerebral hemodynamic response adult behavior. Similar behavioral changes have
to invasive procedures involving transgression of been observed during the later childhood of ex-
the fetal body, which is consistent with the “brain- preterm neonates who were exposed to prolonged
sparing” effect (Teixeira et al. 1999). Increased periods of neonatal intensive care: infants who are
cerebral blood flow is not necessarily indicative born prematurely or seriously ill are commonly
of pain, as this response is thought to constitute a exposed to multiple painful and stressful events as
“brain-sparing” mechanism associated with hyp- part of their prolonged hospitalizations and
oxia (Woo et al. 1987) and intrauterine growth required medical procedures. There is now evi-
restriction (Wladimiroff et al. 1987). Neverthe- dence that early events not only induce acute
less, fetal plasma concentrations of cortisol, changes, but that permanent structural and func-
endorphin, and noradrenaline increase after tional changes may also result (Porter et al. 1999).
intrauterine needling of the hepatic vein to a Recent studies suggest that although early painful
greater degree than of the umbilical cord memories are not accessible to conscious recall,
(Giannakoulopoulos et al. 1994, 1999). they might be encoded in “procedural memory”
and lead to abnormal behavioral patterns or
25.5.1.1 Long-Term Consequences altered sensory processing in later life. Taddio et
The evidence for adverse consequences on future al. demonstrated that infants circumcised at birth
neural development due to early exposure to nox- without analgesia showed a stronger pain
ious stimuli is increasing. Ruda et al. studied an response to subsequent routine vaccination than
animal neonatal model of persistent hind paw uncircumcised infants or than those who
peripheral inflammation. They found that, as underwent the procedure with analgesia (Taddio
adults, these animals exhibited spinal neuronal et al. 1997). It is becoming increasingly clear that
circuits with increased input and segmental neonatal painful experiences may leave a legacy
changes in nociceptive primary afferent axons of altered sensitivity to subsequent pain, perhaps
and altered responses to sensory stimulation for the entire life of the individual (Anand 1996,
(Ruda et al. 2016). Preterm infants who spend 2000; Valeri et al. 2015).
25 Neonatal Pain: Neurophysiology, Recognition, Prevention, and Management with. . . 369
25.6 Overcoming Procedural Pain 25.6.2 Recognition
25.6.1 Prevention Caregivers should be able to recognize the main
physical signs associated with pain. Most are
Manipulations and painful procedures must be nonspecific: babies can cry for reasons other than
reduced in number. Younger babies have a pain, and pain is expressed through complex behav-
lower pain threshold than older babies “because ior. This does not mean that a crying baby should be
of the immaturity of their pain inhibition system” ignored “because we are not sure” that he/she is
(Ranger et al. 2015), and they undergo a mean crying for pain. On the contrary, this should alarm
number of 14 painful procedures/day when in the us as if it were pain: our duty is to exclude it and/or
NICU (Simons et al. 2003). Any manipulation is to treat it. Newborns show a distinct pattern of
potentially stressful if not painful: changes in tem- behavior to painful stimuli. This includes a wide
perature, light, and noise can disrupt their behav- range of expressions including screwing up the
ioral states with harmful consequences. eyes, frowning, opening the mouth, extending the
Reduction of stress induced by clinical trials. fingers, kicking, as well as clenching. For a thor-
Clinical trials often provoke manipulations unnec- ough assessment, pain scales exist.
essary to a baby’s health. Moreover, studies of Chronic pain scales. It is mandatory to monitor
painkillers should never have placebo (Bellieni pain in order to prevent its occurrence, mainly
and Johnston 2015) treated babies as a reference after surgery or in ventilated babies. For this pur-
group, because we cannot impose pain on anyone pose, scales exist to evaluate the level of pain and
without his/her consent: parents should not be stress in intubated babies or after surgery, in order
given the burden of deciding whether to enter to adjust or introduce an effective analgesia.
their baby in a painful experiment, since pain Acute pain scales. Many scales exist in this field
must never be part of neonatal research (for a and are scarcely used. There are two reasons for
control group, a commonly recognized painkiller this: first, the difficulty of applying scales where
should be used). Unfortunately, preventing pain many items have to be assessed simultaneously
is not among the preeminent concerns of (Bellieni et al. 2007b) and, second, the lack of
researchers: 75% of the studies considered in a any point in assessing pain after it has occurred.
recent review (Bellieni et al. 2008) showed that Acute pain scales are useful for research purposes.
infants suffered pain during the research because It is not always useful for clinical practice to assess
placebo, no treatment, or otherwise inadequate the actual level of pain; it is more useful to be aware
pain management was applied. of whether we are actually provoking pain or rather
Providing newborns with an environment tai- if we might provoke it before we start. Acute pain
lored to their needs. Babies in incubators are scales are retrospective and assess pain only after it
exposed to very high electromagnetic fields (Bellieni has been provoked. So it has been proposed to
et al. 2008), loud noises, disturbing lights, and stress- assess pain preventively: acute pain scales include
ful manipulations, and sometimes they are isolated many data, but the type of the stimulus and the
from their family. Studies (Bellieni et al. 2003, region of the body (with or without nociceptors)
2004a, 2005) to overcome some of these forms of where it is applied are decontextualized. It has been
environmental pollution have been performed, and proposed (Bellieni et al. 2015) to foresee pain using
effective developmental care, centered on the single a contextual model. The context of the stimulus is
baby and his/her family, is now recommended crucial: stimuli that might provoke pain applied to
(Als et al. 2004). It is important to treat the baby an innervated area will not be painful if applied
with humanity during the procedures, with special where nociceptors are absent, and the invasiveness
attention to non-pharmacologic analgesia and a of a procedure often is proportional to the pain it
baby-tailored environment: both can reduce the provokes. Thus we should proceed first assessing if
risks of neurodevelopmental compromise. the site and the stimulus are adequate to provoke
370 C. V. Bellieni et al.
Fig. 1 Detecting pain. A
congruous stimulus applied
on a place full of
nociceptors provokes pain,
and this is pointed out by an
increase of heart rate or by
crying onset
pain and then assessing the reaction to this stimulus Table 1 ABC pain scale
(Fig. 1) to detect if pain has been felt. When we Absent Intermediate Full
may provoke pain-activating nociceptors, we Acuteness of the first 0 / 2
should use easily noticeable signs such as crying cry
or heart rate to detect pain. Crying and increased Burst rhythmicity 0 / 2
heart rate both show a high sensitivity for pain in Continuity in time of 0 1 2
crying loudness
studies made for the validation of pain scales
(Codipietro et al. 2008; Mandel et al. 2012): neither
crying nor heart rate is specific to pain (Barr 2000),
couples to become true parents. In the NICU this
but the sudden appearance of a reaction (crying or
often happens through the foresight of the care-
increase of heart rate) overcomes this limit. The
givers. Parents should be accompanied to meet
first cry after a heel prick is high pitched if it is very
their baby, gently be encouraged to call him/her
painful. Babies cry in 1-s bursts separated by short
by name, and dedicate all the time needed to
and regular pauses when pain is high (Bellieni et al.
them; in some cases, they may require the help of
2004b). The ABC scale stands on this basis
a psychologist (Arockiasamy et al. 2008). Parents’
(Bellieni et al. 2004b, 2007c), which, unlike most
pain and stress will have two negative conse-
other scales, can be used by the caregiver who is
quences: they may increase the difficulty of com-
performing the procedure, without interrupting it to
munication with physicians, leading to bad
score pain, as it is uniquely based on recognizing
compliance and discussion, and will be transferred
the acoustic features of crying (Table 1).
to the baby who may change his/her behavior
accordingly.
25.7 Overcoming Parents’ Pain/
Anxiety
25.8 Overcoming Healthcare
In the treatment of neonatal pain, it is important to Professionals’ Pain/Anxiety
consider additional but often concealed parental
pain, also because parents play an important role Healthcare professionals’ pain/anxiety pain is
in the improvement of the baby. Caregivers should often underestimated (Bellieni and Buonocore
give adequate relationship-based care and help 2009), but it is useful to consider that people
25 Neonatal Pain: Neurophysiology, Recognition, Prevention, and Management with. . . 371
work in a NICU side by side with death and suffering (Carbajal et al. 2003; Bellieni et al.
pain on a daily basis, sometimes in difficult 2007a; Bellieni and Buonocore 2008; Butler and
conditions. These people bear all this along Als 2008). Medical intervention should not be
with their own fears and anxieties. Much should limited to drugs and technical procedures. What
be done to help them to find ways to cope with is required is “advocacy.” Nurses and neonatolo-
all this pain, to avoid their beautiful and impor- gists should be advocates. They should also sup-
tant work becoming a routine, losing much of port parents to become active advocates; not to be
its usefulness, and sometimes reflecting upon frightened by their baby’s apparent fragility,
the type of treatment they give babies (Barr immaturity, and lack of reactivity; and to be able
2007). Caregivers should be trained to have a to interpret their baby’s discomfort.
positive vision of the baby and encouraged to
exploit any effort of the parents and any pro-
gress of the baby. Caregivers’ anxieties can lead 25.10 Procedural Pain Management
to unnecessary overtreatment or undertreatment with Non-pharmacological
(Wyatt 2007). Interventions
Neonates who are born preterm spend weeks in
25.9 A Therapeutic Tripod the neonatal intensive care unit (NICU) and
undergo numerous painful procedures as part
The therapeutic tripod represents an approach to of their routine care (Simons et al. 2003). In
pain relief. Neonatal pain can be relieved only by spite of evidence of negative effects and
taking care of all of the legs (Fig. 2), considering published guidelines on pain control, about
not only procedural pain but also caregivers’ one third of procedures remain unmanaged
Fig. 2 Representation of neonatal pain (NP). Treating only one of the three legs of this tripod will be utterly insufficient
372 C. V. Bellieni et al.
(Carbajal et al. 2008; Johnston et al. 2011). varies across procedures; the strongest and most
While pain requires management, common studied examine needle-related procedures such
approaches with older populations are not as venipuncture and heel lance although benefit
appropriate for neonates, particularly preterm has also been demonstrated for non-tissue break-
neonates. To date, there are several difficulties ing yet commonly performed stressful procedures
with pharmacological interventions for proce- such as insertion of orogastric tubes (Nimbalkar
dural pain. Topical anesthetics have been et al. 2013) while less so for echocardiogram
shown not to be effective with heel lance or (Lavoie et al. 2015; Potana et al. 2015). In one
venipuncture, the most common painful proce- study pain scores measured using the Premature
dures in neonates (Stevens et al. 1999). Infant Pain Profile (PIPP) (Stevens et al. 1996)
Systemic drugs, specifically opiates, have sig- were significantly lower for infants assigned to
nificantly slower clearance in neonates (Zuppa receive sucrose prior to undergoing echocardio-
et al. 2009) and are also not necessarily effective gram compared to a no-treatment control arm
for acute procedural pain (Carbajal et al. 2005). (Potana et al. 2015), but another study found no
Given the frequency of painful procedures in added benefit of 25% glucose compared to the
NICUs and the difficulties with pharmacologi- provision of nonnutritive sucking with a pacifier
cal management, different approaches are (Lavoie et al. 2015).
required. Effective non-pharmacological inter- Adjuvant strategies such as nonnutritive suck-
ventions with strong supportive evidence will ing, swaddling, or facilitated tucking when com-
be reviewed. bined with sweet taste have been associated with a
greater benefit (Stevens et al. 2013; Pillai Riddell
et al. 2015) especially for immunizations (McNair
et al. 2013; Taddio et al. 2015). Minimal (da Costa
25.11 Oral Sweet Solutions et al. 2013) or no benefit (Kataria et al. 2015;
Nesargi et al. 2015) has been reported when
Oral sweet solutions are currently recommended 25% glucose was provided for the reduction of
in rigorously developed clinical practice guide- the moderate to severe pain associated with eye
lines (CPGs) for the optimal management of examination for retinopathy of prematurity or
mild to moderately painful procedures in infants treatment using laser therapy with or without con-
(Lee et al. 2014; Committee on Newborn Pain comitant topical anesthesia.
2016). Studies using sucrose, the most studied Concentrations of studied sweet-tasting solu-
sweet taste, began in the late 1980s (Blass et al. tions have varied from 5% to 50%. Although one
1987; Blass and Hoffmeyer 1991) and have study reports a flat dose-response function (Blass
been meta-analyzed (Stevens et al. 2013). Cumu- and Shah 1995), there seems to be a dose-response
lative data from 57 randomized controlled trials effect in the reduction of crying with increasing
including 4,730 infants with gestational ages concentration of sucrose (Abad et al. 1996) with
ranging from 25 to 44 weeks concluded that concentrations greater than 18% being considered
sucrose is safe and effectively reduces biobehav- most effective (Stevens et al. 2013). While the
ioral response during single acute needle or lance- exact mechanism of action remains unknown,
related procedures and the inclusion of placebo sweet-tasting solutions appear to be mediated by
control groups are no longer considered ethical taste and are most efficacious when administered
when designing sucrose trials (Stevens et al. 2013; orally to the anterior portion of the tongue 2 min
Bellieni and Johnston 2015). Similarly, a meta- before a painful stimulus, with effects lasting up to
synthesis of non-sucrose sweet-tasting solutions, 4 min (Johnston et al. 1999; Lefrak et al. 2006;
most notably oral glucose or dextrose, demon- Stevens et al. 2013).
strated similar pain-reducing benefits for proce- Despite extensive and rigorous evidence,
dural pain in infants (Bueno et al. 2013). The numerous questions remain related to optimal
degree of effectiveness of sweet-tasting solutions dose, sustained effect, potential for long-term
25 Neonatal Pain: Neurophysiology, Recognition, Prevention, and Management with. . . 373
adverse outcome, and concern regarding sedative 25.12 Breastfeeding
versus analgesic properties related to the
repeated use of sweet-tasting solutions to reduce Several studies have also examined the possible
infant pain. Currently, a 20-fold variation of benefits of breastfeeding or supplemental breast
recommended doses from 0.05 ml of 24% to milk in full-term neonates. In a systematic review
2.0 ml of 50% solution of sucrose exists, and the of 20 clinical trials, breastfeeding (ten studies) and
minimum effective dose (i.e., the smallest dose breast milk (ten studies) were shown to provide
associated with a clinically significant reduction analgesia during routine procedural pain from heel
in pain intensity scores) has not yet been stick and venipuncture (Shah et al. 2012). Supple-
established (Stevens et al. 2013). Few studies mental breast milk alone does not appear to be as
have examined the repeated use of sucrose related analgesic as sweet taste or direct breastfeeding
to sustained efficacy or potential for associated (Shah et al. 2012). Six studies have examined
consequences. The first study conducted by breastfeeding and breast milk analgesia in preterm
Johnston, examining outcomes associated with neonates. Supplemental breast milk was not found
repeated use of sucrose, reported delayed to be as effective as sweet taste (Skogsdal et al.
neurobehavioral development (alertness and ori- 1997; Bueno et al. 2012; Simonse et al. 2012; Ou-
entation, motor vigor) in infants who had received Yang et al. 2013), and direct breastfeeding was not
higher doses of sucrose over the first week of found to provide more analgesia than nonnutritive
life (Johnston et al. 2002). Conversely, a study sucking (Holsti et al. 2011) in preterm infants
conducted over 4 weeks found no difference in undergoing heel lance. One study examining the
neurobiological risk scores but did not measure analgesic effect of breastfeeding combined with
development (Stevens et al. 2005), and another standard care (anesthetic drops, swaddling, and
over 3 days only examined sustained efficacy and nesting) for retinopathy of prematurity exams
did not report on any long-lasting effects (Taddio found that the addition of breastfeeding signifi-
et al. 2008). Two recent studies examining the cantly reduced pain scores when compared to
effect of sucrose exposure in infants born preterm standard care alone (Rosali et al. 2015). On the
have been conducted with varying results. Plasma other hand, breastfeeding has been shown to be as
markers of ATP degradation and oxidative stress effective as sucrose for the relief of procedural
measured before and after the heel lance in 131 pain (Carbajal et al. 2003). There is some evidence
preterm infants were found to be significantly that breastfeeding may be superior to sucrose
higher in those infants receiving a single dose of (Codipietro et al. 2008; Marín Gabriel et al.
oral sucrose given just prior to heel lance when 2013) and glucose (Weissman et al. 2009).
compared to those provided with nonnutritive suck- The benefits of glucose and breastfeeding during
ing or no-treatment control (Asmerom et al. 2013). heel lance (Gradin et al. 2004) and EMLA and
In a similar group of preterm infants, receiving breastfeeding during immunization (Gupta et al.
0.5 ml of 25% sucrose for every painful procedure 2013) may be cumulative when provided
for three consecutive days during hospitalization, simultaneously.
there did not appear to be any adverse effect on Maternal presence appears to play a valuable
outcomes related to feeding patterns or weight role. Healthy full-term infants cried and grimaced
gain compared to infants in the no-treatment con- less by 91% and 84%, respectively, when held
trol group (Linhares et al. 2014). One study found during breastfeeding rather than swaddled in a
that although sucrose decreased pain scores bassinet during heel stick (Gray et al. 2002).
according to the Premature Infant Pain Profile Breastfeeding and maternal holding with pacifier
(PIPP), there was still a nociceptive-specific significantly reduced full-term infants’ crying
potential measured on EEG, raising concern that behavior during heel stick when compared to the
additional examination of the exact analgesic group being held by an assistant with pacifier
properties of sucrose use is warranted (Slater et (Phillips and Chantry 2002). During heel lance,
al. 2010). being held by a mother and breastfed was
374 C. V. Bellieni et al.
compared to being held by a mother with pacifier not prove better than KC alone. Since this
and to being held by a non-mother with pacifier review, four studies (Marin Gabriel et al. 2013;
(Phillips et al. 2005). In the first two conditions, Mosayebi et al. 2014; Gao et al. 2015; Liu et al.
infants cried significantly less (33% and 45%) 2015) (n = 320) have evaluated the efficacy of
compared to being held by a non-mother (66%, KC to reduce pain from heel lance, one
p < 0.01 and p = 0.03, respectively). However, (Kostandy et al. 2013) (n = 36) from intramus-
other components of the breastfeeding interven- cular injection and one (Nanavati et al. 2013)
tion must play a role in efficacy beyond maternal (n = 50) from tape removal. KC was associated
presence, as breastfeeding has been shown to sig- with decreased NIPS scores, cry time,
nificantly reduce behavioral and biobehavioral grimacing, heart rate, DAN score, and PIPP.
pain scores compared to maternal holding without The duration of KC has not been systematically
breastfeeding during immunization (Modarres compared, although studies in the review ranged
et al. 2013) and heel lance (Leite et al. 2009; from 2 min to 3 h nor has the repeated use of KC
Weissman et al. 2009; Obeidat and Shuriquie been studied. A few studies compared sweet
2015). There is some evidence to suggest that taste or breastfeeding to KC with results show-
the analgesic efficacy of direct breastfeeding in ing either no difference (Okan et al. 2010), KC
preterm infants is dependent on sucking pattern to be more effective (Freire et al. 2008;
maturity (Holsti et al. 2011). Chermont et al. 2009) or to have a cumulative
effect (Marin Gabriel et al. 2013). No adverse
effects have been reported.
25.13 Skin-to-Skin Care or
Kangaroo Care
25.14 Nonnutritive Sucking
Interest in kangaroo care (KC), described as the
mother holding the baby naked with only a Among non-pharmacological interventions,
diaper in a prone upright position against her nonnutritive sucking (NNS), or pacifier use,
bare breasts, for pain is recent. The effects of was the first to be studied in the mid-1980s.
KC on infants’ pain response were first studied Its use in term and preterm infants treated in
in full-term infants (Gray et al. 2000) and were neonatal intensive care and in minimal care
shown to reduce crying by 82% and grimacing shows that behavioral distress, namely, percent
by 65%, compared to infants who stayed in the time spent in the fussing and crying state, is
crib during heel lance. Similar results have been reduced during and after heel stick (Bellieni
reported in full-term neonates receiving intra- 2007a). In a recently updated Cochrane sys-
muscular injection (Kashaninia et al. 2008). The tematic review of non-pharmacological strate-
first study in preterm infants of 32–36 weeks’ gies for pain, six studies examined the effect
gestational age was in 2003 (Johnston et al. of NNS on pain reactivity (reactions immedi-
2003) and other studies followed. These studies ately after painful stimuli) and immediate pain
consistently show that KC significantly reduced regulation (reactions after the initial pain
biobehavioral responses. A Cochrane system- response period) for preterm infants (Pillai
atic review (Johnson et al. 2014) for KC for Riddell et al. 2015). For pain reactivity, NNS
pain in term and preterm neonates (19 studies, was not found to be effective for preterm infants
n = 1,594) found that KC was associated with (SMD 0.31, 95% CI 0.65 to 0.04, I2 = 72%),
improved heart rate recovery, serum, and sali- but there were statistically significant benefits for
vary cortisol; PIPP scores at 30, 60, and 90 s; full-term neonates (SMD 1.20, 95% CI 1.54
neonatal facial coding system scores; neonatal to 0.25, I2 = 84) (Pillai Riddell et al. 2015).
infant pain scale scores; and sleep-wake state. For immediate pain regulation, there was a statis-
The addition of rocking, singing, and sucking in tically significant effect for preterm infants (SMD
infants of 32–36 weeks of gestational age did 0.43, 95% CI 0.63 to 0.23, I2 = 0) and
25 Neonatal Pain: Neurophysiology, Recognition, Prevention, and Management with. . . 375
neonates (SMD 0.90, 95% CI 1.54 to 0.25, 25.16 Rocking
I2 = 84%) (Pillai Riddell et al. 2015).
Rocking, compared to pacifiers and routine care
after heel lance, promoted arousal levels, while
25.15 Containment/Facilitated pacifiers promoted sleep and reduced heart rate
Tucking and Swaddling (Campos 1994). Based on studies of rocking
being effective in full-term neonates and on stud-
Containment refers to restricting the premature ies of simulated rocking promoting quiet sleep
infants’ motions by holding or using an arm to (Campos 1994), simulated rocking was tested for
place the neonate’s arms and legs near the trunk pain in 85 preterm neonates, and rocking alone
to maintain a flexed in utero posture with limbs was no better than control unless coupled with
placed in body midline (Huang et al. 2004). It is sucrose. In a randomized controlled trial compar-
also referred to as facilitated tucking (Axelin et ing maternal holding to lying supine during
al. 2006). The effects of facilitated tucking have immunization, holding was found to not signifi-
been examined in preterm infants undergoing cantly reduce Neonatal Facial Coding Scale indi-
commonly performed tissue-breaking proce- cators, cry duration, or visual analog scale scores
dures in the NICU and have been shown to in full-term born infants ranging from 2 to
diminish the magnitude of physiological, behav- 6 months (Ipp et al. 2004). As such, the evidence
ioral, and composite biobehavioral indicators of for the analgesic efficacy of holding and rocking is
pain response (Corff et al. 1995; Axelin et al. limited.
2006, 2009; Cignacco et al. 2012; Liaw et al.
2012, 2013; Peyrovi et al. 2014; Pillai Riddell
et al. 2015). 25.17 Auditory Recognition/Music
Similar to facilitated tucking in respect to
containment and midline positioning, swaddling The human fetus is thought to be capable of audi-
consists of wrapping the infant in a sheet or tory perception by 29 weeks of gestational age
blanket (Aucott et al. 2002). The first study (Hepper and Shahidullah 1994) and have the abil-
was published almost 30 years ago (Campos ity to remember auditory stimuli from their intra-
1989) where it was less efficacious in reducing uterine environment (Fifer et al. 1995). There is a
pain than a pacifier. In preterm infants with a paucity of high-quality, recently conducted trials
postconceptual age greater than 31 weeks, swad- from which to draw conclusions. The most com-
dling improved pain response (Shu et al. 2014) prehensive Cochrane systematic review of non-
and recovery (Fearon et al. 1997) after heel lance pharmacological interventions included a single
compared to no treatment, but may have less of crossover trial (n = 19) assessing efficacy of a
an effect in infants with a postconceptual age recording of the mother’s voice modified to simu-
less than 31 weeks (Fearon and Kisilevsky late the in utero environment. This was not found to
1997) and may not be more efficacious than be effective (SMD 0.29, 95% CI 0.94 to 0.35)
heel warming (Shu et al. 2014). A meta-analysis (Pillai Riddell et al. 2015). In a three-arm repeated
of four studies in Thailand reports that the effect measures RCT, 35 preterm infants were random-
size of swaddling compared to no intervention ized to one of the three conditions during heel
on pain scores during heel lance was greater in lance: music, glucose, or control. Groups were
term infants (0.79 (95% CI = 0.53, 1.05)) than compared based on the change from baseline
in preterm infants (0.53 (95% CI = 0.27, 0.80)) PIPP score, with the music (median = þ2) and
(Prasopkittikun 2003). Comparing containment glucose (median = þ1) conditions showing signif-
to swaddling, there is little difference between icant improvement over the control (þ3) condi-
their effects, and therefore these interventions tions ( p = 0.008). In a crossover design study
can be used interchangeably (Huang et al. with infants 30–41 weeks’ gestational age, music
2004; Pillai Riddell et al. 2015). therapy alone consisting of intrauterine maternal
376 C. V. Bellieni et al.
pulse sounds with soothing music, music therapy et al. 2012). In a rapid review of all trials
combined with nonnutritive sucking, nonnutritive employing sensorial saturation for the reduction
sucking alone, and no intervention were compared of pain response in neonates, eight papers
when used for 5 min after heel lance (Bo and (n = 709) were retrieved (Bellieni et al. 2012).
Callaghan 2000). Music therapy alone had the Procedures were primarily heel lance (7/8) with a
strongest effect on neonates’ heart rate. Butt and single study assessing response to endotracheal
Kisilevsky (Butt and Kisilevsky 2000), in a ran- suctioning. Outcomes included validated pain
domized crossover design, exposed 16 preterm scales, cry time, and intracranial pressure. Most
neonates to vocal or instrumental music for (7/8) studies found results indicating the sensorial
10 min after the end of a heel lance. Infants above saturation was effective. The group that
31 weeks in the music group had a significantly conducted this review tested the feasibility of
more rapid recovery. training mothers to use sensorial saturation with
Similar findings were not observed in a study the removal of baby oil to scent the hands and
examining a recorded and filtered maternal “sing- found that they were as effective as highly trained
song” voice versus no voice during heel stick staff and more effective than glucose and pacifier
procedure (Johnston et al. 2007). These results by two points on their pain score based on crying
may have been affected by the high volume of (Bellieni et al. 2007a, c). Several trials found that
the recorded sound (70 db) or may indicate that sensorial saturation is more effective than any
familiar sound alone may not be sufficient to other procedure in preventing pain from heel-
ameliorate the effects of a tissue-breaking proce- prick.
dure in younger more immature infants.
25.20 Conclusions
25.18 Olfactory/Aromatherapy
Recognition The above review provides strong evidence for
the efficacy of a variety of non-pharmacological
There is now compelling evidence that both term interventions. By engaging sensory modalities
and preterm infants remember, recognize, and pre- such as olfactory, touch, oragustatory, auditory,
fer smell that is associated with their intrauterine temperature, and vestibular, the nociceptive sen-
environment and their mothers and that olfactory sations can be dampened. The precise mecha-
stimuli can provide infants with comfort and mod- nisms, whether it is simply the competing
ulate pain response (Goubet et al. 2003, 2007). sensations or that these sensations evoke endog-
These results were seen in both full term (Rattaz enous opiates or regulatory hormones, are not
et al. 2005; Goubet et al. 2007) and preterm (aver- known. However, given the efficacy of numerous
age 32.3 weeks’ gestational age) (Goubet et al. non-pharmacological interventions (Cignacco
2003). Pillai-Ridell et al. (2015), in a recent et al. 2007) for procedural pain in neonates, and
Cochrane systematic review, included one RCT the difficulties with pharmacological agents in this
(n = 90) in an analysis of the effect of familiar population for common painful procedures such as
and unfamiliar odor on immediate pain regulation heel lance and venipuncture, non-pharmacological
(definition). Familiar odor was determined to be interventions should be the first choice in
effective (SMD 1.04, 95% CI 1.47 to 0.61). uncompromised infants (American Academy of
Pediatrics: Committee on Fetus and Newborn, Sec-
tion on Surgery and Canadian Paediatric Society:
25.19 Sensorial Saturation Fetus and Newborn Committee 2006). They are
cost-effective and easy to administer. Mothers are
As described by Bellieni, sensorial saturation is an clearly implicated in breastfeeding and kangaroo
intervention consisting of a combination of tactile, care, but can also be included in other interventions
gustative, auditory, and visual stimuli (Bellieni such as sensorial saturation (Bellieni et al. 2007a;
25 Neonatal Pain: Neurophysiology, Recognition, Prevention, and Management with. . . 377
Axelin et al. 2009). Initially, there is a requirement Barr R (2000) Crying as a sign, a symptom, & a signal:
to train staff and parents in these methods, and it clinical, emotional and developmental aspects of infant
and toddler crying. Mac Keith Press, London
may seem easier to give a solution in an intravenous Barr P (2007) Relationship of neonatologists’ end-of-life
line than to coordinate care to coincide with parental decisions to their personal fear of death. Arch Dis Child
visiting. Nevertheless, parents find pain the most Fetal Neonatal Ed 92:F104–F107. https://doi.org/
distressing aspect of the NICU and also wish to 10.1136/adc.2006.094151
Bartocci M, Bergqvist LL, Lagercrantz H, Anand KJ
actively participate in comforting their infant (2006) Pain activates cortical areas in the preterm new-
(Franck et al. 2004). These approaches are consis- born brain. Pain 122:109–117. https://doi.org/10.1016/
tent with modern family-centered care in neonatal j.pain.2006.01.015
units in which the best interests of the infant and Bellieni CV, Buonocore G (2008) Neonatal pain treatment:
ethical to be effective. J Perinatol 28:87–88. https://doi.
family are put ahead of staff convenience. org/10.1038/sj.jp.7211899
Bellieni CV, Buonocore G (2009) Flaws in the assessment
of the best interests of the newborn. Acta Paediatr Int J
References Paediatr 98:613–617. https://doi.org/10.1111/j.1651-
2227.2008.01185.x
Abad F, Diaz N, Domenech E et al (1996) Oral sweet Bellieni CV, Johnston CC (2015) Analgesia, nil or placebo
solution reduces pain-related behaviour in preterm to babies, in trials that test new analgesic treatments for
infants. Acta Paediatr Int J Paediatr 05:54–58 procedural pain. Acta Paediatr Int J Paediatr. https://
Als H, Duffy FH, McAnulty GB et al (2004) Early expe- doi.org/10.1111/apa.13210
rience alters brain function and structure. Pediatrics Bellieni CV, Buonocore G, Pinto I et al (2003) Use of
113:846–857. https://doi.org/10.1542/peds.113.4.846 sound-absorbing panel to reduce noisy incubator rever-
American Academy of Pediatrics: Committee on fetus and berating effects. Biol Neonate 84:293–296. https://doi.
newborn, section on surgery and S on A and PM, org/10.1159/000073637
Canadian paediatric society: fetus and newborn commit- Bellieni C, Pinto I, Stacchini N (2004a) Vibration risk
tee (2006) prevention and management of pain in the during neonatal transport. Minerva Pediatr 56:207–212
neonate : An Update. https://doi.org/10.1542/peds.2006- Bellieni CV, Sisto R, Cordelli DM, Buonocore G (2004b)
2277 Cry features reflect pain intensity in term newborns: an
Anand KS (1996) New perspectives on the definition of alarm threshold. Pediatr Res 55:142–146. https://doi.
pain. Pain 67:3–6 org/10.1203/01.PDR.0000099793.99608.CB
Anand KJ (2000) Pain, plasticity, and premature birth: a Bellieni CV, Bagnoli F, Pinto I et al (2005) Reduction of
prescription for permanent suffering? Nat Med exposure of newborns and caregivers to very high
6:971–973. https://doi.org/10.1038/79658 electromagnetic fields produced by incubators. Med
Anand KJ, Coskun V, Thrivikraman KV et al (1999) Long- Phys 32:149–152. https://doi.org/10.1118/1.1829404
term behavioral effects of repetitive pain in neonatal rat Bellieni CV, Cordelli DM, Marchi S et al (2007a) Sensorial
pups. Physiol Behav 66:627–637. https://doi.org/ saturation for neonatal analgesia. Clin J Pain 23:219–221
10.1016/S0031-9384(98)00338-2 Bellieni CV, Cordelli DM, Caliani C et al (2007b) Inter-
Arockiasamy V, Holsti L, Albersheim S (2008) Fathers’ observer reliability of two pain scales for newborns.
experiences in the neonatal intensive care unit: a search Early Hum Dev 83:549–552. https://doi.org/10.1016/j.
for control. Pediatrics 121:e215–e222. https://doi.org/ earlhumdev.2006.10.006
10.1542/peds.2007-1005 Bellieni CV, Maffei M, Ancora G et al (2007c) Is the ABC
Asmerom Y, Slater L, Boskovic DS et al (2013) Oral pain scale reliable for premature babies? Acta Paediatr
sucrose for heel lance increases adenosine triphosphate Int J Paediatr. https://doi.org/10.1111/j.1651-2227.
use and oxidative stress in preterm neonates. J Pediatr. 2007.00355.x
https://doi.org/10.1016/j.jpeds.2012.12.088 Bellieni CV, Acampa M, Maffei M et al (2008) Electro-
Aucott S, Donohue PK, Atkins E, Allen MC (2002) magnetic fields produced by incubators influence heart
Neurodevelopmental care in the NICU. Ment Retard rate variability in newborns. Arch Dis Child Fetal Neo-
Dev Disabil Res Rev 8:298–308 natal Ed 93:F298–F301. https://doi.org/10.1136/
Axelin A, Salantera S, Lehtonen L (2006) “Facilitated adc.2007.132738
tucking by parents” in pain management of preterm Bellieni CV, Tei M, Coccina F, Buonocore G (2012) Sensorial
infants-a randomized crossover trial. Early Hum Dev saturation for infants’ pain. J Matern Neonatal Med 25
82:241–247. https://doi.org/10.1016/j.earlhumdev.2005. (Suppl 1):79–81. https://doi.org/10.3109/14767058.
09.012 2012.663548
Axelin A, Salantera S, Kirjavainen J, Lehtonen L (2009) Oral Bellieni CV, Tei M, Buonocore G (2015) Should we assess
glucose and parental holding preferable to opioid in pain pain in newborn infants using a scoring system or just a
management in preterm infants. Clin J Pain 25:138–145. detection method? Acta Paediatr Int J Paediatr
https://doi.org/10.1097/AJP.0b013e318181ad81 104:221–224. https://doi.org/10.1111/apa.12882
378 C. V. Bellieni et al.
Bijlani V, Rizvi T, Wadhwa S (1988) Development of spinal Codipietro L, Ceccarelli M, Ponzone A (2008)
substrate for nociception in man. Pain 87:167–179 Breastfeeding or oral sucrose solution in term neonates
Blass EM, Hoffmeyer LB (1991) Sucrose as an analgesic receiving heel lance: a randomized, controlled trial.
for newborn infants. Pediatrics 87:215–218. https://doi. Pediatrics 122:e716–e721. https://doi.org/10.1542/
org/10.1097/00132586-199112000-00033 peds.2008-0221
Blass EM, Shah A (1995) Pain-reducing properties of Committee on Newborn Pain APP (2016) Prevention and
sucrose in human newborns. Chem Senses 20:29–35 management of procedural pain in the neonate: an
Blass E, Fitzgerald E, Kehoe P (1987) Interactions between update. Pediatrics 137:1–13. https://doi.org/10.1542/
sucrose, pain and isolation distress. Pharmacol peds.2015-4271
Biochem Behav 26:483–489 Corff KE, Seideman R, Venkataraman PS et al (1995)
Bo L, Callaghan P (2000) Soothing pain-elicited distress in Facilitated tucking: a nonpharmacologic comfort mea-
Chinese neonates sure for pain in preterm neonates. J Obstet Gynecol
Bueno M, Stevens B, de Camargo PP et al (2012) Breast Neonatal Nurs 24:143–147. https://doi.org/10.1111/
milk and glucose for pain relief in preterm infants: a j.1552-6909.1995.tb02456.x
noninferiority randomized controlled trial. Pediatrics da Costa MC, Unchalo Eckert G, Gastal Borges Fortes B,
129:664–670. https://doi.org/10.1542/peds.2011-2024 Borges Fortes Filho J, Silveira R, Procianoy R, Coelho
Bueno M, Yamada J, Harrison D, et al (2013) A systematic de Costa M (2013) Oral glucose for pain relief during
review and meta-analyses of nonsucrose sweet solu- exam for ROP. Clin Sci 62:199–203
tions for pain relief in neonates. Pain Res Manag Fearon I, Kisilevsky BS, Hains S, Muir DW, Tranmer J
18(3):153–161 (1997) Swaddling after heel lance: age specific effects
Butler S, Als H (2008) Individualized developmental care on behavioral recovery in preterm infants. J Dev Behav
improves the lives of infants born preterm. Acta Pediatr 18(4):222–232
Paediatr Int J Paediatr 97:1173–1175. https://doi.org/ Fifer WP, Moon C LJ et al (1995) The effects of fetal
10.1111/j.1651-2227.2008.00916.x experience with sound fetal development. A psychobi-
Butt ML, Kisilevsky B (2000) Music modulates behaviour ological perspective. In: Lawrence Erlbaum Associ-
of premature infants following heel lance. Can J Nurs ates. Hillsdale, pp 351–366
Res 31:17–39 Franck LS, Miaskowski C (1997) Measurement of neona-
Campos RG (1989) Soothing pain-elicited distress in infants tal responses to painful stimuli: a research review. J
with swaddling and pacifiers. Child Dev 60:781–792 Pain Symptom Manag 14:343–378. https://doi.org/
Campos RG (1994) Rocking and pacifiers: two comforting 10.1016/S0885-3924(97)00222-4
interventions for heelstick pain. Res Nurs Heal Franck LS, Cox S, Allen A, Winter I (2004) Parental
17:321–331 concern and distress about infant pain. Arch Dis Child
Carbajal R, Veerapen S, Couderc S et al (2003) Analgesic Fetal Neonatal Ed 89:F71–F75. https://doi.org/
effect of breast feeding in term neonates: randomised 10.1136/fn.89.1.F71
controlled trial. BMJ 326:13 Freire NB, Garcia JB, Lamy ZC (2008) Evaluation of
Carbajal R, Lenclen R, Jugie M et al (2005) Morphine does analgesic effect of skin-to-skin contact compared to
not provide adequate analgesia for acute procedural pain oral glucose in preterm neonates. Pain 139:28–33.
among preterm neonates. Pediatrics 115:1494–1500 https://doi.org/10.1016/j.pain.2008.02.031
Carbajal R, Rousset A, Danan C et al (2008) Epidemiology Gao H, Xu G, Gao H et al (2015) Effect of repeated Kan-
and treatment of painful procedures in neonates in garoo Mother Care on repeated procedural pain in pre-
intensive care units. JAMA 300:60–70. https://doi. term infants: a randomized controlled trial. Int J Nurs
org/10.1001/jama.300.1.60 Stud 52:1157–1165. https://doi.org/10.1016/j.ijnurstu.
Chermont AG, Falcão LFM, de Souza Silva EHL et al (2009) 2015.04.006
Skin-to-skin contact and/or oral 25% dextrose for proce- Giannakoulopoulos X, Sepulveda W, Kourtis P et al (1994)
dural pain relief for term newborn infants. Pediatrics 124: Fetal plasma cortisol and β-endorphin response to intra-
e1101–e1107. https://doi.org/10.1542/peds.2009-0993 uterine needling. Lancet 344:77–81. https://doi.org/
Cignacco E, Hamers JP, Stoffel L et al (2007) The efficacy 10.1016/S0140-6736(94)91279-3
of non-pharmacological interventions in the manage- Giannakoulopoulos X, Sepulveda W, Kourtis P (1999)
ment of procedural pain in preterm and term neonates. Human fetal and maternal noradrenaline responses to
A systematic literature review. Eur J Pain 11:139–152. invasive procedures. Pediatr Res 45:494–499
https://doi.org/10.1016/j.ejpain.2006.02.010 Goubet N, Rattaz C, Pierrat V et al (2003) Olfactory expe-
Cignacco EL, Sellam G, Stoffel L et al (2012) Oral sucrose rience mediates response to pain in preterm newborns.
and “facilitated tucking” for repeated pain relief in Dev Psychobiol. https://doi.org/10.1002/dev.10085
preterms: a randomized controlled trial. Pediatrics Goubet N, Strasbaugh K, Chesney J (2007) Familiarity
129:299–308. https://doi.org/10.1542/peds.2011-1879 breeds content? Soothing effect of a familiar odor on
Clancy B, Silva-Filho M, Friedlander MJ (2001) Structure full-term newborns. J Dev Behav Pediatr. https://doi.
and projections of white matter neurons in the postnatal org/10.1097/dbp.0b013e31802d0b8d
rat visual cortex. J Comp Neurol 434:233–252. https:// Gradin M, Finnstrom O, Schollin J (2004) Feeding and oral
doi.org/10.1002/cne.1174 glucose – additive effects on pain reduction in
25 Neonatal Pain: Neurophysiology, Recognition, Prevention, and Management with. . . 379
newborns. Early Hum Dev 77:57–65. https://doi.org/ (1):CD008435. https://doi.org/10.1002/14651858.
10.1016/j.earlhumdev.2004.01.003 CD008435.pub2
Gray L, Watt L, Blass EM (2000) Skin-to-skin contact is Kashaninia Z, Sajedi F, Rahgozar M, Noghabi FA (2008)
analgesic in healthy newborns. Pediatrics 105, e14 The effect of kangaroo care on behavioral responses to
Gray L, Miller LW, Philipp BL, Blass EM (2002) pain of an intramuscular injection in neonates. J Spec
Breastfeeding is analgesic in healthy newborns. Pedi- Pediatr Nurs 13:275–280. https://doi.org/10.1111/
atrics 109:590–593 j.1744-6155.2008.00165.x
Gupta NK, Upadhyay A, Agarwal A et al (2013) Kataria M, Narang S, Chawla D et al (2015) Oral dextrose
Randomized controlled trial of topical EMLA and for pain management during laser treatment of retinop-
breastfeeding for reducing pain during wDPT vaccina- athy of prematurity under topical anesthesia. Indian J
tion. Eur J Pediatr 172:1527–1533. https://doi.org/ Pediatr 82:694–697. https://doi.org/10.1007/s12098-
10.1007/s00431-013-2076-6 015-1718-2
Guyatt GH, Oxman AD, Vist GE et al (2009) GRADE: Kostandy RR, Anderson GC, Good M (2013) Skin-to-skin
an emerging consensus on rating quality of evidence contact diminishes pain from hepatitis B vaccine injec-
and strength of recommendations. Chin J Evid-Based tion in health full-term neonates. Neonatal Netw
Med 9:8–11. https://doi.org/10.1136/bmj.39489. 32:274–280
470347.AD Kostoví I, Judaš M (2002) Correlation between the sequen-
Hepper PG, Shahidullah S (1994) Development of fetal tial ingrowth of afferents and transient patterns of cor-
hearing. Arch Dis Child 71:8–1 tical lamination in preterm infants. Anat Rec 267:1–6.
Hevner RF (2000) Development of connections in the https://doi.org/10.1002/ar.10069
human visual system during fetal mid-gestation: a DiI- Kostovic I, Goldman-Rakic PS (1983) Transient cholines-
tracing study. J Neuropathol Exp Neurol 59:385–392 terase staining in the mediodorsal nucleus of the thala-
Holsti L, Oberlander TF, Brant R (2011) Does mus and its connections in the developing human and
breastfeeding reduce acute procedural pain in preterm monkey brain. J Comp Neurol 219:431–437
infants in the neonatal intensive care unit? A random- Kostović I, Jovanov-Milosevic N (2008) Subplate zone of
ized clinical trial. Pain 152:2575–2581. https://doi.org/ the human brain: historical perspective and new con-
10.1016/j.pain.2011.07.022 cepts. Coll Antropol 32:3–8
Huang CM, Tung WS, Kuo LL, Ying-Ju C (2004) Com- Kostović I, Rakic P (1990) Developmental history of the
parison of pain responses of premature infants to the transient subplate zone in the visual and somatosensory
heelstick between containment and swaddling. J Nurs cortex of the macaque monkey and human brain. J
Res 12:31–40 Comp Neurol 297:441–470
Ipp M, Taddio A, Goldbach M et al (2004) Effects of age, Kostović I, Fucic A, Mrzljak L (1991) Prenatal and perinatal
gender and holding on pain response during infant development of the somatostatin containing neurons in
immunization. Can J Clin Pharmacol J Can Pharmacol the human prefrontal cortex. Neurosci Lett 124:153–156
Clin 11:2–7 Kostović I, Judas M, Rados M, Hrabac P (2002) Laminar
Johnston CC, Stevens BJ (1996) Experience in a neonatal organization of the human fetal cerebrum revealed by
intensive care unit affects pain response. Pediatrics histochemical markers and magnetic resonance imag-
98:925–930 ing. Cereb Cortex 12:536–544. https://doi.org/
Johnston CC, Stremler R, Horton L et al (1999) Effect of 10.1093/cercor/12.5.536
repeated doses of sucrose during heel stick procedure in Lavoie PM, Stritzke A, Ting J et al (2015) A randomized
preterm neonates. Biol Neonate 75:160–166 controlled trial of the use of oral glucose with or with-
Johnston CC, Filion F, Snider L et al (2002) Routine out gentle facilitated tucking of infants during neonatal
sucrose analgesia during the first week of life in neo- echocardiography. PLoS ONE. https://doi.org/
nates younger than 31 weeks’ postconceptional age. 10.1371/journal.pone.0141015
Pediatrics 110:523–528 Lee GY, Yamada J, Kyololo OM et al (2014) Pediatric
Johnston CC, Stevens B, Pinelli J et al (2003) Kangaroo clinical practice guidelines for acute procedural pain:
care is effective in diminishing pain response in preterm a systematic review. Pediatrics 133:500–515. https://
neonates. Arch Pediatr Adolesc Med 157:1084–1088. doi.org/10.1542/peds.2013-2744
https://doi.org/10.1001/archpedi.157.11.1084 Lefrak L, Burch K, Caravantes R et al (2006) Sucrose
Johnston CC, Filion F, Nuyt AM (2007) Recorded mater- analgesia: identifying potentially better practices.
nal voice for preterm neonates undergoing heel lance. Pediatrics 118:S197–S202. https://doi.org/10.1542/
Adv Neonatal Care 7:258–266. https://doi.org/ peds.2006-0913R
10.1097/01.ANC.0000296634.26669.13 Leite AM, Linhares MBM, Lander J et al (2009) Effects
Johnston C, Barrington KJ, Taddio A et al (2011) Pain in of breastfeeding on pain relief in full-term newborns.
Canadian NICUs have we improved over the past 12 Clin J Pain 25:827–832. https://doi.org/10.1097/
years? Clin J Pain 27:225–232 AJP.0b013e3181b51191
Johnston C, Campbell-Yeo M, Fernandes A, Inglis D, Liaw J-J, Yang L, Katherine Wang K-W et al (2012)
Streiner D, Zee R (2014) Skin-to-skin care for proce- Non-nutritive sucking and facilitated tucking relieve
dural pain in neonates. Cochrane Database Syst Rev preterm infant pain during heel-stick procedures: a
380 C. V. Bellieni et al.
prospective, randomised controlled crossover trial. Int J Nesargi SV, Nithyanandam S, Rao S et al (2015) Topical
Nurs Stud 49:300–309. https://doi.org/10.1016/j. anesthesia or oral dextrose for the relief of pain in
ijnurstu.2011.09.017 screening for retinopathy of prematurity: a randomized
Liaw JJ, Yang L, Lee CM et al (2013) Effects of combined controlled double-blinded trial. J Trop Pediatr
use of non-nutritive sucking, oral sucrose, and facili- 61:20–24. https://doi.org/10.1093/tropej/fmu058
tated tucking on infant behavioural states across heel- Nimbalkar S, Sinojia A, Dongara A (2013) Reduction of
stick procedures: a prospective, randomised controlled neonatal pain following administration of 25% lingual
trial. Int J Nurs Stud. https://doi.org/10.1016/j. dextrose: a randomized control trial. J Trop Pediatr.
ijnurstu.2012.08.021 https://doi.org/10.1093/tropej/fms072
Linhares MBM, Gaspardo CM, Souza LO et al (2014) Obeidat HM, Shuriquie MA (2015) Effect of breast-feeding
Examining the side effects of sucrose for pain relief in and maternal holding in relieving painful responses in
preterm infants: a case-control study. Braz Med Biol full-term neonates. J Perinat Neonatal Nurs 29:248–254.
Res. https://doi.org/10.1590/1414-431X20143659 https://doi.org/10.1097/JPN.0000000000000121
Liu M, Zhao L, Li XF (2015) Effect of skin contact Okado N (1981) Onset of synapse formation in the human
between mother and child in pain relief of full-term spinal cord. J Comp Neurol 201:211–219
newborns during heel blood collection. Clin Exp Obstet Okan F, Ozdil A, Bulbul A et al (2010) Analgesic effects of
Gynecol 42:304–308 skin-to-skin contact and breastfeeding in procedural pain
Lowery CL, Hardman MP, Manning N et al (2007) in healthy term neonates. Ann Trop Paediatr 30:119–128.
Neurodevelopmental changes of fetal pain. Semin https://doi.org/10.1179/146532810X12703902516121
Perinatol 31:275–282. https://doi.org/10.1053/j. Ou-Yang MC, Chen IL, Chen CC et al (2013) Expressed
semperi.2007.07.004 breast milk for procedural pain in preterm neonates: a
Mandel R, Ali N, Chen J et al (2012) Nitrous oxide anal- randomized, double-blind, placebo-controlled trial.
gesia during retinopathy screening: a randomised con- Acta Paediatr Int J Paediatr 102:15–21. https://doi.
trolled trial. Arch Dis Child Fetal Neonatal Ed 97: org/10.1111/apa.12045
F83–F87. https://doi.org/10.1136/adc.2011.210740 Perkins L, Hughes E, Glover A (2005) Exploring subplate
Marin Gabriel MA, Del Rey Hurtado de Mendoza B, evolution of the fetal cortex using magnetic resonance
Jimenez Figueroa L et al (2013) Analgesia with imaging. In: Neonatal Society
breastfeeding in addition to skin-to-skin contact during Peyrovi H, Alinejad-Naeini M, Mohagheghi P, Mehran A
heel prick. Arch Dis Child Fetal Neonatal Ed. https:// (2014) The effect of facilitated tucking position during
doi.org/10.1136/archdischild-2012-302921 endotracheal suctioning on physiological responses
Marín Gabriel MÁ, del Rey Hurtado de Mendoza B, Jiménez and coping with stress in premature infants: a random-
Figueroa L et al (2013) Analgesia with breastfeeding in ized controlled crossover study. J Matern Neonatal
addition to skin-to-skin contact during heel prick. Arch Med. https://doi.org/10.3109/14767058.2013.868429
Dis Child Fetal Neonatal Ed 98:F499–F503. https://doi. Phillips RM, Chantry CJ (2002) Is breastfeeding more
org/10.1136/archdischild-2012-302921 analgesic than pacifier? In: Pediatric Academic Socie-
McNair C, Campbell-Yeo M, Johnston C, Taddio A ties’ Annual Meeting. Baltimore
(2013) Nonpharmacological management of pain Phillips RM, Chantry CJ, Gallagher MP (2005) Analge-
during common needle puncture procedures in sic effects of breast-feeding or pacifier use with
infants: current research evidence and practical con- maternal holding in term infants. Ambul Pediatr
siderations. Clin Perinatol 40:493. https://doi.org/ 5:359–364
10.1016/j.clp.2013.05.003 Pillai Riddell RR, Racine NM, Turcotte K, et al (2015)
Modarres M, Jazayeri A, Rahnama P, Montazeri A (2013) Non-pharmacological management of infant and
Breastfeeding and pain relief in full-term neonates dur- young child procedural pain. Cochrane Database Syst
ing immunization injections: a clinical randomized Rev CD006275. https://doi.org/10.1002/14651858.
trial. BMC Anesthesiol 13:22. https://doi.org/10.1186/ CD006275.pub2
1471-2253-13-22 Porter FL, Grunau RE, Anand KJ (1999) Long-term effects
Mosayebi Z, Javidpour M, Rahmati M, et al (2014) The of pain in infants. J Dev Behav Pediatr 20:253–261
effect of kangaroo mother care on pain from heel lance Potana NT, Dongara AR, Nimbalkar SM et al (2015) Oral
in preterm newborns admitted to neonatal intensive sucrose for pain in neonates during echocardiography: a
care unit : a crossover randomized clinical trial. J randomized controlled trial. Indian Pediatr 52:493–497
Compr Ped 5(4) Prasopkittikun TTF (2003) Management of pain from
Mrzljak L, Uylings HB, Kostovic I (1988) Prenatal devel- heel stick in neonates: an analysis of research
opment of neurons in the human prefrontal cortex: I. A conducted in Thailand. J Perinat Neonatal Nurs 17:
qualitative golgi study. J Comp Neurol 271:355–386 304–312
Nanavati RN, Balan R, Kabra NS (2013) Effect of kanga- Rainville P, Duncan GH, Price DD et al (1997) Pain affect
roo mother care vs expressed breast milk administra- encoded in human anterior cingulate but not somato-
tion on pain associated with removal of adhesive tape in sensory cortex. Science 277(5328):968–971
very low birth weight neonates: a randomized con- Rainville P, Carrier B, Hofbauer RK et al (1999) Dissoci-
trolled trial. Indian Pediatr 50:1011–1015 ation of sensory and affective dimensions of pain using
25 Neonatal Pain: Neurophysiology, Recognition, Prevention, and Management with. . . 381
hypnotic modulation. Pain 82:159–171. https://doi.org/ Stevens B, Yamada J, Gy L et al (2013) Sucrose for
10.1016/S0304-3959(99)00048-2 analgesia in newborn infants undergoing painful pro-
Ranger M, Zwicker JG, Chau CMY et al (2015) Neonatal cedures. Cochrane Database Syst Rev 1, CD001069.
pain and infection relate to smaller cerebellum in very https://doi.org/10.1002/14651858.CD001069.pub4
preterm children at school age. J Pediatr 167:292–298. Taddio A, Katz J, Ilersich AL, Koren G (1997) Effect of
https://doi.org/10.1016/j.jpeds.2015.04.055 neonatal circumcision on pain response during subse-
Rattaz C, Goubet N, Bullinger A (2005) The calming effect quent routine vaccination. Lancet 349:599–603. https://
of a familiar odor on full-term newborns. J Dev Behav doi.org/10.1016/S0140-6736(96)10316-0
Pediatr. https://doi.org/10.1097/00004703-200504000- Taddio A, Shah V, Hancock R et al (2008) Effectiveness of
00003 sucrose analgesia in newborns undergoing painful
Rosali L, Nesargi S, Mathew S et al (2015) Efficacy of medical procedures. C Can Med Assoc J 179:37–43.
expressed breast milk in reducing pain during ROP https://doi.org/10.1503/cmaj.071734
screening – a randomized controlled trial. J Trop Pediatr Taddio A, McMurtry CM, Shah V et al (2015) Reducing
61:135–138. https://doi.org/10.1093/tropej/fmu073 pain during vaccine injections: clinical practice guide-
Ruda MA, Ling Q, Hohmann AG, et al (2016) Altered line. CMAJ 187:975–982. https://doi.org/10.1503/
nociceptive neuronal circuits after neonatal peripheral cmaj.150391
inflammation. 289:628–630 Teixeira JMA, Glover V, Fisk NM (1999) Acute cerebral
Shah PS, Herbozo C, Aliwalas LL, Shah VS (2012) redistribution in response to invasive procedures in the
Breastfeeding or breast milk for procedural pain in human fetus. Am J Obstet Gynecol 181:1018–1025.
neonates. Cochrane Database Syst Rev 12, CD00 https://doi.org/10.1016/S0002-9378(99)70340-6
4950. https://doi.org/10.1002/14651858.CD004950. Valeri BO, Ranger M, Chau C, et al (2015) Neonatal
pub3 invasive procedures predict pain intensity at school
Shu SH, Lee YL, Hayter M, Wang RH (2014) Efficacy of age in children born very preterm
swaddling and heel warming on pain response to heel Valman HB, Pearson JF (1980) What the fetus feels. Br
stick in neonates: a randomised control trial. J Clin Med J 280:233–234
Nurs. https://doi.org/10.1111/jocn.12549 Van de Velde M, Jani J, De Buck F, Deprest J (2006) Fetal
Simons SH, van Dijk M, Anand KS et al (2003) Do we still pain perception and pain management. Semin Fetal
hurt newborn babies? A prospective study of procedural Neonatal Med 11:232–236. https://doi.org/10.1016/j.
pain and analgesia in neonates. Arch Pediatr Adolesc siny.2006.02.012
Med 157:1058–1064. https://doi.org/10.1001/ Vanhatalo S, Van Nieuwenhuizen O (2000) Fetal pain?
archpedi.157.11.1058 Brain Dev 22:145–150. https://doi.org/10.1016/
Simonse E, Mulder PG, van Beek RH (2012) Analgesic S0387-7604(00)00089-9
effect of breast milk versus sucrose for analgesia during Weissman A, Aranovitch M, Blazer S, Zimmer EZ (2009)
heel lance in late preterm infants. Pediatrics Heel-lancing in newborns: behavioral and spectral
129:657–663. https://doi.org/10.1542/peds.2011-2173 analysis assessment of pain control methods. Pediatrics
Skogsdal Y, Eriksson M, Schollin J (1997) Analgesia in 124:e921–e926. https://doi.org/10.1542/peds.2009-0598
newborns given oral glucose. Acta Paediatr Int J Wladimiroff JW, van den Wijngaard JA, Degani S et al
Paediatr 86:217–220 (1987) Cerebral and umbilical arterial blood flow
Slater R, Cantarella A, Gallella S et al (2006) Cortical pain velocity waveforms in normal and growth-retarded
responses in human infants. J Neurosci 26:3662–3666. pregnancies. Obstet Gynecol 69:705–709
https://doi.org/10.1523/jneurosci.0348-06.2006 Woo JS, Liang ST, Lo RL, Chan FY (1987) Middle cere-
Slater R, Cornelissen L, Fabrizi L, et al (2010) Oral sucrose bral artery doppler flow velocity waveforms. Obstet
as an analgesic drug for procedural pain in newborn Gynecol 70:613–616
infants: a randomised controlled trial. Lancet 376 Wyatt J (2007) End-of-life decisions, quality of life and the
(9748):1225–1232. https://doi.org/10.1016/S0140- newborn. Acta Paediatr Int J Paediatr 96:790–791.
6736(10)61303-7 https://doi.org/10.1111/j.1651-2227.2007.00349.x
Stevens B, Johnston C, Petryshen P, Taddio A (1996) Yew DT, Luo CB, Luo JM et al (2001) Substance P and
Premature infant pain profile: development and initial enkephalin containing fibers in the developing
validation. Clin J Pain 12:13–22 nucleus dorsalis of the human spinal cord. Neurosci
Stevens B, Johnston C, Taddio A et al (1999) Management Lett 312:87–90. https://doi.org/10.1016/S0304-3940
of pain from heel lance with lidocaine-prilocaine (01)02200-5
(EMLA) cream: is it safe and efficacious in preterm Zuppa AF, Mondick JT, Davis L, Cohen D (2009) Popu-
infants? J Dev Behav Pediatr 20:216–221 lation pharmacokinetics of ketorolac in neonates and
Stevens B, Yamada J, Beyene J et al (2005) Consistent young infants. Am J Ther 16:143–146
management of repeated procedural pain with sucrose
in preterm neonates: is it effective and safe for repeated
use over time? Clin J Pain 21:543–548
Neonatal Anesthesia
26
Nicola Disma, Leila Mameli, Rachele Bonfiglio,
Clelia Zanaboni, and Pietro Tuo
Contents
26.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384
26.2 Anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384
26.2.1 Preanesthesia Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384
26.2.2 Intraoperative Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384
26.2.3 Anesthesia for Preterm and Ex-Premature Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
26.2.4 Regional Anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
26.2.5 Anesthesia Outside the Operating Room . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
26.3 Analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
26.3.1 Effects of Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
26.3.2 Pain in the Neonatal Intensive Care Unit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
26.3.3 Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
26.3.4 Paracetamol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
26.3.5 Ketamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392
26.3.6 Midazolam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392
26.3.7 Neonatal Anesthesia and the Risk of Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . 392
26.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
Abstract neonatal age, in order to correctly apply the
Administration of the anesthetic drugs, surgery principles of the neonatal anesthesia. The peri-
and the underlying disease, can interfere with natal period and the delivery provide us impor-
the developmental changes of the neonatal life. tant details for the complete medical history, and
For this reason, it is mandatory for the pediatric the complete preoperative anesthetic evaluation
anesthetist to know the pathophysiology of the should be focussed on the infants’ transition
from the fotal to the neonatal life. Moreover,
the techniques for induction and maintenance
N. Disma (*) · L. Mameli · R. Bonfiglio · C. Zanaboni · of anesthesia may vary with the infant’s size, the
P. Tuo gestational age, medical status, and surgical
Department of Anesthesia, Pediatric and Neonatal
procedure. Regional anesthesia is widely used
Intensive Care, Istituto Giannina Gaslini, Genoa, Italy
e-mail: [email protected]; [email protected]; for intra- and postoperative analgesia and spinal
[email protected]; lea.bonfi[email protected]; anesthesia, and it can be considered a useful
lea.bonfi[email protected]; [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 383
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_176
384 N. Disma et al.
alternative to general anesthesia, especially to drugs administered to this vulnerable population
prevent the risk of postanesthesia apnea. and the consequent long-term cognitive effects.
Postoperative pain can be pharmacologi- This task will be discussed in detail at the end of
cally safely treated with opioid, paracetamol, this chapter.
or regional anesthesia, when handled by an For all the above mentioned reasons, pediatric
experienced pediatric acute pain service. anesthesiologists should know the pathophysiol-
ogy of the neonatal age, the interference of under-
lying diseases with anesthesia, and the correct
26.1 Salient Points application of basic principles for neonatal anes-
thesia. In addition, neonates and young infants
• Neonates represent a fragile population, prone should undergo anesthesia and surgery only in
to perioperative complications and life- specialized centers, where a neonatal resuscitation
threatening events. or intensive care is available. All neonates and
• Appropriate perioperative management is small infants should always receive the most
mandatory for improving short- and long- appropriate, timely and safe treatment.
term outcomes.
• Isotonic fluids should be used for intra- and
immediate postoperative management. 26.2.1 Preanesthesia Assessment
• Regional anesthesia has to be considered as
part of multimodal analgesia program, when- The intrauterine, the perinatal, and the delivery
ever applicable. period are all relevant parts of the medical history
• Inadequate pain treatment has detrimental and the preanesthesia assessment for those neo-
effects on postoperative outcome. nates undergoing anesthesia. In particular, the
• Recent studies performed in animals have intrauterine environment can interfere with the
raised concern that anesthetic drugs can be growth and the ability of the neonate to adapt to
neurotoxic. The GAS Study is the only RCT extrauterine life.
that has demonstrated no negative effects on Maternal exposure to some drugs (e.g., phenyt-
long-term neurological outcome in children. oin, alcohol, steroids) or placental blood flow
abnormalities may result in poor growth of the
fetus or premature labor. A complicated labor
26.2 Anesthesia and delivery may result in respiratory, cardiovas-
cular, and metabolic instability for a variable
About 1.5 million neonates are exposed to anes- length of time. Also the gestational age and the
thesia every year, and it is well established that weight can be related to some perinatal problems.
this population of patients is very fragile and The physical examination starts with the ges-
prone to perioperative complications and life- tational age and the weight of the baby. Infants are
threatening events. This is due to several factors: classified as “term” if greater than 37 weeks ges-
the peculiar physiology of neonates, the immatu- tational age and “low birth weight” if weight less
rity of organs and systems, the frequent coexisting than 2.5 kg. A complete examination must be
comorbidities (such as extreme prematurity, con- performed before withholding anesthesia in an
genital malformations, congenital heart disease infant, with particular care to some body areas
and others), and the incomplete understanding of and systems, as summarized in the Table 1.
the pharmacology of the routinely used anes-
thetics drug. Moreover, even when anesthesia is
correctly delivered, there could be the risk that it 26.2.2 Intraoperative Management
interferes with the normal development of the
neonatal brain. In fact, there is increased aware- Safe and effective intraoperative management of
ness of the potential neurotoxicity of anesthetic the newborn depends on a profound understanding
26 Neonatal Anesthesia 385
Table 1 Interaction between anesthesia and neonatal physiology
Organs/
systems Pathophysiology Anesthetic implication
Head and neck Micrognathia Possible difficulties in airway management
CHARGE syndrome Peculiar embryology and anatomy in preterm and term
infants
Respiratory Immaturity of control mechanism Respiratory depression in case of hypoxia
More compliant chest wall Airway collapse
10–25% type I fibers Predisposition to respiratory fatigue
Surfactant deficiency RDS
Oxygen toxicity BPD development
Cardiovascular Hypoxemia or acidosis Return to fetal circulation, persistent fetal circulation
(PFC), persistent pulmonary hypertension of the newborn
(PPHN)
CNS Fragile vessels Increased risk of hemorrhage
Immaturity of cerebral blood flow Hypoxia, acidosis, seizures may disrupt autoregulation
Renal Immaturity Lost of electrolytes
Metabolic Active transplacentar delivery of Hypocalcemia
calium and transient Hypoglicemia
hypoparathyroidism
Delay in normal feeding
Table 2 Airway management in neonate
Anatomy of the newborn Action during tracheal intubation
Prominent occiput and “Sniffing position” without the additional support of a pillow under the head neck
large head
Larynx is cephalad Extension of the neck may impede visualizing of the vocal cords, gentle pressure with
(C4) and anterior finger can facilitate larynx view
Epiglottis Large and with “Ʊ form”, difficult visualization of the vocal cords
Narrow nostril and large Obligate nasal breathing, airway obstruction, possible bleeding
tongue
Cricoids Is the narrowest airway of the newborn, small and uncuffed tubes
of physiology and pharmacology. Moreover, tech- Neonates with expected difficult airway man-
nical aspects of monitoring and anesthesia equip- agement (micrognathia, macroglossia, protruding
ments have to be considered. maxilla, cleft palate, masses obstructing the air-
way) must not be paralyzed. Tracheal intubation
26.2.2.1 Induction of Anesthesia can be performed with a pharmacological seda-
and Tracheal Intubation tion and the infant in spontaneous breathing.
The techniques for induction of anesthesia vary Topic anesthesia with lidocaine on the vocal
with the infant’s size, the gestational age, medical cords can facilitate tracheal intubation.
status, and surgical procedure. The anatomical peculiarities of the neonate and
A specific case is the infant with a full stomach. the subsequent anesthetic implications are sum-
An “awake” or a rapid sequence intubation should marized in Table 2.
be performed, but the first is associated with sig- The Miller-0 straight laryngoscope blade is the
nificant morbidity (increased intracranial pressure, most commonly recommended device for visual-
bradycardia, desaturation, etc) and the second is a izing the airway for tiny neonate, preterm or of
real challenge especially in small preterms. low birth weight, and the Miller-1 is used in the
386 N. Disma et al.
term neonate. Uncuffed 3.0–3.5 mm endotracheal 4. Other fluid losses. They include those from
tubes are usually the appropriate size to intubate suction or removal of gastric intestinal or
the trachea in neonates, and the choice of cuffed drainage of an ileostomy, diarrhea, or exces-
tubes is an effective alternative if the pressure of sive sweat losses. In these cases the electrolyte
the cuff is carefully monitored (<20 cmH2O). A content of the fluid losses should be measured
tightly fitting tube can damage the subglottic to determine replacement fluids.
mucosa, causing edema and postoperative stridor
or more rarely subglottic stenosis. A small leak Urine output indicates normal hydratation
around the tube during manual positive breath (0.5–2 ml/kg/h). Serum osmolarity is also a useful
(about 20 cmH2O pressure) ensures that the size monitor of electrolyte and fluid therapy.
of the endotracheal tube is adequate. Standard hemodynamic intraoperative moni-
Ensuring the appropriate depth in the trachea toring contributes to assessing the adequacy of
of the newborn also requires attention. The dis- fluid therapy.
tance from the vocal cords to the carina in the term Similar to older infants, the decision to deliver
infant is about 4 cm. blood during surgery depends on the underlying
and current cardiorespiratory status, ongoing
26.2.2.2 Intraoperative Fluid Therapy blood loss, anticipated further blood loss, and
It has four components: baseline hemoglobin. Transfusion of other com-
ponents of blood should be guided by a combina-
1. Maintenance fluid. Fluid loses consist primar- tion of laboratory studies and the clinical status.
ily of insensible water loss from the respiratory
system, evaporation from the skin, and urinary 26.2.2.3 Anesthetic Drugs: Inhaled
and fecal loss. 100 ml/kg/day is the normal and Intravenous Agents
requirement. Isotonic fluids are mandatory dur- The aim of anesthesia is to provide insensibility to
ing anesthesia to minimize the risk of cerebral pain and immobility during surgery. Anesthesia
edema. may be provided by regional or general anesthesia
2. Fluid deficits. They are caused primarily by or the combination of both. General anesthesia
preoperative fasting or excessive gastrointesti- can be delivered using both inhaled and intrave-
nal losses without parenteral replacement. It is nous drugs for a variety of surgical procedures.
calculated by multiplying the hourly mainte- Minimum alveolar concentration (MAC)
nance requirement by the number of hours defines the anesthetic depth for inhaled agents at
since the last fluid intake. which 50% of patients respond to painful stimulus
3. Third space fluid loss. Surgical trauma can result with movement. It has been found that MAC is
in translocation of extracellular fluid from the considerably less in preterm than in full-term
intravascular space into the interstitial space infants and that 1 MAC of inhaled drugs results
(edema in bowel wall and mesentery during in 20–30% reduction in arterial pressure.
intraabdominal surgery). Guidelines for replace- Sevoflurane, newer inhaled agent, affords a rapid
ment of third space losses include the following: induction and emergence from general anesthesia
(a) Superficial surgery: 1–2 ml/kg/h and is widely used for anesthesia in infants. More-
(b) Abdominal, chest of hip surgery: over, sevoflurane possesses less airway irritability
3–4 ml/kg/h than isoflurane and desflurane, and it can be used
(c) Extensive abdominal surgery: 6–10 ml/kg/h for inhaled induction and in infants with bronco
or more pulmonary dysplasia. The traditional mask induc-
Third space loss must be replaced with an tion of anesthesia is accomplished with incremental
isotonic or isoosmotic solution such as normal increases in sevoflurane up to 7–8%, in a mixture
saline solution, lactate ringer’s solution, or of oxygen and air. Maintenance of anesthesia is
other balanced salt solutions. performed with up to 1 MAC of sevoflurane, and
26 Neonatal Anesthesia 387
Table 3 Principal drugs used for neonatal anesthesia and their doses
Induction Maintenance
Sevoflurane Incremental, up to 8% 0.5–2 MAC
Ketamine 1–2 mg/kg Not recommended
Propofol 2–5 mg/kg 50–200 μ/kg/min
Thiopentanl 4–6 mg/kg Not recommended
Midazolam 0.05–0.2 mg/kg 100–200 μ/kg/h
Fentanil 0.5–3 μ/kg Up to 100 μ/kg for cardiac or major surgery
Remifentanil 0.1–1 μ/kg/min 0.1–1 μ/kg/min
it can be reduced in case of opioid administration or anesthetics. The benefit of providing adequate
combination with regional anesthesia. anesthesia and analgesia must be carefully bal-
Intravenous drugs for anesthesia may include anced with the significant risk of cardiorespiratory
opioids, benzodiazepines, propofol, ketamine, depression in this fragile population.
barbiturates, and dexmedetomidine, which is
recently introduced in clinical practice. Opioids
26.2.4 Regional Anesthesia
possess analgesic and sedative properties, and
they are usually combined with hypnotic drugs
Epidural analgesia in combination with light
as propofol or benzodiazepines. Pharmacokinetic
general anesthesia is a useful alternative for
of fentanyl has been studied in infants and the
infants and neonates undergoing major surgery,
elimination half-time has been found to be from
avoiding the adverse effects related to systemic
6 to 32 h, which is significantly longer than in
administration of opioids and other agents. Apart
adults. Remifentanil, a synthetic short acting opi-
from providing good intraoperative and postoper-
oid, is rapidly inactivated by esterases in blood and
ative analgesia, epidural blockade has beneficial
tissues and due to its short half-life is administered
effects on the humoral, metabolic, hemodynamic
by continuous infusion. For this reason it is now
responses to surgery and it may improve postop-
largely used in all ages and is a suitable opioid even
erative respiratory performance.
in small infants (Sammartino et al. 2010).
The complication rate of epidural analgesia
Doses of some anesthetic drugs are summa-
performed by experienced hands is very low.
rized in Table 3.
Caudal epidural anesthesia remains the most
frequently performed regional anesthesia tech-
26.2.3 Anesthesia for Preterm nique in infants and children. It is a popular “sin-
and Ex-Premature Infants gle shot” technique characterized by a high level
of efficacy and safety.
Preterm and ex-premature infants undergoing elec- Because the level of the plasma protein α1-acid
tive surgery are more likely to encounter perioper- glycoprotein, albumin, and bicarbonate reserves
ative apnea than term infants. Factor predisposing are lower in neonates compared with children,
premature infants to apnea include hypoglycemia, neonates are at gratest risk of local anesthetic
hypoxia, hyperoxia, sepsis, anemia, hypocalcemia, toxicity, like severe cardiac dysrhythmia, hemo-
and pharmacologic effects of general anesthesia on dynamic instability, respiratory arrest, or seizures
the immature respiratory centers. As a conse- that are the most common clinical presentation.
quence, postoperative monitoring is mandatory This can be avoided using bolus doses and infu-
for the 24 h following anesthesia. sion rates within recommended guidelines and by
Preterm and ex-premature infants may have taking into account pharmacokinetics of local
dramatic responses to narcotics and potent inhaled anesthetics in neonates.
388 N. Disma et al.
Table 4 Dose of local anesthetics for regional block in use at Gaslini Hospital
Regional Local anesthetic Bolus Continuous infusion
anesthesia (LA) Concentration (%) Dose LA/adjuvant Concentration Infusion rate
Caudal Naropine 0.2 1 ml/kg – Not
Levobupivacaine Clonidine 1–2 mcg/kg frequently
used
Lumbar Naropine 0.2 0.8–1 ml/kg 0.1% 0.2–0.4 ml/
epidural Levobupivacaine Clonidine 1–2 mcg/kg kg/h
Thoracic Naropine 0.2 0.6–0.8 ml/kg 0.1% 0.2–0.4 ml/
epidural Levobupivacaine Clonidine 1–2 mcg/kg kg/h
Spinal Naropine 0.5–0.75 1 mg/kg (minimum – –
Levobupivacaine 2.5 mg)
Bupivacaine Clonidine 1 mcg/kg
(selected cases)
The low intrinsic toxicity of new local anes- levobupivacaine, or bupivacaine 0.5% (less fre-
thetics like ropivacaine and levobupivacaine quently 0.75%) . Adjuvants like clonidine at the
make them ideal for regional anesthesia in children. dose of 1 mcg/kg can be added in case of expected
The use of spinal anesthesia for hernia repair prolonged surgery (Davidson et al. 2015a).
in premature infants with or without RDS is Doses of local anesthetics for regional anesthe-
reportedly a safe and satisfactory alternative to sia are displayed in Table 4.
general anesthesia. Even if the review of Craven
recently published in The Cochraine Database of
Systematic Reviews (Craven et al. 2003) shows 26.2.5 Anesthesia Outside
no reliable evidence of the effects of spinal anes- the Operating Room
thesia compared to general anesthesia on the inci-
dence of apnea, bradycardia, or oxygen Sedation outside the operating room or in remote
desaturation in ex-preterm infants, spinal anesthe- locations is increasingly called, particularly for
sia can be considered a safe procedure to avoid radiologic procedures and medical interventions.
general anesthesia-related risks. Providing anesthesia in locations far from the oper-
Data from the recently published GAS study ating room requires familiarity with the procedures
provided evidence that the incidence of early as well as careful and extensive planning and
apnea (from the end of anesthesia up to the first resources in order to manage life-threatening situa-
30 min) is significantly reduced with spinal anes- tions. Some of remote locations that may require
thesia compared with general anesthesia, but not sedation include dental clinics, gastroenterology
the incidence of late apnea. In fact, the overall suites, cardiology sites, plastic surgery centers, radi-
incidence of apnea after both regional or general ology suites, and oncology areas. It is advisable to
anesthesia is comparable in infants undergoing delegate a team of anesthetists that is committed to
inguinal hernia repair. The interpretation of this providing off-site anesthesia care. Each member of
recently published data is that with modern anes- the anesthesia team should rotate regularly through
thesia based on sevoflurane and caudal block the different off-site areas to maintain a familiarity
the incidence of postoperative anesthesia is simi- not only with the procedures and personnel but also
lar to spinal anesthesia alone, but a successful with the particular anesthesia demands unique to
regional anesthesia significantly reduces the inci- each area. A standard anesthesia cart should be at
dence of early apnea. The commonly used dosage each anesthesia site, fully stocked with essential
of local anesthetics for spinal anesthesia is of medications, necessary adjuvant equipment, a vari-
1 mg/kg (minimum 2.5 mg) of ropivacaine, ety of oral/nasopharyngeal airways, spare Ambu
26 Neonatal Anesthesia 389
bag, laryngoscope handles and blades, endotracheal aroused but respond after pain-
tubes, alternate airway devices including laryngeal ful stimulation. The ability to
mask airways (LMAs), suction catheters, and intra- independently maintain ventila-
venous supplies. tory function may be impaired.
The most important topic to be considered Patients may require assistance
before performing a sedation outside the operat- in maintaining a patent airway,
ing room, especially in infants younger than and spontaneous ventilation
1 month of age, are: may be inadequate.
General A drug-induced loss of con-
• History of ongoing apnea or prematurity with anesthesia sciousness during which
postconceptual age less than 60 weeks patients are not arousable, even
• Respiratory compromise and abnormal airway to painful stimulation. The abil-
• Congenital cardiac disease or unstable cardiac ity to independently maintain
status ventilatory function is often
• High-risk procedure impaired. Patients often require
• Inadequate qualified personnel or inadequate assistance in maintaining a pat-
anesthesia and resuscitation equipment ent airway, and positive pressure
ventilation may be required
A clear understanding of the definition of seda- because of depressed spontane-
tion is mandatory to recognize when the child has ous ventilation or drug-induced
progressed to a deeper level of sedation than depression of neuromuscular
anticipated and is at increased risk (i.e., from function. Cardiovascular func-
moderate sedation to deep sedation or from deep tion may be impaired.
sedation to general anesthesia). Recognition of
this transition allows escalation of monitoring Several anesthetics drugs (Michel and
and care to avoid complications. Constantin 2009; Cravero 2009) can be used for
The following are the definitions of the Amer- sedation in infants (Table 5). Our experience at
ican Academy of Paediatrics (AAP) and the Gaslini Hospital with neonatal sedation for MRI
American Society of Anaesthesiologists (ASA) and TC is with sevoflurane. Induction and mainte-
(American Society of Anesthesiologists Task nance in full-term babies without other
Force on Sedation and Analgesia by comorbidities is performed with sevoflurane as a
Non-Anesthesiologists 2002), strong considering single anesthetic drug. Airway manipulation is
that infants may quickly move from one level of minimized maintaining patients in spontaneous
sedation to another. breathing through a face mask or LMA, and
tracheal intubation is decided uniquely in case of
Minimal A drug-induced state during
respiratory or cardiac instability. About
sedation which patients respond nor-
1,200–1,500 pediatric sedations each year are
mally to verbal commands.
performed at Gaslini, and the incidence of respira-
Moderate A drug-induced depression of
tory depression or airway obstruction is negligible.
sedation consciousness during which
patients respond to light tactile
stimulation. No interventions
are required to maintain a patent 26.3 Analgesia
airway, and spontaneous venti-
lation is adequate. Interest in newborn and preterm pain has greatly
Deep A drug-induced depression of increased in the last three decades, including the
sedation consciousness during which pain associated with intensive care and surgery. In
patients cannot be easily the past, pain relief in these very vulnerable
390 N. Disma et al.
Table 5 Sedative drugs and doses for infants
Drug Doses Comments
Midazolam 0.5–0.75 mg/kg PO or ER Possible paradoxical effects. Doses must be reduced in
0.025–0.05 mg/kg IV case of concomitant opioid administration
0.02–0.03 mg/kg intranasal
Dexmedetomidine 2–5 mcg/kg PO Possible hemodynamic effects
1–2 mcg/kg IV (bolus in 10–15 min) Excellent respiratory drive
Ketamine 1–2 mg/kg IV Possible laryngospasm, apnea, agitation, hallucinations.
3–4 mg/kg IM Anticholinergic to control secretions. Frequent
4–6 mg/kg PO or ER associated tachycardia, hypertension, and
bronchodilatation. No antagonist available
Nitrous oxide 50% in 50% oxygen for “minimal Requires specialized equipment for delivery,
sedation,” up to 70% for moderate monitoring, and scavenging. When used alone or with
sedation local anesthesia is considered “minimal sedation.”
Contraindications include respiratory failure, altered
mental status, otitis media, bowel obstruction, and
pneumothorax
Sevoflurane 1–2 MAC inhalational Safely used for MRI and TC. It has little toxicity and it is
hemodynamic, and respiratory depressive effects are
moderate and well tolerated
Naloxone 0.01–0.1 EV or IM, may be repeated Specifically antagonizes opioid effects. Adverse
every two minutes reactions: nausea, vomiting, tachycardia, hypertension.
Reversal after long-term opioid use may lead to acute
withdrawal
Flumazenil 0.01–0.02 EV, may be repeated Specific benzodiazepine antagonist. Does not
every one minute antagonize opioids or other sedatives. Resedation may
occur in 1 h. Prolonged observation (2 h) required. Not
for routine sedation reversal
subjects has been neglected, reflecting the current of pain responses, resulting in possible future
beliefs and the resistance to change the normal behavior disorders.
practice.
26.3.2 Pain in the Neonatal Intensive
26.3.1 Effects of Pain Care Unit
The fetus is able to respond to noxious stimuli Though guidelines to manage pain in the Neonatal
increasing stress hormone levels and cerebral Intensive Care Unit (NICU) have been issued
blood flow, whereas fentanyl dampens the stress (American Academy of Pediatrics et al. 2006),
response of preterms undergoing surgery (Lowery many newborns undergo repetitive noxious proce-
et al. 2007). These observations support that auto- dures without adequate pain relief. Acute pain
nomic and metabolic reactions are triggered assessment can be a difficult task, either in discrim-
before the pain pathways are completed. Between inating pain from other causes of distress or in
17 and 25 weeks of gestational age, several neu- recognizing the pain cues in the most compromised
ronal types and dendritic and axonal network dif- babies. Moreover, signs of ongoing pain can be
ferentiate from subplate neurons, assigned to missing because of limited energy reserves and
guide the development of cortical and thalamic exhaustion in the sickest populations. Other obsta-
structures. Because of the nervous system plastic- cles in pain management can be the fear of respi-
ity, repetitive noxious stimuli reaching the sub- ratory depression, routine practice, old beliefs, and
plate neurons may result in formation of lack of validated prolonged pain assessment scales
permanent abnormal synapses and hyperactivity (Ranger et al. 2007).
26 Neonatal Anesthesia 391
Beyond procedural, perioperative and disease- of fentanyl are rapid development of tolerance and
related pain relief, sedation in neonates mechani- chest wall rigidity, particularly harmful in non-
cally ventilated has been advocated, aiming at pro- intubated infants. Fentanyl is usually administered
moving stress reduction, blood pressure stability, intravenously at the dosage of 1–3 μg/kg as a single
and ventilator synchrony, leading finally to a dose, followed by infusion of 0.5–2 μg/kg/h.
decrease of cerebral injury and death. In 2004 the Tolerance develops more rapidly with fentanyl
NEOPAIN multicenter trial evaluated 898 venti- (3–9 days) than with morphine and with continu-
lated preterm newborns randomized to receive ous infusion than with intermittent doses. Non-
morphine or placebo. The study did not demon- pharmacological measures and switching from
strate any difference in the incidence of intraven- opioids to sedatives (when appropriate) can
tricular hemorrhage, periventricular leukomalacia, reduce the risk of developing tolerance. More-
and death between the groups, while the morphine over, opioid tapering protocols should be
group reported hypotension, prolonged ventilation, implemented in every NICU.
and feeding intolerance (Anand et al. 2004). Codeine is a prodrug administered only by
Even if at the moment opioids cannot be enteral route, needing CYP2D6 to be metabolized
recommended for routine sedation in ventilated to morphine. Poor and intermediate metabolizers
neonates, they should be routinely administrated can udergo dose-related toxicity or therapeutic fail-
during surgery, invasive procedures, and inflam- ure. On the contrary, ultrarapid metabolizers under
matory diseases, on the basis of pain evaluation tramadol treatment that are breast-feeding mothers
and clinical judgement (Bellu et al. 2005). can expose their babies to the risk of life-threatening
respiratory depression (Madadi et al. 2008).
Tramadol is an analogue of codeine, acting
26.3.3 Opioids both as μ-receptor agonist and monoamines reup-
take inhibitor. CYP2D6 metabolizes tramadol to
The most commonly used opioids in NICU are O-demethyl tramadol, which shows a much higher
morphine and fentanyl. Morphine shows an onset affinity for μ-receptors than the parent compound.
time of 5 min and a peak effect at 10–30 min. The In term neonates, CYP2D6 activity seems to be
duration lasts 3–8 h, owing to the neonate drugs’ equal to adult slow metabolizers and reaches adult
half-life prolongation. Clearance reaches adult activity level at 44 weeks. Tramadol is administered
values at 6 months. The relative permeability of at the dose of 1–2 mg/kg as a bolus and 5–8 mg/kg/
the newborn blood–brain barrier facilitates the day as a continuous infusion (Allegaert et al. 2008).
penetration of morphine into the central nervous
system compared to older subjects. Morphine is
administrered for perioperative analgesia, while it 26.3.4 Paracetamol
has not proven to be so effective during proce-
dural acute pain. Usual intravenous dosage in Paracetamol is a very common analgesic in
infants receiving ventilatory support is infancy, but in neonates poor pain relief is reported
50–100 μg/kg as a single dose, followed by infu- after its administration for painful procedures,
sion of 10–30 μg/kg/h. Lower dosages are ade- probably depending on its inadequacy for this
quate for lower gestational ages, and small type of pain. Newborns are relatively protected
incremental doses (25–50% of the usual) are from the paracetamol hepatotoxicity, because of
advised for nonventilated infants. lower CYP450 level and lower glucuronide/sulfate
Fentanyl is more lipid soluble and has a potency metabolism ratio (Palmer et al. 2008). Increased
of 100-fold that of morphine. The peak effect is unconjugated hyperbilirubinemia reflects the
reached by 5–15 min, and the duration time is hepatic conjugating ability and can be a marker of
1–2 h. Fentanyl is less sedating and has minimal reduced paracetamol clearance.
cardiovascular effects, suitable for hemodynami- The relative bioavailability of rectal versus oral
cally unstable patients. Nevertheless, disadvantages formulations is higher in neonates and approaches
392 N. Disma et al.
unity, while the rate of duodenal absorption is neuropoprotective mechanisms, contradicted by
slower, and the rate of rectal absorption is slower subsequent studies demonstrating its neurotoxic
and more erratic in neonates, when compared effects. However, the applicability of these reports
with older infants. To reach the target plasma con- to clinical situations needs further confirmations.
centration of 10–20 μg/ml, a loading dose is
recommended. Doses should be adjusted in rela-
tion to weight, gestational age, postnatal age, and 26.3.6 Midazolam
route of administration. Term newborns should not
receive more than 60 mg/kg/day of drug at dosing Benzodiazepines (BDZs) are the most popular
interval of 6 h, whereas preterms should receive sedative drugs used in children, often combined
lower doses (30–40 mg/kg/day) at longer intervals with opioids. They share the same GABA-ergic
(8–12 h) (Bartocci and Lundberg 2007). Intrave- mechanism of action with propofol and barbitu-
nous paracetamol can be given alone or associated rates, resulting in hyperpolarization of the neuro-
with opioid as opioid sparing drug. According to nal membrane and producing anxyolisis, amnesia,
Allegaert et al. neonates aged between 32 and sedation, muscle relaxation, and anticonvulsant
44 weeks should receive a loading dose of 20 mg/kg effects. Potential adverse effects are hypo-
of intravenous paracetamol, followed by 10 mg/kg ventilation/apnea and hypotension. Midazolam is
every 6 h. The full dosage should not be continued characterized by faster onset time and shorter
for more than 4 days (Allegaert et al. 2011). duration than others such as diazepam and loraze-
pam. The immaturity of enzyme systems involved
in the metabolism of the drug (CYP450 and
26.3.5 Ketamine glycuronil-tranferase), linked to gestational and
postnatal age, organ dysfunction, and drug inter-
Ketamine is a “dissociative” drug, providing anes- actions, explains the marked interpatient variabil-
thesia, analgesia and amnesia, while displaying ity in dosage requirements to produce sedation in
a safe respiratory and hemodinamic profile. critically ill pediatric patients (Ng et al. 2003).
The new S(+) ketamine seems to be more favor- In the last years the use of midazolam in NICU
able when compared with the older racemic has been reassessed on the grounds of both clini-
compound. Drug action is mediated mainly by cal and experimental observations. The
N-methyl-D-aspartate (NMDA) receptors antago- NEOPAIN trial showed a statistically significant
nism. An intravenous dose of 1–2 mg/kg exhibit higher incidence of adverse neurologic events and
an onset time of 1 min, a peak effect by 5–10 min, death in the midazolam group compared with the
and a duration of 30–60 min. In NICU procedural morphine or placebo groups (Anand et al. 1999).
pain, ketamine reduces the discomfort associated More recently, the potential of midazolam to
with tracheal suctioning (Saarenma et al. 2001). induce apoptotic neurodegeneration in the brain,
Recently the Food and Drug Administration have while failing to sedate and sensitizing cutaneous
invited the anesthesia community to address the reflexes in neonatal rats, has raised concerns about
issue of the potential neurotoxicity of anesthetic the safety of midazolam in the first days of life. At
agents in neonates, on the basis of their neurode- the moment, the use of midazolam infusion for
generative effects on the developing brain in sedation in NICU cannot be recommended.
experimental trials (Mellon et al. 2007). Indeed
NMDA receptors antagonists and γ-aminobutyric
acid (GABA) agonists, in doses and durations of 26.3.7 Neonatal Anesthesia
exposure exceeding those clinically used, induce and the Risk of Neurotoxicity
neuronal injury and death in the brain of juvenile
rodents. The main part of these studies regards A great deal of concern has recently arisen
ketamine, as the first observations had suggested regarding the safety of anesthesia in infants. The
a possible role of NMDA antagonists in first study on the possible neurotoxic effects of
26 Neonatal Anesthesia 393
anesthetics was published in 1999, when a simi- multiple exposures, as well as the impact of surgery
larity between the ethanol, antiepileptic drugs, and underlying conditions (Davidson et al. 2015b;
and general anesthetic was demonstrated in Disma et al. 2016).
puppy rats. The pathohistological changes found
in animals were subsequently shown to be associ-
ated with both short- and long-term behavioral 26.4 Conclusion
changes. These preclinical findings have raised
concern that similar effects can happen in humans Physiology and pathophysiology of the neonatal age
and that young children undergoing anesthesia for and the pharmacology of the anesthetic and analge-
surgical or diagnostic procedures may suffer from sic drugs are the basis for a correct anesthesia man-
long-term neurocognitive consequences (Sanders agement of the newborn. Small infants, preterms
et al. 2008; Sun 2010; Loepke and Soriano 2008). and neonates with complex syndromes should be
Several epidemiological studies have also been managed by experienced pediatric anesthetists only.
performed to investigate if an association between
anesthesia exposure in early life and long-term
neurological effects exists, but results have been
contradictory. Two large prospective trials are
References
currently running in children, with the aim to
Allegaert K, van den Anker JN, de Hoon JN et al (2008)
show if early exposure to anesthesia may result Covariates of tramadol disposition in the first months of
to long-term neurological consequences: the GAS life. Br J Anaesth 100:525–532
and the PANDA. The first is a trial comparing Allegaert K, Palmer G, Anderson B (2011) The pharmaco-
kinetics of intravenous paracetamol in neonates: size
general and regional anesthesia for infants under-
matters most. Arch Dis Child 96:575–580
going hernia repair, with administration of vali- American Academy of Pediatrics, Committee on Fetus and
dated scales for neurocognitive assessment at Newborn and Section on Surgery, Canadian Paediatric
2 and 5 years of age as primary outcomes Society and Fetus and Newborn Committee (2006)
Prevention and management of pain in the neonate: an
(https://clinicaltrials.gov/ct2/show/NCT00756600).
update. Pediatrics 118:2231–2241
Results from the first interim follow-up of the American Society of Anesthesiologists Task Force on Seda-
GAS study have recently been published in the tion and Analgesia by Non-Anesthesiologists (2002)
Lancet (Davidson et al. 2016). This secondary Practice guidelines for sedation and analgesia by
non-anesthesiologists. Anesthesiology 96(4):1004–1017
outcome, based on a neurocognitive assessment
Anand KJ, Barton BA, McIntosh N et al (1999) Analgesia
plus the administration of the full scales of the and sedation in preterm neonates who require ventila-
Bayley III test, showed that a sevoflurane-based tory support: results from the NEOPAIN trial. Neonatal
anesthesia of about one hour at the average post- Outcome and Prolonged Analgesia in Neonates. Arch
Pediatr Adolesc 153:331–338
menstrual age of 45 weeks do not produce signif-
Anand KJ, Hall RW, Desai N et al (2004) Effects of
icant neurocognitive changes compared with awake morphine analgesia in ventilated preterm neonates: pri-
regional anesthesia for inguinal hernia repair. The mary outcomes from the NEOPAIN randomized trial.
other trial is the PANDA, which is an Lancet 363:1673–1682
Bartocci M, Lundberg S (2007) Intravenous paracetamol: the
ambidirectional study that includes a large popula-
“Stockolm protocol” for postoperative analgesia of term
tion of children exposed to anesthesia before the age and preterm neonates. Pediatr Anesth 17:1111–1121
of 3 years and prospectively followed up to the age Bellu R, de Waal KA, Zanini R (2005) Opioids for neo-
of 8 and 15 years (https://clinicaltrials.gov/ct2/ nates receiving mechanical ventilation. Cochrane Data-
base Syst Rev 1, CD004212
show/NCT00881764). Unfortunately, the GAS
Craven PD, Badawi N, Henderson-Smart DJ, O’Brian N
and PANDA studies can only answer some of the (2003) Regional (spinal, epidural, caudal) versus gen-
questions regarding pediatric anesthesia and the eral anaesthesia in preterm infants undergoing inguinal
associated risk of neurotoxicity, and multiple differ- herniorrhaphy in early infancy. Cochrane Database
Syst Rev (3), CD003669
ent questions readily emerge that will need to be
Cravero JP (2009) Risk and safety of pediatric sedation/
addressed, e.g., the effect of different drugs and anesthesia for procedures outside the operating room.
doses, age at exposure, duration of exposure, Curr Opin Anaesthesiol 22(4):509–513
394 N. Disma et al.
Davidson AJ, Morton NS, Arnup SJ, de Graaff JC, depression in breastfed infants following maternal
Disma N, GAS Consortium (2015a) Apnea after codeine use. Paediatr Drugs 10:399–404
awake regional and general anesthesia in infants: the Mellon RD, Simone AF, Rappaport BA (2007) Use of
general anesthesia compared to spinal anesthesia study- anesthetic agents in neonates and young children.
comparing apnea and neurodevelopmental outcomes, a Pediatr Anesth 104:509–520
randomized controlled trial. Anesthesiology 123:38–54 Michel F, Constantin JM (2009) Sevoflurane inside and
Davidson AJ, Becke K, de Graaff J, Giribaldi G, Habre W, outside the operating room. Expert Opin Pharmacother
Hansen T et al (2015b) Anesthesia and the developing 10(5):861–873
brain: a way forward for clinical research. Paediatr Ng E, Taddio A, Ohlsson A (2003) Intravenous midazolam
Anaesth 25:447–452 infusion for sedation of infants in the neonatal intensive
Davidson AJ, Disma N, de Graaff JC, Withington DE, care unit. Cochrane Database Syst Rev (1), CD002052
Dorris L, Bell G et al (2016) Neurodevelopmental Palmer GM, Atkins M, Anderson BJ et al (2008)
outcome at 2 years of age after general anaesthesia I.V. acetaminophen pharmacokinetics in neonates
and awake-regional anaesthesia in infancy (GAS): an after multiple doses. Br J Anaesth 101:523–530
international multicentre, randomised controlled trial. Ranger M, Johnstone CC, Anand KJS (2007) Current
Lancet 387:239–250 controversies regarding pain assessment in neonates.
Disma N, Mondardini MC, Terrando N, Absalom AR, Semin Perinatol 31:283–288
Bilotta F (2016) A systematic review of methodology Saarenma E, Neuvonen PJ, Huttunen P et al (2001) Keta-
applied during preclinical anesthetic neurotoxicity stud- mine for procedural pain relief in newborn infants.
ies: important issues and lessons relevant to the design of Arch Dis Chil Fetal Neonatal Ed 85:F53–F56
future clinical research. Paediatr Anaesth 26:6–36 Sammartino M, Garra R, Sbaraglia F, De Riso M,
Loepke AW, Soriano SG (2008) An assessment of the Continolo N (2010) Remifentanil in children. Paediatr
effects of general anesthetics on developing brain Anaesth 20(3):246–255
structure and neurocognitive function. Anesth Analg Sanders RD, Ma D, Brooks P, Maze M (2008) Balancing
106(6):1681–1707 paediatric anaesthesia: preclinical insights into analge-
Lowery CL, Hardman MP, Manning N, Whit Hall R, sia, hypnosis, neuroprotection, and neurotoxicity. Br J
Anand KJS (2007) Neurodevelopmental changes of Anaesth 101(5):597–609
fetal pain. Semin Perinatol 31:275–282 Sun L (2010) Early childhood general anaesthesia expo-
Madadi P, Shirazi F, Walter FG, Koren G (2008) sure and neurocognitive development. Br J Anaesth
Establishing causality of cerebral nervous system 105(Suppl 1):i61–i68
Neonatal Care in the Delivery Room:
Initial Management and Approach 27
to Low Risk Newborns
Tara M. Randis and Jennifer M. Duchon
Contents
27.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
27.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
27.3 Delivery Room Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
27.4 Determining Need for Resuscitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
27.5 Thermal Stability in the Delivery Room . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
27.6 Positioning and Clearing the Airway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400
27.7 Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400
27.8 Assessment of Resuscitation Efforts: The Apgar Score . . . . . . . . . . . . . . . . . . 400
27.9 Postnatal Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
27.10 Physical Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
27.11 Initiation of Breastfeeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
27.12 Vital Signs and Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
27.12.1 Vital Signs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
27.12.2 Hemoglobin and Hematocrit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
27.12.3 Monitoring of Glucose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
27.13 Common Routine Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404
27.13.1 Eye Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404
27.13.2 Vitamin K . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
27.14 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
T. M. Randis
Department of Pediatrics, New York University School of
Medicine, New York, NY, USA
e-mail: [email protected]
J. M. Duchon (*)
Division of Neonatology, St. Joseph’s Regional Medical
Center, Paterson, NJ, USA
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 395
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_177
396 T. M. Randis and J. M. Duchon
Abstract • National and international evidence-based
Successful resuscitation hinges upon prepared- standards of care
ness. Newborn infants who do not require • And most importantly
resuscitation can be rapidly identified upon • The health of the newborn through maternal-
delivery by answering the following three crit- infant bonding and breastfeeding
ical questions:
1. Term gestation?
27.2 Introduction
2. Good tone?
3. Breathing or crying?
Ancient accounts of neonatal resuscitation strate-
gies may be found in the Old Testament, the
If the answer to all three questions is “yes,”
Talmud, and early writings of Hippocrates
the newly born infant may stay with the mother
(O’Donnell et al. 2006). Mouth-to-mouth resusci-
for routine care. Most initial care of low risk,
tation of newborns was described as early as
healthy newborns can be provided while skin-to
1472 in a textbook on childhood diseases written
skin contact with the mother is maintained.
by Bagellardeus (Wiswell and Gibson 2005).
Breastfeeding should be initiated as soon as pos-
While, some of these early resuscitation practices
sible. Policies relating to routine newborn care
were truly revolutionary, the vast majority
should be continually assessed to provide the
reflected a limited understanding of the dramatic
best care while minimizing unnecessary invasive
physiologic changes that take place during birth.
interventions, as well as adhering to national and
Techniques including swinging the infant upside
international standards as appropriate.
down, immersion in cold water, electric shock,
shaking, yelling, slapping, and even insufflation
of tobacco smoke into the rectum were widely
27.1 Salient Points practiced as recently as the early twentieth century
(O’Donnell et al. 2006; Wiswell and Gibson
• Successful resuscitation hinges upon 2005; Raju 1999). In 1953, Virginia Apgar
preparedness. wrote the following regarding the resuscitation
• Newly born infants who do not require resus- of newborn infants:
citation can be generally identified upon deliv-
Seldom have there been such imaginative ideas,
ery by rapidly assessing the answers to the such enthusiasm, and dislikes, and such unscientific
following three critical questions (Wyckoff observations and study about one clinical picture.
et al. 2015): There are outstanding exceptions to these state-
ments, but the poor quality and lack of precise
– Term gestation?
data of the majority of papers concerned with infant
– Good tone? resuscitation are interesting. (Apgar 2015)
– Breathing or crying?
• Skin-to-skin contact is adequate for providing Over the past several decades, an improved
thermal stability, facilitates mother-infant understanding of neonatal transition to extra-
bonding, and should occur as soon as possible uterine life accompanied by major advancements
after delivery. in medical technology have led to dramatic
• Breast feeding should be initiated in the deliv- improvement in the care of the compromised new-
ery room without delay. born. Recognition of the growing need for stan-
• Practices relating to healthy newborns in the dardization of delivery room practices has led to the
first few hours of life should be geared development of national committees dedicated to
towards: the establishment of consensus guidelines for new-
• The needs and practices of the surrounding born resuscitation. A global movement towards the
community practice of evidence-based care in the delivery
27 Neonatal Care in the Delivery Room: Initial Management and Approach to Low Risk Newborns 397
room emerged, and in 1992 the International Liai- Table 1 Neonatal resuscitation supplies and equipment
son Committee on Resuscitation (ILCOR) was (Adapted from American Academy of Pediatrics et al.
(2016))
established to provide a forum for liaison between
resuscitation organizations in the developed world Suction equipment
(Chamberlain and Founding Members of the Inter- Suction bulb syringe
Mechanical suctioning and tubing
national Liaison Committee on Resuscitation
Suction catheters (5 F or 6 F, 8 F, 10 F, 12 F or 14 F)
2005). Importantly, this committee not only pro-
8 F feeding tube and large syringe
vides recommendations regarding the care of the
Meconium aspirator
newborn but also has acknowledged ongoing con-
Positive-pressure ventilation equipment
troversies and identified areas in which additional Device for delivery of positive pressure ventilation
research is needed. In addition, the training of Face masks, newborn and premature sizes
caregivers in the delivery room has become the Oxygen source
focus of recent clinical investigations, as innova- Compressed air source
tive educational strategies such as video recording Oxygen blender to mix oxygen and compressed air
of resuscitations and simulator-based teaching (flow rate set to 10 L/min) and tubing
become an integral part of many pediatric training Pulse oximeter with sensor and cover
programs (Halamek 2008; Carbine et al. 2000). Target oxygen saturation table
The following text is based primarily on evidence Intubation equipment
presented in the 2015 International Consensus on Laryngoscope with straight blade, No. 0 (preterm) and
No. 1 (term)
Cardiopulmonary Resuscitation and Emergency
Extra bulbs and batteries for laryngoscope
Cardiovascular Care Science With Treatment Rec-
Endotracheal tubes (sizes 2.5, 3, and 3.5 mm ID)
ommendations (Wyckoff et al. 2015). Stylet (optional)
Scissors
Tape or other securing device for endotracheal tube
27.3 Delivery Room Preparation Alcohol sponges
CO2 detector or capnograph
Successful resuscitation hinges upon preparedness. Laryngeal mask and 5-mL syringe
Nearly 10% of newborns require some assistance 5 F or 6 F orogastric tube if insertion port present on
to begin breathing at birth and approximately 1% laryngeal mask
will require extensive resuscitation. Personnel Medications
trained in basic resuscitation skills (including initi- Epinephrine: 1:10,000 concentration (0.1 mg/mL)
[3 mL or 10 mL ampules]
ation of positive pressure ventilation and chest
Normal saline for volume expansion, 100 or 250 mL
compressions) should be present at every delivery.
Dextrose 10 %, 250 mL
A person trained in Advanced Life Support tech-
Normal saline for flushes
niques should be readily available for low-risk Syringes (1-mL, 3-mL or 5-mL, 20–60-mL)
deliveries and present in the delivery room for Umbilical vessel catheterization supplies
those considered high-risk. Because a newborn Sterile gloves
without apparent risk factors may unexpectedly Antiseptic prep solution
require resuscitation, each institution should have Umbilical tape
a procedure in place for rapidly mobilizing a team Small clamp
with complete newborn resuscitation skills for any Forceps (optional)
birth. Published recommendations regarding the Scalpel
necessary equipment and drugs for resuscitation Umbilical catheters (3.5 F, 5 F)
of the newly born infant exist and delivery rooms Three-way stopcock
should be stocked accordingly (Table 1) (American Syringes (3–5 mL)
Academy of Pediatrics et al. 2016). Delivery rooms Needle or puncture device for needless system
should be maintained at a temperature between Normal saline for flushes
36.5 C and 37.5 C. (continued)
398 T. M. Randis and J. M. Duchon
Table 1 (continued) 27.4 Determining Need
Clear adhesive dressing to temporarily secure for Resuscitation
umbilical venous catheter to abdomen (optional)
Miscellaneous Newly born infants who do not require resuscita-
Gloves and appropriate personal protection tion can be generally identified upon delivery by
Radiant warmer or other heat source rapidly assessing the answers to the following
Temperature sensor with sensor cover for radiant three critical questions (Wyckoff et al. 2015):
warmer (for use during prolonged resuscitation)
Firm, padded resuscitation surface
4. Term gestation?
Timer/clock with second hand
Warmed linens
5. Good tone?
Hat 6. Breathing or crying?
Stethoscope (with neonatal head)
Tape, 1/2 or 3/4 in. If the answer to all three questions is “yes,” the
Electronic cardiac (ECG) monitor leads and ECG newly born infant may stay with the mother for
monitor routine care. In this context, “routine care” means
Interosseous needle (optional) the infant is dried, placed skin to skin with the
For very preterm babies mother, and covered with dry linen to maintain a
Size-00 laryngoscope blade (optional) normal temperature. Note that observation of
Food-grade plastic bag (1 gal size) or plastic wrap breathing, activity, and color must be ongoing. If
Thermal mattress the answer to any of these assessment questions is
Transport incubator to maintain baby’s temperature
“no,” the infant should be moved to a radiant
during move to the nursery
warmer and the providers should proceed with the
initial steps in stabilization which include:
warming and maintaining normal temperature,
Communication with maternal care providers positioning, clearing of secretions if necessary,
is critical, as a thorough maternal history will drying, and providing stimulation which are
often identify those neonates most likely to discussed in more detail below. The decision to
require resuscitation. In 2008, Aziz et al. (2008) progress beyond these initial steps is determined
published a prospective, clinical trail identifying by simultaneous assessment of two vital character-
both antepartum and intrapartum factors that were istics: respirations and heart rate. If there is apnea,
strongly associated with the need for positive labored breathing, or heart rate less than 100 beats
pressure ventilation in the delivery room. These per minute maneuvers to achieve ventilation (pos-
included multiple pregnancy, maternal infection, itive pressure ventilation, continuous positive air-
maternal hypertension, oligohydramnios, preterm way pressure) should be initiated. These initial
delivery, breech presentation, meconium-stained stabilization steps, subsequent reevaluation of
amniotic fluid, nonreassuring heart rate patterns, infant, and initiation of ventilation if needed should
and emergency C-section. occur within the first 60 s of life, aptly referred to as
Current evidence suggests that cord clamping “The Golden Minute” (Wyckoff et al. 2015).
should be delayed for at least 30–60 s for most
vigorous term and preterm newborns. If placental
circulation is not intact, such as after a placental 27.5 Thermal Stability
abruption, bleeding placenta previa, bleeding vasa in the Delivery Room
previa, or cord avulsion, the cord should be
clamped immediately after birth. There is insuffi- Fetal temperature in utero is tightly regulated.
cient evidence to recommend an approach to cord Fetal metabolism results in a net production of
clamping for newborns who require resuscitation heat that is removed by placental blood flow and
at birth. is ultimately dispersed through the mother. As a
27 Neonatal Care in the Delivery Room: Initial Management and Approach to Low Risk Newborns 399
result, there is a slight temperature gradient, with temperature may be exerting a tremendous
fetal temperature approximately 0.5 C greater amount of energy to maintain this temperature
than the maternal core temperature (Walker et al. and therefore is cold stressed. While it has been
1969). Upon parturition, the neonate rapidly loses recognized for decades that cold stress at birth has
heat through a variety of mechanisms as the ambi- a negative impact upon infant survival, particu-
ent temperature falls dramatically from 37 C in larly in low birth weight infants (Silverman et al.
utero to approximately 25 C in the delivery room. 1958), it is surprising to learn that despite dra-
Because the newborn is coated with amniotic matic advances in neonatal care, temperature
fluid, there is substantial evaporative heat loss. management in the delivery room remains an
Circulating air currents in the delivery room con- ongoing challenge. A large, multicenter, observa-
tribute to convective heat loss. Conductive heat tional study published by Laptook et al. examined
loss occurs when the infant is placed upon cooler the distribution of body temperatures in low birth
surfaces such as unwarmed mattresses and blan- weight infants admitted to the neonatal intensive
kets. Finally, heat is lost through radiation to care unit. The study included more than 5,000
cooler surfaces surrounding the infant but not in very low birth weight infants and found that
direct contact with the infant. The newborn is nearly 47% had low admission temperatures
capable of sensing this cold stress and immedi- defined as less than 36 C (Laptook et al. 2007).
ately triggers homeothermic mechanisms to min- Furthermore, there was a significant association
imize further heat loss. Vasoconstriction of the between the extent of reduced temperature upon
dermal arterioles minimizes the flow of warm admission and late-onset sepsis and in-hospital
blood to the cooler surface of the skin. Non- mortality. These findings were similar to those
shivering thermogenesis, in which brown fat published earlier in the EPIcure study, where
stores undergo exothermic reactions thereby gen- approximately 40% of infants less than 26 weeks
erating heat, is initiated. Despite these adaptive gestation had admission temperatures below
measures, the core temperature of the newborn 35 C, and this was correlated with decreased
will continue to fall unless interventions by care- survival (Costeloe et al. 2000). Intraventricular
takers occur in a timely manner. Recent guidelines hemorrhage (Gleissner et al. 2000; Van de Bor
state that the temperature of newly born non- et al. 1986), hypoglycemia (Lenclen et al. 2002;
asphyxiated infants be maintained between Zayeri et al. 2005), and respiratory compromise
36.5 C and 37.5 C after birth through admission (Zayeri et al. 2005; Russo et al. 2014) have also
and stabilization (Wyckoff et al. 2015). Further- been linked to low admission temperatures. Inter-
more, they recommend that admission tempera- ventions to limit heat loss in the delivery room
ture should be recorded as a predictor of outcomes include maintaining delivery room temperature
as well as a quality indicator. between 36.5 C and 37.5 C, prewarming of
The low birth weight infant is exquisitely sus- blankets and mattresses, rapidly drying the new-
ceptible to heat loss in the immediate postnatal born, and removing wet blankets from infant con-
period as they have a larger surface area to weight tact. Swaddling infants in a warmed blanket is
ratio and limited subcutaneous fat. The preterm generally sufficient for stable, term infants. Early
infant, in particular, is less able to adapt to these initiation of kangaroo care, allowing for direct
environmental changes secondary to an immature skin-to-skin contact with the parent, is another
epidermal barrier and a paucity of brown fat effective means of maintaining the newborn’s
stores. For these reasons, the preterm infant has temperature (Anderson et al. 2003). Overhead
often been referred to as a functional poikilo- heaters are necessary for those infants requiring
therm. It is generally accepted that the newborn further resuscitative efforts. Occlusive wraps
should have a core body temperature at or near (polyurethane, polyethlylene, or polyvinyl) may
37 C. However, it is important to recognize that be beneficial in minimizing heat loss in extremely
even a newborn with a normal core body preterm infants, as their use has been associated
400 T. M. Randis and J. M. Duchon
with higher admission temperatures to the inten- respond to tactile stimulation such as gentle rub-
sive care unit (Cramer et al. 2005). bing of the back, as occurs with drying of the
While it has long been recognized that neonatal infant, or gently flicking the bottom of the feet.
hypothermia is associated with decreased survival, Failure of the infant to respond to these measures
potential morbidities related to hyperthermia have indicates the infant may be experiencing second-
more recently been described (Perlman 2006). Neo- ary apnea and will require positive pressure ven-
natal hyperthermia may occasionally be iatrogenic tilation. Resuscitative measures beyond these
in nature (inappropriate use of radiant warmers, initial few steps are discussed in detail in subse-
occlusive wraps). However, it most often results quent chapters.
from an elevated maternal temperature secondary
to epidural anesthesia, prolonged labor or
chorioamnionitis. Shalak et al. examined a cohort 27.8 Assessment of Resuscitation
of term infants with clinical chorioamnionitis and Efforts: The Apgar Score
found that elevated temperature at 30 min of life
was correlated with neonatal depression at birth In 1952, Virginia Apgar created a scoring system
(requiring positive pressure ventilation or Apgar to rapidly assess the physical condition of infants
score less than 5 at 5 min) and admission to the shortly after birth in order to recognize those
neonatal ICU (Shalak et al. 2005). Other investiga- infants in need of further interventions to estab-
tors have demonstrated an association between lish breathing (Apgar 2015). The Apgar score,
maternal fever and neonatal encephalopathy which includes evaluation of heart rate, respira-
(Impey et al. 2001). Because these studies utilize tory effort, muscle tone, reflex irritability, and
maternal fever as a surrogate for neonatal hyper- color, remains widely used today as a measure
thermia, it remains unclear if maternal fever alone is of the infants response to resuscitative efforts.
sufficient to cause neurologic insult or if it is simply Several investigators have attempted to expand
a marker for other intrapartum risk factors. the utility of the Apgar score beyond the scope of
the delivery room, using it as a measurement of
risk for later impairment. While there is some
27.6 Positioning and Clearing evidence to suggest that a low 5-min Apgar
the Airway score may be associated with future neurologic
disability, the American Academy of Pediatrics
Placement of the newborn on his or her back cautions against its use as a predictor of long-term
under a radiant warmer with the head in a slightly outcome or as a specific marker of intrapartum
extended position will open the airway. If respira- asphyxia, as this was not the original intent
tory efforts are present but ineffective (retractions, (American Academy of Pediatrics Committee on
inadequate chest wall movement or poor air Fetus and Newborn and American College of
entry), the airway may be obstructed. Secretions Obstetricians and Gynecologists Committee on
should be cleared first from the oropharynx and Obstetric Practice 2015). Apgar score has limita-
then the nasopharynx with either a bulb syringe or tions, and it is inappropriate to use it alone to
suction catheter. Care must be taken to avoid deep establish the diagnosis of asphyxia. Numerous
or vigorous suctioning as this may result on laryn- factors may influence the Apgar score, including
geal spasm and/or vagal bradycardia. maternal sedation or anesthesia, congenital
malformations, gestational age, trauma, and
interobserver variability (Executive Summary
27.7 Stimulation 2014). A low 5-min Apgar score (0–3) is a valid
predictor of neonatal mortality (Casey et al.
Most infants cry spontaneously upon delivery and 2001). The Apgar score is affected by gestational
establish regular respiration by 1 min of age. If age and therefore its significance in preterm
this does not occur, the majority of infants will infants remains unclear.
27 Neonatal Care in the Delivery Room: Initial Management and Approach to Low Risk Newborns 401
27.9 Postnatal Assessment discussed in detail in later chapters and has a
different goal. As previously stated, the purpose
Early assessment of the low risk newborn should of the physical exam in the delivery room should
be geared towards identification and prevention of be to assess the newborn for any features that may
conditions that may require more extensive care indicate the need for immediate intervention or for
or evaluation. further investigations and follow up during the
nursery stay. Important findings to identify are:
• Skin-to-skin contact is adequate for providing
thermal stability, facilitates mother-infant • Visually patent and normally placed anus
bonding, and should occur as soon as possible • Normal external genitalia
after delivery. • Presence of cleft lip or palate
• Breast feeding should be initiated in the deliv- • Intact spine and sacral area
ery room without delay.
• There is no evidence for routine sampling of Most major congenital malformations are dis-
hematocrit or blood glucose in healthy, low covered during routine prenatal care, and second
risk newborns. trimester ultrasound at 18–22 weeks gestational
• Prophylaxis against neonatal ophthalmia and age remains the most common imaging modality.
vitamin K deficiency should be provided, but When performed at tertiary care or University
may wait until after the first breastfeed. affiliated institutions, second trimester ultrasound
• Practices relating to healthy newborns in the has been shown to have good specificity and fair
first few hours of life should be geared towards: sensitivity for the detection of fetal anomalies
1. The needs and practices of the surrounding (Fadda et al. 2009). However, defects such as
community those listed above, especially small facial anoma-
2. National and international evidence-based lies, are frequently difficult to detect with tradi-
standards of care tional two-dimensional ultrasound techniques. As
And most importantly more sophisticated techniques such as three-
3. The health of the newborn through dimenstional ultrasound or fetal MRI come into
maternal-infant bonding and breastfeeding wider use, the detection rate for these anomalies,
especially spinal and facial defects, may improve
Several key aspects of continuing care of the (Lee and Simpson 2007). It is not recommended
well newborn in the delivery room and during the to perform a rectal probe exam, such as a rectal
recovery period will be discussed. In the healthy temperature, to document patency of the anus.
term newborn the goal of delivery room care should Deep suctioning of the nasal and/or oral cavities
be to assess the newborn for any features that may is also neither necessary nor recommended to
confer the need for closer monitoring and follow determine patency of the nares or esophagus, as
up, and to promote the natural bonding between this may lead to trauma or perforation of the
mother and infant. In this regard, much of the mucosal tissues. This is supported by recommen-
continuing care of the newborn can be done in dations from The American Academy of
such as way as to be minimally invasive to the Pediatrics (AAP) section on breastfeeding, which
infant and not disruptive to the mother–infant dyad. states that unnecessary, excessive, and over-
vigorous suctioning of the oral cavity, esophagus,
and airways may traumatize the infant and lead to
aversive feeding behavior (Pediatrics 2005). The
27.10 Physical Exam initial physical examination of the infant can also
document normal variants such as molding or caput
Every newborn should be assessed with a brief of the scalp, Mongolian spots or sucking blisters,
physical examination in the delivery room. The whereby the pediatrician may reassure parents of
complete physical exam of the newborn will be the benign nature of such findings. The initial
402 T. M. Randis and J. M. Duchon
physical assessment of the baby can be performed Institutional policies surrounding routine care
while skin-to-skin contact with the mother is taking of healthy newborn should be developed with
place. the goal of safety and the promotion of the
mother-infant bond, as opposed to convenience
of the medical and ancillary staff.
27.11 Initiation of Breastfeeding
The full physiology and nutrition of 27.12 Vital Signs and Measures
breastfeeding and breast milk will be discussed
in a dedicated section of this manual. For the 27.12.1 Vital Signs
purpose of the care of the infant in the delivery
room, the initiation of breastfeeding may be Noninvasive vital signs, such as heart rate, respi-
considered one of the most important contribu- ratory rate, and temperature, as well as the proce-
tions to the health and well being of a dure of weighing and measuring the infant, are
newborn. Briefly, the AAP recommendations often performed in the delivery room. Some insti-
for breastfeeding and breast milk include: tutions also have protocols involving more inva-
sive measures, such as screening for oxygen
• Breast milk for all infants for whom it is not saturation, hypoglycemia, anemia, or polycythe-
medically contraindicated mia. A vigorous term infant who has been
• Exclusive breastfeeding for the first 6 months ascribed good Apgar scores is unlikely to have
of life major derangements in pulse or respiratory rate.
• Continuation of breastfeeding for at least Mild tachypnea may be a physiologic part of the
1 year transition from fetal to extrauterine life. The
• Peripartum practices that facilitate increased pulmonary vascular resistance of the
breastfeeding newborn as manifest by oxygen saturation takes
time to normalize. Studies have demonstrated that
The alert, healthy newborn infant is capable of healthy full term neonates rarely reach oxygen
latching on to a breast without specific assistance saturations of greater than 90% until after the
within the first hour after birth (Section on first 10 min of life, and may have lower postductal
Breastfeeding 2012; Righard and Alade 1990). saturations for an even longer period (Mariani
In keeping with the previous discussion on tem- et al. 2007; Altuncu et al. 2008).
perature regulation, the AAP recommendations
to promote breastfeeding in the delivery encour-
age that well, full term infants be placed 27.12.2 Hemoglobin and Hematocrit
and remain in direct skin-to-skin contact with
their mothers immediately after delivery until Healthy full term infants have, in past years, been
the first feeding is accomplished (Section on targeted for treatment of anemia or polycythemia
Breastfeeding 2012; Righard and Alade 1990). based on values obtained from routine screening
Weighing, measuring, bathing, and other non- at birth. This can be troublesome from several
urgent interventions should be delayed until perspectives. The definition of both anemia and
after the first feed is completed. For both bonding polycythemia can vary. Most practitioners define
and breastfeeding purposes, the newborn infant anemia as a greater than two standard deviations
should remain with the mother throughout the below the mean hemoglobin, or less than the fifth
recovery period. A Cochrane review confirms percentile. For full term neonates, this is approx-
that institutional changes in maternity care prac- imately 13 g/dL from a sample of blood drawn
tices effectively increased rates of breastfeeding centrally, or 14.5 g/dL drawn from capillary sam-
initiation and duration (Dyson et al. 2005). pling. Symptoms of anemia in the immediate
27 Neonatal Care in the Delivery Room: Initial Management and Approach to Low Risk Newborns 403
newborn period may range from pallor to there are several mechanisms to maintain ade-
tachypnea to severe respiratory distress and cir- quate energy to the infant:
culatory collapse. Polycythemia can be defined
in a similar manner, but has traditionally been • Glycogenolysis
diagnosed as a hematocrit greater than 65% • Gluconeogenesis
drawn centrally or 70% drawn from a capillary • Lipolysis
specimen. Risk factors include macrosomic • Fatty acid oxidation and ketogenesis
infants, or infants who are born to mothers who • Hormonal/endocrine regulation of these
have conditions that affect placental blood flow, as systems
a compensatory mechanism from the fetus. Symp-
toms of polycythemia include CNS manifestations Serum glucagon, catecholamines, and growth
such as lethargy and tremulousness, hypoglycemia, hormone rise after cord clamping and insulin
as well as evidence of organ failure such as respi- levels fall, favoring glycogenolysis, lipolysis,
ratory distress, renal failure, congestive heart fail- and gluconeogenesis. Full term infants are born
ure, or intestinal symptoms. Both obstetric with adequate glycogen stores, but these are
practices, such as method of delivery and timing depleted within the first several hours after birth
of cord clamping and positioning of the infant unless feeding is established. Lipolysis can occur
relative to cord clamping, can affect these values, shortly after birth and releases free fatty acids that
as do the timing of blood sampling relative to can be used as an energy source by many tissues,
delivery (Hutton and Hassan 2007; Merenstein although not by the brain. Fatty acid oxidation and
et al. 1993). The degree to which an individual ketogenesis take place in the liver and produce
infant is symptomatic at a particular hemoglobin ß-hydroxybutyrate, acetoacetate, and ketones
or hematocrit is extremely variable. It is also very which can be used by as an energy source for the
difficult to differentiate the clinical effects, both brain. Several of the major hormones required for
short and long term, of polycythemia and anemia control of these systems rise in the first few hours
in an asymptomatic infant from the effects of the of life, leaving the production of usable energy
cause of the abnormal indices. Especially for poly- from both gluconeogenesis and hepatic ketogen-
cythemia, there is no evidence to suggest that the esis delayed. This leaves free fatty acids from
treatment modality, partial exchange transfusion, of lipolysis and glucose from breakdown of glyco-
an asymptomatic infant improves outcome. The gen stores as the major energy sources immedi-
most sensible approach would be to consider ately after birth (Taeusch et al. 2005; Polin et al.
screening infants who are at risk for anemia from 2011). In infants with poor stores of adipose tissue
fetal or intrapartum complications, and may war- or glycogen, such as preterm or growth-restricted
rant closer follow up, or for any infant who displays infants, maintaining an adequate supply of fuel for
symptoms of abnormal hemoglobin or hematocrit the metabolic needs of the brain becomes of great
(Merenstein et al. 1993). concern. Infants who are well may also be at risk.
Nonshivering thermogenesis is the major mecha-
nism of heat production in the neonate, and cold
27.12.3 Monitoring of Glucose stress in the delivery room can occur. A newborn
infant left unattended in an environment at typical
There has been much discussion in recent years as “room temperature” experiences energy losses of
to the measurement and management of glucose approximately 150 kcal per minute, rapidly using
levels in the low risk infant. up energy stores (Soll 2008). Delay in enteral
The fetus has a complete and continuous sup- feeding for routine newborn care can also exacer-
ply of glucose from the mother from placental bate hypoglycemia. This provides further evi-
transfer, via carrier-mediated facilitated diffusion. dence for care to be performed skin to skin with
After birth, when this supply is abruptly cutoff, the mother with early initiation of breastfeeding.
404 T. M. Randis and J. M. Duchon
Many nurseries still monitor serum glucose 27.13 Common Routine Treatments
levels in low risk, healthy infants as part of rou-
tine care. A problem can then arise, as debate 27.13.1 Eye Care
occurs what level of serum glucose should be
considered abnormal and require intervention in Neonatal ophthalmia is defined as conjunctivitis
an asymptomatic, otherwise well newborn. When that occurs within the first 28 days of life. It is a
it was first recognized as a pathologic state, hypo- relatively common illness, occurring in 1–12% of
glycemia was defined as less than 20 mg/dl newborn infants. Historically, neonatal ophthalmia
(1.1 mmol/l) in preterm infants and less than referred to conjunctivitis in the newborn caused by
30 mg/dL (1.7 mmol/l) in full term infant. Cohort infection with Neisseria gonorrhoeae, but now the
studies later showed that infants with symptom- term refers to any conjunctivitis in this age group,
atic hypoglycemia had poorer neurodeve- regardless of the cause (Embree 2002). Gonococcal
lopmental outcomes (Pildes et al. 1974). Since ophthalmia was, in the past, a leading cause of
that time, there has been little agreement about blindness, but is now rare in most developed
minimum acceptable level of glucose in healthy populations with access to screening and treatment
term infants (Adamkin and Polin 2016). Some during pregnancy. It is for this historical reason that
authors portend that 45 mg/dl (2.5 mmol/l) is delivery room prophylaxis was geared towards pre-
the lower limit for all infants (Cornblath et al. vention of blindness from this pathogen. Since the
2000; Inder 2008). Others maintain that due to diminishment of gonococcal ophthalmia, there has
the key time in development, and lack of evi- been debate about which agent, if any, to use as
dence for compensatory mechanisms that protect prophylaxis against conjunctivitis in the delivery
the neonatal brain from hypoglycemic injury, room. Most cases of conjunctivitis in the neonatal
glucose values should be similar in newborns as period are due to either chemical conjunctivitis or
in older children, greater than 60 mg/dl or nonsexually transmitted colonizing bacteria. Chla-
3.3 mmol/l (Taeusch et al. 2005). Symptoms mydia trachomatis also comprises a portion of oph-
from hypoglycemia include tremulousness, leth- thalmia, depending on local incidence. With the
argy, seizures, hypothermia, or can mimic respi- exception of Gonococcal and Chlamydial conjunc-
ratory distress. Infants who are considered at risk tivitis, the condition is mild, and usually responds
for hypoglycemia are those who are small or large well to local treatment with no long-term sequelae
for gestational age, or who have maternal risk with appropriate therapy. For these reasons, the
factors for abnormal glucose such as gestational Canadian Paediatric Society (CPS) no longer rec-
diabetes or medications affecting glucose metab- ommends routine eye prophylaxis be given (Moore
olism. Also at high risk for sequelae from et al. 2016). However, this practice is still endorsed
hypoglycemia are those infants who have evi- by the AAP and legally mandated in many states
dence of infection, hypothermia, polycythemia, and provinces/territories in North America. If pro-
or hypoxia-ischemia (Cornblath et al. 2000; Inder phylaxis must be given, 0.5% erythromycin oint-
2008). It is generally accepted that healthy term ment is recommended. The medication should be
infants, either breastfed or formula fed, who do instilled as soon as possible in the delivery room and
not have risk factors for compromised metabolic should not be wiped off. There is no data suggesting
adaptation and who are asymptomatic need not that delaying administration until after the first
have routine glucose monitoring (Merenstein breastfeed in any way affects efficacy. Erythromy-
et al. 1993; Committee on Fetus and Newborn cin ointment has replaced other forms of prophy-
and Adamkin 2011). Any infant who appears laxis in the United States (USA) and Canada, as data
symptomatic from hypoglycemia, or in whom suggested that there may be protection against Chla-
risk factors for increased altered glucose mydial species. Later studies disproved this (Chen
metabolism exists, should be evaluated and 1992) probably due to the fact that local treatment
treated if necessary (Committee on Fetus and will not eradicate nasophargyngeal colonization of
Newborn and Adamkin 2011). the organism. Erythromycin potentially causes less
27 Neonatal Care in the Delivery Room: Initial Management and Approach to Low Risk Newborns 405
chemical conjunctivitis than silver nitrate or compared to the daily requirement of 5–10 μg in
aminoglycosides, and the drug remains in wide infants. The dose of 1 mg appears to have been
usage. This is not the case in other countries, chosen fairly arbitrarily, with no formal studies
where aminoglycoside, chloramphenicol, or no pro- being performed to establish what dose might be
phylaxis is used (Guala et al. 2005). appropriate. Intramuscular form became the route
of choice based primarily on the available formu-
lation at the time (Hey 2003). In the 1990s, a study
27.13.2 Vitamin K from Britain linked the administration of intra-
muscular vitamin K at birth to childhood cancers
Due to limited stores at birth, neonates are prone to and leukemia (Golding et al. 1990). Later studies
vitamin K deficiency if no sufficient intake is failed to confirm this association, but the guide-
provided. The clinical syndrome associated with lines for universal prophylactic vitamin K were
vitamin K deficiency has been termed hemor- revised in many countries to include enteral dos-
rhagic disease of the newborn and comprises age. It is universally accepted that vitamin K is
three distinct presentations. The very early form necessary to prevent all forms of clinical disease in
presents within 24 h of birth and is almost exclu- newborns. However, the method of administration
sively seen in infants of mothers taking drugs that and timing remain nonuniform across guidelines.
inhibit vitamin K. These drugs include certain For infants at risk from maternal medications,
anticonvulsants, some antibiotics and vitamin K traumatic delivery, or prematurity, the intramuscu-
antagonists, many of which are now avoided in lar route is preferred. For healthy term newborns at
pregnancy. Clinical presentation can be severe, low risk, the AAP recommends that vitamin K
with cephalohematomas and intracranial and should be given as a single intramuscular dose of
intraabdominal hemorrhage. Classical vitamin K 1.0 mg to all newborns within the first 6 h after
deficiency occurs between 24 h and 7 days of life birth (Pediatrics 2003). For infants whose parents
and is associated with delayed or insufficient feed- refuse an intramuscular injection, an oral dose of
ing. Clinical presentation is often mild, with 2.0 mg of vitamin K at the time of the first feeding
bruises, gastrointestinal bleeding, or bleeding with dosages repeated at 2–4 weeks and 6–8
from the umbilicus and puncture sites. The late weeks of age may be used (McMillan 1997).
presentation of vitamin K deficiency is associated Some countries have investigated the use of a
with exclusive breastfeeding. It occurs between small daily dose of enteral vitamin K in lieu of
the ages of 2 and 12 weeks and infants can be large doses less frequently in breastfeeding infants
gravely ill, with a mortality rate of 20%. Intracra- who did not receive the injection at birth, with
nial hemorrhage occurs in up to 50% of those apparent success (Van Winckel et al. 2009). Par-
affected (Van Winckel et al. 2009). After the dis- ents choosing oral dosing should be advised of the
covery of vitamin K in the mid twentieth century, necessity of follow-up doses and be cautioned that
it was shown that treatment with vitamin K could their infants remain at an increased risk of late
abolish hemorrhagic disease of the newborn. It vitamin K deficiency (including the potential for
then became standard practice to administer the intracranial hemorrhage) using the oral as opposed
drug soon after birth to all infants. Controversy to parenteral route (McMillan 1997).
has arisen about this practice for several reasons.
Both classic and late vitamin K deficiency are
relatively rare; recent reviews cite estimates of 27.14 Conclusion
0.01–0.44% in the general population for the clas-
sic form, and between 4.4/100,000 and 7.2/ A 1995 study performed across several Italian
100,000 births for the late form in fully breast- nurseries showed that despite the availability of
fed infants who did not receive vitamin K at birth evidence-based national and international guide-
(Van Winckel et al. 2009). The present dose of lines pertaining to routine newborn care, practices
1 mg represents a very large amount when were guided by long standing habit and
406 T. M. Randis and J. M. Duchon
previously developed experiences (Guala et al. newborn infants. N Engl J Med 344:467–471. https://
2005). This can be extrapolated to many aspects doi.org/10.1056/NEJM200102153440701
Chamberlain D, Founding Members of the International
of neonatal care. However, in the low risk, well Liaison Committee on Resuscitation (2005) The Inter-
newborn, the guiding principle should be to national Liaison Committee on Resuscitation
ensure the health and well being of the baby, and (ILCOR)-past and present: compiled by the Founding
facilitate practices that will encourage continued Members of the International Liaison Committee on
Resuscitation. Resuscitation 67:157–161. https://doi.
health through maternal child interaction. org/10.1016/j.resuscitation.2005.05.011
Chen J-Y (1992) Prophylaxis of ophthalmia neonatorum:
comparison of silver nitrate, tetracycline, erythromycin
and no prophylaxis. Pediatr Infect Dis J 11:1026
References Committee on Fetus and Newborn, Adamkin DH (2011)
Postnatal glucose homeostasis in late-preterm and term
The Task Force on Neonatal Encephalopathy: D’Alton M, infants. Pediatrics 127:575–579. https://doi.org/
Hankins G, Berkowitz R, Bienstock J, Ghidini A, Gold- 10.1542/peds.2010-3851
smith J, Higgins R, Moore T, Natale R, Nelson K, Papile Cornblath M, Hawdon JM, Williams AF et al (2000)
L, Peebles D, Romero RJ, Schendel D, Spong CY, Controversies regarding definition of neonatal hypogly-
Waldman R, Wu Y, American College of Obstetricians cemia: suggested operational thresholds. Pediatrics
and Gynecologists’ staff: Joseph G, Hawks D, Politzer A, 105:1141–1145. https://doi.org/10.1542/peds.105.5.1141
Emig C, Thomas K. (2014) Executive summary: neonatal Costeloe K, Hennessy E, Gibson AT et al (2000) The
encephalopathy and neurologic outcome, second edition. EPICure study: outcomes to discharge from hospital
Report of the American College of Obstetricians and for infants born at the threshold of viability. Pediatrics
Gynecologists’ task force on neonatal encephalopathy. 106:659–671
Obstet Gynecol 123:896–901. https://doi.org/10.1097/01. Cramer K, Wiebe N, Hartling L et al (2005) Heat loss
AOG.0000445580.65983.d2 prevention: a systematic review of occlusive skin
Adamkin DH, Polin R (2016) Neonatal hypoglycemia: wrap for premature neonates. J Perinatol 25:763–769.
is 60 the new 40? The questions remain the same. https://doi.org/10.1038/sj.jp.7211392
J Perinatol 36:10–12. https://doi.org/10.1038/jp.2015.125 Dyson L, McCormick F, Renfrew MJ (2005) Interventions
Altuncu E, Özek E, Bilgen H et al (2008) Percentiles of for promoting the initiation of breastfeeding. Cochrane
oxygen saturations in healthy term newborns in the first Database Syst Rev CD001688. https://doi.org/10.1002/
minutes of life. Eur J Pediatr 167:687–688. https://doi. 14651858.CD001688.pub2
org/10.1007/s00431-007-0540-x Embree J (2002) Recommendations for the prevention
American Academy of Pediatrics Committee on Fetus and of neonatal ophthalmia. Paediatr Child Health
Newborn, American College of Obstetricians and 7:480–488
Gynecologists Committee on Obstetric Practice Fadda GM, Capobianco G, Balata A, Litta P, et al (2009)
(2015) The Apgar score. Pediatrics 136:819–822. Routine second trimester ultrasound screening for pre-
https://doi.org/10.1542/peds.2015-2651 natal detection of fetal malformations in Sassari Uni-
American Academy of Pediatrics, American Heart Associ- versity Hospital, Italy: 23 years of experience in 42,256
ation, Weiner GM, Zaichkin J (2016) Textbook of pregnancies. Eur J Obstet Gynecol Reprod Biol; e-
neonatal resuscitation (NRP), 7th edn. American Acad- publication
emy of Pediatrics, Elk Grove Village Gleissner M, Jorch G, Avenarius S (2000) Risk factors for
Anderson GC, Moore E, Hepworth J, Bergman N (2003) intraventricular hemorrhage in a birth cohort of 3721
Early skin-to-skin contact for mothers and their healthy premature infants. J Perinat Med 28:104–110. https://
newborn infants. Birth 30:206–207 doi.org/10.1515/JPM.2000.013
Apgar V (2015) A proposal for a new method of evaluation Golding J, Paterson M, Kinlen LJ (1990) Factors associ-
of the newborn infant. Anesth Analg 120:1056–1059. ated with childhood cancer in a national cohort study.
https://doi.org/10.1213/ANE.0b013e31829bdc5c. Br J Cancer 62:304–308
Originally published in July 1953, 32:250–259 Guala A, Guarino R, Zaffaroni M et al (2005) The impact
Aziz K, Chadwick M, Baker M, Andrews W (2008) Ante- of national and international guidelines on newborn
and intra-partum factors that predict increased need for care in the nurseries of Piedmont and Aosta Valley,
neonatal resuscitation. Resuscitation 79:444–452. Italy. BMC Pediatr 5:1. https://doi.org/10.1186/1471-
https://doi.org/10.1016/j.resuscitation.2008.08.004 2431-5-45
Carbine DN, Finer NN, Knodel E, Rich W (2000) Video Halamek LP (2008) The simulated delivery-room environ-
recording as a means of evaluating neonatal resuscita- ment as the future modality for acquiring and
tion performance. Pediatrics 106:654–658 maintaining skills in fetal and neonatal resuscitation.
Casey BM, McIntire DD, Leveno KJ (2001) The continu- Semin Fetal Neonatal Med 13:448–453. https://doi.org/
ing value of the Apgar score for the assessment of 10.1016/j.siny.2008.04.015
27 Neonatal Care in the Delivery Room: Initial Management and Approach to Low Risk Newborns 407
Hey E (2003) Vitamin K—what, why, and when. Arch Dis Raju TN (1999) History of neonatal resuscitation. Tales of
Child Fetal Neonatal Ed 88:F80–F83. https://doi.org/ heroism and desperation. Clin Perinatol
10.1136/fn.88.2.F80 Righard L, Alade MO (1990) Effect of delivery room
Hutton EK, Hassan ES (2007) Late vs early clamping routines on success of first breast-feed. Lancet
of the umbilical cord in full-term neonates: 336:1105–1107. https://doi.org/10.1016/0140-6736
systematic review and meta-analysis of controlled tri- (90)92579-7
als. JAMA 297:1241–1252. https://doi.org/10.1001/ Russo A, McCready M, Torres L et al (2014) Reducing
jama.297.11.1241 hypothermia in preterm infants following delivery.
Impey L, Greenwood C, MacQuillan K et al (2001) Fever Pediatrics 133:e1055–e1062. https://doi.org/10.1542/
in labour and neonatal encephalopathy: a prospective peds.2013-2544
cohort study. BJOG 108:594–597 Section on Breastfeeding (2012) Breastfeeding and the use
Inder T (2008) How low can I go? The impact of hypogly- of human milk. Pediatrics 129:e827–e841. https://doi.
cemia on the immature brain. Pediatrics 122:440–441. org/10.1542/peds.2011-3552
https://doi.org/10.1542/peds.2008-1417 Shalak LF, Perlman JM, Jackson GL, Laptook AR (2005)
Lee YM, Simpson LL (2007) Major fetal structural Depression at birth in term infants exposed to maternal
malformations: the role of new imaging modalities. chorioamnionitis: does neonatal fever play a role?
Am J Med Genet C Semin Med Genet 145:33–44 J Perinatol 25:447–452. https://doi.org/10.1038/sj.
Laptook AR, Salhab W, Bhaskar B, Neonatal Research jp.7211326
Network (2007) Admission temperature of low birth Silverman WA, Fertig JW, Berger AP (1958) The influence
weight infants: predictors and associated morbidities. of the thermal environment upon the survival of newly
Pediatrics 119:e643–e649. https://doi.org/10.1542/ born premature infants. Pediatrics 22:876–886
peds.2006-0943 Soll RF (2008) Heat loss prevention in neonates. J Peri-
Lenclen R, Mazraani M, Jugie M et al (2002) Use of a natol 28:S57–S59. https://doi.org/10.1038/jp.2008.51
polyethylene bag: a way to improve the thermal envi- Stanley C, Pallotto E (2005) Avery’s diseases of the
ronment of the premature newborn at the delivery newborn. Taeusch HW, Ballard RA, Gleason CA,
room. Arch Pediatr 9:238–244 Avery ME, (Eds). Elsevier Health Sciences, pp
Mariani G, Dik PB, Ezquer A et al (2007) Pre-ductal and 1410–1422
post-ductal O2 saturation in healthy term neonates after Van de Bor M, Van Bel F, Lineman R, Ruys JH (1986)
birth. J Pediatr 150:418–421. https://doi.org/10.1016/j. Perinatal factors and periventricular-intraventricular
jpeds.2006.12.015 hemorrhage in preterm infants. Am J Dis Child
McMillan DD (1997) Routine administration of vitamin K 140:1125–1130
to newborns. Paediatr Child Health 2:429–434 Van Winckel M, De Bruyne R, Van De Velde S, Van
Moore ER, Bergman N, Anderson GC, Medley N (2016) Biervliet S (2009) Vitamin K, an update for the paedi-
Early skin-to-skin contact for mothers and their healthy atrician. Eur J Pediatr 168:127–134. https://doi.org/
newborn infants. Cochrane Database of Systematic 10.1007/s00431-008-0856-1
Reviews. Issue 11. Art. No.: CD003519. https://doi. Walker D, Walker A, Wood C (1969) Temperature of the
org/10.1002/14651858.CD003519.pub4. human fetus. J Obstet Gynaecol Br Commonw
O’Donnell CPF, Gibson AT, Davis PG (2006) Pinching, 76:503–511
electrocution, ravens’ beaks, and positive pressure ven- Wiswell TE, Gibson AT (2005) Historical evolution of
tilation: a brief history of neonatal resuscitation. Arch neonatal resuscitation. American Academy of Pediat-
Dis Child Fetal Neonatal Ed 91:F369–F373. https:// rics, Neonatal Resuscitation Program, Instructor
doi.org/10.1136/adc.2005.089029 Resources
Perlman JM (2006) Hyperthermia in the delivery: Wyckoff MH, Aziz K, Escobedo MB et al (2015) Part 13:
potential impact on neonatal mortality and morbidity. Neonatal resuscitation: 2015 American Heart Associa-
Clin Perinatol 33:55–63–vi. https://doi.org/10.1016/j. tion guidelines update for cardiopulmonary resuscita-
clp.2005.11.002 tion and emergency cardiovascular care. Circulation
Pildes RS, Cornblath M, Warren I et al (1974) A prospec- 132:S543–S560, Lippincott Williams & Wilkins
tive controlled study of neonatal hypoglycemia. Pedi- Zayeri F, Kazemnejad A, Ganjali M et al (2005) Hypo-
atrics 54:5–14 thermia in Iranian newborns. Incidence, risk
Policy statement: breastfeeding and the use of human milk factors and related complications. Saudi Med J
(2005) Pediatrics 115:496–506 26:1367–1371
Early Detection of Neonatal
Depression and Asphyxia 28
Paolo Biban and Davide Silvagni
Contents
28.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
28.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
28.3 Incidence and Definition of Neonatal Asphyxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
28.4 Intrapartum Asphyxial Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
28.5 Immediate Postpartum Asphyxial Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
28.5.1 Apgar Score . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
28.5.2 Acid–Base Measurements in Umbilical Cord Blood . . . . . . . . . . . . . . . . . . . . . . . . . 413
28.5.3 Blood Lactate at Birth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414
28.6 Asphyxial Markers in the Early Neonatal Period . . . . . . . . . . . . . . . . . . . . . . . . . 415
28.6.1 Postasphyxial Neonatal Encephalopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415
28.6.2 Multiorgan Failure Consistent with Neonatal Encephalopathy . . . . . . . . . . . . . . . 416
28.6.3 Urinary Lactate/Creatinine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416
28.6.4 Nucleated Red Blood Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417
28.6.5 Amplitude Integrated EEG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417
28.6.6 Early Neuroimaging Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417
28.6.7 Magnetic Resonance Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418
28.6.8 Biochemical Markers in Early Detection of Neonatal Asphyxia . . . . . . . . . . . . . 418
28.7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
Abstract period. The variable degree of depression is
Neonatal depression is a general term to inversely related to the Apgar score, with
describe the condition of any newborn show- 1 min scores of 0–3 indicating the most severe
ing a prolonged transition from intrauterine to forms, which may include perinatal asphyxia.
extrauterine life, in the immediate postnatal Despite major advances in obstetric and
neonatal care, perinatal asphyxia remains a
serious condition which may occur in the
P. Biban (*) · D. Silvagni
intrapartum, immediate postpartum, and early
Azienda Ospedaliera Universitaria Integrata Verona, neonatal period.
Verona, Italy
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 409
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_178
410 P. Biban and D. Silvagni
Perinatal asphyxia can be associated either 28.2 Introduction
with an uneventful course or with significant
mortality and long-term morbidity. Therefore, Perinatal asphyxia is an insult to the fetus or new-
reliable diagnostic and prognostic indicators are born due to hypoxia and/or ischemia, persisting long
essential for a prompt recognition and treatment enough to cause pathological biochemical changes
of newborns at risk for subsequent negative and a variable degree of injury to various organs,
outcome. including the brain. The effects of hypoxia and
However, the early detection of perinatal ischemia are often difficult to separate clinically.
asphyxia still constitutes a challenging target Hypoxia refers to an arterial concentration of oxy-
in neonatology. gen that is less than normal, while ischemia occurs
Despite several biochemical markers of when the blood flow to the cells or organs is insuf-
asphyxia are available nowadays, none of ficient to maintain normal function. In its more
them have shown sufficient reliability in pre- severe forms, the impaired gas exchange secondary
dicting long-term neurological outcome. to asphyxia is also associated with tissue lactic aci-
Electrophysiological and neuroimaging dosis and hypercapnia (Aurora and Snyder 1997).
investigations, such as aEEG, diffusion Neonatal depression is a general term to
weighted MRI, or magnetic resonance spec- describe the condition of any newborn in the
troscopy, may provide early valuable informa- immediate postnatal period (approximately the
tion, but may be not easily available. Further first hour after birth) showing a prolonged transi-
research is still needed to validate prediction tion from intrauterine to extrauterine life. The
models capable to identify neonates at risk of degree of depression may be described using the
dismal outcome due to perinatal asphyxia, allo- Apgar score: a 1 min score of 4–6 is considered as
wing an adequate and timely diagnosis, treat- moderate depression, and a score of 0–3 indicates
ment, and counselling. severe neonatal depression, which usually
requires immediate resuscitative interventions.
Notably, the Apgar score cannot be used to deter-
28.1 Salient Points mine the need for initial resuscitation.
• Neonatal depression refers to any newborn
showing a prolonged transition from intrauter- 28.3 Incidence and Definition of
ine to extrauterine life, in the immediate post- Neonatal Asphyxia
natal period.
• Perinatal asphyxia remains a serious condi- Despite major advances in monitoring technol-
tion which may occur in the intrapartum, ogy, obstetric care, and knowledge of fetal and
immediate postpartum, and early neonatal neonatal pathologies, asphyxia remains a serious
period. condition causing significant mortality and long-
• Perinatal asphyxia can be associated either term morbidity. According to the World Health
with an uneventful course or with significant Organisation (WHO), 4–9 million cases of new-
mortality and long-term morbidity. Accurate born asphyxia occur each year (World Health
diagnostic and prognostic indicators are essen- Organization 2005). More than a million new-
tial for a prompt recognition and treatment of borns that survive asphyxia at birth develop
newborns at high risk of injury. long-term problems such as cerebral palsy, mental
• The combination of clinical, instrumental, and retardation, speaking, hearing, visual, and learn-
biochemical indicators could provide predic- ing disabilities (World Health Organization 2005).
tive models to identify neonates at risk of Globally, it is estimated that out of four million
dismal outcome due to perinatal asphyxia, neonatal deaths annually, nearly one fourth are
allowing timely diagnosis, treatment, and attributable to asphyxia (Lawn et al. 2005). In
counselling. the developing world, the incidence of asphyxia
28 Early Detection of Neonatal Depression and Asphyxia 411
is believed to be considerably higher due to the Approximately 1–2 infants per 1000 live term
increased prevalence of risk factors. However, the births are affected by hypoxic-ischemic encepha-
incidence of birth asphyxia may vary markedly, lopathy, with outcomes ranging from complete
depending on the definition used, as well as the recovery to death (Levene et al. 1985). HIE is a
gestational age of the infant. Many definitions of well-recognized clinical syndrome, with a large
perinatal asphyxia can be found throughout the spectrum of clinical manifestations ranging from
available literature, but a universal definition is mild to severe. The clinical staging of Sarnat and
still lacking (Low 1997; The Task Force on Cere- Sarnat has been widely used since the 1970s to
bral Palsy and Neonatal Asphyxia of the Society estimate the severity of the hypoxic-ischaemic
of Obstetricians and Gynecologists of Canada insult in infants of 36 or more weeks of gestation
1996; Phelan et al. 2005). One of the most utilized (Sarnat and Sarnat 1976). In most cases, the sever-
is that promulgated in 2003 by the American ity of the encephalopathy predicts the risk of death
Academy of Pediatrics and the American College and long-term neurodisability (Sarnat and Sarnat
of Obstetrician and Gynecologists, which 1976; Shankaran 2009). However, an hypoxic
includes the following criteria (American College ischemic encephalopathy secondary to
of Obstetricians and Gynecologists et al. 2003): intrapartum asphyxia cannot reliably predict the
consequent neurodevelopmental outcome (Volpe
1. Metabolic or mixed acidosis (pH < 7.00) in an 2008; Perlman and Risser 1996). Most term new-
arterial cord blood sample borns with perinatal asphyxia have uneventful
2. Apgar score 0–3 for more than 5 min after birth courses and a low likelihood of subsequent neu-
3. Evidence of neurologic signs in the immediate rological sequelae (Volpe 2008; Goodwin 1999).
neonatal period Perinatal depression, when defined as low Apgar
4. Evidence of multiorgan failure in the immedi- scores in the first minutes of life, may be not only
ate neonatal period related to birth asphyxia but also to other factors
carrying a much lower risk of unfavorable short-
More recently, the following neonatal signs and long-term outcome, including a vagal
have been proposed as consistent with an acute response due to nasopharyngeal stimulation, low
peripartum or intrapartum event (American Col- gestational age, depression because of maternal
lege of Obstetrics and Gynecology et al. 2014): anaesthesia (Volpe 2008). The prognosis for any
given baby remains uncertain and reliable diag-
(a) Apgar score of less than 5, at 5 and 10 min nostic and prognostic indicators related to perina-
(b) Umbilical artery acidemia (pH less than 7.0 tal asphyxia are still needed. Accurate markers of
and/or base deicit 12 mmol/L) severe asphyxia and predictors of outcome would
(c) Evidence of brain injury consistent with hyp- facilitate parental counselling as well as the choice
oxia-ischemia, by means of brain magnetic of appropriate levels of care, which may include
resonance imaging or magnetic resonance withdrawal of intensive care or the initiation of
spectroscopy neuroprotective strategies.
(d) Multisystem organ failure consistent with Perinatal asphyxia may be categorized as
hypoxic-ischemic encephalopathy occurring in three phases: (1) intrapartum; (2)
immediate postpartum; and (3) early neonatal
Newborn infants suffering episodes of perina- period.
tal asphyxia are at high risk of dying or develop-
ing brain damage. Postasphyxial hypoxic-
ischemic encephalopathy (HIE) is viewed as the 28.4 Intrapartum Asphyxial Markers
hallmark and most important consequence of
asphyxia, being a major cause of death and of Assessment of the intrapartum condition of the
disability in term and near-term newborn infants fetus includes electronic fetal heart rate monitor-
in developed countries (Volpe 2008). ing (EFM), the observation of meconium in the
412 P. Biban and D. Silvagni
amniotic fluid, fetal scalp blood sampling for sequelae (Nelson and Grether 1998). Currently,
acid–base, and lactate measurements (see the meconium passage in utero is considered neither
comprehensive ▶ Chap. 2, “Risk Factors for Ges- a significant nor a specific marker of fetal distress
tational Diseases” by Petraglia and coll.). unless associated with other abnormalities (Volpe
2008; Glantz and Woods 2004).
Electronic Fetal Monitoring Electronic fetal
monitoring (EFM) has been used to predict fetal Fetal Scalp Blood Sampling Fetal scalp blood
distress or well being. Heart rate abnormalities sampling (FBS) was introduced by Bretscher and
have been identified as a marker of asphyxia during Saling in 1962 and was primarily based on pH
labor, fetal bradycardia being one of the most seri- analysis (Bretscher and Saling 1967). They defined
ous (Williams and Galerneau 2003). However, EFM pH cut-off values as normal (>7.25), preacidotic
has been shown to be imprecise in detecting fetuses (7.20–7.25), and acidotic (<7.20), recommending
with metabolic acidosis and predicting those likely prompt delivery for cases with acidosis. These
to develop an hypoxic-ischemic encephalopathy guidelines are still regarded as the “gold standard”
(Larma et al. 2007; Graham et al. 2008). for diagnosing intra-partum fetal distress. Fetal
A recent study evaluated the accuracy of EFM in acidemia due to an hypoxic-ischemic insult is usu-
predicting neonatal encephalopathy requiring hypo- ally metabolic and a consequence of anaerobic gly-
thermia therapy. Disappointingly, the fetal heart colysis due to prolonged intrauterine hypoxia. In a
tracing during the last hour before delivery was large retrospective study, Kruger et al. (1999)
poorly predictive of neonatal encephalopathy performed 814 lactate and/or 1221 pH scalp blood
requiring whole-body cooling treatment (Graham measurements when fetal distress was suspected. In
et al. 2014). Nonetheless, another study determined terms of sensitivity and specificity, lactate performed
that some EFM features best predicated fetal better than pH in the prediction of severe neonatal
acidemia, including repetitive prolonged decelera- morbidity (Kruger et al. 1999). In addition, Kruger
tions, baseline tachycardia, repetitive variable decel- et al. (1998) demonstrated a good correlation
erations, and repetitive late decelerations (Cahill et between lactate obtained by FBS close to delivery
al. 2012). Newer technologies, such as fetal pulse and from cord arterial blood immediately after deliv-
oximetry and fetal electrocardiography, have been ery. The potential usefulness of fetal scalp and cord
investigated to identify fetuses at risk more accu- blood lactate measurements to monitor the peri-
rately. In particular, fetal electrocardiogram analysis partum conditions of the fetus has been recently
of the ST segment (STAN) monitoring has been reviewed by Nordstrom (2004). Fetal scalp blood
adopted in several European countries in addition acid–base and lactate measurements, especially
to conventional EFM. However, a recent large con- when combined with fetal heart rate monitoring,
trolled trial performed in the USA, comparing con- seem to be of value in predicting the condition of
ventional EFM versus conventional EFM with newborns at birth. However, this invasive approach
STAN, did not find any substantial difference in can be performed only after rupture of membranes
terms of perinatal morbidity, mortality, or operative and is not widely used. Associated complications,
delivery rates (Belfort et al. 2015). Other techniques, although rarely observed, are soft tissue damage and
such as Doppler measurement of blood flow veloc- scalp infections (Carbonne and Nguyen 2008).
ity, near infrared spectroscopy, and fetal electroen-
cephalogram, are less suitable for a routine clinical
application (Volpe 2008). 28.5 Immediate Postpartum
Asphyxial Markers
Meconium Passage in Utero Meconium pas-
sage in utero is frequently cited as a sign of fetal Common markers of asphyxia used immedi-
stress, but several studies have failed to demon- ately after birth include low Apgar scores,
strate a correlation between meconium stained umbilical artery acidemia, and high blood lac-
amniotic fluid and permanent neurological tate concentrations.
28 Early Detection of Neonatal Depression and Asphyxia 413
28.5.1 Apgar Score Although the Apgar score has been used to
predict specific neurological outcome in the term
In a classic paper appeared in 1953 (Apgar 1953), infant, several studies have demonstrated a weak
Dr. Virginia Apgar, an obstetric anesthesiologist correlation between low Apgar scores and severe
at Columbia University in New York, proposed a birth asphyxia and subsequent adverse neurolog-
scoring system based on five signs pertaining to ical development (Goodwin 1999; Ehrenstein
the condition of the infant at birth, including heart 2009). Nevertheless, the Apgar score is still
rate, respiratory efforts, color, muscle tone, and widely used and is useful for describing the con-
reflex irritability. Each sign was given a score of 0, dition of newly born infants and their response to
1, or 2, somewhat quantifying the degree of neo- resuscitation. While it is not appropriate to use it
natal depression by checking the presence of bra- alone to establish the diagnosis of asphyxia, when
dycardia, apnea or gasping, cyanosis or pallor, combined with other conventional markers, such
hypotonia, as well as depressed reactivity. In the as arterial umbilical cord pH and base deficits, it
following years, the Apgar score was rapidly has some predictive value for the development of
adopted by most perinatal centres worldwide, hypoxic-ischemic encephalopathy (Kruger et al.
being originally used as a rapid method of 1999; Carter et al. 1998). Conversely, according
assessing the need for newborn resuscitation and to the ACOG, if the Apgar score at 5 min is greater
to define newborn asphyxia. However, the Apgar than or equal to 7, it is unlikely that severe hyp-
score has a number of limitations, mainly due to a oxic-ischemic events have occurred in the peri-
considerable interobserver variability and the dif- partum period (American College of Obstetrics
ferent physiological implications of the five fac- and Gynecology et al. 2014).
tors which make up the final score. Furthermore,
causes other than asphyxia may result in low
Apgar scores but without a high risk of brain 28.5.2 Acid–Base Measurements in
injury, such as resuscitation procedures, infec- Umbilical Cord Blood
tions, congenital malformations, and maternal
anesthesia (American College of Obstetricians Because Apgar scores are poor markers of severe
and Gynecologists et al. 2003). Moreover, Apgar birth asphyxia, some investigators have suggested
scores assigned during resuscitation are not equiv- the use of early acid–base status as a more objec-
alent to scores assigned to spontaneously breath- tive indicator and the finding of a severe metabolic
ing infants. In fact, many of the components acidosis in the umbilical cord arterial blood at
which contributes to the score calculation are birth are probably the most objective assessment
altered by the resuscitation manoeuvres, To this of intrapartum hypoxic ischemia (American Col-
end, the adoption of an expanded Apgar score lege of Obstetricians and Gynecologists et al.
report form, accounting for resuscitative interven- 2003). Metabolic acidosis occurs because of a
tions, has been recently encouraged by the ACOG prolonged tissue oxygen deficit, reflecting hyp-
and the AAP (American College of Obstetrics and oxia or impaired blood gas exchange of significant
Gynecology et al. 2015). duration to allow the accumulation of fixed acids,
Finally, the significance of low Apgar scores mainly lactic acid. Most studies assess acid–base
calculated in extremely premature babies are status on the arterial cord blood as soon as possi-
likely to differ from those awarded to term or ble after birth (American College of Obstetricians
near-term infants. In fact, score elements such as and Gynecologists et al. 2003). The acid–base
color, tone, and reflex irritability may markedly criteria commonly used to diagnose intrapartum
affect the score value in preterm infants, and asphyxia are a pH <7.00 and a base deficit (BD)
even healthy preterm newborns with no signs value >16 mmol/L in umbilical arterial blood at
of depression at birth may be assigned a low birth or during the first postnatal hour (The Task
score because of their immaturity (Hegyi et al. Force on Cerebral Palsy and Neonatal Asphyxia
1998). of the Society of Obstetricians and Gynecologists
414 P. Biban and D. Silvagni
of Canada 1996; American College of Obstetri- index of prolonged asphyxia, reflecting the sever-
cians and Gynecologists et al. 2003; MacLennan ity and duration of intra-partum asphyxia. Shah
1999). In a cohort of term infants with an umbil- et al. (2003) evaluated the rate of recovery of base
ical arterial Ph <7.00, nearly two-thirds did not deficit in 244 term infants with HIE due to intra-
require admission in NICU and had no apparent partum asphyxia. In their series, BD values nor-
neurological sequelae (Perlman and Risser 1993). malized by the first 4 h in the 96% of infants.
The need for cardiopulmonary resuscitation and Notably, infants with severe adverse outcome at
adrenaline administration in the delivery room 12 months had a similar BD recovery rate com-
identified those neonates with pH <7.00 at pared to those with a relatively good outcome.
greatest risk for a short-term adverse outcome Thus, although the rate of recovery of base deficit
(Perlman and Risser 1993). In a comprehensive may reflect the ability of the infant to recuperate
review, Graham et al. (2008) searched for studies from the oxygen debt, it is not predictive of long-
reporting the incidence of umbilical arterial pH term outcome (Shah et al. 2003). More recently,
<7.00. Combining data from seven different stud- the ACOG and AAP confirmed an arterial cord
ies, they found the mean incidence of umbilical blood gas pH less than 7.0 and/or a base deficit
arterial pH <7.00 at term in 3.7/1000 infants. Of 12 mmol/L as neonatal signs of perinatal
386 infants, about 17% survived with neurologi- asphyxia (American College of Obstetrics and
cal morbidity, 16% developed seizures, and 6% Gynecology et al. 2014). In a cohort study,
died during the neonatal period. The combined Knutzen et al. compared arterial umbilical cord
incidence of neonatal neurological morbidity and elevated base deficit to decreased pH. They
mortality for term infants with an umbilical arte- hypothesized the addition of base excess would
rial pH <7.00 at birth was 23%, with the have not further increased the ability of low pH to
remaining 77% being neurologically normal at identify term infants at-risk of neurologic
the time of neonatal discharge (Graham et al. sequelae (Knutzen et al. 2015). In fact, in the
2008). In another study, the incidence of enceph- setting of acidemia, they did not observe any
alopathy in 109 term infants with umbilical artery additional value in identifying term infants with
pH <7.00 was 31%: seizures occurred in 9% of neurologic morbidity when the metabolic compo-
infants with pH between 6.90 and 6.99, and in nent was included.
80% of those with pH between 6.61 and 6.70
(Goodwin et al. 1992). In a smaller study, Nagel
et al. (1995) reviewed 21 infants born with a pH 28.5.3 Blood Lactate at Birth
<7.00 over a 19-month period. Two out of 21
infants died in the neonatal period, but when the Lactate is produced as a consequence of hypoxia
survivors were evaluated at 1–3 years, they and poor tissue perfusion (da Silva et al. 2000).
showed normal developmental scores. Therefore, When a critical reduction in oxygen and substrate
even though a pH value <7.00 at delivery seems delivery occurs, aerobic metabolism through
to be a good marker of severity of acidosis, it Kreb’s cycle cannot be sustained and tissues use
appears less well related to short- and long-term anaerobic metabolism to meet their energy
neurological outcomes. Conventionally, in the requirements. This in turn leads to an increase in
newborn, the degree of metabolic acidosis is mea- the production and accumulation of blood lactate
sured also by the umbilical artery base deficit. (Deshpande and Ward Platt 1997). A significant
Studies have shown that a base deficit excess association has been found between blood lactate
greater than 16 mmol/L is predictive of neonatal concentrations and neurological evolution. da
encephalopathy. Low et al. (1997) observed a Silva et al. (2000) measured blood lactate at
significant increase in moderate and severe 30 min of life in 115 term infants with suspected
encephalopathy with an umbilical artery base def- asphyxia. Significantly higher blood lactate con-
icit >12 mmol/L, suggesting that a base deficit centrations were observed in neonates with mod-
excess measured in arterial cord blood is a good erate to severe HIE (da Silva et al. 2000). In a
28 Early Detection of Neonatal Depression and Asphyxia 415
group of 61 full-term infants with suspected HIE. They used relatively simple clinical and labo-
asphyxia, Shah et al. (2004a) observed that ratory observations available within the first 4 h of
blood lactate concentrations were significantly life and identified three significant predictors: chest
higher and took longer to normalize in neonates compressions >1 min, onset of spontaneous breath-
with moderate to severe HIE, compared to those ing >30 min and a base deficit value >16 mmol/L
with mild or no HIE. Furthermore, blood lactate in any blood gas analysis within the first 4 h. In this
concentrations greater than 7.5 mmol/L at 1 h of cohort of term infants with HIE, a severe adverse
age were associated with a higher risk of neuro- outcome was found in 93% of subjects in whom all
logical and systemic complications, with a sensi- three predictors were present. However, infants with
tivity of 94% and a specificity of 67%. Of note, none of the three predictors also had a high possi-
sensitivity and negative predictive value of lactate bility of adverse outcome (46%) (Shah et al. 2006).
in the first hour of life were higher than either pH Therefore, more accurate prediction models are
or base deficit (Shah et al. 2004a) These findings still needed for the early identification of those
have been recently confirmed in a retrospective infants most likely to benefit from interventions.
cohort study by Tuuli and co-workers, who found At present, the occurrence of abnormal neurologi-
that a high umbilical arterial lactate (>3.9 mmol/L) cal features after signs of intrauterine asphyxia,
was more specific and sensitive for neonatal mor- namely postasphyxial hypoxic-ischemic encepha-
bidity if compared with low pH or elevated base lopathy, remains the best indicator of a newborn
excess (Tuuli et al. 2014). Interestingly, a recent infant at risk of subsequent neurological impair-
study by Murray et al. (2008) found that a nor- ment (Volpe 2008). Other early markers include
malization time of blood lactate concentrations multiorgan dysfunction, urinary lactate/creatinine
greater than 10 h was associated with a high risk ratio, and nucleated red blood cells counts. Finally,
of encephalopathy (Murray et al. 2008). several techniques are available to evaluate the
However, despite ongoing efforts of presence and degree of neurological injury, includ-
researchers, the value of available surrogate ing early electrophysiological and neuroimaging
markers to identify infants at high risk of morbid- studies, such as amplitude integrated electroen-
ity still remains to be elucidated. Even though cephalogram (aEEG), cranial ultrasound, magnetic
umbilical arterial measures will continue to pro- resonance imaging (MRI), and computed tomog-
vide useful clinical information, it must be empha- raphy (CT) (see also ▶ Chap. 132, “The Timing of
sized that most term infants with low pH, high Neonatal Brain Damage”.
base excess, and elevated lactate level will not
yield obvious neurological abnormalities at
short- and long-term follow-up. 28.6.1 Postasphyxial Neonatal
Encephalopathy
28.6 Asphyxial Markers in the Early Neonatal encephalopathy (NE) is characterized by
Neonatal Period abnormal consciousness, tone and reflexes, and
seizure activity. The main cause of NE is
Suspected intrapartum asphyxia causing brain intrapartum hypoxic ischemia, followed by
injury can be confirmed in the first hours after trauma, infections, metabolic diseases, and devel-
birth by various clinical, biochemical, and other opmental abnormalities. Prognosis is related to
measures. Some authors have attempted to the severity of the HIE syndrome, the onset of
develop models able to predict early and reliably seizures, and the duration of the neurological
the development of HIE and/or subsequent neu- abnormalities. Although several classifications
rological sequelae in asphyxiated newborns. In a are available, the most popular remains that pro-
large retrospective cohort study, Shah et al. (2006) posed by Sarnat and Sarnat in 1976, to indicate the
tried to validate a prognostic model for term severity of the hypoxic ischemic insult in infants
infants with moderate to severe postasphyxial of 36 or more weeks of gestation (Sarnat and Sarnat
416 P. Biban and D. Silvagni
1976). The sequential appearance and resolution of of the neonatal postasphyxial syndrome (American
the various transient clinical signs in the first 2 College of Obstetricians and Gynecologists Com-
weeks suggest the extent of neurologic impairment mittee Opinion 1998). However, this assumption
and define different clinical categories in the early has been questioned by several authors and the
assessment of infants with HIE (Aurora and Snyder incidence of MOF in asphyxiated infants is variable.
1997). The Sarnat and Sarnat staging of HIE ranges Such variability may partly depend on differences of
from mild (grade I) to severe (grade III). Grade I selection criteria, definitions of MOF, or timing of
comprises a mild encephalopathy with the infant the diagnosis of MOF.
being hyper alert, irritable, and oversensitive to In term newborns with arterial cord pH <7.00,
stimuli, but with a normal EEG. Virtually all Goodwin et al. (1992) observed an incidence of
these patients have a normal neurological outcome. MOF of 30%. In a retrospective cohort study, all
In grade II, there is a moderate encephalopathy, infants with severe HIE had evidence of MOF.
with the infant displaying lethargy, hypotonia and However, the presence of MOF, regardless of the
proximal weakness, low resting heart rate, and combination of different organs involved, did not
small pupils. The EEG is abnormal and 70% of correlate with long-term neurological outcome
the infants will have seizures. About 20% of these (Shah et al. 2004b). Thus, MOF may reinforce the
patients may manifest abnormal neurological out- suspicion of intrapartum hypoxic ischemia in new-
come. In grade III, there is a severe encephalopathy borns with HIE, but it is not a useful criterion for the
with the infant stuporous, flaccid, and no reflexes. early identification of infants at risk for an adverse
EEG is abnormal with decreased background activ- neurological outcome. Recently, the Task Force on
ity and/or voltage suppression. About half of these neonatal encephalopathy has released an updated
patients die, whereas the surviving 50% suffer report on neonatal encephalopathy and neurologic
major neurological injury, with epilepsy and men- outcome (American College of Obstetrics and
tal retardation (Aurora and Snyder 1997; Sarnat Gynecology et al. 2014). Although the presence of
and Sarnat 1976). Recently, a revised definition organ dysfunction increases the risk of hypo-
by the ACOG and AAP describes neonatal enceph- xic–ischemic encephalopathy in the setting of neo-
alopathy associated with a peripartum event as a natal encephalopathy, the severity of brain injury
disturbance of neurologic function, which is evi- seen on neuroimaging does not always correlate
dent in the first days after birth in an infant born at with the degree of injury to other organ systems.
or beyond 35 weeks of gestation. NE is character-
ized by a subnormal level of consciousness and
depressed tone and reflexes, with or without sei- 28.6.3 Urinary Lactate/Creatinine
zures, and often with impaired respiration and feed-
ing abilities, both considered of presumed central Huang and coworkers investigated the role of
origin (American College of Obstetrics and Gyne- urinary lactate/creatinine ratio to differentiate nor-
cology et al. 2014; McAdams and Juul 2016). mal infants (58 subjects) from infants with
asphyxia (40 subjects) (Huang et al. 1999). The
measurements of urinary lactate and creatinine
28.6.2 Multiorgan Failure Consistent were obtained by proton nuclear magnetic reso-
with Neonatal Encephalopathy nance spectroscopy (1H NMR) within 6 h of birth
and at 48 and 72 h. Sixteen of the infants with
Multiple organ failure is a marker of a perinatal asphyxia went on to develop an encephalopathy.
hypoxic ischemic insult. It can include renal, hepatic Within 6 h after birth, the mean lactate/creatinine
or gastrointestinal injury, hematologic abnormali- ratio in infants who subsequently developed
ties, cardiac dysfunction, metabolic derangements, encephalopathy was 186 times as high as the
or a combination of these. In 1998, the American ratio in normal controls, and 88 times as high as
College of Obstetrician and Gynaecologists consid- that in infants with asphyxia not progressing to
ered multiorgan failure (MOF) as a constant feature HIE. A urinary lactate/creatinine ratio of 0.64 or
28 Early Detection of Neonatal Depression and Asphyxia 417
higher showed 94% sensitivity and 100% speci- the asphyxiated term newborn (Shalak et al.
ficity for predicting the development of HIE. 2003). Changes in background activity and sei-
Thus, even if measurement technique by 1H zure activity are relatively easy to identify, allo-
NMR is expensive and not readily available, uri- wing for prompt intervention. aEEG may provide
nary lactate/creatinine ratio could be a potentially useful information about the functional integrity
useful marker for the early identification and treat- of the brain, presence or onset of subclinical sei-
ment of infants at high risk for HIE (Huang et al. zure activity, and the effect of anticonvulsant
1999). More recent papers partially confirmed the drugs. It may also aid the selection of patients
good predictive value of elevated urinary lactate suitable for neuroprotective interventions and in
to creatinine ratios for the development of neona- the early prediction of neurodevelopmental out-
tal encephalopathy and subsequent neurodeve- come (Gluckman et al. 2005; de Vries and
lopmental abnormalities. In a multicenter trial, Hellstrom-Westas 2005; Eken et al. 1995). A sys-
Oh et al. reported that urinary lactate to creatinine tematic review reported that aEEG performed
ratios were significantly associated with death or within 24 h of birth has a sensitivity of 93% and
moderate/severe neurodevelopmental disability specificity of 91% (Van Laerhoven et al. 2013).
(William et al. 2008). However, there was a
large variability and considerable overlap of the
data between infants with a normal outcome and 28.6.6 Early Neuroimaging
those with a poor outcome, thus limiting the pre- Investigations
dictive value of this marker (William et al. 2008).
Advanced neuroimaging techniques such as cranial
ultrasonography (CUS), MRI, and CT can be used
28.6.4 Nucleated Red Blood Cells in the early postpartum phase. CUS is a noninva-
sive and widely available technique. Up to 50% of
The nucleated red blood cell (NRBC) count is a newborns with HIE may initially show a normal
marker of fetal hypoxia in term and preterm CUS. Furthermore, it is not difficult to visualize
infants. In 1996, Korst et al. (1996) reported a parasagittal cerebral lesions, cortical, or brain stem
raised NRBC in cord blood from a group of neu- injuries. CUS is of value in the identification of
rologically impaired term infants compared with focal areas of necrosis (especially if hemorrhagic)
controls. In a prospective study, Buonocore et al. in the thalamus and basal ganglia as well as for the
(1999) observed that the NRBC count in umbili- detection of necrotic and cystic components of
cal cord blood was significantly higher in infants periventricular white matter injury (PVL) and,
showing abnormal neurodevelopment at age 3 although not optimal, in the evaluation of focal
when compared to normal controls. In a more ischaemic injuries. CUS may also be used to
recent study a relationship between HIE staging study the evolution of brain lesions (Volpe 2008).
and nucleated RBC was found: the higher the HIE MRI is considered the gold standard for the
staging the higher was the mean NRBC/100 early evaluation of the infant with hypoxic-ische-
WBC. In the same study NRBC count as marker mic injury. Particularly with the development of
for fetal asphyxia had a positive predictive value diffusion weighted imaging (DWI), MRI is consid-
of 98%, negative predictive value of 94% with an ered by some to be the method of choice to assess
overall accuracy of 96% (Goel et al. 2013). the newborn brain even in the first few days of life,
providing valuable information on the location and
extent of the neurological damage in moderately to
28.6.5 Amplitude Integrated EEG severely asphyxiated infants (Barkovich et al.
2006; Rutherford et al. 2006). DWI MRI typically
Continuous monitoring by amplitude integrated shows modifications due to ischemia earlier than
EEG (aEEG) can be done soon after admission conventional MRI, but it may underestimate the
to a NICU. It is helpful in the early assessment of extent of tissue injury during the first 24 h
418 P. Biban and D. Silvagni
following birth. Although DWI is complementary (CK-BB), S100b, serum IL-8, serum ionized cal-
to conventional MRI, visual analysis of DWI does cium, cerebrospinal fluid NSE, cerebrospinal fluid
not seem to significantly improve the prognostic or serum IL-1b, and serum IL-6 (Gazzolo et al.
accuracy of MRI in infants with HIE during the 2009; Merchant and Azzopardi 2015; Savman
first week after birth (Van Laerhoven et al. 2013). et al. 1998). Among these markers, S100b and
Because of radiation exposure and its poorer NSE are proved to be an early index of CNS damage
imaging definition compared to MRI, CT is less and correlate to the extent of brain damage due to
frequently used for infants with hypoxic- hypoxia/asphyxia (Massaro et al. 2013). Interest-
ischaemic injury. CT is, however, still occasion- ingly, the evolution of serum NSE and S100b during
ally useful for the identification of focal ischemic the first 72 h following birth has been reported in
or hemorrhagic brain injuries and when MRI is neonates treated for HIE with hypothermia: NSE
not readily available (Volpe 2008). and S100b levels at baseline and at 72 h strongly
predicted death or neurological abnormalities, or
MRI-detected brain injury, at 14 days of age. Thus,
28.6.7 Magnetic Resonance early measurement of NSE and S100b levels may be
Spectroscopy useful as biomarkers of brain injury following HIE,
even though information on long-term outcomes is
Magnetic Resonance Spectroscopy (MRS) enables still lacking (Massaro et al. 2013).
in vivo quantitative analysis of cerebral metabolites Since multiple organ dysfunction is commonly
(such as N-acetyl aspartate, choline-containing seen in HIE and circulating proinflammatory
compounds, creatine plus phosphocreatinine, lac- cytokines are involved in the final common path-
tate, myoinositol, alanine, glutamine, and gluta- way of brain injury, inflammatory cytokines
mate), detecting patterns of impairment of (interleukins 1b, 6, and 8 and tumor necrosis
cerebral energy metabolism in infants with HIE. factor) levels in cord, serum, and cerebrospinal
Impairment of cerebral metabolism occurs follow- fluid have been used to predict adverse outcomes
ing a delay of several hours after resuscitation in following HIE. However, at present no definitive
moderately or severely encephalopathic infants. and univoque data allow the use of these markers
Characteristic changes in spectral peaks are in a clinical setting to predict neurological out-
observed in infants with HIE according to cerebral come (Chalak et al. 2013).
metabolic disturbances due to asphyxia. Elevation Novel biomarkers, possibly with better speci-
of lactate, which indicates tissue ischaemia and ficity for predicting brain injury, have recently
hypoxia, as well as a fall in N-acetyl aspartate, been evaluated, along with the effects of therapeu-
which reflects neuronal injury, is typically found tic hypothermia. For instance, glial fibrillary
in HIE. Concentration or peak area ratios are com- acidic protein (GFAP), which is a cytoskeletal
monly described, but MRS is reported to have a intermediary filament protein found in astrocytes,
low specificity (approximately 58%) during the as well as ubiquitin carboxyl-terminal hydrolase
first week after birth (Cheong et al. 2012). L1 (UCHL1), which is a neuron-specific cytoplas-
mic enzyme present in dendrites and neuronal
cytoplasm, are involved in the pathogenesis of
28.6.8 Biochemical Markers in Early traumatic brain injury. These biomarkers have
Detection of Neonatal Asphyxia been shown to reflect the severity of neuronal
injury (Fraser et al. 2011). Furthermore, in recent
Serum, urine, and cerebrospinal fluid have been studies cord GFAP and UCHL1 levels seemed to
used to measure biomarkers of brain injury. Some correlate with the severity of HIE and were sig-
of the biomarkers which have been evaluated nificantly higher in infants with adverse outcomes
include urine lactate, urine S100, cord blood inter- than in those with favorable outcomes (Massaro
leukin (IL)-6, serum non-protein-bound iron, serum et al. 2013; Chalak et al. 2013). Moreover, GFAP
CD14, NFKB activation, creatine kinase brain band was able to correctly identify infants with
28 Early Detection of Neonatal Depression and Asphyxia 419
abnormal outcomes at 20 months (Massaro et al. American College of Obstetricians and Gynecologists,
2013; Chalak et al. 2013). Task Force on Neonatal Encephalopathy and Cerebral
Palsy, American Academy of Pediatrics (2003) Neona-
tal encephalopathy and cerebral palsy: defining the
pathogenesis and pathophysiology. American College
28.7 Conclusions of Obstetricians and Gynecologists, Washington, DC
American College of Obstetrics and Gynecology, Task
Force on Neonatal Encephalopathy, American Acad-
Early detection of perinatal asphyxia still consti- emy of Pediatrics (2014) Neonatal encephalopathy and
tutes a challenging target in neonatology. In addi- neurologic outcome, 2nd edn. American College of
tion, birth asphyxia can be associated either with an Obstetricians and Gynecologists, Washington, DC
uneventful course or with significant mortality and American College of Obstetrics and Gynecology, Commit-
tee on Obstetric practice, American Academy of Pedi-
long-term morbidity. Therefore, reliable diagnostic atrics (2015) The Apgar score. Committee opinion N.
and prognostic indicators are essential for a prompt 644. Obstet Gynecol 126:e52–e55
recognition and treatment of newborns at risk for Apgar V (1953) A proposal for a new method of evaluation
subsequent negative outcome. In the last decades, of the newborn infant. Curr Res Anesth Analg
32:260–267
many biochemical markers of asphyxia have been Aurora S, Snyder EY (1997) Perinatal asphyxia. In:
identified, both in cord blood and in blood samples Cloherty JP, Eichenwald EC, Stark AR (eds) Manual
after birth, including arterial pH, base excess, and of neonatal care, 4th edn. Lippincott Williams & Wil-
lactate. However, such indicators have shown a kins, Philadephia, pp 536–555
Barkovich AJ, Miller SP, Bartha A et al (2006) MR imag-
limited value in predicting long-term neurological ing, MR spectroscopy, and diffusion tensor imaging of
outcome. Other promising biochemical markers, sequential studies in neonates with encephalopathy.
e.g., urinary lactate/creatinine ratio, nucleated red AJNR Am J Neuroradiol 27:533–547
blood cells, S100 B protein, NSE, GFAP, and Belfort MA, Saade GR, Thom E et al (2015) A randomized
trial of intrapartum fetal ECG ST-segment analysis. N
UCHL1 still need further evaluation before their Engl J Med 373:632–641
inclusion in the routine assessment of asphyxia. Bretscher J, Saling E (1967) pH values in the human fetus
Some recent electrophysiological and neuro- during labor. Am J Obstet Gynecol 97:906–911
imaging investigations, such as amplitude inte- Buonocore G, Perrone S, Gioia D et al (1999) Nucleated
red blood cell count at birth as an index of perinatal
grated EEG, diffusion weighted MRI, or brain damage. Am J Obstet Gynecol 181:1500–1505
magnetic resonance spectroscopy, may also pro- Cahill AG, Roehl KA, Odibo AO et al (2012) Association
vide early valuable information on brain damage and prediction of neonatal acidemia. Am J Obstet
and outcome of asphyxiated babies. However, Gynecol 207:206.e1–206.e8
Carbonne B, Nguyen A (2008) Fetal scalp blood sampling
these techniques are not always available and for pH and lactate measurement during labour. J
could be difficult to perform in critically ill neo- Gynecol Obstet Biol Reprod 375:S65–S71
nates. Further research is still required to over- Carter BS, McNabb F, Merenstein GB (1998) Prospective
come the limitations due to the assessment of validation of a scoring system for predicting neonatal
morbidity after acute perinatal asphyxia. J Pediatr
perinatal asphyxia by single parameters. The com- 132:619–623
bination of clinical and biochemical indicators Chalak LF, Sanchez PJ, Adams-Huet B et al (2013) Bio-
should aim to validate prediction models capable markers for severity of neonatal hypoxic–ischaemic
to identify neonates at risk of dismal outcome due encephalopathy and outcomes in newborns receiving
hypothermia therapy. J Pediatr 164:468–474
to asphyxia, allowing an adequate and timely Cheong JL, Coleman L, Hunt RW et al (2012) Prognostic
diagnosis, treatment, and counselling. utility of magnetic resonance imaging in neonatal
hypoxic–ischaemic encephalopathy: substudy of a
randomized trial. Arch Pediatr Adolesc Med 166:
634–640
References da Silva SD, Hennebert N, Denis R, Wayenberg JL (2000)
Clinical value of single postnatal lactate measurement
American College of Obstetricians and Gynecologists after intrapartum asphyxia. Acta Paediatr 89:320–323
Committee Opinion (1998) Inappropriate uses of the de Vries LS, Hellstrom-Westas L (2005) Role of cerebral
terms fetal distress and birth asphyxia. Int J Gynecol function monitoring in the newborn. Arch Dis Child
Obstet 61:309–310 Fetal Neonatal Ed 90:F201–F207
420 P. Biban and D. Silvagni
Deshpande SA, Ward Platt MP (1997) Association Kruger K, Kublickas M, Westgren M (1998) Lactate in
between blood lactate and acid base status and mortal- scalp and cord blood from fetuses with ominous fetal
ity in ventilated babies. Arch Dis Child Fetal Neonatal heart rate patterns. Obstet Gynecol 92:918–922
Ed 76:F15–F20 Kruger K, Hallberg B, Blennow M et al (1999) Predictive
Ehrenstein V (2009) Association of Apgar scores with value of fetal scalp blood lactate concentration and pH
death and neurologic disability. Clin Epidemiol 1: as marker for neurologic disability. Am J Obstet
45–53 Gynecol 181:1072–1078
Eken P, Toet MC, Groenendaal F et al (1995) Predictive Larma JD, Silva AM, Holcroft CJ et al (2007) Intrapartum
value of early neuroimaging, pulsed Doppler and neuro- electronic fetal heart rate monitoring and the identifica-
physiology in full term infants with hypoxic-ischaemic tion of metabolic acidosis and hypoxic- ischaemic
encephalopathy. Arch Dis Child Fetal Neonatal Ed 73: encephalopathy. Am J Obstet Gynecol 197:301.
F75–F80 e1–301.e8
Fraser DD, Close TE, Rose KL et al (2011) Severe trau- Lawn JE, Cousens S, Zupan J (2005) 4 million neonatal
matic brain injury in children elevates glial fibrillary deaths: when? where? Why? Lancet 365:891–900
acidic protein in cerebrospinal fluid and serum. Pediatr Levene ML, Kornberg J, Williams TH (1985) The inci-
Crit Care Med 12:319–324 dence and severity of post-asphyxial encephalopathy in
Gazzolo D, Frigiola A, Bashir M et al (2009) Diagnostic full-term infants. Early Hum Dev 11:21–26
accuracy of S100B urinary testing at birth in full-term Low JA (1997) Intrapartum fetal asphyxia: definition,
asphyxiated newborns to predict neonatal death. PLoS diagnosis, and classification. Am J Obstet Gynecol
One 4(2):e4298 176:957–959
Glantz JC, Woods JR (2004) Significance of amniotic fluid Low JA, Lindsay BG, Derrick EJ (1997) Threshold of
Meconium. In: Creasy RK, Resnik R, Iams JD (eds) metabolic acidosis associated with newborn complica-
Maternal-fetal medicine: principles and practice, 5th tions. Am J Obstet Gynecol 177:1391–1394
edn. WB Saunders, Philadelphia MacLennan A (1999) A template for defining a causal
Gluckman PD, Wyatt JS, Azzopardi D et al (2005) Selec- relation between acute intrapartum events and cerebral
tive head cooling with mild systemic hypothermia after palsy: international consensus statement. BMJ 319:
neonatal encephalopathy: multicentre randomised trial. 1054–1059
Lancet 365:663–670 Massaro AN, Jeromin A, Kadom N et al (2013) Serum bio-
Goel M, Dwivedi R, Gohiya P, Hegde D (2013) Nucleated markers of MRI brain injury in neonatal hypoxic
red blood cell in cord blood as a marker of perinatal ischaemic encephalopathy treated with whole-body
asphyxia. J Clin Neonatol 2:179–182 hypothermia: a pilot study. Pediatr Crit Care Med 14:
Goodwin TM (1999) Clinical implications of perinatal 310–317
depression. Obstet Gynecol Clin North Am 26: McAdams RM, Juul SE (2016) Neonatal encephalopathy:
711–723 update on therapeutic hypothermia and other novel
Goodwin TM, Belai I, Hernandez P et al (1992) Asphyxial therapeutics. Clin Perinatol 43:485–500
complications in the term newborn with severe umbil- Merchant N, Azzopardi D (2015) Early predictors of out-
ical acidemia. Am J Obstet Gynecol 167:1506–1512 come in infants treated with hypothermia for hypo-
Graham EM, Ruis KA, Hartman AL et al (2008) A sys- xic–ischaemic encephalopathy. Dev Med Child
tematic review of the role of intrapartum hypoxia- Neurol 57(Suppl 3):8–16
ischaemia in the causation of neonatal encephalopathy. Murray DM, Boylan GB, Fitzgerald AP (2008) Persistent
Am J Obstet Gynecol 199:587–595 lactic acidosis in neonatal hypoxic-ischaemic encepha-
Graham EM, Adami RR, McKenney SL et al (2014) Diag- lopathy correlates with EEG grade and electrographic
nostic accuracy of fetal heart rate monitoring in the seizure burden. Arch Dis Child Fetal Neonatal Ed 93:
identification of neonatal encephalopathy. Obstet F183–F186
Gynecol 124:507–513 Nagel HT, Vandenbussche FP, Oepkes D et al (1995)
Hegyi T, Carbone T, Anwar M et al (1998) The Apgar score Follow-up of children born with an umbilical arterial
and its components in the preterm infant. Pediatrics blood pH < 7. Am J Obstet Gynecol 173:1758–1764
101:77–81 Nelson KB, Grether JK (1998) Potentially asphyxiating
Huang CC, Wang ST, Chang YC et al (1999) Measurement conditions and spastic cerebral palsy in infants of nor-
of the urinary lactate:creatinine ratio for the early iden- mal birth weight. Am J Obstet Gynecol 179:507–513
tification of newborn infants at risk for hypoxic- Nordstrom L (2004) Fetal scalp and cord blood lactate.
ischaemic encephalopathy. N Engl J Med 341:328–335 Best Pract Res Clin Obstet Gynaecol 18:467–476
Knutzen L, Svirko E, Impey L (2015) The significance of Perlman JM, Risser R (1993) Severe fetal acidemia: neo-
base deficit in acidemic term neonates. Am J Obstet natal neurologic features and short term outcome.
Gynecol 213:373.e1–373.e7 Pediatr Neurol 9:277–282
Korst LM, Phelan JP, Ahn MO et al (1996) Nucleated red Perlman JM, Risser R (1996) Can asphyxiated infants at
blood cells: an update on the marker for fetal asphyxia. risk for neonatal seizures be rapidly identified by cur-
Am J Obstet Gynecol 176:843–846 rent high-risk markers. Pediatrics 97:456–462
28 Early Detection of Neonatal Depression and Asphyxia 421
Phelan JP, Martin GI, Korst LM (2005) Birth asphyxia and with an early neurologic examination enhances predic-
cerebral palsy. Clin Perinatol 32:61–76 tion of term infants at risk for persistent encephalopa-
Rutherford M, Srinivasan L, Dyet L et al (2006) Magnetic thy. Pediatrics 111:351–357
resonance imaging in perinatal brain injury: clinical Shankaran S (2009) Neonatal encephalopathy: treatment
presentation, lesions and outcome. Pediatr Radiol 36: with hypothermia. J Neurotrauma 26:437–443
582–592 The Task Force on Cerebral Palsy and Neonatal Asphyxia
Sarnat HB, Sarnat MS (1976) Neonatal encephalopathy of the Society of Obstetricians and Gynecologists of
following fetal distress: a clinical and electroencepha- Canada (1996) Policy statement (part I). J Soc Obstet
lographic study. Arch Neurol 33:696–705 Gynecol Can 18:1267–1279
Savman K, Blennow M, Gustafson K et al (1998) Cytokine Tuuli MG, Stout MJ, Shanks A et al (2014) Umbilical cord
response in cerebrospinal fluid after birth asphyxia. arterial lactate compared with pH for predicting neona-
Pediatr Res 43:746–751 tal morbidity at term. Obstet Gynecol 124:756–761
Shah PS, Raju NV, Beyene J, Perlman M (2003) Recovery Van Laerhoven H, de Haan TR, Offringa M et al (2013)
of metabolic acidosis in term infants with postasphyxial Prognostic tests in term neonates with hypo-
hypoxic-ischaemic encephalopathy. Acta Paediatr 92: xic–ischaemic encephalopathy: a systematic review.
941–947 Pediatrics 131:88–98
Shah S, Tracy M, Smyth J (2004a) Postnatal lactate as an Volpe JJ (2008) Hypoxic-ischaemic encephalopathy: clin-
early predictor of short-term outcome after intrapartum ical aspects. In: Volpe JJ (ed) Neurology of the new-
asphyxia. J Perinatol 24:16–20 born, 5th edn. WB Saunders, Philadelphia
Shah P, Riphagen S, Beyene J, Perlman M (2004b) Multi- William OHW, Perritt R, Shankaran S et al (2008) Associ-
organ dysfunction in infants with post-asphyxial hyp- ation between urinary lactate to creatinine ratio and
oxic-ischaemic encephalopathy. Arch Dis Child Fetal neurodevelopmental outcome in term infants with hyp-
Neonatal Ed 89:F152–F155 oxic-ischemic encephalopathy. J Pediatr 153:375–378
Shah PS, Beyene J, To T et al (2006) Postasphyxial hyp- Williams KP, Galerneau F (2003) Intrapartum fetal heart
oxic-ischaemic encephalopathy in neonates: outcome rate patterns in the prediction of neonatal acidemia. Am
prediction rule within 4 hours of birth. Arch Pediatr J Obstet Gynecol 188:820–823
Adolesc Med 160:729–736 World Health Organization (2005) The World health report
Shalak LF, Laptook AR, Velaphi SC, Perlman JM (2003) 2005. Make every mother and child count. http://www.
Amplitude-integrated electroencephalography coupled who.int/entity/whr/2005/whr2005_en.pdf
Resuscitation of the Newborn
29
Ola D. Saugstad
Contents
29.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424
29.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424
29.3 Preparation for Resuscitation and Selection of Risk Cases . . . . . . . . . . . . . . 424
29.4 Indication for Resuscitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
29.5 Guidelines for Resuscitation of the Newly Born . . . . . . . . . . . . . . . . . . . . . . . . . . 425
29.6 Physiological and Biochemical Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
29.7 Initial Evaluation and Stabilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
29.7.1 Response to Birth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
29.7.2 Initial Stabilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
29.8 Meconium Aspiration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
29.9 Preterm Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
29.10 Withholding and Withdrawing Resuscitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
29.11 Post-Resuscitation Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
29.11.1 Hypothermia Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
29.12 Documentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
29.13 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
Abstract within 10–30 s of birth. In the USA, 5–10% of
In 2015, the International Liaison Committee on all newborn infants require basic life support in
Resuscitation estimated that 85% of babies born the delivery room or nursery. There are similar
at term will initiate spontaneous respirations figures for Western Europe.
Approximately 1% of newborns require
more extensive resuscitation procedures.
O. D. Saugstad (*) Recent estimates indicate that worldwide
Department of Pediatric Research, Rikshospitalet, Oslo 814,000 die and an equal number develops
University Hospital, University of Oslo, Oslo, Norway sequels after birth asphyxia. Thus, it is
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 423
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_179
424 O. D. Saugstad
important to anticipate which infants are at 814,000 die and an equal number develop sequels
risk, and the antepartum and intrapartum his- after birth asphyxia (Black et al. 2010).
tory often can be a help in predicting which However, data from, for instance, California
infants will need resuscitation. indicate that birth asphyxia is decreasing from
14.8 to 1.3 per 1000 in the period of 1991–2000,
and data from England show that there is a reduced
29.1 Salient Points need of ventilation at birth (Wu et al. 2004; Little et al.
2007). In spite of that, there is no doubt that both
• Always be prepared that a newborn infant in industrialized and low-income countries, a
might require resuscitation immediately after large number of newborn infants are in need of
birth. resuscitation at birth. Therefore and because a vast
• 3–5% of all newborn infants receive positive number of deliveries throughout the world still
pressure ventilation at birth. However, <1 per occur at home without authorized health person-
1000 needs chest compressions and/or adrena- nel present, it is also important to develop simple
line. Therefore ventilation constitutes the back- resuscitation routines.
bone of basic newborn resuscitation.
• The “golden minute” is crucial and starts when
the whole body is out. 29.3 Preparation for Resuscitation
• A satisfactory response in heart rate is the best and Selection of Risk Cases
assessment of the success of resuscitation. A
20 bpm increase the first 30 s of adequate Approximately 95% of deliveries are uneventful,
ventilation is a satisfactory response. and the adaptation to extrauterine life occurs
• Term and near-term infants in need of positive smoothly. Only in some infants should more vigor-
pressure ventilation are started with air. ous resuscitation procedures be carried out. As men-
Immature infants probably need at least 30% tioned above, as many as 5% or more need basic
oxygen initially. An oxygen blender is needed resuscitation including ventilation using a bag and
in all delivery units. mask. However, only a few newborn infants need
• Thermal care – to avoid hypothermia – is of advanced resuscitation. In 1:100 to 1:700, endotra-
great importance. cheal intubation is needed, 1:1000 needs chest com-
pression, 6:10,000 need epinephrine (adrenaline),
and as few as 1:12,000 of near-term and term infants
29.2 Introduction need volume therapy (Wyckoff et al. 2005; Barber
and Wyckoff 2006). For preterm infants, these num-
Each year 6–10 million of the approximately 130 bers are higher (Fig. 1).
million newborn infants born in the world need It is important to anticipate which infants are at
some kind of resuscitation at birth. Recently the risk, and the antepartum and intrapartum history
International Liaison Committee on Resuscitation often can be a help in predicting which infants will
(ILCOR) estimated that 85% of babies born at term need resuscitation. Fetal movement counting,
will initiate spontaneous respirations within 10–30 s non-stress testing, fetal biophysical profile, elec-
of birth (Perlman et al. 2015). In the USA, 5–10% of tronic fetal monitoring, and scalp pH measure-
all newborn infants require basic life support in the ment all contribute to an identification of infants
delivery room, or nursery, constituting at least at risk for low Apgar scores and need of resusci-
200,000 newborn infants in the USA alone. In tation. Electronic fetal heart monitoring combined
Western Europe, there are similar figures. Approx- with scalp pH determinations improves the spec-
imately 1% of newborns require more extensive ificity; however, sensitivity is low. In spite of these
resuscitation procedures (Perlman et al. 2010; measures, the need for resuscitation can often not
Kattwinkel et al. 2010; Richmond and Wyllie be foreseen, and 20–50% of the infants requiring
2010). Recent estimates indicate that worldwide resuscitation have no identifiable risk factors. This
29 Resuscitation of the Newborn 425
Interventions in term or near term newborn in the delivery room
INTERVENTION FREQUENCY
Assess baby’s response to birth 100/100
130 mill
Dry, keep baby warm, position correctly
B
Stimulate to breathe by drying A
20 mill Clear airways 15/100 S
I
Establish effective bag & mask ventilation C
4-6 mill Start with air 3 – 5/100
1 -2 mill Endotracheal intubation
1- 2/100 A
1 mill Provide chest compressions
with oxygen < 1/1000 D
Adrenaline 6/10 000 V
1 mill A
Volume N
0.1 mill expansion 1/12000 C
E
D
Saugstad OD
Fig. 1 Need of different interventions related to new born stabilization/resuscitation. Note the distinction between basic
and advanced resuscitation (blue horizontal line)
implies that at every delivery, the health provider Committee on Resuscitation 2005), a fourth and
should be prepared to perform resuscitation. a fifth question were included: (4) Is the color
Equipment and facilities should be ready. Further, pink? (5) Is amniotic fluid clear of meconium?
every health personnel attending deliveries needs Recent data, however, indicate that a newborn
to be trained in resuscitation skills. If a preterm baby not necessarily needs to be pink the first
(<37 weeks gestation) is expected, special prepa- few minutes of life; in fact there are strong indica-
ration is required. tions this may be harmful. This question therefore
was removed from the 2005/2006 ILCOR guide-
lines (Perlman et al. 2015; International Liaison
29.4 Indication for Resuscitation Committee on Resuscitation 2005). In the 2010
ILCOR guidelines, no firm recommendations for
The decision to resuscitate is based on clinical suctioning of babies with meconium-stained
judgment. By observing breathing movements, amniotic fluid were given, and consequently this
tone, color, and not least heart rate, it is decided fifth question was removed (Perlman et al. 2010).
whether the infant is in need of resuscitation or
not. Every time a child is delivered, the following
three questions should according to the ILCOR 29.5 Guidelines for Resuscitation of
and American Heart Association’s guidelines the Newly Born
(Perlman et al. 2010) be answered: (1) Is the
baby born at term? (2) Is the baby breathing or There are several sets of international guidelines
crying? (3) Is there a good muscle tone? If the for newborn resuscitation. The World Health
answer is “no” to any of these questions, resusci- Organization (WHO) published their revised
tation should be considered. In former guidelines guidelines for basic newborn resuscitation in
(Kattwinkel et al. 1999; International Liaison 2012 (World Health Organization, Department
426 O. D. Saugstad
of Reproductive Health and Research 1998). deficit is 10 mmol/L at 1 h of age, it probably was
These are applicable for most children around approximately 16–17 mmol/L at birth. Such cal-
the world. The ILCOR and American Heart culations can be useful for assessing prognosis
Association’s guidelines are widely used interna- and for court cases.
tionally; these were first published in 1992
(Emergency Cardiac Care Committee and Sub-
committees of the American Heart Association 29.7 Initial Evaluation and
1992) and revised in 1999 (Kattwinkel et al. Stabilization
1999), 2005 (International Liaison Committee
on Resuscitation 2005), 2010 (Perlman et al. ABCD for resuscitation is the same whatever size
2010), and 2015 (Perlman et al. 2015). American of the patient.
Heart Association (AHA) and American Acad- A: Airways should be cleared and the infant
emy of Pediatrics (AAP) and European Resusci- positioned correctly.
tation Council (ERC) in close collaboration B: Breathing should be stimulated or performed.
with ILCOR produced their own guidelines C: Circulation should be assessed by heart rate
(Kattwinkel et al. 2010; Richmond and Wyllie and skin color.
2010). A number of countries have their own D: Drugs are rarely needed in the newborn.
national guidelines modifying the ILCOR guidelines.
29.7.1 Response to Birth
29.6 Physiological and Biochemical
Changes Resuscitation is a team work: optimally, two
trained persons should actually perform the resus-
The physiological changes during asphyxia are citation, and one should assist. Each team member
well described in animal experiments. should identify themselves, and it should be clear
Traditionally the asphyxial process has been who the team leader is. Each order should be
divided into primary and secondary apnea. During stated clearly and repeated by the recipient.
primary apnea, heart rate is still present even as high As soon as the infant is delivered, that is when
as 100 beats per minute (bpm), and there is cyanosis the whole body is out (Saugstad 2015), a clock is
in mucus membranes and the skin. In secondary started, and, during the transport to the resuscita-
apnea, the baby is pale, and the heart rate is low tion table, the personnel should make a prelimi-
or not present. In some guidelines, different app- nary opinion regarding the seriousness of the
roaches are recommended for a primary and a sec- situation. First and foremost, the respiratory
ondary apneic situation. However, it is probably not efforts are assessed, and the heart rate is recorded.
wise to spend time to figure out in which of these Heart rate should, after the short initial stabiliza-
stages the infant is. Preterm infants have a more tion, be monitored more precisely. Bradycardia
rapid drop in heart rate than term infants, and the combined with no respiratory efforts or gasping
distinction between primary and secondary apnea in is a warning of immediate intervention. Central
the smallest infants probably is not very useful. cyanosis indicates insufficient oxygenation.
A metabolic and respiratory acidosis exists in Pallor may be a sign of reduced cardiac output,
newborns with birth asphyxia. Both animal and anemia, hypovolemia, hypothermia, or acidosis.
clinical studies have shown that base deficit is Apgar scoring is not performed before 1 min of
eliminated at a constant rate of 6–7 mmol/L/h life, and in addition it takes some time. Apgar
(Saugstad et al. 2005). This elimination seems to score therefore in itself should never be used as a
be constant independently of the severity of birth criterion for resuscitation.
asphyxia. Therefore, if the acid base status at birth The golden minute, the first 60 s of life, is of
is not known, this figure can be used to extrapolate importance. During the first 30 s, the infant should
back to the situation at birth. For instance, if base be positioned correctly, dried, and stimulated to
29 Resuscitation of the Newborn 427
breathe as needed. Infants <28 weeks of gestation is, however, no justification for the practice of
should be place in polythene bags without drying. routine suctioning in the mouth and pharynx or
During the last 30 s, heart rate and respiration gastric emptying not even after C-section, because
rate should be assessed, and a pulse oximeter, if such suctioning might even be harmful. A child
available, is connected to the right wrist. If needed who starts to breathe spontaneously within
positive pressure ventilation should be initiated. 10–15 s most probably does not need to be
suctioned. In addition, it seems that the esophagus
functions as a seal and a closed esophagus there-
29.7.2 Initial Stabilization fore helps in blowing air into the lungs instead of
the stomach during bag and mask ventilation.
Start out by assessing the baby’s response to birth Opening the esophagus with a suctioning catheter
and keep the baby warm and position it correctly; will result in more air into the stomach in case of
supine with the head close to the examiner, and bag and mask ventilation. However, occasionally
keep airways clear. the mouth, nose, and pharynx should be suctioned
Most infants require only to be delivered into a to clear airways. Remember that the mouth should
warm room where they can be dried immediately. be suctioned before the nose to prevent aspiration
The umbilical cord should be cut with sterile if the newborn should gasp when his or her nose is
equipment, and the breathing pattern should be suctioned. Suctioning deep in the pharynx or the
observed. The mother herself is most often the larynx, especially the first 5 min of life, may elicit
best caregiver and provider of warmth, food, and bradycardia and bronchospasm. Airways are best
protection from infections. opened with the head in the “sniffing position”;
The cord is usually cut after 60 s. At that overextension should be avoided. Tactile stimula-
time approximately 70% of the placental blood has tion as gentle rubbing of the back may be useful,
been transfused to the baby. In an emergency cord but do not shake the baby and do not waste time
milking might be an alternative, even in extremely by tactile stimulating an apneic child.
low birth weight infants (Saugstad 2015).
Heat loss should be prevented, and this is one 29.7.2.2 B: Breathing
important reason why deliveries should be According to a study from the UK in 2000, bag
performed in a warm room. For preterm infants, and mask ventilation was performed in 2.6% of all
a temperature in the room of 23–25 C is deliveries. This was a decrease from 3.9% in 1988
recommended. The newborn should be quickly (Wyckoff et al. 2005). These figures are lower
dried with towels, giving particular attention to than given above from the USA and indicate that
the drying of the head, and swept into preferably the need for bag and mask ventilation may vary
pre-warmed towels or other linens. It is throughout the world and is less than 5% in
recommended that the infant be placed supine Western Europe. Still the number who would
under a radiant heater on a table designed for need bag and mask ventilation is high.
resuscitation with the head toward the person Clinical judgment for when to initiate ventila-
performing resuscitation. Infants <28 weeks are tion should be based on heart rate, breathing effi-
put into polythene plastic bags before dried. This ciency, color, and tone. However, the formal
secures a more stable temperature until the child indications are very simple:
is put into an incubator. Hypothermia (<36 C) as
well as hyperthermia (>38 C) should be Start ventilation
avoided.
If the newborn is apneic or there is insufficient
29.7.2.1 A: Airways breathing movements and/or heart rate < 100 bpm
after administration of the initial steps as drying
Stimulate the infant to breathe by drying. Airways and stimulation.
are secured both by suctioning and by positioning If the newborn is breathing with heart rate > 100 bpm
the infant correctly in the supine position. There but is persistently cyanotic.
428 O. D. Saugstad
Apneic infants with heart rate >100 bpm prob- recently published values for heart rate the first
ably represent those with primary apnea, and they 10 min of life in normal non-asphyxiated newborns
often require tactile stimulation and a few with no medical intervention (Dawson et al.
inflations with a bag and mask only. Apnea and 2010a). At 1 min of age, term infants have in
heart rate <100 bpm may represent secondary mean a heart rate of 99 bpm with interquartile
apnea, and ventilation should be initiated. In most range of 66–132 bpm. For preterm infants, the
of these cases, the heart rate improves, and sponta- values are 96 (72–122) bpm. Recent studies indi-
neous ventilation quickly develops. Ventilation, cate that the heart rate is underestimated by auscul-
when needed, should start within the golden tation (Kamlin et al. 2006).
minute, preferably not later than 30 s after birth. New ECG devices pick up heart rate quickly,
The recommended rate of ventilation according within seconds of birth. It seems that the initial drop
to the AHA/AAP is 40–60 breaths per minute. An in pulse rate found by pulse oximetry the first
initial inflation pressure of 20 cm H2O is often seconds of life to some extent represents an artifact.
sufficient; however, even greater pressures as In term or near-term infants, the pulse very
30 cm H2O or even more may occasionally be quickly picks up during a successful resuscitation
needed for term babies in order to open the lungs. procedure, for instance, increasing from typically
For preterm infants, peak inspiratory pressure of, 90 beats per minute (bpm) at 1 min of age to
for instance, 20 cm H2O is often adequate, however, 110 bpm at 90 s of life. In babies with the lowest
depending on the size of the baby. The best way to Apgar score, heart rate is initially lower but typi-
monitor successful ventilation is to follow the heart cally increases with 20 bpm during the first 30 s of
rate which should be rapidly increasing. In addition, resuscitation (Saugstad et al. 1998, 2005). In
observe improvement in color and muscle tone and infants <30 weeks of gestation, the heart rate
movements. Recently it has been shown that it is increase is slower. It takes in median 73 s
difficult to make an assessment of color (O’Donnell (interquartile range 24–165 seconds) to reach a
et al. 2007), and in the most recent guidelines, there heart rate of 100 bpm and 243 (191–351) s to
is therefore less emphasis on color assessment. reach 120 bpm. The heart rate in such small babies
Observation of the chest wall movements is diffi- is not stable until it reaches 120 bpm (Dawson
cult. Recent data indicate that tidal volumes may be et al. 2010a). An adequate response to adequate
too high when there is a clear rise and fall of the ventilation therefore should for most term and
chest during the respiratory cycle. It has also been near-term infants be approximately 20 bpm
shown that assessment of tidal volume by observ- increase the first 30 s of bag and mask ventilation,
ing chest rise is extremely difficult (Poulton et al. however slower in preterm infants. After adequate
2011; Schmölzer et al. 2010a). ventilation has been established for 30 s, the heart
rate should be recorded for not longer than 10 s. If
Heart Rate the heart rate is at least 100 bpm and spontaneous
Traditionally a cutoff for heart rate < or >100 bpm respirations are established, positive pressure ven-
has been used. This has been based on the assump- tilation may be discontinued. If the heart rate is
tion that a heart rate <100 bpm in a newborn >60 bpm and improving, ventilation should con-
indicates bradycardia which in most cases is caused tinue. If the heart rate is less than 60 bpm and not
by asphyxia. It was demonstrated two decades ago improving, assisted ventilation is continued, and
that it takes 1–2 min to establish an efficient gas external heart massage is started (Perlman et al.
exchange in vaginally delivered babies and a few 2015; Kamlin et al. 2006; Saugstad et al. 1998;
more minutes are needed after C-section (Palme- Yam et al. 2011).
Kilander et al. 1993; Palme-Kilander and Tunell Auscultation of the heart with a stethoscope is
1993). Because there is a relation between gas still the gold standard for heart rate assessment,
exchange and heart rate, it may be normal not to although ILCOR suggests the use of ECG. Pulse
achieve a heart rate of 100 bpm or more even at an oximetry is reliable; however, the response time is
older age than 1 min. Supporting this are the slow (Saugstad 2016).
29 Resuscitation of the Newborn 429
Ventilation tested out in animal models (Jobe et al. 2002;
A self-inflating bag, a flow-inflating bag, or a T- Probyn et al. 2004). There is, however, not much
piece resuscitator can be used. Recently a T-piece evidence regarding the use of PEEP or not in the
device was compared with self-inflating bags. delivery room. However, one randomized con-
There was no difference between the T-piece trolled trial in preterm infants showed that more
resuscitator and a self-inflating bag in achieving infants were subsequently intubated and venti-
an HR of 100 bpm at 2 min in newborns lated in a group without continuous positive air-
26 weeks gestational age resuscitated at birth. way pressure (CPAP)/PEEP compared with a
However, the use of the T-piece decreased the group ventilated with a 10 s prolonged inflation
intubation rate and the maximum pressures followed immediately by CPAP/PEEP (Polglase
applied. However, air leaks, use of drugs/chest et al. 2008). It is becoming more and more com-
compressions, mortality, and days on mechanical mon to apply PEEP during ventilation in the
ventilation did not differ significantly between delivery room. CPAP in many centers is applied
groups (Szyld et al. 2014). The use of a bag and immediately for low birth or extremely low birth
mask requires experience, and it is possible to weight infants (ELBWI). More and more centers
practice on mannequins. By inserting a resuscita- are using a T-piece device when ventilating the
tion monitor which is a hot-wire anemometer newborn in the delivery room. This delivers a
placed between a ventilation device and the face PEEP that can be adjusted to the wanted level.
mask or endotracheal tube, the operator can min- Figure 2 shows recording when a mannequin is
imize leaks by adjusting the face mask position ventilated by the author with a self-inflating bag
(Finer et al. 2009; Schmölzer et al. 2010b). In an (Fig. 2a) and a T-piece device (Fig. 2b). By using a
Australian study, an average of 60% leaks were T-piece device, peak inspiratory pressure and vol-
found around the face mask; however after the ume are similar from breath to breath.
operators adjusted the mask position, the leak Studies have shown that a T-piece device
was reduced to 10% (Schmölzer et al. 2010b). delivers more exact peak inspiratory pressures
It is not easy to deliver an adequate tidal vol- than a self-inflating or a flow-inflating bag, in
ume by bag and mask ventilation. However, it addition to delivering an exact PEEP.
seems that starting ventilation in many instances In premature infants, especially in ELBWI, ven-
stimulates the baby to breathe because the infla- tilation may be difficult because of airway obstruc-
tion pressure induces the baby to make inspiratory tion. In such cases, airways and the mask must be
efforts (Head’s paradoxical reflex) securing an repositioned (Finer et al. 2009). Figure 3 illustrates
adequate tidal exchange (Milner et al. 1984). leak during bag and mask ventilation of a 27 weeks
The optimal tidal volume for newborn resuscita- gestation newborn (Schmölzer et al. 2010a).
tion is not known. However, a range between 4 Sustained inflation (inspiration time >5 s) is
and 8 mL/kg is often recommended. Excessive not recommended by ILCOR. Some guidelines
tidal volume may lead to volutrauma (Björklund recommend a few opening ventilations with pro-
et al. 1997), and a too low tidal volume leads to longed inspiration time; however this is not evi-
atelectasis and inadequate gas exchange. Both dence based.
conditions may trigger cytokine release and
inflammatory changes in the lung (Jobe and Endotracheal Intubation
Ikegami 1998; Jobe et al. 2002). Recommended Endotracheal intubation is necessary when bag-
ventilator rate is 40–60 per minute. mask ventilation is not efficient to normalize the
heart rate and establish spontaneous respiration. If
PEEP or CPAP? chest compressions do not quickly improve, heart
In order to oxygenate, the lungs must be ventilated rate or prolonged assisted ventilation is antici-
to develop a functional residual capacity. Infants pated; endotracheal intubation should also be car-
who do not breathe will need respiratory support. ried out. A newborn infant without any heart beat
Positive end-expiratory pressure (PEEP) has been or respiratory movement should also promptly be
430 O. D. Saugstad
Fig. 2 (a) Ventilation of a
mannequin with a self-
inflating bag. Notice the
variable peak inspiratory
pressure (P), flow (F),
volume (V ), and the lack of
positive end-expiratory
pressure (PEEP). (b)
Ventilating a mannequin
with a T-piece device.
Notice the identical and
exact peak inspiratory
pressures (P), the presence
of PEEP, and the uniform
flow and volume delivered
intubated, as bag and mask ventilation probably is gas flow in and out of the trachea (Wood et al.
not very efficient. Some infants in secondary 2008; Schmörzel et al. 2010). By observing the
apnea also need intubation and the most immature leak, it is also possible to make an assessment
infants who often do not have sufficient muscle whether the size of the tube is correct or not
strength for their respiratory drive. The ILCOR (see Fig. 4).
guidelines recommend that exhaled CO2 is mon- Endotracheal intubation is rarely needed in
itored for confirmation of tracheal tube placement term infants. In one study from the USA, it was
by, for instance, a colorimetric detector. Their use carried out in approximately 1 per 1000 deliveries
and limitations have been described in the litera- (Wu et al. 2004). A study from the UK has shown
ture and is reliable in most cases (Leone et al. a decrease in the need of intubation between 1993
2006a; Schmölzer et al. 2011; Garey et al. 2008). and 1997 from 2.4% but still as high as 1.2%, of
By using a resuscitation monitor, a correct place- all live born (Little et al. 2007). This indicates a
ment of the endotracheal tube can in most cases be wide variation in intubation practice from approx-
established after the first breath by observing the imately 1 per 100 to less than 1 per 1000 babies.
29 Resuscitation of the Newborn 431
Fig. 3 Airway leak in a 27-week infant ventilated with displayed as a straight line in the tidal volume curve.
face mask. The area underneath the inflation flow curve is Notice the variable leaks (From Schmölzer et al. 2010a,
greater than that under the expiratory flow curves. Leak is with permission)
In another UK study, the need of endotracheal scientific basis for such recommendations. New
intubation for all weight groups decreased in the studies have shown that even the most depressed
period 1988–2000 from 0.51% to 0.07% (Little term or near-term newborn infants are adequately
et al. 2007). However, for infants with birth resuscitated with room air. Several meta-analyses
weight <1500 g, this decrease was not very evi- (Rabi et al. 2007; Saugstad et al. 2008), now
dent, and their intubation need was 50-fold including ten studies enrolled more than 2000
increased compared with babies with birth weight newly born infants in need of resuscitation
3000–3500 g. If Apgar score at 5 min was 0–3, (Saugstad et al. 2008), have shown that early
intubation rate was increased 234-fold. Even an recovery is faster if resuscitation is carried out
Apgar score at 5 min of 4–5 increased the intuba- with ambient air instead of 100% O2; time to
tion rate 100-fold. Emergency C-section and first breath was registered 30 s earlier, and heart
breech delivery increased the need of intubation rate at 90 s and 5 min Apgar score were higher
two- to threefold (Allwood et al. 2003). This (Saugstad et al. 1998). More importantly is that
dramatic reduction in intubation rates indicates neonatal mortality is significantly reduced with
both a reduction in birth asphyxia and an increase 30–40% in room air-resuscitated babies (Rabi et
in C-section and also a more restrictive attitude al. 2007; Saugstad et al. 2008). In a meta-analysis
regarding need of newborn intubation. from European countries, relative risk for neona-
tal death was in fact reduced 69% from 3.2% to
Oxygen Supplementation 1.1% in those resuscitated with 21% compared
High concentration of supplemental oxygen with 100% oxygen (Saugstad et al. 2008). For
(80–100%) was used until 2010 recommended this reason, 100% oxygen should be avoided as
by most textbooks and guidelines dealing with a routine for newborn resuscitation. The 2010
newborn resuscitation. There was, however, no ILCOR guidelines state it is for term babies
432 O. D. Saugstad
1 second
50 1 second 50
a b
Ventilation Pressure
(cmH2 O)
0 0
50 50
Inspiratory
Flow
Gas Flow
(mL/sec)
No expiratory −50
−50
30 Flow 30
Expiratory
Flow
Tidal Volume
(mL)
0 0
Fig. 4 (a) Correct endotracheal tube placement in a 26- indicating gas flow toward the endotracheal tube. In con-
week infant. Both inflation and expiratory flow curves trast there is no expiratory flow curve indicating endotra-
return to baseline, indicating a correct placement of the cheal tube placement in esophagus (From (Schmölzer et al.
endotracheal tube. (b) Esophageal tube placement in a 2010a), with permission)
piglet. The inspiratory flow curve returns to baseline
“best to start resuscitation with air.” For babies started. However, some smaller studies have so
<32 weeks, a blender is often needed, and for far shown that 30% oxygen is at least as efficient
babies with gestational age between 32 and as 90% oxygen. ELBWIs who need resuscitation
37 weeks, the optimal initial FiO2 is not known therefore can be initiated with FiO2 of 0.30 and
(Perlman et al. 2010). For newborn infants adjust according to response in SpO2 (Escrig et al.
<28 weeks gestation, it is recommended to start 2008; Wang et al. 2008; Vento et al. 2009a).
with 30% or more for stabilization/resuscitation. However, the optimal FiO2 for these smaller new-
Recent animal data also show that the pulmo- borns is not known.
nary resistance by and large is reduced as effi- If room air resuscitation is not successful
ciently with 21% as with 100% oxygen within 90 s, we still supplement with oxygen. In
(Lakshminrusimha et al. 2007). In addition, it such case, it probably is optimal to monitor the
seems that the exposure of hyperoxia increases arterial oxygen saturation by pulse oximetry. The
the reactivity of the pulmonary vessels subse- arterial oxygen saturation at 1 min of life in non-
quently increasing the risk of pulmonary hyper- asphyxic term or near-term babies is typically
tension (Lakshminrusimha et al. 2006). 60–70% and may be as low as 40% the first
As mentioned above, extremely low birth 3–4 min of life. Within 5–7 min, approximately
weight infants may need some oxygen to get 50% of these babies have reached a SaO2 of 90%.
29 Resuscitation of the Newborn 433
After C-section, the saturation is in general 2 min If the cardiac arrest is not of asphyxial genesis,
behind the values found in babies born after vag- a ratio of 15:2 may be considered (Perlman et al.
inal delivery (Saugstad 2006). In high altitude, 2010).
the SaO2 is lower than at sea level; still it is Animal studies show no advantage regarding
recommended to start resuscitation with air also the use of 100% oxygen for chest compressions.
in such areas of the world. ILCOR still suggests it is prudent to try increasing
The oxygen supply in all delivery units supplementary oxygen concentrations during this
should have a blender, so that the oxygen con- procedure. If supplementary oxygen is used, it
centration can be adjusted to the requirement. If should be weaned as soon as the heart rate has
justified to give supplemental oxygen, it is recovered (Wyckoff and Wyllie 2006).
recommended to start with not more than
30–40% oxygen and adjust according to the 29.7.2.4 D: Drugs
clinical response, preferably following oxygen When oxygenation is established through an ade-
saturation measured by pulse oximetry. It is in quate ventilation of the asphyxiated infant, it is
case recommended that oxygen saturation follow extremely rare that drugs are needed. Epinephrine
the 10th to 25th percentile of recently published (adrenaline) was in one study indicated in 1:1200
nomograms for normal SpO2 values the first deliveries (Barber and Wyckoff 2006) and is indi-
minutes of life of non-asphyxiated newborn cated in asystole or in sustained bradycardia (Hr
babies (Dawson et al. 2010b). The aim is to <60 bpm) in spite of adequate ventilation and
reach a SpO2 of 90% after 5–10 min in term oxygenation and at least 30 s of coordinated
and near-term infants and 85% in premature chest compressions and ventilations. One study
infants less than 32 weeks. showed that even trained resuscitators are not
able to give epinephrine earlier than 4–5 min of
29.7.2.3 C: Circulation age (Barber and Wyckoff 2006). Epinephrine
Chest compressions are rarely needed and not (1:10,000 solution) is given as a bolus as rapid
included for basic newborn resuscitation. If bra- as possible preferably intravenously in a dose of
dycardia persists with a heart rate of less than 60 0.01–0.03 mg/kg (0.1–0.3 mL/kg) which may be
per minute and no signs of improvement after repeated every 3–5 min if needed. If the endotra-
adequate ventilation, chest compressions should cheal route is chosen (Solevåg et al. 2010), a
be started. This is needed in 0.5 to 1 per 1000 higher dose can be used (0.05–0.01 mg/kg). Bra-
births (Wyckoff et al. 2005). dycardia due to insufficient ventilation technique
Chest compression should always be carried out should be corrected by adequate ventilation
simultaneously with adequate ventilation (Wyckoff before administration of epinephrine. The optimal
and Berg 2008). Chest compressions and ventila- epinephrine dose for newborn resuscitation has
tory rate of 3:1 should be synchronized giving 90 not been studied systematically.
compressions and 30 breaths per minute. The two-
thumb technique is recommended (Christman et al. Volume Therapy
2011). An adequately performed resuscitation with Hypovolemia is rare, and volume infusion was in
chest compressions obviously requires at least two one study administered in 1:3000 deliveries; how-
trained persons. Heart rate should be assessed after ever hypovolemia was found in only 25% of
30 s of well-coordinated chest compressions and these. Thus hypovolemia is an extremely rare
ventilation. When the spontaneous pulse rate has event occurring in only 1:12,000 near-term or
reached 60 per minute, chest compressions should term infants (Wyckoff et al. 2005). Hypovolemic
be discontinued, and positive pressure ventilation shock should be suspected if there is an obvious
is continued at a rate of 40–60 breaths per minute. hemorrhage, there is pallor, there is delayed cap-
There are not much data, if any, supporting why a illary refill, there are weak pulses, there is persis-
ratio of 3:1 between compressions and ventilation tently low heart rate, or the circulatory status does
is chosen for newborns. not improve in response to the treatment steps
434 O. D. Saugstad
described above. Shock may be treated with ILCOR guidelines, it is written that “the available
repeated transfusions of volume expanders, usu- evidence does not support or refute the routine
ally 10 mL/kg. As volume expanders, normal endotracheal suctioning of depressed infants
saline or Ringer’s lactate is recommended. The born through meconium-stained amniotic fluid”
volume expander may be given over 5–10 min (Perlman et al. 2010). Thus, there has been a
and repeated. Albumin or other plasma substitutes shift in recent years from a very active to a less
are not so much recommended anymore. Blood active approach in these children. In 2015, this has
volume expanders during acute resuscitation are been taken a step further when ILCOR is stating it
only indicated when there are unmistakable signs is insufficient published human evidence to sug-
of shock with evidence of acute blood loss, gest routine tracheal intubation for suctioning of
including feto-maternal hemorrhage. If there has meconium in non-vigorous infants born through
been blood loss, O-negative blood cross-matched meconium-stained amniotic fluid.
with the mother’s blood is given. Avoid rapid
boluses of volume expanders or hyperosmolar
solutions to premature newborn infants. In one 29.9 Preterm Infants
experimental study in hypovolemic and asphyxi-
ated newborn piglets, the use of volume therapy There are no or very few studies on optimal
seemed to be counterproductive (Wyckoff et al. resuscitation of premature infants. This means
2007). Volume therapy therefore should be given that even the extremely low gestational age
on strict indications only. newborn infants are often resuscitated according
Sodium bicarbonate, THAM, or naloxone has to the guidelines and principles established for
no routine place in newborn resuscitation term and near-term infants. Recent studies have
(Perlman et al. 2010; Wyckoff and Perlman 2006). shown that cardiorespiratory resuscitation of
these in the delivery room is not futile and a
more active approach seems therefore to be
29.8 Meconium Aspiration established (Finer et al. 1999) and this has led to
a more active approach (Leone et al. 2005, 2006b;
If the amniotic fluid is meconium stained, there Finer and Leone 2009; Brugada 2008; Vento et al.
is no evidence that suctioning the oropharynx 2009b). It is also clear that preterm infants need
before the thorax is delivered has any beneficial intervention more often than near-term or term
effects. There are today no indications that an newborn infants. In one study from the USA,
infant with thick meconium-stained amniotic 5% of babies with birth weight between 500 and
fluid benefits from routine intubation and 1500 g needed chest compressions and 4%
suctioning. received epinephrine (Finer et al. 1999).
The previous practice of tracheal suctioning Babies with gestational age < 28 weeks should
does not seem to have reduced the incidence of be put into polyethylene wraps or a plastic bag up
meconium aspiration syndrome or mortality to their neck, before drying, in order to maintain
(Gupta et al. 1996). It is therefore not anymore the temperature (Perlman et al. 2015). They
recommended that suctioning of the nose, mouth, often need to be intubated given surfactant, and
and posterior pharynx be carried out thoroughly in some centers, they are immediately extubated,
before delivery of the shoulder and thorax. the so-called INSURE (INtubation SURfactant
According to previous guidelines, the trachea Extubation) approach (Victorin et al. 1990). Ven-
should be suctioned in “non-vigorous” child. If tilation should be carried out using a PEEP of
the child is vigorous, the mouth and nose should 5–6 cm H2O. Today it is recommended to start
be suctioned only and resuscitation proceeded as these babies directly on CPAP (Morley and Davis
required. “Vigorous” is defined as a newborn hav- 2008). These infants should be handled as gently
ing strong respiratory efforts, good muscle tone, as possible. Avoid rapid boluses of fluid and quick
and a heart rate greater than 100 bpm. In the 2010 changes in body positions.
29 Resuscitation of the Newborn 435
Preliminary data indicate that the extremely child. This also allows one to inform the parents
low birth weight infant in need of resuscitation so that they can become prepared and participate
often would need a brief exposure of oxygen, for in the discussion and decisions about subsequent
instance, start out with 30% O2 in order to get an therapy. An Apgar score of 0 at 10 min is a strong
adequate heart rate response (Escrig et al. 2008; predictor of mortality and morbidity. The ILCOR
Wang et al. 2008; Vento et al. 2009a). More data committee suggests that in babies with an Apgar
are needed before firmer recommendation for score of 0 after 10 min of resuscitation, if the
these tiny infants are given. heart rate remains undetectable, it may be rea-
In newborn infants <32 weeks delivery room sonable to stop resuscitation. However, it is
temperature should be between 23 C and 25 C; underlined that the decision whether or not to
the babies should be covered by warm blankets redirect care should be individualized (Perlman
and, if <28 weeks, put in plastic wrapping before et al. 2015).
drying and a cap. ILCOR recommends the use In babies with Apgar score of 1–3 at 20 min of
of thermal mattresses to reduce hypothermia age and gestational age > 34 weeks, ILCOR
(<36 C); however thermal mattresses seem to suggests that it may be reasonable to stop assisted
increase hyperthermia (>38 C). ventilation in babies with no spontaneous breath-
ing despite the presence of heart rate or Apgar
score of 1–3 at 20 min or more.
29.10 Withholding and Withdrawing
Resuscitation
29.11 Post-Resuscitation Care
In some cases, resuscitation should be withheld or
withdrawn (Skupski et al. 2010). The ILCOR After a successful resuscitation, heat loss should
recommendations state that resuscitation could be prevented. The child should be labeled and
be withheld for neonates at the margins of viabil- frequently checked with regard to breathing
ity or those with conditions which predict a high efforts, respiratory rate, color, heart rate, and
risk of mortality or morbidity. Many centers do signs of birth injury or malformations. If the resus-
not resuscitate newborn infants with gestational citation was brief and the situation was not too
age of less than 23 weeks. In earlier recommen- dramatic, the newborn could be monitored in the
dations, resuscitation was not recommended if nursery provided an adequate respiration is
there was anencephaly, bilateral renal agenesis, established. The child could be placed so that
spinal muscular atrophy type I (Werdnig-Hoff- skin-to-skin contact with the mother is obtained.
mann disease) with neonatal onset, trisomy 13, However, this depends on the local conditions and
or trisomy 18. However, according to the newer the possibilities for adequate observation by a
guidelines (Perlman et al. 2010) and I agree in trained observer.
that, strict indications should not be given for Even if the infant is not in need of artificial
which newborns who should not be resuscitated. ventilation following resuscitation, the child is
This author resuscitates and tries to stabilize often brought to the intensive care unit for further
infants with a gestational age of 23 weeks or close follow-up which includes monitoring of the
more. Recent data, for instance, from the Express heart rate, ventilation, determination of arterial pH
study from Sweden support this practice (Serenius and blood gases, treatment of any hypotension
et al. 2013). with volume expanders or pressors, appropriate
Often, neither the exact diagnosis nor the ges- fluid therapy, and treatment of any seizures. Any
tational age is known at birth. A liberal policy of hypoglycemia or electrolyte disturbances should
resuscitation is recommended whenever doubt be corrected. Breast-feeding should be encour-
about the care of the individual infant exists. aged, if possible, as soon as 1 h after birth. If the
This allows the doctor to collect more informa- resuscitation was unsuccessful and the child died,
tion about the clinical status and prognosis of the the parents need a close follow-up.
436 O. D. Saugstad
Every baby who has been resuscitated, even supplementation for premature infants and which
briefly, is at risk and should be followed up care- oxygen saturation one should aim at in term
fully both at short and long term. Blood glucose babies not responding adequately to the initial
should be kept within normal ranges (McGowan resuscitation. How the optimal use of supplemen-
and Perlman 2006). tal oxygen during chest compressions is not
known. The optimal adrenaline concentration
and the effect of volume therapy are uncertain.
29.11.1 Hypothermia Therapy Further, the optimal procedure for chest compres-
sions is not defined. None of the guidelines dis-
Moderate hypothermia as a protective treatment to cuss the importance of pCO2 and a moderate
term infants with hypoxic ischemic encephalopa- hypercapnia in order to restore cerebral blood
thy is recommended. Hypothermia should in case flow. This should be an area of research for the
be induced in a controlled way following written coming years.
protocols (Azzopardi et al. 2009). In the delivery In spite of that, there is general agreement that
room, it is important to avoid hyperthermia the most important is to start ventilation as soon as
because this may augment any brain injury in this is indicated. In most cases a few blows of air is
severe asphyxia (Perlman 2006). sufficient to restore the heart rate and help the
baby start breathing on its own. By avoiding non-
evidence-based detrimental procedures such as
29.12 Documentation hyperoxygenation of the child, the results will be
much improved. The new resuscitation program
It is useful if one attending person observes named Helping Babies breathe is rolled out in
and immediately writes down the procedures many parts of the world. This program was
performed. A thorough documentation in the made possible when air substituted 100% oxygen
medical record of all observations and actions for resuscitation of term and near-term newborns.
and names of the participants is required before “Give a breath – save a life” was the name of a
the resuscitation is complete. Each institution large Indian campaign for newborn resuscitation
should keep records documenting the condition launched in the 1990s. This is what it is all about,
and procedures carried out at birth. Every institu- to give breaths and to save lives.
tion that provides deliveries must develop its own
standards for newborn resuscitation, and a plan of
action should exist. The personnel should gain References
and maintain skills in newborn resuscitation by
training using manikins, and an evaluation of the Allwood AC, Madar RJ, Baumer JH et al (2003) Changes
in resuscitation practice at birth. Arch Dis Child Fetal
training is necessary.
Neonatal Ed 88:F375–F379
Azzopardi DV, Strohm B, Edwards AD, TOBY Study
Group et al (2009) Moderate hypothermia to treat peri-
29.13 Conclusions natal asphyxial encephalopathy. N Engl J Med
361:1349–1358. [Erratum in: N Engl J Med
2010;362:1056]
Newborn resuscitation is not yet fully evidence Barber CA, Wyckoff MH (2006) Use and efficacy of
based. However, recent years a rapid development endotracheal versus intravenous epinephrine during
has occurred, and a more evidence-based practice neonatal cardiopulmonary resuscitation in the delivery
room. Pediatrics 118:1028–1034
has been established. Still there are numerous
Björklund LJ, Ingimarsson J, Curstedt T et al (1997)
unanswered questions. Manual ventilation with a few large breaths at birth
The optimal PEEP has not been determined. compromises the therapeutic effect of subsequent sur-
Today a low oxygen approach should be chosen factant replacement in immature lambs. Pediatr Res
42:348–355
for newborn resuscitation starting with air in near-
Black RE, Cousens S, Johnson HL, Child Health Epide-
term and term babies. However, there are still miology Reference Group of WHO and UNICEF et al
uncertainties regarding the use of oxygen (2010) Global, regional, and national causes of child
29 Resuscitation of the Newborn 437
mortality in 2008: a systematic analysis. Lancet Kattwinkel J, Perlman JM, Aziz K et al (2010) Part 15:
375:1969–1987 neonatal resuscitation: 2010 American Heart Associa-
Brugada M (2008) Using intensive care technology in the tion guidelines for cardiopulmonary resuscitation and
delivery room: a new concept for the resuscitation of emergency cardiovascular care. Circulation 122(18
extremely preterm neonates. Pediatrics 122:1113–1116 Suppl 3):S909–S919
Christman C, Hemway RJ, Wyckoff MH, Perlman JM Lakshminrusimha S, Russell JA, Steinhorn RH et al (2006)
(2011) The two-thumb is superior to the two-finger Pulmonary arterial contractility in neonatal lambs
method for administering chest compressions in a man- increases with 100% oxygen resuscitation. Pediatr
ikin model of neonatal resuscitation. Arch Dis Child Res 59:137–141
Fetal Neonatal Ed 96:F99–F101 Lakshminrusimha S, Russell JA, Steinhorn RH et al (2007)
Dawson JA, Kamlin CO, Wong C et al (2010a) Changes in Pulmonary hemodynamics in neonatal lambs resusci-
heart rate in the first minutes after birth. Arch Dis Child tated with 21%, 50%, and 100% oxygen. Pediatr Res
Fetal Neonatal Ed 95:F177–F181 62:313–318
Dawson JA, Kamlin CO, Vento M et al (2010b) Defining Leone TA, Rich W, Finer NN (2005) Neonatal intuba-
the reference range for oxygen saturation for infants tion: success of pediatric trainees. J Pediatr 146:
after birth. Pediatrics 125:e1340–e1347 638–641
Emergency Cardiac Care Committee and Subcommittees Leone TA, Lange A, Rich W, Finer NN (2006a) Disposable
of the American Heart Association (1992) Guidelines colorimetric carbon dioxide detector use as an indicator
for cardiopulmonary resuscitation and emergency car- of a patent airway during noninvasive mask ventilation.
diac care, IV: pediatric basic life support. J Am Med Pediatrics 118:e202–e204
Assoc 268:2276–2281 Leone TA, Rich W, Finer NN (2006b) A survey of
Escrig R, Arruza L, Izquierdo I et al (2008) Achievement delivery room resuscitation practices in the United
of targeted saturation values in extremely low gesta- States. Pediatrics 117:e164–e175
tional age neonates resuscitated with low or high oxy- Little M, Järvelin M-R, Neasham DE et al (2007) Factors
gen concentrations: a prospective, randomized trial. associated with fall in neonatal intubation rates in the
Pediatrics 121:875–881 United Kingdom-prospective study. Br J Obstet
Finer N, Leone T (2009) Oxygen saturation monitoring for Gynaecol 114:156–164
the preterm infant: the evidence basis for current prac- McGowan JE, Perlman JM (2006) Glucose management
tice. Pediatr Res 65:375–380 during and after intensive delivery room resuscitation.
Finer NN, Horbar DH, Carpenter JH, the Vermont Oxford Clin Perinatol 33:183–196
Network (1999) Cardiopulmonary resuscitation in the Milner AD, Vyas H, Hopkin IE (1984) Efficacy of facemask
very low birth weight infant: the Vermont Oxford resuscitation at birth. Br Med J (Clin Res Ed)
Experience. Pediatrics 104:428–434 289:1563–1565
Finer NN, Rich W, Wang C, Leone T (2009) Airway Morley CJ, Davis PG (2008) Advances in neonatal resus-
obstruction during mask ventilation of very low birth citation: supporting transition. Arch Dis Child Fetal
weight infants during neonatal resuscitation. Pediatrics Neonatal Ed 93:F334–F336
123:865–869 O’Donnell CP, Kamlin CO, Davis PG et al (2007) Clinical
Garey DM, Ward R, Rich W et al (2008) Tidal volume assessment of infant colour at delivery. Arch Dis Child
threshold for colorimetric carbon dioxide detectors avail- Fetal Neonatal Ed 92:F465–F467
able for use in neonates. Pediatrics 121:e1524–e1527 Palme-Kilander C, Tunell R (1993) Pulmonary gas
Gupta V, Bhatia BD, Mishra OP (1996) Meconium stained exchange during facemask ventilation immediately
amniotic fluid: antenatal, intrapartum and neonatal after birth. Arch Dis Child 68:11–16
attributes. Indian Pediatr 33:293–297 Palme-Kilander C, Tunell R, Chiwei Y (1993) Pulmonary
International Liaison Committee on Resuscitation (2005) gas exchange immediately after birth in spontaneously
International consensus on cardiopulmonary resuscita- breathing infants. Arch Dis Child 68:6–10
tion and emergency cardiovascular care science with Perlman JM (2006) Hyperthermia in the delivery: potential
treatment recommendations. Part 7: neonatal resuscita- impact on neonatal mortality and morbidity. Clin Peri-
tion. Resuscitation 67:293–303 natol 33:55–63
Jobe AH, Ikegami M (1998) Mechanisms initiating lung Perlman JM, Wyllie J, Kattwinkel J, Neonatal Resuscita-
injury in the preterm. Early Hum Dev 53:81–94 tion Chapter Collaborators et al (2010) Part 11: neona-
Jobe AH, Kramer BW, Moss TJ et al (2002) Decreased tal resuscitation: 2010 International consensus on
indicators of lung injury with continuous positive expi- cardiopulmonary resuscitation and emergency cardio-
ratory pressure in preterm lambs. Pediatr Res 52:387–392 vascular care science with treatment recommendations.
Kamlin CO, O’Donnell CO, Everest NJ et al (2006) Accu- Circulation 122(16 Suppl 2):S516–S538
racy of clinical assessment of infant heart rate in the Perlman JM, Wyllie J, Kattwinkel J, Wyckoff MH et al
delivery room. Resuscitation 71:319–321 (2015) Neonatal resuscitation chapter collaborators.
Kattwinkel J, Niermeyer S, Nadkarni V et al (1999) Part 7: neonatal resuscitation: 2015 international
Resuscitation of the newly born infant: an advisory consensus on cardiopulmonary resuscitation and
statement from the pediatric working Group of the emergency cardiovascular care science with treatment
International Liaison Committee on resuscitation. recommendations. Circulation 132(16 Suppl 1):
Resuscitation 40:71–88 S204–S241
438 O. D. Saugstad
Polglase GR, Hillman NH, Pillow JJ et al (2008) Skupski DW, Chervenak FA, McCullough LB et al (2010)
Positive end-expiratory pressure and tidal volume Ethical dimensions of periviability. J Perinat Med
during initial ventilation of preterm lambs. Pediatr 38:579–583
Res 64:517–522 Solevåg AL, Dannevig I, Nakstad B, Saugstad OD (2010)
Poulton DA, Schmölzer GM, Morley CJ, Davis PG (2011) Resuscitation of severely asphyctic newborn pigs with
Assessment of chest rise during mask ventilation of cardiac arrest by using 21% or 100% oxygen. Neona-
preterm infants in the delivery room. Resuscitation tology 98:64–72
82:175–179 Szyld E, Aguilar A, Musante GA, Vain N, Prudent L,
Probyn ME, Hooper SB, Dargaville PA et al (2004) Fabres J, Carlo WA, Delivery Room Ventilation
Positive end expiratory pressure during resuscitation Devices Trial Group (2014) Comparison of devices
of premature lambs rapidly improves blood gases with- for newborn ventilation in the delivery room. J Pediatr
out adversely affecting arterial pressure. Pediatr Res 165:234–239
56:198–204 te Pas AB, Walther FJ (2007) A randomized, controlled
Rabi Y, Rabi D, Yee W (2007) Room air resuscitation of trial of delivery-room respiratory management in very
the depressed newborn: a systematic review and meta- preterm infants. Pediatrics 120:322–329
analysis. Resuscitation 72:353–363 Vento M, Moro M, Escrig R et al (2009a) Preterm resusci-
Richmond S, Wyllie J (2010) European resuscitation tation with low oxygen causes less oxidative stress,
council guidelines for resuscitation 2010 section 7. inflammation, and chronic lung disease. Pediatrics
Resuscitation of babies at birth. Resuscitation 124:e439–e449
81:1389–1399 Vento M, Cheung PY, Aguar M (2009b) The first golden
Saugstad OD (2006) Oxygen saturations immediately after minutes of the extremely-low-gestational-age neonate:
birth. J Pediatr 148:569–570 a gentle approach. Neonatology 95:286–298
Saugstad OD (2015) Delivery room management of term Victorin LH, Deverajan LV, Curstedt T, Robertson B
and preterm newly born infants. Neonatology (1990) Surfactant replacement in spontaneously breath-
107(4):365–371 ing babies with hyaline membrane disease—a pilot
Saugstad OD, Soll RF (2016) Assessing heart rate at birth: study. Biol Neonate 58:121–126
auscultation is still the gold standard. Neonatology Wang CL, Anderson C, Leone TA et al (2008) Resuscita-
110:238–240 tion of preterm neonates by using room air or 100%
Saugstad OD, Rootwelt T, Aalen O (1998) Resuscitation of oxygen. Pediatrics 121:1083–1089
asphyxiated newborn infants with room air or oxygen: Wood FE, Morley CJ, Dawson JA, Davis PG (2008) A
an international controlled trial: the Resair 2 study. respiratory function monitor improves mask ventila-
Pediatrics 102:e1 tion. Arch Dis Child Fetal Neonatal Ed 93:F380–F381
Saugstad OD, Ramji S, Rootwelt T, Vento M (2005) World Health Organization, Department of Reproductive
Response to resuscitation of the newborn: early prog- Health and Research (1998) Basic newborn resuscita-
nostic variables. Acta Paediatr 94:890–895 tion: a practical guide. WHO, Geneva. http://whqlibdoc.
Saugstad OD, Ramji S, Soll RF, Vento M (2008) who.int/hq/1998/WHO_RHT_MSM_98.1.pdf
Resuscitation of newborn infants with 21% or 100% Wu YW, Backstrand KH, Zhao S et al (2004) Declining
oxygen: an updated systematic review and meta-anal- diagnosis of birth asphyxia in California: 1991–2000.
ysis. Neonatology 94:176–182 Pediatrics 114:1584–1590
Schmölzer GM, Kamlin OC, O’Donnell CP et al Wyckoff MH, Berg RA (2008) Optimizing chest compres-
(2010a) Assessment of tidal volume and gas leak sions during delivery-room resuscitation. Semin Fetal
during mask ventilation of preterm infants in the Neonatal Med 13:410–415
delivery room. Arch Dis Child Fetal Neonatal Ed Wyckoff MH, Perlman JM (2006) Use of high-dose epi-
95:F393–F397 nephrine and sodium bicarbonate during neonatal
Schmölzer GM, Dawson JA, Kamlin CO et al (2010b) resuscitation: is there proven benefit? Clin Perinatol
Airway obstruction and gas leak during mask ventila- 33:141–151
tion of preterm infants in the delivery room. Arch Dis Wyckoff MH, Wyllie J (2006) Endotracheal delivery of
Child Fetal Neonatal Ed 96(4):F254–F257 medications during neonatal resuscitation. Clin Peri-
Schmölzer GM, Poulton DA, Dawson JA et al (2011) natol 33:153–160
Assessment of flow waves and colorimetric CO(2) Wyckoff MH, Perlman JM, Laptook AR (2005) Use of
detector for endotracheal tube placement during neo- volume expansion during delivery room resuscitation
natal resuscitation. Resuscitation 82:307–312 in near-term and term infants. Pediatrics 115:950–955
Schmörzel GM, Kamlin CO, Dawson JA et al (2010) Wyckoff M, Garcia D, Margraf L et al (2007) Randomized
Respiratory monitoring of neonatal resuscitation. trial of volume infusion during resuscitation of asphyx-
Arch Dis Child Fetal Neonatal Ed 95:F295–F303 iated neonatal piglets. Pediatr Res 61:415–420
Serenius F, Källén K, Blennow M et al (2013) Neurodeve- Yam CH, Dawson JA, Schmölzer GM et al (2011) Heart
lopmental outcome in extremely preterm infants at 2.5 rate changes during resuscitation of newly born infants
years after active perinatal care in Sweden. JAMA <30 weeks gestation: an observational study. Arch Dis
309:1810–1820 Child Fetal Neonatal Ed 96:F102–F107
Oxygen Toxicity in Newborns
30
Rodolfo Bracci, Serafina Perrone, Maximo Vento, and
Giuseppe Buonocore
Contents
30.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440
30.2 Reactive Oxygen Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441
30.3 Oxidative Stress in Perinatal Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444
30.4 Hyperoxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
30.5 Clinical Aspects and Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
30.5.1 Diagnostic Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
30.5.2 Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
30.5.3 Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
30.5.4 Intracellular Redox Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
30.5.5 DNA Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
30.5.6 Prevention of ROS Tissue Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451
30.5.7 Protective Effect of Human Milk in the Preterm Infant . . . . . . . . . . . . . . . . . . . . . . . 452
30.5.8 Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452
30.6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453
Abstract
The first evidence of a relationship between
oxygen toxicity and neonatal diseases emerged
R. Bracci (*) · G. Buonocore in the early 1950s, when retinopathy was ob-
University of Siena, Siena, Italy served in premature infants breathing high con-
e-mail: [email protected]; giuseppe. centrations of oxygen. Oxygen toxicity is due
[email protected]
to the development of reactive oxygen species
S. Perrone (ROS), such as the superoxide anion (O2 ),
Department of Molecular and Developmental Medicine,
hydrogen peroxide (H202), lipid peroxide
University Hospital of Siena, Siena, Italy
e-mail: [email protected] (LOOH), peroxyl radicals RO∙, electron
delocalized phenoxyl radical (C6H50), nitric
M. Vento
Neonatal Research Unit, Health Research Institute oxide (NO), and the hydroxyl radical (OH∙).
Hospital La Fe, University and Polytechnic Hospital La Fe, OH∙ is one of the strongest oxidants in nature
Valencia, Spain and may damage tissues. There is no specific
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 439
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_180
440 R. Bracci et al.
scavenger for this radical, and once released, prudent approach would be not to tolerate pos-
OH∙ reacts with lipoproteins, cell membranes, sible hypoxia and not to accept SpO2 values
lipids, proteins, DNA, amino acids, and other associated with potential hyperoxia, setting the
molecules causing structural and functional low alarm never <85% and the high alarm
damage to these structures. The main sources of never more than 95%. It is imperative to avoid
ROS are NADPH oxidase reactions (principally a flip-flop phenomenon that leads to acute and
in phagocytes after activation upon exposure significant changes and fluctuations in SpO2.
to microbes, microbial products, or inflamma- Preterm infants should be fed early with hu-
tory mediators), mitochondrial metabolism, man expressed milk, which offers an additional
hypoxia-reoxygenation (hypoxanthine-xanthine protection against free radicals. Although the
oxidase reaction), hyperoxia, and paradoxi- usefulness of antioxidant protection during
cally hypoxia. Abnormal percentage of ROS pregnancy and in the neonatal period is still
generation can have pathological consequences under investigation, the risk of tissue damage
if they are lower as well as they are higher than due to oxidative stress in perinatal period
normal. An excess of ROS, in relation to detox- should not be underestimated.
ification capacity, is called oxidative stress, a
term which expresses the imbalance between
oxidants and antioxidants that is a potential 30.1 Salient Points
cause of damage. If oxidative stress is mild,
cell defenses may increase by a mechanism • Oxygen is one of the most important elements
which generally involves enhanced gene ex- in newborn resuscitation, and inappropriate
pression of ROS scavenging activities. Severe oxygen administration would profoundly af-
oxidative stress is generally followed by cell fect the outcomes of babies.
injury and plays a role in many kinds of cell • Oxygen toxicity is due to the development
death, i.e., apoptosis, necrosis, autophagy, and of reactive oxygen species (ROS), such as
mitophagy. Oxidative stress has been sug- superoxide anion (O2 ), hydrogen peroxide
gested as a causative agent in pregnancy- (H2O2), lipid peroxide (LOOH), peroxyl radi-
related disorders such as recurrent pregnancy cals (RO.), electron delocalized phenoxyl rad-
loss, preeclampsia, preterm premature rupture ical (C6H50), nitric oxide (NO), and the
of membranes, intrauterine growth restriction, hydroxyl radical (OH.).
and fetal death. In the fetal-to-neonatal transi- • The main sources of ROS are NADPH oxi-
tion, both blood oxygen content and oxygen dase reactions (principally in phagocytes after
availability abruptly increase in the first few activation upon exposure microbes, microbial
minutes after birth, eliciting the generation of a products, or inflammatory mediators), mito-
burst of ROS. Oxidative stress following chondrial metabolism, hypoxia-reoxygenation
hyperoxia has been recognized to be responsi- (hypoxanthine-xanthine oxidase reaction), hy-
ble for lung, retina, and red blood cell injury peroxia, and paradoxically hypoxia.
and possibly generalized tissue damage. • ROS contribute to worsen cellular function by
Several methods have been proposed in the oxidizing and damaging numerous cellular
attempt to detect the presence and the severity components, in particular impairing mitochon-
of the oxidative stress. Measurements of pro- drial function and oxygen utilization. More-
tein, lipid, and DNA bases oxidation and intra- over a systemic inflammatory response that
cellular redox status are accurate methods. can be triggered by the ischemia-reperfusion
Prevention of ROS tissue damage involves the injury can contribute to tissue injury.
avoidance of conditions such as infections, • An excess of ROS, in relation to detoxification
asphyxia, hyperoxia, and retinal light exposure, capacity, is called oxidative stress, a term which
under which excessive ROS occurs. When sup- expresses the imbalance between oxidants and
plemental oxygen is needed for care, the most antioxidants that is a potential cause of damage.
30 Oxygen Toxicity in Newborns 441
• Severe oxidative stress is generally followed are the highly reactive electron delocalized
by cell injury and plays a role in many kinds of phenoxyl radical (C6H50) and nitric oxide (NO).
cell death, i.e., apoptosis, necrosis, autophagy, The term ROS includes free radicals, which are
and mitophagy. atoms or molecules with one or more unpaired
• In the fetal-to-neonatal transition, both blood electrons. Free radicals may react with other rad-
oxygen content and oxygen availability abruptly icals, the unpaired electrons forming a covalent
increase in the first few minutes after birth, bond. The resulting molecule may decompose
eliciting the generation of a burst of ROS. other molecules into toxic products. Free radicals
• Hyperoxia has been recognized to be respon- may react with non-radical molecules in free rad-
sible for lung, retina, and red blood cell injury ical chain reactions, which are stopped by antiox-
and possibly generalized tissue damage. idant molecules, enzymes, or protein reactions.
• Measurements of protein, lipid, and DNA base Superoxide anion is the precursor of most ROS
oxidation and intracellular redox status are and is a mediator in oxidative chain reactions.
accurate methods to detect the presence and Dismutation of O2 by superoxide dismutase
the severity of the oxidative stress. (SOD) produces H2O2 that in turn may be fully
• Prevention of ROS tissue damage involves the reduced to water by glutathione peroxidase (GSH-
avoidance of conditions such as infections, Px) and catalase (Cat) or, alternatively, partially
asphyxia, hyperoxia, and retinal light expo- reduced to the OH.. The latter reaction is called the
sure, under which excessive ROS occurs. Fenton-Haber-Weiss reaction and is catalyzed by
• Because of the limited benefit of maintaining reduced transition metals, particularly iron, but
potentially harmful supranormal oxygen levels, also copper and zinc (Jankov et al. 2001; Fig. 1).
oxygen supplementation and mechanical ven- There is no specific scavenger for the hydroxyl
tilation should be titrated to maintain an oxy- radical, and once released, OH. reacts with lipopro-
gen saturation between 85% and 95% in teins, cell membranes, lipids, proteins, DNA, amino
preterm babies. acids, and other molecules causing structural and
functional damage to the cell. OH∙ is one of the
strongest oxidants in nature and may damage tis-
30.2 Reactive Oxygen Species sues. Since the OH. is formed by the Fenton reac-
tion, which is dependent on nonprotein-bound iron
Although the toxic effects of oxygen were already (NPBI), the condition of intracellular or extracellu-
noticed at the end of the nineteenth century (Smith lar availability of nonprotein-bound iron is one of
1899), the first evidence of a relationship between the most important sources of ROS-dependent tis-
oxygen toxicity and neonatal diseases emerged sue damage. Superoxide has low activity and poor
only in the early 1950s, when retinopathy was
observed in premature infants breathing high con-
centrations of oxygen (Patz et al. 1952). At about
the same time, the red blood cells of newborns were
demonstrated to have increased susceptibility to
oxygen damage and a fetal and neonatal deficiency
of antioxidant factors became evident (Gordon et
al. 1955). Great advances in our understanding of
the toxic effects of oxygen were made in the years
Fig. 1 Iron-mediated oxygen radical formation. Sche-
that followed when oxygen toxicity was recognized matic representation of the sequence of events involved
to be due to the development of reactive oxygen in Fenton reaction. Initially, electron donors can convert
species (ROS). The main ROS are the superoxide oxygen to superoxide anion. Superoxide anion is rapidly
converted to hydrogen peroxide. Hydrogen peroxide can
anion (O2 ), hydrogen peroxide (H202), lipid per- further form hydroxyl radicals (OH.) in the Fenton reaction
oxide (LOOH), peroxyl radicals (RO.), and the in the presence of ferrous ions which are oxidized to form
hydroxyl radical (OH.). Other important radicals ferric ions
442 R. Bracci et al.
reactivity. However it may participate in nitric inside phagocytes during infection and cytokine
oxide-mediated reactivity generating oxidative tis- production is an essential defense mechanism.
sue damage. Superoxide and nitric oxide readily It also alters the extracellular oxidative bal-
react to form an extremely reactive substance called ance and harms tissues, since the cells undergo
peroxynitrite (ONOO ) (Jankov et al. 2001). an efflux of O2 (Koenig and Yoder 2004).
In general, the main sources of ROS are Opsonization and activation of phagocytes are
NADPH oxidase (NOX) reactions, mitochondrial also known to occur not only following infection
metabolism, hypoxia-reoxygenation (hypoxan- but even as a consequence of asphyxia and par-
thine-xanthine oxidase reaction), hyperoxia, and ticularly hypoxanthine-xanthine oxidase reaction
paradoxically hypoxia (Jankov et al. 2001; Ullrich and therefore during hypoxia-reoxygenation (Sies
and Bachscmid 2000; Koenig and Yoder 2004; 1991; Halliwell 2007; Fig. 2).
Sies 1991; Halliwell 2007). Each of these will be The complex mechanism of ROS production
discussed in turn. has been extensively investigated in mitochon-
dria where ROS generation can have physiologi-
The NOX Enzyme has been found in virtually cal and pathological effect (Ullrich and Bachscmid
every tissue and modulates fundamental biologi- 2000). The mitochondrial respiratory chain is a
cal processes (Murphy 2009) While the most rel- major source of ROS in eukaryotic cells (Fig. 3).
evant generation of ROS by NOX occurs in The role of mitochondria goes beyond the cre-
phagocytes after activation upon exposure mi- ation of molecular fuel. The organelle also gener-
crobes, microbial products, or inflammatory ates ROS that are deeply involved in signaling
mediators, ROS are produced via NOX in a vari- pathways which regulate a wide variety of physio-
ety of cell types in response to normal physiolog- logical events. ROS generation by mitochondria is
ical signals such as insulin, angiotensin II, growth mainly dependent on complexes I and III and
factors, and various classes of receptors such is highly dependent on metabolic conditions and
as formyl peptide receptors (FPRs) and Toll-like on the intramitochondrial balance between oxi-
receptors (TLRs) (Murphy 2009; Lambeth and dative and antioxidative factors (Lismont et al.
Neish 2014). Furthermore, NOX-dependent ROS 2015; Kalogeris et al. 2014). The respiratory
generation has been suggested to trigger adaptive chain process involves a set of distinct electron
response of a variety of stressors (Lambeth and carriers designed to minimize the unwanted leak
Neish 2014). However, NOX-induced ROS gen- of electrons from reduced cofactors onto molecular
eration can activate the NRF2 pathway which oxygen and hence ROS generation, at least under
increases antioxidant protection during inflamma- normal circumstances. Mitochondria comprise a
tion (Menshicova et al. 2010). ROS released very effective antioxidant defense which provides
Fig. 2 Xanthine I
oxidoreductase system R
E
S
P
C E
R XREDUCTASE
H F Ca ׀ ׀Proteases
U
E XOXIDASE NOO–
ADENOSINE S NO
M I
O H2O2
O2 O–
I INOSINE
N O 2– Fc++
A
HYPOXANTHINE URIC ACID
30 Oxygen Toxicity in Newborns 443
GPX
H2O+O2 H2+O2 O--
CAT SOD Cytosol
O--
Outer Mitochondrial Membrane
H+ H+ H+
H+ e-
e– e–
CoQ
Cyt c
Complex II Complex III Complex IV
Complex I Complex V
FAD FADH2 H+
NADH NAD+ ADP+P ATP+
Inner Mitochondrial Membrane
Fig. 3 Mitochondrial oxygen radical formation. Sche- anion. Superoxide anion is rapidly converted to hydrogen
matic representation of the sequence of events involved in peroxide. Hydrogen peroxide can further form hydroxyl
oxidative phosphorylation. This process, which takes place radicals (OH.) in the Fenton reaction in the presence of
in mitochondria, is the major source of ATP in aerobic ferrous ions which are oxidized to form ferric ions. SOD
organisms. ATP is formed as a result of the transfer of superoxide dismutase, CAT catalase, GPX glutathione per-
electrons from NADH to O2 by a series of electron carriers. oxidase, CoQ coenzyme Q, Cyt c cytochrome c.
Initially, electron donors can convert oxygen to superoxide
redox status stability (Drӧse and Brandt 2012). death, i.e., apoptosis, necrosis, autophagy, and
Therefore, mitochondrial function actively contrib- mitophagy (Vento 2014).
utes to the redox balance through the equilibrium The release of ROS from mitochondria as well
between pro-oxidant and antioxidant processes. as from peroxisomes strongly depends upon phys-
This complex variability leads to a serious diffi- iological or pathological state of the cell. Damage
culty in the detection and analysis of oxidative stress of mitochondrial DNA appears to damage mito-
in adults and particularly in newborns (Fig. 4). chondrial DNA-encoded proteins in electron-trans-
Under physiologic conditions, approximately porting chain, causing more superoxide to be
98% of O2 undergoes a complete reduction to produced. Therefore, the normal limit of 2–3%
form H2O2. A 2% of electrons will leak, causing O2- release by the ETC can be greatly increased
a partial reduction of the oxygen and producing if substrates are available but energy consumption
ROS. The monovalent reduction of O2 produces is low (Kohlhaas and Maack 2013). This theory,
superoxide anion, and monovalent reduction of called “A Mitochondrial Superoxide Theory”
anion superoxide generates H2O2. A third mono- (Indo et al. 2015), has been proposed to explain
valent reduction generates the highly reactive the initiation of numerous chronic diseases. Reduc-
hydroxyl radical. The reactivity of superoxide is ing excess amounts of mitochondria-generated
relatively low. However, when elevated levels of superoxide seems important to protecting against
NO• are present, nitric oxide binds to mitochon- oxidative stress-related diseases.
drial-generated superoxide. Subsequently, ONOO- It is important to note that abnormally low
is formed with the rate constant close to that of the levels of ROS can also have pathological conse-
reaction between OH. and ascorbic acid. Then, quences (Zorov et al. 2014). Metabolic conditions
ONOO- produces hydroxyl radicals and nitrogen and O2 levels modify the rate of ROS genera-
dioxide and oxidizes and nitrates DNAs, lipids, tion (Hoffman and Brookes 2009). During hyp-
and proteins. Free radicals generated from mito- oxia, redox signals to and from mitochondria are
chondria could play a role in many kinds of cell activated (Collins et al. 2012). In particular, the
444 R. Bracci et al.
O2
Surfactant layer
O2.-
Lining fluid
SOD3
Cell
membrane
GPX
SOD1
GSH GSSG
H2O2
Interstitial O2.- H2O2
tissue SOD2
Catalase
H2O
NOX2-4
Capillary
H2O2 + O2.-
Fig. 4 Oxidative stress following hyperoxia
respiratory chain increases ROS production stim- the delivery of blood-borne elements that are acti-
ulating the signaling pathway to induce hypoxia- vated by and release ROS. ROS may also induce
induced factor (HIF)-dependent gene expression. cell dysfunction and death by indirect mechanisms
Intermittent hypoxia increases the ROS content by interacting with NO, fatty acids, or free iron to
of carotid bodies, which induces increased syn- form peroxynitrite, peroxyl radicals, and hydroxyl
thesis and stability of hypoxia-inducible factor 1a radicals. Oxygen-derived ROS also acts to enhance
(HIF-1a) and calpain-dependent degradation of the inflammatory response to reperfusion via for-
H1F-2a (Semenza and Prabhakar 2012). Thus, mation of oxidant-dependent pro-inflammatory
intermittent hypoxia will cause a disruption of mediators (Kalogeris et al. 2014; Vento 2014).
the equilibrium between HIF-1α and HIF-2a, A third stage of I/R injury constitutes the repar-
causing a loss of redox homeostasis (Semenza ative phase and involves ROS-dependent genera-
and Prabhakar 2012; Yuan et al. 2013). Although tion of growth factors that promote angiogenesis,
an increase in mitochondrial ROS is important to vascular remodeling, and activation of matrix
activate HIF, a sustained increase in ROS produc- metalloproteinases and other factors that contrib-
tion can be detrimental under chronic hypoxia and ute to fibrosis, tissue remodeling, and formation of
can induce cell death (Kalogeris et al. 2014). scar tissue (Kalogeris et al. 2014).
Reperfusion is the second phase of ischemia/
reperfusion (I/R) injury and is characterized by 30.3 Oxidative Stress in Perinatal
the generation of ROS after reintroduction of Period
molecular oxygen to the tissues. Xanthine oxidase-
and phagocyte NADPH oxidase- derived ROS can It is important to emphasize that ROS reactions are
damage biomolecules in cells and tissues. In this a normal occurrence in living organisms and ROS
phase, the blood supply to ischemic tissues causes are involved in a myriad of physiological reactions.
30 Oxygen Toxicity in Newborns 445
They have a key role in oxidation-reduction, or Oxidative balance, therefore, is an intrigu-
“redox,” reactions, which are an integral part of ing problem, and much recent research has
signaling pathways in various cellular processes increased our knowledge of the relations between
such as energy metabolism, gene expression, pro- ROS and human diseases.
tein import, and folding (Lismont et al. 2015). Oxidative stress in the fetus and newborn may
Hydrogen peroxide and superoxide are deeply result from decreased antioxidants, increased
involved in cell signaling and transcriptional regu- ROS, or both. The various pathways of ROS
lation (Kaludercic et al. 2014). ROS are also pro- generation should be considered, and it is neces-
duced in response to a variety of ligands including sary to take into account the complexity of redox
growth factors cytokines and G protein-coupled equilibrium and therefore correctly interpret the
receptors (Lambeth 2014). The mechanism by origin of oxygen toxicity in fetus and newborn.
which ROS affect these pathways may be direct The well-known deficiency of antioxidant factors,
or indirect, though certain cysteine-containing pro- characteristic of the neonate, is only a piece of a
teins are direct target of oxidation. cohort of factors which can be involved in the fetal
Shift in redox potential may favor beneficial or and neonatal oxidative stress.
detrimental consequences according to various Antioxidant capacity is lower in the newborn
factors. High levels of ROS and excessive low and particularly the premature infant in com-
levels of ROS can alter the balance between pro- parison to adults. Free radical scavenger enzyme
oxidant and antioxidant elements which is essen- activity and many other components of the anti-
tial for biological processes (Lismont et al. 2015). oxidant system increase during intrauterine life
An excess of ROS, in relation to detoxification and are low in the neonate (Saugstad 2005;
capacity, is called oxidative stress, a term which Chandel and Shumacker 2000).
expresses the imbalance between oxidants and Therefore, premature infants are almost cer-
antioxidants that is a potential cause of damage. tainly developmentally unprepared for extrauter-
If oxidative stress is mild, cell defenses may ine life in an oxygen-rich environment and exhibit
increase by a mechanism which generally in- a unique sensitivity to oxidant injury. Further-
volves enhanced gene expression of ROS scav- more, the greater the prematurity, the higher is
enging activities (Halliwell et al. 1992). Severe the associated risk of oxidant injury.
oxidative stress is generally followed by cell The main antioxidant enzymes include copper,
injury. ROS can be responsible for a wide range zinc, and manganese containing superoxide
of molecular damage: lipid peroxidation, protein dismutase (SOD), GSH peroxidase (GPx), cata-
oxidation and nitration, protein-thiol depletion, lase (Cat), thioredoxin (TRX), peroxiredoxin
nucleic acid hydroxylation and nitration, and (PRDX), glutathione reductase (GSR), and
DNA strand breakage (Vento 2014). ROS can thioredoxin reductase (TXNRD). The major non-
damage DNA bases which can result in mutagen- enzymatic antioxidants are GSH, coenzyme
esis (Lambeth and Neish 2014). Lipid peroxida- A ubiquinol, vitamin C, and vitamin E (Lismont
tion can alter membrane structure disrupting et al. 2015).
membrane permeability properties and alter cellu- Of note is that the level and activity of the most
lar components. At lower concentrations ROS can relevant antioxidant enzymes such as superoxide
perturb cells and tissue functions by more subtle dismutases, catalase, and glutathione peroxidase
and often transient and reversible mechanism change dynamically during development and
(Lambeth and Neish 2014). Under stressful con- mature in the last weeks of gestation, preparing
ditions ROS may induce apoptosis and/or necrosis the fetus for lung respiration (Frank and Sosenko
(Vento 2014). Excess of ROS can also induce 1987; Friel et al. 2004; Tiina et al. 1998).
abnormalities in cell membrane proteins with Nonenzymatic antioxidant factors are reported
numerous functional consequences including, for to be lower in the fetus and newborn than in
instance, for recognition of cells in the immune adults and older babies (Rogers et al. 2000). One
response (Lambeth and Neish 2014). of the most studied antioxidant deficiencies of the
446 R. Bracci et al.
fetus and newborn is tissue and erythrocyte low role in protecting against the nonprotein-bound
α-tocopherol. Other factors are important. Re- iron (NPBI)-promoted oxidative stress due to
duced glutathione (GSH) is the most abundant OH. release (Buonocore et al. 2001; Berger et al.
intracellular nonenzymatic antioxidant and is in- 1995). In this regard, low ceruloplasmin and
volved in the GSH-GPx and GSH-T enzyme transferrin may play an important role in neonatal
activity. There are also complex interactions with susceptibility to oxidative stress and particularly
environmental factors triggering oxidative stress to metal-induced OH• production (Lindeman
(Njålsson and Norgren 2005). Since, in the cell, et al. 2000). The finding of increased bleomycin-
the glutathione tripeptide is assembled from cys- detectable iron in premature and some full-term
teine and glycine and then glutamate by consecu- infants is evidence of the real risk of the increased
tive actions of enzymes such as y-cystathionase, pro-oxidant effects of iron in neonates (Evans
y-glutamylcysteine synthetase, and glutathione et al. 1992). High saturation of transferrin is there-
synthetase, the possible problems with this mech- fore probably a risk factor for oxidative stress. It is
anism may be due to recognizable inborn errors of generally accepted that NPBI is a pathological
metabolism or nutritional deficiencies (Njålsson manifestation and in fact is extremely rare in
and Norgren 2005; Yeung 2006). Several ob- adults (Buonocore et al. 2001). Levels of NPBI
servations have shown that, depending on age, in plasma of newborns are correlated with other
preterm infants have lower plasma concentrations markers of oxidative stress and are higher in hyp-
of GSH and higher concentrations of glutathione oxic newborns (Marzocchi et al. 2005). Interest-
disulfide (GSSO) than adults (Smith et al. 1993). ingly, plasma-esterified F2-isoprostanes not only
This occurrence may due to low OSH and low correlate with NPBI in the samples of cord blood
activity of GSH synthetase in VLBW infants of newborns, but they increased after incubation
(Yeung 2006). of plasma with ammonium iron sulfate (Signorini
In this regard, there have been conflicting et al. 2008). This observation strongly suggests
reports in the literature as to whether L-cysteine the role of NPBI in enhancing oxidative stress
is an essential amino acid for the preterm infant in the neonate. High plasma NPBI has been
as the result of the low activity of hepatic g- found in hypoxic newborns with poor outcome
cystathionase. Thus, studies performed in preterm (Buonocore et al. 2003).
infants revealed that plasma cystathionine con- Oxidative stress has been suggested as a caus-
centrations in ELBW infants were significantly ative agent in pregnancy-related disorders such
higher than in term infants, whereas cysteine con- as recurrent pregnancy loss, preeclampsia, pre-
centrations were higher in term than in preterm. term premature rupture of membranes, intrauter-
Furthermore, erythrocytes from preterm infants ine growth restriction, and fetal death. In utero
synthesize glutathione at a much lower rate than stressors contribute to ROS production and re-
term infants when incubated with methionine, a sulting in tissue damage. Markers of oxidative
process dependent on the g-cystathionase path- stress, such as nonprotein-bound iron, have been
way. These findings underscore the immaturity measured in cord blood as an indicator of intra-
of the trans-sulfuration pathway and the condi- uterine ROS production. These markers have
tional essentiality of L-cysteine in the parenteral been associated with the development of several
and enteral nutrition of very preterm neonates. postnatal disease processes, suggesting that in
Moreover, it also explains the tendency toward utero oxidative stress is a significant risk factor,
oxidative stress (Viña et al. 1995). Iron-binding especially in premature neonates (Perrone et al.
proteins have major antioxidant activity, pro- 2010). Pregnancy, in fact, is a state associated with
tecting against metal-induced OH• production enhanced oxidative stress due to the high meta-
(Halliwell and Gutteridge 1990). Therefore, among bolic turnover and elevated tissue oxygen require-
nonenzymatic antioxidant factors, the metal trans- ments. During intrauterine life, many factors such
porter proteins have an important function. In as hypoxia, inflammation, and infections can
particular, transferrin concentration has a key induce overproduction of ROS. Whenever
30 Oxygen Toxicity in Newborns 447
produced, these toxic species can induce oxida- molecules modulating maturation of specific met-
tive stress and tissue injury. The placenta repre- abolic pathways (Forman et al. 2008; Martín et al.
sents an important source of lipid peroxides, 2007).
because of its high polyunsaturated fatty acid Oxidative stress following hyperoxia has been
content (Marseglia et al. 2014). extensively investigated and has been recognized
The process is well balanced in healthy preg- to be responsible for lung injury and possibly
nancy by the enzymatic and nonenzymatic anti- generalized tissue damage (Saugstad 2005). The
oxidant redox systems. The ability of placental sequence of, first, the inhalation of a high level
antioxidant defenses to reduce the effects of of oxygen (even for a short time), followed by
highly reactive and potentially damaging ROS is membrane-bound NADPH oxidase activation,
critical for healthy placental function and the opti- ROS production, and DNA damage with cell apo-
mal growth and development of the fetus. Occa- ptosis has been suggested as a consequence of
sionally, however, the developing fetus may be exposure to high oxygen concentration (Chandel
exposed to high levels of oxidative stress due to an and Shumacker 2000).
overproduction of ROS and/or reduced antioxi- Hyperoxic resuscitation showed accumulation
dant defense capability (Marseglia et al. 2014). of 8-oxoG in a newborn mouse model (Sejersted
Fluctuating oxygen conditions can contribute to et al. 2009) pointing at insufficient repair and a
increased ROS production, as ROS act as signal- possible risk for genetic instability after the use
ing molecules for this condition. This may be of supplementary oxygen during resuscitation.
particularly pertinent to tissues which have a Oxidative stress due to supplementary oxygen
high-energy demand or those which contain use in newborn piglets may reduce nucleotide-
large amounts of mitochondria, such as the pla- excision repair which could be compensated for
centa and fetal tissues. Another important factor by antioxidant supplementation (Langie Sabine
which can be responsible for ROS increase in et al. 2010).
fetus and newborn is the inflammation (Pereira Modification of neuronal nuclear membrane
et al. 2015; Poggi and Dani 2014). function leading to increased nuclear Ca++ influx,
Individual genetic characteristics may condi- activation of Ca++/Calmodulin-dependent protein
tion the onset and the magnitude of the inflamma- kinase, and protein-mediated apoptotic protein
tory and immune responses triggered by specific expression have been reported in animals exposed
stimuli in the fetus and in the preterm newborn to high oxygen concentration (Chang et al. 2007).
(Poggi and Dani 2014). Particularly, a recent An important example of the various conditions
model of the pathogenesis of the complications capable of modifying ROS production and creat-
of prematurity suggests that a hyperresponsive ing serious oxidative stress occurs in the endothe-
phenotype activating excessive inflammatory lium. It is well known that endothelium
cytokines and ROS production increases the risk dysfunction is mainly due to oxidative stress
of oxidative stress-related complications (Poggi enhanced by various factors such as cytokines,
and Dani 2014). ischemia reoxygenation, glucose, LDL choles-
terol, angiotensin II, shear stress, and vascular
endothelial growth factor (VEGF) (Li and Shah
30.4 Hyperoxia 2004). The occurrence of endothelium oxidative
stress is important in neonatology, taking into
In the fetal-to-neonatal transition, both blood oxy- account that endothelium is deeply involved in
gen content and oxygen availability abruptly infection-mediated alteration of the coagulation
increase in the first few minutes after birth system and vascular troubles in the neonate.
to their adult values, eliciting the generation of Oxygen toxicity is particularly harmful for the
a burst of ROS (Comporti et al. 2004; House et al. lungs. The mechanism of damage is complex.
1987; Vento et al. 2002). Free radicals in the fetal- Lung injury may be caused directly by ROS pro-
to-neonatal transition may act as signaling duction in response to hyperoxia or indirectly by
448 R. Bracci et al.
ROS due to phagocyte activation and inflamma- with increased markers of oxidative stress and
tion. The two mechanisms seem to be integrated. inflammation in the first days of life developed
In vitro and in vivo exposure to hyperoxia res- with significantly higher incidence of BPD and
ults in downregulation of peroxisome proliferator- stayed more days on oxygen and mechanical ven-
activated receptor gamma (PPARy) augmenting tilation (Vento et al. 2009b). Effects of hyperoxia
the transdifferentiation of pulmonary lipofibroblasts in the lung and a close relationship between oxi-
(LIFs), which provide protection against oxygen dative stress and inflammation have been demon-
free radicals, to myofibroblasts (MYFs). Trans- strated (Denis et al. 2001; Bhandari 2008).
differentiated lipofibroblasts (Myf) are unable to Magnetic resonance studies have confirmed the
maintain pulmonary epithelial cell growth and previously reported experimental data on the con-
differentiation, resulting in failed alveolarization, sequences of hyperoxia in the lungs of premature
seen characteristically in bronchopulmonary dys- newborn animals, namely, edema, congestion,
plasia (BPD) (Torday and Rehan 2016). immune cell infiltration, and decreased number
The hyperoxia-induced morphologic, molecu- of alveoli per square meter (Appleby and Towner
lar, and immunohistochemical changes are almost 2001). The finding of a large number of neutro-
entirely prevented by pretreatment with a potent phils and high concentrations of IL-8 and leuko-
PPARc signaling pathway agonist, rosiglitazone trienes in bronchopulmonary lavage of infants
(RGZ), suggesting the possibility of treatment of with severe chronic lung disease (CLD) demon-
BPD based on physiological principles rather than strates the role of inflammatory reactions and
pure pharmacology (Richter et al. 2016). ROS production in the development of this dis-
The particular toxicity of ROS in the immature ease (Kotecha et al. 1995).
lung is mainly due to the low antioxidant capacity However, in extremely premature infants, the
of premature infants, as well as to the possibly combination of an immature antioxidant system
high toxicity of ROS in rapidly developing tissues and predisposition to altered redox potential plus a
(Frank 1991). Increased production of ROS under surfactant-deficient lung and the need for therapy
certain conditions may also play a role. The main with oxygen supplementation and mechanical
sources of ROS production in the immature lung ventilation together predispose the newborn to
are ischemia, reperfusion, phagocytosis, and oxidative stress, lung-stretch damage, inflamma-
hyperoxia (Vento et al. 2009a, b). The lung is tion, and impairment of alveolar development,
highly susceptible to high oxygen concentrations ultimately increasing the risk of chronic lung dis-
especially when administered with positive pres- ease (Asikainen and White 2004; Halliday 2008).
sure. In a prospective clinical study, extremely Generalized use of antenatal steroids has signifi-
low gestational age (ELGA) neonates were ran- cantly reduced mortality and the incidence of
domly assigned to become ventilated with higher severe complications in preterms younger than
(90%) and lower (30%) oxygen concentrations as 34 weeks of gestational age. ELGA neonates
initial inspiratory fraction of oxygen. Of note is with antenatal steroids spend less days on oxygen
that those neonates receiving more oxygen load and on mechanical ventilation and have less
during fetal-to-neonatal transition had a higher severe complications such as BPD, patent ductus
oxidative stress as detected by a decreased GSH/ arteriosus (PDA), intra-periventricular hemor-
GSSG ratio. Moreover, urinary determination of rhage (IPVH), or retinopathy of prematurity
ortho-tyrosine/phenylalanine ratio and 8-oxo- (ROP). Moreover, in spite of the increased anti-
dihydroguanosine/2-de-oxyguanosine ratio oxidant enzyme (AOE) activity and reduced oxi-
revealed that premature infants who received dative stress and damage to proteins and DNA
more oxygen had increased oxidation of circulat- after antenatal steroid administration, the level of
ing proteins and higher damage to nuclear DNA. AOE activity was significantly lower than
In addition, markers of inflammation (interleukin- assessed in term infants or adults. Intriguingly,
8 [IL8] and tumor necrosis factor-α [TNF-α]) the response to antenatal steroids is conditioned
increased at the same time. Interestingly, infants both by when they are administered before birth
30 Oxygen Toxicity in Newborns 449
and also by gender, with female neonates having a susceptibility of the fetus and newborn to oxida-
significantly increased response compared to male tive stress. Increased release and decreased detox-
neonates (Vento et al. 2009a). ification in the newborn appear to be negatively
The key role of oxygen toxicity in the devel- correlated with the gestational age.
opment of the retinopathy has been recognized for
more than half a century and will be discussed in .
▶ Chap. 136, “Retinopathy of Prematurity.” 30.5 Clinical Aspects and Prevention
Oxidative stress is involved in the increased
hemolysis and anemia of the newborn and partic- 30.5.1 Diagnostic Procedures
ularly of the premature infant. The red cells of
newborns appear to be more susceptible to the ROS have an important role in the development
toxic effects of oxidative stress than those of retinopathy, chronic lung disease, necrotizing
of adults (Gross et al. 1967), and the free iron enterocolitis, renal failure, hemolytic anemia,
content of red cells, a risk factor for hemolysis, septic shock, and also brain damage. The clinical
is higher in newborns in comparison with the care of these pathologies is treated in the cor-
adults (Buonocore et al. 1998). It is interesting responding chapters. Several methods have been
that during aerobic and also hypoxic incubation, proposed in the attempt to detect the presence and
increased O2 production, free iron release, the severity of the oxidative stress. Some fre-
and senescence antigen production showed the quently used approaches such as the measurement
highest significant differences between adults of erythrocyte antioxidant defenses are not accu-
and neonates (Ciccoli et al. 2004). rate since the red cell enzyme activities are age
Increased markers of oxidative stress such as dependent and values may be an expression of an
hypoxanthine, total hydroperoxide, and advanced old or young red cell population (Halliwell and
oxidation protein products have been reported in Whiteman 2004).
hypoxic newborns and in preterm neonates at
birth and on the seventh day of life (Buonocore
et al. 2000, 2002). Increased F2-isoprostanes have 30.5.2 Lipids
been also found in growth-restricted fetuses sug-
gestive of oxidative stress and hypoxia (Longini The thiobarbituric acid (TBA) test should not be
et al. 2005). These observations demonstrate that used to measure lipid peroxidation because most
oxidative stress follows hypoxia with a mecha- of TBA-reactive material is not related to lipid
nism of hypoxia reoxygenation, NADP oxidase peroxidation. Measurements of malondialdehyde
reactions, or, paradoxically, by release of ROS by (MDA) by HPLC, 4-hydroxynoneal, and particu-
hypoxic cells. Oxidative stress is also involved in larly isoprostanes are more accurate (Halliwell
tissue damage induced by infection and sepsis. and Whiteman 2004). The most work has been
Although there is general agreement that neonatal done with F2 isoprostanes which arises from ara-
phagocytes, especially those of premature infants, chidonic acid non-cyclooxygenase (COX) perox-
have abnormalities of various functions, active idation. Neuroprostane or F4 isoprostanes has also
neonatal secretion of pro-inflammatory cytokines been measured (Halliwell and Whiteman 2004).
suggests a very complex situation in which oxi-
dative stress following infection may be more 30.5.2.1 Isofurans
dangerous in newborns, especially if premature, The prostanoid profile can be affected by oxygen
than in adults (Bracci and Buonocore 2003). This tension. An oxygen insertion step blocks the inter-
finding suggests that hyperoxia and hypoxia may mediates from the IsoPs pathway to form various
generate red cell damage via ROS and possibly compounds termed isofurans (IsoFs) that contain
have a role in the increased hemolysis in the a substituted tetrahydrofuran ring. Like the IsoPs,
neonate. In conclusion, experimental studies the IsoFs are chemically and metabolically stable
and clinical observations demonstrated high and are well suited to act as in vivo biomarkers
450 R. Bracci et al.
of oxidative damage. The ratio of IsoFs to IsoPs oxidative products of lipids, peptides, and amino
also provides information about the relative oxy- acids (Halliwell and Whiteman 2004). Allantoin
gen tension where the lipid peroxidation is occur- and 8-hydroxydeoxyguanosine can be measured
ring. This was clearly shown in pigs, in which in plasma and urine, and the levels are high in
exposure to high oxygen tension increased IsoFs conditions of oxidative stress (Mikami et al.
production and reduced IsoPs levels in the brain 2000; Drury et al. 1998). Nitrosyn levels have
(Solberg et al. 2012; de La Torre et al. 2014). been reported as a marker of ONOO- production
from leukocyte activation (Eiserich et al. 1998). A
30.5.2.2 Neuroprostanes very specific, useful, and noninvasive mean to
The oxidation both in vivo and in vitro of do- monitor oxidative damage to circulating proteins
cosahexaenoic acid (DHA), a major component and amino acids is the measurement of ortho-tyro-
of neuronal membranes, leads to the formation of sine. Oxidation of phenylalanine produces three
IsoPs-like compounds termed neuroprostanes different metabolites, ortho-, para-, and meta-tyro-
(NPs) (Arneson and Roberts 2007). The most sine, which can be detected in urine by high-per-
studied series is the four-series NeuroPs, mainly formance liquid chromatography coupled to mass
F4-NeuroPs. The NPs are the only quantitative in spectrometry (Lubec et al. 1997). This works since
vivo biomarker of oxidative damage selective for only ortho-tyrosine is produced by physiologic
neurons, and thus they are specific and reliable metabolic pathways and derives from hydroxyl-
marker of cerebral gray matter lipid oxidation. derived oxidation of phenylalanine. A significant
correlation between the amount of oxygen given
30.5.2.3 Neurofurans during resuscitation and the urinary elimination of
Similarly to IsoFs, in high oxygen tension condi- ortho-tyrosine has been detected (Solberg et al.
tions, an alternative pathway of oxidation of DHA 2007); moreover, the increased antioxidant capac-
leads to the formation of compounds termed neu- ity of preterm human milk has also been assessed
rofurans (NFs). Thus hyperoxic or hypoxic by this methodology (Ledo et al. 2009).
conditions can be detected through quantitative
assessment of NFs and IsoFs in vivo. Given
the abundance of DHA in the brain, analysis 30.5.4 Intracellular Redox Status
of NFs may have particular value in the quantitative
assessment of lipid peroxidation in brain damage A major marker of oxidative stress is the GSH/
(Tataranno et al. 2015). Isofurans and neurofurans GSSG ratio which directly reflects changes in the
are new promising markers, and recently their intracellular redox status since, when oxidative
potentialities are being investigated since they can stress exceeds the reductive capacity of GSH
be good markers of oxidative injury in conditions of reductase, the cell loses glutathione, exporting
high oxygen tension, but few data exists in humans, the excess of oxidized glutathione (Njålsson and
mostly due to a lack of commercially standard ref- Norgren 2005). NPBI levels appear to be a very
erences (Milne et al. 2011; Song et al. 2008). reliable marker of oxidative stress, particularly
in newborns, as previously indicated. Measure-
ments of ethane in expired air may also be use-
30.5.3 Proteins ful in detecting oxidative stress (Halliwell and
Whiteman 2004).
Detection of oxidation of proteins can be obtained
by measurement of carbonyl groups, and the use of
proteomics appears to be a promising method in 30.5.5 DNA Damage
order to identify specifically oxidized proteins
(Halliwell and Whiteman 2004). Assay of total Determination of oxidized bases of DNA has been
hydroperoxides represents a measure of overall carried out by HPLC coupled to MS/MS (Ledo
oxidative stress given that they are the intermediate et al. 2009).
30 Oxygen Toxicity in Newborns 451
30.5.6 Prevention of ROS Tissue <95% compared to those kept at more than 95%
Damage (Sun 2002). Shulze et al. (1995) did not observe
signs of mismatch between systemic oxygen
Avoidance of conditions such as infections, as- delivery and demand in low birth weight infants
phyxia, hyperoxia, and retinal light exposure, kept at 93–96% O2 and 89–92% saturation. How-
under which excessive free radical release occurs, ever, Poets et al. (Poets et al. 2003) reported
is the best defense against development of imbal- higher incidence of ROP in infants <30 weeks’
ances in pro-oxidant and antioxidant factors in the gestation using oxygen saturation limits of
neonate. Frequent reports of NPBI in plasma of 80–92% in comparison with 92–97%. Therefore,
neonates suggest that indiscriminate iron supple- the relationship between haemoglobin oxygen
mentation should also be avoided. saturation, risk of oxidative stress, and oxygen
The concept of optimal oxygenation of new- toxicity is still a problem. This is presumably
borns has recently been revised in order to clarify due to the complex mechanism of oxygen toxicity
whether the optimal oxygen saturation unani- which may be expressed at different percentages
mously accepted for normal infants and adults is of O2 saturation under different conditions. Con-
also the best for sick neonates, especially if pre- ventional indications suggest that optimal oxygen
mature. In an attempt to avoid the risk of tissue tension should be maintained between 50 and
damage caused by ROS in the first hours of life, 70 mmHg (Wolkoff and Narula 2000). However,
when susceptibility to oxidative stress is particu- it should be taken into account that the ability
larly high, the effects of O2 were investigated. As of pulse oximetry to reliably detect hyperoxia
previously reported, hyperoxia-induced lung remains controversial, and it has been shown
injury has been demonstrated. Indications on the that oxygen saturation of more than 90% can be
use of oxygen were reported by Chow et al. associated with an arterial oxygen tension of more
(Chow et al. 2003) in a 5-year study in a tertiary than 80 mmHg (Tin and Gupta 2007). Based on
neonatal center where oxygen therapy was all the actually available evidence, the most pru-
adjusted to optimize neonatal care and decrease dent approach would be not to tolerate possible
the incidence of ROP. They recommended avoid- hypoxia and not accept SpO2 values associated
ance of repeated increase and decrease in FiO2 in with potential hyperoxia in infants breathing sup-
response to the oxygen saturation monitor and plemental oxygen. For infants breathing supple-
maintenance of oxygen saturation within “accept- mental oxygen, setting the low alarm at 1% below
able” limits. They also recommended setting an the lower SpO2 chosen in the clinically intended
alarm for oxygen saturation below 85% and above range has been suggested, but never <85%, and
93% for newborns under 32 weeks of age. More setting the high alarm at 1% above the higher
recently, comparison of two populations of high- SpO2 chosen, but never more than 95%. For
risk newborns kept at O2 saturations of 88–98% example, if the intended range is 91–94%, the
and 70–90% showed a significant reduction in alarms would be set at 90% and 95%. Finally,
ROP in the group at lower O2 saturation but no the delay time should not be longer than 20 sec,
differences in mortality or morbidity (Tin and to ensure that significant events are not missed
Gupta 2007). Data from clinical outcomes seem (Sola et al. 2014). It is imperative to control the
to demonstrate that low birth weight infants cared low limit but also to increase compliance with the
for with liberal approaches had more cognitive upper limit and avoid a flip-flop phenomenon that
disability compared with those cared for with leads to acute and significant changes and fluctu-
more restrictive approaches after 10 years (Tin ations in SpO2 (Bancalari and Claure 2012;
and Gupta 2007). Data collected from the Oxford Zapata et al. 2014).Recent guidance from the
Vermont Network in extremely low birth new- American Academy of Pediatrics Committee on
borns demonstrate significant lower incidence Fetus and Newborn advises that “recent RCTs
of chronic lung disease and ROP among suggest that a targeted oxygen saturation range
babies carried with target oxygen saturation of of 90% to 95% may be safer than 85% to 89%”
452 R. Bracci et al.
(Cummings and Polin 2016). The results from the 30.5.8 Antioxidants
Cochrane review concur with this conclusion
(Askie et al. 2017). This metaanalysis of five Substances inhibiting phagocyte activation or xan-
randomised trials found no significant difference thine oxidase and arachidonic acid metabolism, or
in the primary outcome of death or major disability decompartmentalizing free iron and making it avail-
in extremely preterm infants when targeting a able for the Fenton reaction, have also been investi-
lower (SpO 85% to 89%) versus higher (SpO gated, together with those scavenging ROS directly
91% to 95%) oxygen saturation range. Compared or repairing ROS-induced membrane injury, like
with a higher target range, a lower target range calcium antagonists and beta-blockers. The subject
significantly increased the incidence of death and has been reviewed by Buonocore and Groenendal
necrotising enterocolitis. Conversely, targeting the (2007). On the whole, the results obtained in new-
lower range significantly decreased the incidence borns have been uncertain. Several antioxidant
of severe or treated retinopathy of prematurity. substances have been used in newborn animals
and humans in an attempt to improve the worst
prognosis of damage, presumed to be due to ROS.
30.5.7 Protective Effect of Human Milk Many, such as superoxide dismutase (SOD),
in the Preterm Infant showed the same disadvantages in newborns.
Other drugs, such as allopurinol and
The antioxidant properties of human milk are desferrioxamine, have shown good results in ani-
reported widely in the literature. In a recent study, mals, but no advantages in human newborns.
Friel et al. (2002) confirmed that human milk of Among the antioxidants, melatonin has a special
term and of preterm mothers provided better anti- place since it has been reported to have several
oxidant protection. They found that human milk interesting effects such as enhancement of antioxi-
produced less ascorbate whether or not oxidative dant enzyme activities and neutralization of H2O2
stress was present. Elevated concentrations of singlet oxygen and peroxynitrite; it appears to scav-
ascorbate are pro-oxidant in the extracellular enge OH• (Tan et al. 1993). Administration of mel-
milieu. Moreover, the antioxidant enzyme activity atonin has been reported to decrease the
of catalase, superoxide dismutase, and glutathi- concentrations of pro-inflammatory cytokines and
one peroxidase increased with time in human markers of oxidative stress in RDS and in septic
milk. Additional studies have shown that human newborns (Gitto et al. 2001, 2004). In animals, a
milk-fed neonates had a higher plasma total anti- study of Carloni et al. (2008) demonstrated that
oxidant and vitamin C content. Biomarkers of melatonin has long-lasting beneficial effects in
oxidative status, such as total peroxide and oxi- cases of brain damage following hypoxia ischemia
dative stress index, were higher in formula-fed which occurs during development. However, the
neonates at 3–6 months’ postnatal age (Aycicek effects of the melatonin may be due to a combina-
et al. 2006). Human milk of preterm mothers at tion of effects since the melatonin, in addition to the
35–36 weeks’ post-conceptional age also seemed antioxidant effects, possesses also endocrine, auto-
to have a positive effect on the oxidant status of crine, and paracrine activity and appears to decrease
their infants. In a recent study, preterm infants inflammation. Vitamin E is a powerful, widely
fed with preterm human milk have significantly tested antioxidant. Conclusions of a recent
lower elimination of markers of hydroxyl radical Cochrane review are that vitamin E supplementation
aggression to protein and DNA, meaning that to preterm infants reduces the risk of intracranial
they produce lower amounts of free radicals. hemorrhage but increases the risk of sepsis; in very
Thus, in the clinical setting even in the acute low birth weight infants, it seems to reduce the risk
stage, preterm infants should be fed early with of retinopathy and blindness (Brion et al. 2003).
human expressed milk, which offers an addi- There is no evidence to support the use of vitamin
tional protection against free radicals (Ledo E at high doses or the aim of keeping serum tocoph-
et al. 2009). erol levels above 3.5 mg/dL (Silvers et al. 2001).
30 Oxygen Toxicity in Newborns 453
It should be remembered that some formulations of Asikainen TM, White CW (2004) Pulmonary antioxidant
vitamin E are poorly adsorbed (Italian Collaborative defenses in the preterm newborn with respiratory dis-
tress and bronchopulmonary dysplasia in evolution:
Group on Preterm Delivery 1991). implications for antioxidant therapy. Antioxid Redox
The efficacy of lutein as an antioxidant agent Signal 6:155–167
has been confirmed in experimental and clinical Asikainen TM, Raivio KO, Saksela M, Kinnula VL (1998)
studies, but its routine use is not recommended Expression and developmental profile of antioxidant
enzymes in human lung and liver. Am J Respir Cell
in perinatal period (Perrone et al. 2014). Innova- Mol Biol 19:942–949
tive frontiers concerning lutein supplementation Askie LM, Darlow BA, Davis PG, Finer N, Stenson B,
are orientated toward cardiometabolic health im- Vento M, Whyte R (2017) Effects of targeting lower
provement and cognitive benefits (Perrone et al. versus higher arterial oxygen saturations on death or
disability in preterm infants. Cochrane Database Syst
2016). Peroxidation products in stored lipid emul- Rev 4:CD011190
sions have been shown to increase lipid peroxi- Aycicek A, Erel O, Kocyigit A et al (2006) Breast milk
dation in vivo in newborns and adults. Since provides better antioxidant power than does formula.
parenteral nutrition has been associated with in- Nutrition 22:616–619
Bancalari E, Claure N (2012) Control of oxygenation dur-
creased formation of ROS, it is necessary to pro- ing mechanical ventilation in the premature infant. Clin
tect intralipids from light and add vitamins Perinatol 39:563–572
(Pitkanen et al. 2004). Finally, although hyper- Berger HM, Mumby S, Gutteridge JMC (1995) Ferrous
bilirubinemia can be regarded as a natural antiox- ions detected in iron-overloaded cord blood plasma
from preterm and term babies: implications for oxida-
idant factor, the risk of brain damage due to high tive stress. Free Radic Res 22:555–559
plasma levels of this molecule, particularly in Bhandari V (2008) Molecular mechanism of hyperoxia
premature babies, should not be underestimated. induced acute lung injury. Front Biosci 13:
6653–6661
Bracci R, Buonocore G (2003) Chorioamnionitis: a risk factor
for fetal and neonatal morbidity. Biol Neonate 83:85–96
30.6 Conclusions Brion LP, Bell EF, Raghuveer TS (2003) Vitamin E sup-
plementation for prevention of morbidity and mortality
The mechanism by which the oxidative stress is in preterm infants. Cochrane Database Syst Rev 3:
CD003665
deeply involved in the development of several
Buonocore G, Groenendal F (2007) Antioxidant strategy.
diseases of the fetus and newborn is complex Semin Fetal Neonatal Med 12:287–295
and probably not yet fully understood. However, Buonocore G, Zani S, Perrone S et al (1998)
multiple observations strongly suggest that in- Intraerythrocyte non protein bound iron and plasma
malondialdehyde in the hypoxic newborn. Free Radic
creased free radical and ROS play a considerable
Biol Med 25:766–770
role as does the deficiency of antioxidants. In Buonocore G, Perrone S, Longini M et al (2000) Total
particular, hyperoxia and inflammation as well as hydroperoxide and advanced oxidation protein
the episode of hypoxia reoxygenation appear to be products in preterm hypoxic babies. Pediatr Res
47:221–224
a source of increased ROS release which may
Buonocore G, Perrone S, Bracci R (2001) Free radicals
cause tissue injury, particularly in the preterm and brain damage in the newborn. Biol Neonate
infant, either by direct effect or as consequences 79:180–186
of endothelium dysfunction. Buonocore G, Perrone S, Longini M (2002) Oxidative
stress in preterm neonate at birth and on seventh day
of life. Pediatr Res 52:46–49
Buonocore G, Perrone S, Longini M et al (2003) Non
References protein bound iron as early predictive marker of neo-
natal brain damage. Brain 126:1224–1230
Appleby C, Towner RA (2001) Magnetic resonance imag- Carloni S, Perrone S, Buonocore G (2008) Melatonin pro-
ing of pulmonary damage in the term and premature rat tects from the long-term consequences of a neonatal
neonate exposed to hyperoxia. Pediatr Res 50:502–507 hypoxic-ischemic brain injury in rats. J Pineal Res
Arneson KO, Roberts LJ 2nd (2007) Measurement of 44:157–164
products of docosahexaenoic acid peroxidation, Chandel NS, Shumacker PT (2000) Cellular oxygen sens-
neuroprostanes, and neurofurans. Methods Enzymol ing by mitochondria: old question, new insight. J Appl
433:127–143 Physiol 88:1880–1889
454 R. Bracci et al.
Chang E, Hornick K, Fritz KI et al (2007) Effects of Gitto E, Reiter RJ, Cordaro SP et al (2004) Oxidative and
hyperoxia on cortical neuronal nuclear function and inflammatory parameters in respiratory distress syn-
programmed cell death mechanism. Neurochem Res drome of preterm newborns: beneficial effects of mel-
32:1142–1149 atonin. Am J Perinatol 21:209–216
Chow LC, Wright KW, Sola A et al (2003) Can changes in Gordon HH, Nitowsky HM, Cornblath M (1955) Studies
clinical practice decrease the incidence of severe reti- of tocopherol deficiency in infants and children. I.
nopathy of prematurity in very low birth weight Hemolysis of erythrocytes in hydrogen peroxide. Am
infants? Pediatrics 111:339–345 J Dis Child 90:669–681
Ciccoli L, Rossi V, Leoncini S et al (2004) Iron release, Gross RT, Bracci R, Rudolph N et al (1967) Hydrogen
superoxide production and binding of autologous IgG peroxide toxicity and detoxification in the erythrocytes
to band 3 dimers in newborn and adult erythrocytes of newborn infants. Blood 29:481–493
exposed to hypoxia and hypoxia-reoxygenation. Halliday H (2008) Surfactant, past, present and future.
Biochim Biophys Acta 1672:203–213 J Perinatol 28(Suppl 1):S47–S56
Collins Y, Chouchani ET, James AM et al (2012) Mito- Halliwell B (2007) Biochemistry of oxidative stress.
chondrial redox signaling at a glance. J Cell Sci Biochem Soc Trans 35:1147–1150
125:801–806 Halliwell B, Gutteridge JMC (1990) The antioxidants of
Comporti M, Signorini C, Leoncini S et al (2004) Plasma human extracellular fluids. Arch Biochem Biophys
F2-isoprostanes are elevated in newborns and inversely 280:1–8
correlated to gestational age. Free Radic Biol Med Halliwell B, Whiteman M (2004) Measuring reactive spe-
37:724–732 cies and oxidative damage in vivo and in cell culture:
Cummings JJ, Polin RA (2016) Oxygen targeting in how should you do it and what do the results mean?
extremely low birth weight infants. Pediatrics 138(2): Br J Pharmacol 142:231–253
e20161576–e20161576 Halliwell B, Gutteridge JMC, Cross CE (1992) Free radi-
Denis D, Fayon MJ, Berger P et al (2001) Prolonged cals, antioxidants, and human disease: where are we
moderate hyperoxia induced hyperresponsiveness and now? J Lab Clin Med 1:598–620
airway inflammation in newborn rats. Pediatr Res Hoffman DL, Brookes PS (2009) Oxygen sensitivity of
50:515–519 mitochondrial reactive oxygen species generation
Drӧse S, Brandt U (2012) Molecular mechanism of super- depends on metabolic conditions. J Biol Chem
oxide production by the mitochondrial respiratory 284:16236–16245
chain. Adv Exp Med Biol 348:145–169 House JT, Schultetus RR, Gravenstein N (1987) Continu-
Drury JA, Jeffers G, Cooke RW (1998) Urinary 8- ous neonatal evaluation in the delivery room by pulse
hydroxydeoxyguanosine in infants and children. Free oximetry. J Clin Monit 3:96–100
Radic Res 28:423–428 Indo HP, Yen HC, Nakanishi I, Matsumoto K, Tamura M,
Eiserich JP, Hristova M, Cross CE et al (1998) Formation Nagano Y, Matsui H, Gusev O, Cornette R, Okuda T,
of nitric oxide-derived inflammatory oxidants by Minamiyama Y, Ichikawa H, Suenaga S, Oki M, Sato T,
myeloperoxidase in neutrophils. Nature 391:393–339 Ozawa T, Clair DK, Majima HJ (2015) A mitochon-
Evans PJ, Evans P, Kovar IZ et al (1992) Bleomycin- drial superoxide theory for oxidative stress diseases and
detectable iron in the plasma of premature and full- aging. J Clin Biochem Nutr 56:1–7
term neonates. FEBS Lett 303:210–212 Italian Collaborative Group on Preterm Delivery (1991)
Forman HJ, Fukuto JM, Miller T et al (2008) The chemistry Absorption of intramuscular vitamin E in premature
of cell signaling by reactive oxygen species and nitro- babies. Dev Pharmacol Ther 16:13–21
gen species and 4-hydroxynonenal. Arch Biochem Jankov RP, Negus A, Tanswell AK (2001) Antioxidants as
Biophys 477:183–195 therapy in the newborn: some words of caution. Pediatr
Frank L (1991) Developmental aspects of experimental Res 50:681–687
pulmonary oxygen toxicity. Free Radic Biol Med Kalogeris T, Bao Y, Korthuis RJ (2014) Mitochondrial
11:463–494. 52 reactive oxygen species: a double edge sword in ische-
Frank L, Sosenko IRS (1987) Prenatal development of mia/reperfusion vs preconditioning. Redox Biol
lung antioxidant enzymes in four species. J Pediatr 2:702–714
110:106–110 Kaludercic N, Deshwal S, Dilisa F (2014) Reactive oxygen
Friel JK, Martin SM, Langdon M et al (2002) Milk from species and compartmentalization. Front Physiol
mothers of both premature and full-term infants pro- 5:1–15
vides better antioxidant protection than does infant Koenig JM, Yoder MC (2004) Neonatal neutrophils: the
formula. Pediatr Res 51:612–618 good, the bad and the ugly. Clin Perinatol 31:39–51
Friel JK, Friesen RW, Harding SV, Roberts LJ (2004) Kohlhaas M, Maack C (2013) Calcium release micro-
Evidence of oxidative stress in full-term healthy domains and mitochondria. Cardiovasc Res
infants. Pediatr Res 56:878–882 98:259–268
Gitto E, Karbownik M, Reiter RJ et al (2001) Effects of Kotecha S, Chan B, Azam N et al (1995) Increase in
melatonin treatment in septic newborns. Pediatr Res interleukin-8 and soluble intercellular adhesion mole-
50:756–760 cule-1 in bronchoalveolar lavage fluid from premature
30 Oxygen Toxicity in Newborns 455
infants who develop chronic lung disease. Arch Dis Njålsson R, Norgren S (2005) Physiological and patholog-
Child 72:F90–F96 ical aspects of GSH metabolism. Acta Paediatr
de La Torre A, Lee YY, Oger C, Sangild PT, Durand T, 94:132–137
Lee JC, Galano JM (2014) Synthesis, discovery, and Patz A, Hoeck I, de la Cruz E (1952) Studies on the effect
quantitation of dihomo-isofurans: biomarkers for in of high oxygen administration in retrolental fibroplasia.
vivo adrenic acid peroxidation. Angew Chem Int Ed Am J Ophthalmol 35:1248–1253
Engl 53:6249–6252 Pereira RD, De Long NE, Wang R et al (2015) Angiogen-
Lambeth JD, Neish AS (2014) Nox enzymes and new esis in the placenta: the role of reactive oxygen species
thinking on reactive oxygen: a double-edged sword signaling. Biomed Res Int 2015:814543
revised. Annu Rev Pathol 9:119–145 Perrone S, Tatarrano ML, Negro S, Longini M et al (2010)
Langie Sabine AS, Pawel K, Barbara T et al (2010) The Early identification of the risk for free radical-related
effect of oxidative stress on nucleotide-excision diseases in preterm newborns. Early Hum Dev
repair in colon tissue of newborn piglets. Mutat Res 86:241–244
695(1–2):75–80 Perrone S, Tei M, Longini M, Santacroce A, Turrisi G,
Ledo A, Arduini A, Asensi MA et al (2009) Human milk Proietti F, Felici C, Picardi A, Bazzini F, Vasarri P,
enhances antioxidant defenses against hydroxyl radical Buonocore G (2014) Lipid and protein oxidation in
aggression in preterm infants. Am J Clin Nutr newborn infants after lutein administration. Oxidative
89:210–215 Med Cell Longev 2014:781454
Li JM, Shah AM (2004) Endothelial cell superoxide gen- Perrone S, Tei M, Longini M, Buonocore G (2016) The
eration: regulation and relevance for cardiovascular multiple facets of lutein: a call for further investigation
pathophysiology. Am J Physiol Integr Comp Phys in the perinatal period. Oxidative Med Cell Longev
287:R1014–R1030 2016:5381540
Lindeman JHN, Lentjes EG, van Zoeren-Grobben D et al Pitkanen OM, Luukkainen P, Andersson S (2004) Attenu-
(2000) Postnatal changes in plasma ceruloplasmin and ated lipid peroxidation in preterm infants during subse-
transferrin antioxidant activities in preterm babies. Biol quent doses of intravenous lipids. Biol Neonate
Neonate 78:73–76 85:184–187
Lismont C, Nordorem M, Van Veldohoven PP, Fransen M Poets C, Arand J, Hummler H et al (2003) Retinopathy
(2015) Redox interplay between mitochondria ad per- of prematurity: a comparison between two centers
oxisomes. Front Cell Dev Biol 3:1–19 aiming for different pulse oximetry saturation levels.
Longini M, Perrone S, Kenanidis A et al (2005) Iso- Biol Neonate 84:A267
prostanes in amniotic fluid: a predictive marker for Poggi C, Dani C (2014) Antioxidant strategy and respira-
fetal growth restriction in pregnancy. Free Radic Biol tory disease of the preterm newborn: an update. Oxida-
Med 38:1537–1541 tive Med Cell Longev 2014:1–10
Lubec G, Widness JA, Hayde M et al (1997) Hydroxyl Richter J, Toelen J, Nagatomo T, Jimenez J, Vanoirbeek J,
radical generation in oxygen-treated infants. Pediatrics Deprest J (2016) Transplacental administration of
100:700–704 rosiglitazone attenuates hyperoxic lung injury in a pre-
Marseglia L, D'Angelo G, Manti S et al (2014) Oxidative term rabbit model. Fetal Diagn Ther 39(4):297–305
mediated aging during the fetal and perinatal period. Rogers S, Witz G, Anwar M et al (2000) Antioxidant
Oxidative Med Cell Longev 2014:1–8 capacity and oxygen radical diseases in the preterm
Martín JA, Pereda J, Martínez-López I et al (2007) Oxida- newborn. Arch Pediatr Adolesc Med 154:544–548
tive stress as a signal to up-regulate gamma- Saugstad OD (2005) Oxidative stress in the newborn – a
cystathionase in the fetal to neonatal transition in 30-year perspective. Biol Neonate 88:228–236
rats. Cell Mol Biol (Noisy-le-Grand) 53(Suppl): Schulze A, White K, Way RC et al (1995) Effect of the
OL1010–OL1017 arterial oxygenation level on cardiac output, oxygen
Marzocchi B, Perrone S, Paffetti P et al (2005) Non protein extraction, and oxygen consumption in low birth
bound and plasma protein oxidant stress at birth. weight infants receiving mechanical ventilation.
Pediatr Res 58:1–5 J Pediatr 126:777–784
Menshicova F, Tkachev V, Zencov N (2010) Redox-depen- Sejersted Y, Aasland AL, Bjørås M, Eide L, Saugstad OD
dent signaling system Nrf2/ARE in inflammation. Mol (2009) Accumulation of 8-oxoguanine in liver DNA
Biol 44(343):57 during hyperoxic resuscitation of newborn mice.
Mikami T, Kita K, Tomita S et al (2000) Is allantoin in Pediatr Res 66:533–538
serum and urine a useful indicator of exercise-induced Semenza GL, Prabhakar NR (2012) The role of hypoxia-
oxidative stress in humans? Free Radic Res inducible factors in oxygen sensing by the carotid body.
32:235–244 Adv Exp Med Biol 758:1–5
Milne GL, Yin H, Hardy KD, Davies SS, Roberts LJ II Sies H (1991) Role of reactive oxygen species in biological
(2011) Isoprostane generation and function. Chem Rev processes. Klin Wochenschr 69:965–968
111:5973–5996 Signorini C, Perrone S, Sgherri C (2008) Plasma esterified
Murphy MP (2009) How mitochondria produce reactive F2-Isoprostanes and oxidative stress in newborns: role
oxygen species. Biochem J 417:1–13 of non protein bound iron. Pediatr Res 63:287–291
456 R. Bracci et al.
Silvers KM, Sluis KB, Darlow BA et al (2001) Limiting Ullrich V, Bachscmid M (2000) Superoxide as a messen-
light-induced lipid peroxidation and vitamin loss in ger of endothelial function. Biochem Biophys Res
infant parenteral nutrition by adding multivitamin prep- Commun 278:1–8
arations to Intralipid. Acta Pediatr 90:242–249 Vento M (2014) Oxygen supplementation in the neonatal
Smith JL (1899) The pathological effects due to increase of period: changing the paradigm. Neonatology 105(4):
oxygen tension in the air breathed. J Physiol 24:19–35 323–331
Smith CV, Hansen TN, Martin NE et al (1993) Oxidant Vento M, Asensi M, Sastre J et al (2002) Hyperoxemia
stress responses in premature infants during exposure caused by resuscitation with pure oxygen may alter
to hyperoxia. Pediatr Res 34:360–365 intracellular redox status by increasing oxidized gluta-
Sola A, Golombek SG, Montes Bueno MT et al (2014) Safe thione in asphyxiated newly born infants. Semin Peri-
oxygen saturation targeting and monitoring in preterm natol 26:406–410
infants: can we avoid hypoxia and hyperoxia? Acta Vento M, Aguar M, Escobar J et al (2009a) Antenatal
Paediatr 103:1009. ISSN 0803-5253 steroids and antioxidant enzyme activity in preterm
Solberg R, Andresen JH, Escrig R et al (2007) Resuscita- infants: influence of gender and timing. Antioxid
tion of hypoxic newborn piglets with oxygen induces a Redox Signal 11:2945–2955
dose dependent increase in markers of oxidative stress. Vento M, Moro M, Escrig R et al (2009b) Preterm resusci-
Pediatr Res 62:559–563 tation with low oxygen causes less oxidative stress,
Solberg R, Longini M, Proietti F, Vezzosi P, Saugstad OD, inflammation, and chronic lung disease. Pediatrics
Buonocore G (2012) Resuscitation with supplementary 124:439–449
oxygen induces oxidative injury in the cerebral cortex. Viña J, Vento M, Garcia-Sala F et al (1995) L-cysteine and
Free Radic Biol Med 53:1061–1067 glutathione metabolism are impaired in premature
Song WL, Lawson JA, Reilly D, Rokach J, Chang CT, infants due to a cystathionase deficiency. Am J Clin
Giasson B, GA FG (2008) Neurofurans, novel indices Nutr 61:1067–1069
of oxidant stress derived from docosahexaenoic acid. Wolkoff LI, Narula P (2000) Issue in neonatal and pedi-
J Biol Chem 283:6–16 atric oxygen therapy. Respir Care Clin N Am 6:
Sun SC (2002) Relation of target SpO2 levels and clinical 675–691
outcome in ELBW infants on supplemental oxygen. Yeung MY (2006) Influence of early postnatal nutritional
Pediatr Res 51:A350 management on oxidative stress and antioxidant
Tan DX, Chen LD, Poeggeler B et al (1993) Melatonin: a defence in extreme prematurity. Acta Paediatr
potent, endogenous hydroxyl radical scavenger. Endocr 95:153–163
J 1:57–66 Yuan G, Peng YJ, Reddy VD et al (2013) Mutual
Tataranno ML, Perrone S, Buonocore G (2015) Plasma antagonism between hypoxia-inducible factors 1á
biomarkers of oxidative stress in neonatal brain injury. and 2 á regulates oxygen sensing and cardiorespi-
Clin Perinatol 42(3):529–539 ratory homeostasis. Proc Natl Acad Sci 110:
Tiina MA, Kari OR, Mika S, Vuokko LK (1998) Expres- E1788–E1796
sion and development profile of antioxidant enzymes in Zapata J, Gomez JJ, Araque Campo R, Matiz Rubio A,
human lung and liver. Am J Respir Cell Mol Biol Sola A (2014) A randomised controlled trial of
19:942–949 an automated oxygen delivery algorithm for pre-
Tin W, Gupta S (2007) Optimum oxygen therapy in pre- term neonates receiving supplemental oxygen
term babies. Arch Dis Child Fetal Neonatal Ed 92: without mechanical ventilation. Acta Paediatr
F143–F147 103:928
Torday JS, Rehan VK (2016) On the evolution of Zorov DB, Juhaazova M, Sollott SJ (2014) Mitochondrial
the pulmonary alveolar lipofibroblast. Exp Cell Res reactive oxygen species (ROS) and ROS-induced ROS
340(2):215–219 release. Physiol Rev 94:909950
Physical Examination of the Newborn
31
Alessandra Coscia, Paola Di Nicola, Enrico Bertino, and
Claudio Fabris
Contents
31.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458
31.2 Why Should Routine Physical Examination Be Performed? . . . . . . . . . . . . 458
31.3 Who Should Perform Physical Examination? . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458
31.4 When Physical Examination Should Be Performed? . . . . . . . . . . . . . . . . . . . . 459
31.5 Where to Perform Physical Examination? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459
31.6 Full Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459
31.7 In Which Order Examination Should Be Performed? . . . . . . . . . . . . . . . . . . . 459
31.8 What Should Be Examined? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460
31.8.1 General Observation and Measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460
31.8.2 Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460
31.8.3 Head and Face . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
31.8.4 Ears . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
31.8.5 Nose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
31.8.6 Eyes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
31.8.7 Mouth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
31.8.8 Neck . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
31.8.9 Examination of Chest and Auscultation of the Heart and Lungs . . . . . . . . . . . . 464
31.8.10 Abdomen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
31.8.11 Genitalia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
31.8.12 Spine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
31.8.13 Limbs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
31.8.14 Hips . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
31.8.15 Neurological Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
31.8.16 Assessment of Gestational Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
A. Coscia (*) · P. Di Nicola · E. Bertino · C. Fabris
Neonatal Unit, University of Turin, Turin, Italy
e-mail: [email protected];
[email protected]; [email protected];
[email protected]
# Springer International Publishing AG, part of Springer Nature 2018 457
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_181
458 A. Coscia et al.
Abstract although there is not international standard, routine
A complete physical examination of every examination is regarded as a good practice in the
newborn should be performed within 24 h guidelines for postnatal care (Royal College of
from birth: although there is not international Anaesthetists et al. 2007; Demott et al. 2006;
standard, routine examination is regarded as a Royal College of Obstetricians and Gynaecologists
good practice in the guidelines for postnatal care. 2016).
Aims of the routine neonatal examination are On this purpose, some questions are needed to
to detect problems arising from maternal or be answered.
familiar diseases; to confirm or not some condi-
tions suspected during antenatal period; to detect
any acute condition requiring urgent diagnosis 31.2 Why Should Routine Physical
and therapy; to diagnose congenital problems not Examination Be Performed?
already identified at birth; to screen some specific
conditions, such as developmental dysplasia of Aims of the routine neonatal examination are:
the hip and congenital cataract; and to provide
initial health and educational advice for the new- 1. To detect problems arising from maternal or
born. In any case, routine examination may be an familiar diseases or from complications of
opportunity for the healthcare provider to discuss labour and delivery
with the parents any questions or worries about 2. To confirm or not some conditions suspected
their baby, to reassure them and to give them during antenatal period (e.g., congenital
appropriate advice. malformations) and to provide information
about management
3. To detect any acute condition requiring urgent
diagnosis and therapy
31.1 Salient Points 4. To diagnose congenital problems not already
identified at birth (e.g., congenital heart dis-
• The initial examination of the newborn is an ease, developmental dysplasia of the hip)
important opportunity to detect congenital 5. To screen some specific conditions, such as
anomalies and assess the infants’ transition developmental dysplasia of the hip and con-
from fetal to extra-uterine life. genital cataract
• Risk factors such as pre- and post-term birth, 6. To provide initial health and educational
small for gestational age and large for gesta- advice for the newborn (e.g., breastfeeding,
tional age, all have associated clinical medical SIDS prevention, late HDN prevention, safe
challenges of which providers should be transport in cars, vaccination)
aware.
• Although a rapid check of the newborn takes In any case, routine examination may be an
place immediately after birth, every newborn opportunity for the healthcare provider to discuss
should have at least one complete examination with the parents any questions or worries about
before discharge, usually within 24 h of life. their baby, to reassure them and to give them
• It would be better first to perform a general appropriate advice.
“gestalt,” whole inspection, and then continue
with a systematic physical examination. The
healthcare provider must make sure he has 31.3 Who Should Perform Physical
not omitted any item, and he must record all Examination?
the findings.
A complete physical examination of the newborn
A complete physical examination of every newborn should be performed by a trained healthcare
should be performed within 24 h from birth: provider, usually by a neonatologist. However
31 Physical Examination of the Newborn 459
in some countries (e.g., UK), other professionals necessary to get information about problems dur-
have recently begun to look after the baby’s ing labor and delivery, as well as about baby’s
examination, such as neonatal nurse practitioners gender, birthweight, and gestational age. All
or experienced midwives, and the satisfaction these items should be collected in the infant’s
level of mothers is usually very high (Wolke medical record.
et al. 2002). The newborn can be properly examined only
without clothes except the nappy.
31.4 When Physical Examination
Should Be Performed? 31.7 In Which Order Examination
Should Be Performed?
Although a rapid check of the newborn
takes place immediately after birth, every new- There is not any strict rule regarding the order of
born should have at least one complete exami- the examination, but some tips can be given. It
nation before discharge, usually within 24 h would be better first to perform a general
of life. “gestalt,” whole inspection, and then continue
with a systematic review (e.g., from head to
foot), as well as take advantage of any period
of quiet or sleeping to check the anterior fonta-
31.5 Where to Perform Physical nelle, to examine the eyes, and to perform the
Examination? auscultation of the heart and the lungs and the
palpation of the abdomen. It is better to leave the
The first quick examination should be performed examination of the hips at the end, because the
immediately after birth, in the delivery room. This Ortolani-Barlow test is unpleasant for the
first step, mainly based on inspection, should newborn.
check that the infant looks well and there are no Regardless the order of examination, the
pathological conditions requiring information to healthcare provider must make sure he has
the parents (e.g., congenital malformations or any not omitted any item, and he must record all
doubt about the baby’s gender) or immediate man- the findings. A suggested sequence is given
agement (e.g., respiratory distress). below:
Complete routine examination should be
performed in presence of the mother or both par- 1. General observation, including posture, tone,
ents, in a quiet warm room, with adequate and movements
lighting. 2. Measurement of head circumference, length,
and recording them, together with the weight
3. Skin (color and characteristics)
31.6 Full Examination 4. Head (facial appearance, fontanelle)
5. Examination and auscultation of heart and
Before introducing himself to the mother, the lungs
healthcare provider must check basic information 6. Femoral pulses
regarding maternal (e.g., maternal age, socio- 7. Palpation of abdomen
economical status, smoking, drug or alcohol 8. Eyes, ears, nose, and mouth
abuse, any chronic disease) and family history, 9. Neck, including the clavicles
previous obstetric history. It is very important to 10. Arms, hands, legs, and feet
inquire if there were any complications in current 11. Genitalia and anus
pregnancy and to know the results of pregnancy 12. Evaluation of nervous system
screening tests and diagnostic procedures (e.g., 13. Hips
ultrasound examinations, amniocentesis). It is 14. Prone position: back and spine
460 A. Coscia et al.
31.8 What Should Be Examined? 31.8.2 Skin
Many conditions that can be observed during The skin of a healthy newborn should be reddish
the examination are very common, and they pink, but peripheral cyanosis (hands, feet, and
have little clinical importance or usually resolve circumoral area) is a common finding during the
spontaneously. On the other hand, there are some first 48 h, as well as traumatic cyanosis, often asso-
conditions, less frequent, that require further ciated with petechiae, affecting presenting part.
investigation or urgent therapy. Some conditions may be present:
– Central cyanosis. It is best observed on the
31.8.1 General Observation tongue and it requires urgent investigation for
and Measurements pulmonary disease or congenital heart
malformations. Plethoric newborns can appear
General observation includes weight, length, and cyanotic because they have more than 5 g per
head circumference measurements. These vari- 100 ml of reduced hemoglobin.
ables must be evaluated using standardized instru- – Pallor. When generalized it can be associated
ments and following the techniques required for with anemia or shock.
accurate measurements as described by Cameron – Jaundice. Jaundice appearing within the first
(Cameron 2004). 24 h of life most indicates hemolysis and
Values obtained should be plotted on appropri- requires further investigation and treatment.
ate neonatal anthropometric charts such as the – Capillary hemangioma (stork bites). These
new international standards (Intergrowth-21st pink macules appear on the upper eyelids, the
project) (Villar et al. 2014). mid forehead, and the nape of the neck: those
If there is any doubt regarding gestational age, on the forehead and eyelids disappear or fade
it should be determined by a scoring scheme over the first year, whereas those on the neck
(Dubowitz and Dubowitz 1981; Ballard et al. are covered with hair (Fig. 2).
1991) (Fig. 1). – Neonatal urticaria (erythema toxicum neo-
Simple observation allows to notice short arms natorum). White papules appear on an ery-
and legs that can indicate the presence of skeletal thematous skin, usually on the second or third
dysplasia. day of life, and migrate to different sites.
Healthy term babies spend most time in – Milia. Retention of keratin and sebum may
quiet or active sleep, but transition between cause these benign white cysts distributed on
behavioral states can be rapid: crying is a the nose and cheeks.
usual finding during the examination (Brazelton – Mongolian blue spots. They are blue-black
1973). Healthy full-term infant usually lies in maculae, more frequent in African-American
flexion position (flexion of the arms at the or Asian babies, located at the base of the spine
elbows and of the legs at the knees), with a or on the buttocks and in some cases also on the
relatively symmetric limb position and postur- legs or in other parts. They fade slowly over the
ing: however, the presentation at birth can first few years of life (Fig. 3).
influence posture in the first days of life. Asym- – Harlequin color change. This is a vasomotor
metric tonic neck reflex can be noted if the instability which causes a longitudinal redden-
head is turned to one side: in this case, there ing down one half of the body and a blanching
is extension of the ipsilateral arm and leg and down the other side.
flexion of the contralateral extremities. Infants – Edema. It may be generalized or localized: if
manifest spontaneous motor activity that con- present, it is always pathologic in the newborn.
sists in moving their limbs in an alternating Pedal edema may be a sign of Turner syndrome
fashion (Swaiman 1999). (Fig. 4).
31 Physical Examination of the Newborn 461
Neuromuscular Maturity
Score −1 0 1 2 3 4 5
Posture
Square
window
(wrist) > 90° 90° 60° 45° 30° 0°
Arm
recoil
180° 140 –180° 110–140° 80–110° < 90°
Popliteal
angle
180° 160° 140° 120° 100° 90° < 90°
Scarf
sign
Heel
to ear
Physical Maturity
Sticky, Gelatinous, Superficial Cracking, Parchment, Leathery,
Smooth, pink; peeling deep
Skin friable, red, pale areas; cracked,
visible veins and/or rash; cracking;
transparent translucent few veins rare veins no vessels wrinkled
Lanugo None Sparse Abundant Thinning Bald areas Mostly bald Maturity
Rating
Heel-toe Anterior Score Weeks
Plantar 40–50 mm: > 50 mm, Faint Creases Creases over
surface –1 no crease red marks
transverse anterior 2/3 entire sole −10 20
< 40 mm: –2 crease only
−5 22
Stippled Raised 0 24
Barely Flat areola, Full areola,
Breast Imperceptible areola, areola, 5 26
perceptible no bud 5–10 mm bud
1–2 mm bud 3–4 mm bud
10 28
Lids fused Lids open; Slightly Well curved Formed and Thick
curved pinna; pinna; firm, 15 30
Eye/Ear loosely: –1 pinna flat; cartilage,
soft; soft but instant 20 32
tightly: –2 stays folded slow recoil ready recoil recoil ear stiff
25 34
Scrotum Testes in Testes Testes
Genitals Scrotum flat, Testes down, 30 36
empty, upper canal, desoending, pendulous,
(male) smooth good rugae 35 38
faint rugae rare rugae few rugae deep rugae
Clitoris Clitoris Majora and 40 40
Clitoris Majora cover
Genitals prominent, prominent, minora Majora large, 45 42
prominent, small enlarging equally minora small citoris and
(female) minora
labia flat labia minora minora prominent 50 44
Fig. 1 Assessment of gestational age by revised Ballard method (From Ballard et al. 1991)
– Port-wine stain (nevus flammeus). They are a When port-wine stain affects distribution
vascular malformation of the capillaries in the of the trigeminal nerve, it may suggest under-
dermis, and they are usually evident at birth, lying intracranial vascular malformations
whereas strawberry nevi (cavernous heman- (Sturge-Weber syndrome), whereas large
gioma) appear only after 1 or 2 months of life. lesions on the limbs may be associated with
462 A. Coscia et al.
Fig. 2 Capillary haemangioma (stork bites)
Fig. 4 Pedal oedema in Turner syndrome
Fig. 3 Mongolian blue spots
bone hypertrophy (Klippel-Trénaunay
syndrome).
Fig. 5 Caput succedaneum
31.8.3 Head and Face
– Caput succedaneum, edema and bruising of
Head dimensions and shape should be evaluated, the presented part, that extends beyond the
and fontanelle and sutures should be palpated. sutures (Fig. 5)
The head can be considerably molded during – Cephalhematoma, collection of blood
labor and delivery. Babies in the breech presenta- between the periosteum and the skull bone,
tion in utero often have the so-called breech head that does not extend beyond the sutures and
(prominent occipital shelf). usually affects parietal bone
There may be some transient phenomena:
– Bruising and abrasions from the use of for- Anterior fontanelle can measure up to 3 3 cm,
ceps, vacuum extractor, or scalp electrodes but its dimension can be variable: its tension
31 Physical Examination of the Newborn 463
(when the baby is not crying) may indicate raised Flaring of the alae nasi is always abnormal and
intracranial pressure, from cerebral edema, intra- indicates the presence of respiratory distress that
cranial hemorrhage, hydrocephalus, or meningitis. requires further investigation.
After delivery, the coronal sutures are
often overriding, but ridging at the suture
lines implies premature fusion of the sutures 31.8.6 Eyes
(craniosynostosis).
Asymmetrie is a frequent finding due to pres- The eyes should be examined both by inspection
sure in utero and during labor and delivery. and with an ophthalmoscope. If the lens is opaque
Palpation of the skull bones can evidence areas from a congenital cataract or glaucoma, the red
of craniotabes, caused by pressure in utero from reflex cannot be elicited: any abnormality of the
maternal pelvis, that occur in 2% of normal full- red reflex requires urgent evaluation by an ophthal-
term newborns and more frequently in the mologist. Congenital cataract is the commonest
preterm baby. form of preventable childhood blindness.
Cutis aplasia (small defect of the scalp) is a Swelling of the eyelids is common; a mucoid
congenital malformation with risk of bleeding or discharge (“sticky eye”) is often present in the first
infection of dural venous sinuses, and it may be a 2 days of life and usually resolves spontaneously.
clue to the presence of a syndrome. A purulent discharge, accompanied by redness
Most newborns resemble one or other parent, and swelling of the eyelids, requires microbiolog-
but when the face appears unusual, the examiner ical investigation and treatment.
should search for other dysmorphic manifesta- Subconjunctival hemorrhages are very com-
tions, to exclude a syndrome. mon due to delivery and usually resolve within
1 to 2 weeks.
The iris is normally blue or gray in the new-
31.8.4 Ears born. Partial defect is called “colobomata,” and it
could be associated with a defect in the retina;
General shape, size, and position have to be evalu- complete absence is called “aniridia,” and it is
ated. Malformations can be associated with hearing associated with an increased risk of Wilms tumor.
loss and require hearing check. Preauricular pits, Size of the cornea has to be checked: if the
skin tags anterior to the ear, and accessory auricles corneal diameter is greater than 13 mm, there
may be associated with an increased risk of renal might be a congenital glaucoma.
abnormalities (Kugelman et al. 1997, 2002).
Low-set ears (when the top of the pinna falls
below a line drawn from the outer canthus of the 31.8.7 Mouth
eye at right angles to the face) are a characteristic
of several syndromes. Direct inspection of the inside of the mouth is
important, in order to exclude cleft palate, even
mild defects (submucous cleft or posterior cleft
31.8.5 Nose palate).
Other harmless findings may be seen, includ-
Newborns have to breathe through the nose, so ing Epstein pearls (small white pearls of micro-
complete nasal obstruction (i.e., from choanal keratosis along the midline of the palate), mucus-
atresia) causes intense respiratory distress and retentioncysts of the gums (epulis) or on the floor
requires prompt investigation and treatment. If of the mouth (ranula), and short frenulum
there is any doubt, a fine catheter should be passed (“tongue tie”). These conditions usually do not
through each nostril to ensure that both nares are need treatment. Natal teeth (rare in Caucasian
patent. race) are best removed.
464 A. Coscia et al.
31.8.8 Neck Peripheral pulses, in particular femoral pulses,
should be always palpated: patent ductus
The newborn has a relatively short neck, but a very arteriosus produces a bounding pulse, whereas
short neck may indicate abnormalities of the cervi- absence or difficulty to feel femoral pulses sug-
cal spine (Klippel-Feil syndrome). A webbed neck gests coarctation. If coarctation is suspected, it can
is one of the characteristics of Turner syndrome, be confirmed by comparing blood pressure in the
and posterior redundant skin may suggest Down’s arms and legs: a difference of 20 mmHg or more
syndrome. Palpation of sternomastoid muscle can suggests coarctation.
evidence “tumors,” caused by bleeding or ische- A heart murmur may be heard, but most are
mia, sometimes resulting in fibrosis. innocent: 60% of normal newborns have a systolic
Clavicle fractures may occur during delivery murmur at 2 h of life: the origin of an innocent
with shoulder dystocia: it is possible to palpate a murmur may be the acute angle at the pulmonary
lump on the clavicle that results from a callus artery bifurcation, or patent ductus arteriosus, or
around the fracture and usually recovers without tricuspid regurgitation (Ainsworth et al. 1999).
treatment. Features that suggest a significant murmur are
the following (McCrindle et al. 1996):
31.8.9 Examination of Chest – Pansystolic
and Auscultation of the Heart – 3/6
and Lungs – Harsh quality
– Best heard in the upper left sternal border
A certain degree of breast enlargement is normal – Abnormal second heart sound
in newborns of either sex, and a few drops of milk – Difficulty to feel femoral pulses
(“witch’s milk”) may be discharged.
Neonatal routine examination detects only a ECG or chest XR rarely changes clinical
half of the infants with congenital heart disease diagnosis (Smythe et al. 1990). Due to the avail-
(CHD), even if the baby has significant structural ability of the ultrasound evaluation, this evalu-
heart lesion. At birth, the pressure difference ation, with an expert consultation, should be
between left and right side may be still low and performed in any infant with a suspected signif-
then newborns with ventricular septal defects icant murmur.
might not have a heart murmur. Abnormal findings upon physical examination
Moreover, ductus-dependent lesions can pre- in the newborn nursery that are consistent with a
sent symptoms only a few days after birth, and differential diagnosis of congenital heart disease
femoral pulses are often palpable at first examina- (CHD), including the presence of murmurs,
tion (Wren et al. 1999; Farrer and Rennie 2003). tachypnea, and overt cyanosis, are not always
Cardiorespiratory state can be deducted by present prior to discharge from the hospital
simple inspection (respiratory rate and signs of (Mahle et al. 2009).
respiratory distress, such as retractions or Physical examination alone has an approxi-
grunting). If cyanosis is present, pulse oximetry mated 50% sensitivity for CHD (Goldstein 2013).
should be performed. Riede et al. (2010) found that in screening for
Normal respiratory rate is 40–60 breaths/min: CHD, pulse oximetry had a sensitivity and speci-
if a baby has a rate persistently above 55/min, he ficity of 77.78% and 99.90%, respectively. Pulse
needs to be carefully evaluated. In a full-term oximetry is found to be very effective in early
newborn, there should be no grunting, no retrac- identification of CHD in which hypoxemia is char-
tions, and no flaring of the alae nasi: if present, acteristic, such as hypoplastic left heart syndrome,
they are symptoms of respiratory distress. pulmonary atresia with an intact septum, tetralogy
Palpation of the precordium may detect thrills of Fallot, total anomalous pulmonary venous
or a pronounced ventricular heave. return, transposition of the great arteries, tricuspid
31 Physical Examination of the Newborn 465
atresia, and truncus arteriosus (Mahle et al. 2009;
Centers for Disease Control and Prevention (CDC)
2013c). It is not as effective in the early identifica-
tion of CHD that may present without hypoxemia,
such as aortic arch atresia or hypoplasia, coarcta-
tion of the aorta, interrupted aortic arch, double-
outlet right ventricle, Ebstein anomaly, pulmonary
stenosis, atrioventricular septal defect, and ventric-
ular septal defect: these are considered secondary
targets of pulse oximetry CHD screening in new-
borns (Mahle et al. 2009; Centers for Disease Con-
trol and Prevention (CDC) 2013c).
Given this, there is no consensus about the use
of pulse oximetry as routine clinical practice.
Fig. 6 Diastasis of the recti muscles
31.8.10 Abdomen normal organ is buried in sovrapubic fat. An
abnormal position of urethral meatus indicates a
Simple observation may reveal any anomaly. Umbi- hypospadia (glandular, coronal, mid-shaft, or per-
licus is a common source of infection, so any dis- ineal): ventral curvature reveals the presence of a
charge or redding of the skin requires attention. chordee. Glandular hypospadia without chordee
A single umbilical artery occurs in 0.3% of does not require any treatment.
newborns, and it is associated with an increased In a full-term baby, testes should be palpable,
risk of congenital malformations, in particular but about 6% of newborns have one testis unde-
renal abnormalities. Ultrasound of renal tract is scended at birth: if at 3 months of age the testis is
probably only reserved for babies who have other still undescended, a pediatric surgeon or urologist
problems, other than single umbilical artery should be consulted.
(Thummala et al. 1998). Neonatal testicular torsion usually occurs
An umbilical hernia is a common finding, before birth: neonatologists should consult a pedi-
especially in African-American babies. atric surgeon, although the testis has usually already
A diastasis of the recti is frequently appreciated undergone infarction (Driver and Losty 1998).
by palpation; the liver edge is usually palpable
1 to 2 cm below the right costal margin (Fig. 6). 31.8.11.2 Female
Also the spleen tip and the kidney are palpable: it At full term, the labia majora cover the labia
is important to detect abnormal renal mass or minora; in preterm baby the clitoris and the labia
enlargement of the bladder that may be a sign of minora appear prominent. There is often a white or
urinary outflow obstruction in a male infant. bloodstained discharge, due to maternal hormone
withdrawal. Small hymenal skin tags, mucoid
cysts, or a ring of vaginal mucosa are common.
31.8.11 Genitalia The position and the tone of the anus must be
checked, and passage of meconium should be
31.8.11.1 Male recorded.
Hydroceles occur very frequently in neonatal
period and usually resolve spontaneously. Ingui-
nal herniae are common, in particular in preterm 31.8.12 Spine
babies. The penis should be checked for length
(usually about 3 cm) and position of urethral Swelling, dimple, hairy patch, or nevus along the
meatus. Sometimes penis looks short, but a spine or over the base of the skull might indicate
466 A. Coscia et al.
underlying vertebral, spinal cord, or brain anom- history, oligohydramnios, any abnormality of the
alies. Simple sacrococcygeal pits are common and lower limb, and any other anomaly suggesting
harmless; simple dimples (less than 2.5 cm from intrauterine compression (i.e., torticollis) (Chan
the anus, less than 5 mm wide, without other et al. 1997).
cutaneous signs) do not indicate occult Clinical screening of DDH (the Ortolani’s and
dysraphism (Gibson et al. 1995; Kriss and Desai Barlow’s tests) has not reduced the number of
1998; Medina et al. 2001). babies requiring surgery (0.7 per 100 live births)
(Godward and Dezateux 1998): moreover, most
infants with abnormal neonatal examination have
31.8.13 Limbs normal hips. Clinical examination by an unex-
perienced examiner is only little better than no
Extremities are examined to inspect shape, pos- screen (Dezateux et al. 2003).
ture, symmetry and size. About 45% of individ- There is another screening strategy, that is,
uals with Down’s syndrome have single ultrasound screening, that can also detect clini-
transverse palmar creases, but the same finding cally stable but anatomically abnormal hips:
may occur in 4% of the Caucasian and in 16.8% of unfortunately universal ultrasound screening is
the Chinese population. Polydactyly is often a expensive and produces a high false-positive rate.
familial trait, but it may be caused by a dysmor- There is not any universal agreement con-
phic syndrome. cerning the best way of DDH screening. Many
Digital remnants should be removed clinicians suggest that clinical neonatal examina-
surgically. tion is the best strategy, if performed by properly
Observation of spontaneous arm movements trained examiners and followed by selective ultra-
and testing passive movements allows to suspect sound, based on risk factors (American Academy
a fracture or a brachial plexus lesion. Lack of of Pediatrics 2000).
active movement and pain on passive movements In the Ortolani-Barlow maneuvers, the baby
indicates a fracture or an infection. In a brachial lies supine, with the legs relaxed. For the
plexus lesion, there is initially a lack of movement Ortolani’s test, first the examiner should
in the arm. After 48 h, in an upper root palsy straighten out the legs and then flex the hips to a
(Erb’s palsy: C5, C6, and sometimes C7), the right angle: after placing the middle finger over
arm is internally rotated, without active abduction. the greater trochanter of each leg and the thumbs
In a complete palsy of upper and lower roots over the internal aspects of the thighs, the exam-
(Klumpke’s palsy: C5, C6, C7, C8, and T1), the iner slowly abducts and externally rotates the
arm is flail and there may be ptosis and Horner’s hips: a definite “clunk” indicates that a previous
syndrome; the hand may be clawed (Evans-Jones dislocated femoral head has slipped into the ace-
et al. 2003). Most brachial plexus lesions recover tabulum (Ortolani 1937). The next maneuver is
spontaneously: if recovery does not occur by the Barlow’s test that allows to dislocate an unsta-
3 months of age, the baby should be referred to a ble hip. Holding the hips and knees as in the
specialist (Pondaag et al. 2004; Malessy and Ortolani’s test, with the hips at about 70 abduc-
Pondaag 2009). tion, the examiner presses forward and medially
each hip in turn: if the hip is dislocated, the fem-
oral head slips into the acetabulum with a “clunk”
31.8.14 Hips (Barlow 1962).
The incidence of developmental dysplasia of the
hip (DDH) and instable hip is about 1–2 per 1000 31.8.15 Neurological Examination
births and 10 per 1000 births, respectively. The
risk of DDH is increased in some conditions: Formal testing is only required in newborns with
female sex, breech presentation, positive family neuromuscular problems. The evaluation should
31 Physical Examination of the Newborn 467
be performed with minimal discomfort to the power or strength, and it may occur together or not
infant, and the main goal is to exclude any suspi- with hypotonia. Hypotonia combined with weak-
cious neurological signs (Ballard et al. 1991). ness usually indicates an involvement of periph-
Neonatal neurological evaluation includes the eral nervous system, whereas hypotonia without
following tests: weakness indicates an involvement of central ner-
vous system (brain or spinal cord).
– General observation Rooting, sucking, grasp, and Moro responses
– Level of consciousness and behavioral states are the most important primitive or developmental
– Mechanical signs: head, spine, and limbs reflexes: they should disappear in the first months
– Motor system: muscle strength and tone and of life. When they persist, an underlying central
spontaneous movements nervous system dysfunction should be suspected.
– Reflexes (deep tendon reflexes and primitive Crossed extension, placing, and stepping reac-
reflexes, i.e., Moro, grasp, suck, root) tion are other primitive reflexes.
– Autonomic function (heart and respiratory rate, The main aim of the neurological evaluation in
bladder and bowel function) the routine examination is to exclude the presence
of suspicious neurological signs.
Motor system function can be assessed by test- The findings that require further evaluation are
ing skeletal muscle posture, tone, and movements. the following:
Full-term infants usually exhibit flexion of the
limbs. Muscular tone consists in an active or pas- – Persistent hypotonia and paucity of spontane-
sive resistance to stretch, and it results from a ous movements
complex interaction between agonistic and antag- – Abnormal posture: frog posture, opisthotonus,
onistic muscles: then any alteration in muscle tone excessive fisting, and fisted thumbs
could represent a sign of a variety of underlying – Asymmetric movements
neurological diseases. – Failure to suck
The assessment of muscle tone includes the – High-pitched cry
observation of posture and movement, the evalu- – Persistent and extreme irritability
ation of resistance to passive movements, and the – Convulsions
production of active or passive movement by spe- – Lesions over the spine
cific maneuvers, such as pull-to-sit maneuver and
ventral suspension. In the pull-to-sit maneuver, as
the infant is pulled up from the supine position by 31.8.16 Assessment of Gestational Age
his wrist, there should be some flexion of elbows
and slight flexion of the neck, with the head com- The most reliable guide for assigning gestational
ing up almost in line with the body. In the ventral age is an early antenatal ultrasound, combined
suspension, as the newborn is held in the air with with the mother’s last menstrual period: early
the examiner’s hand under the chest, flexed arms antenatal ultrasound estimation is accurate with a
and the head lie almost on a plane with the body margin of less than 7 days.
for a few seconds. Several methods can be used to assess gesta-
Increased resistance to passive movement may tional age: those based on physical criteria, those
indicate hypertonicity, often associated with an based on neurological development, and those
opisthotonic posture and obligate extension dur- that combine physical and neurological
ing ventral suspension. examination.
Babies with reduced resistance to passive Physical criteria progress in orderly fashion
movements and unrestricted movements usually with increasing gestational age and can be
tend to drape over the examiner’s hands in the assessed immediately after delivery. Neurological
horizontal plane: these findings indicate hypoto- criteria include the assessment of posture, passive
nia, whereas weakness is a reduction in muscle and active tone, reflexes, and righting reaction and
468 A. Coscia et al.
require the infant to be in an alert rested state, not Dezateux C, Brown J, Arthur R et al (2003) Performance,
so easy to obtain until the second day of life. treatment pathways, and effects of alternative policy
options for screening for developmental of the hip in
The most accurate method to assess gestational the United Kingdom. Arch Dis Child 88:753–759
age is to combine the physical criteria and the Driver CP, Losty PD (1998) Neonatal testicular torsion. Br
neurological assessment: Dubowitz and J Urol 82:855–858
Dubowitz scoring system involves 11 physical Dubowitz L, Dubowitz V (1981) The neurological assess-
ment of the preterm and full-term newborn infant. Clin
criteria and 10 neurological findings (Dubowitz Dev Med No 79. SIMP/Heinemann, London
and Dubowitz 1981), whereas simplified Ballard Evans-Jones G, Kay SPJ, Weindling AM et al (2003)
system includes 6 physical and 6 neurological Congenital brachial palsy: incidence, causes and out-
criteria to shorten the time taken (Fig. 1). The come in the UK and Republic of Ireland. Arch Dis
Child Fetal Neonatal Ed 88:F185–F189
new Ballard score is valid for extremely prema- Farrer KFM, Rennie JM (2003) Neonatal murmurs: are
ture infants (Ballard et al. 1991; Ballard and senior house officers good enough? Arch Dis Child
Novak 1979). Fetal Neonatal Ed 88:F147–F151
In any case, these methods are accurate only to Gibson P, Britton J, Hall DMB et al (1995) Lumbosacral
skin markers and identification of occult spinal
2 weeks, with an overestimation in extremely dysraphism in neonates. Acta Pediatr 84:208–209
premature infants. Godward S, Dezateux C (1998) Surgery for congenital
dislocation of the hip in the UK as a measure of out-
come of screening. Lancet 351:1149–1152
Goldstein M (2013) Critical complex congenital heart dis-
ease (CCHD). Congenital Cardiology Today 11(3):1–10
References Kriss VM, Desai NS (1998) Occult spinal dysraphism
in neonates: assessment of high risk cutaneous stigmata
Ainsworth SB, Wyllie JP, Wren C (1999) Prevalence and on sonography. AJR Am J Roentgenol 171:1687–1693
clinical significance of cardiac murmurs in neonates. Kugelman A, Hadab B, Ben-David J et al (1997) Pre-
Arch Dis Child Fetal Neonatal Ed 80:F43–F45 auricular tags and pits in the newborn: the role of
American Academy of Pediatrics (2000) Clinical practice hearing tests. Acta Paediatr 86:170–172
guideline: early detection of developmental dysplasia Kugelman A, Tubi A, Bader D et al (2002) Preauricular
of the hip. Pediatrics 105:896 tags and pits in the newborn: the role of renal ultraso-
Ballard JL, Novak KK, Driver MA (1979) A simplified nography. J Pediatr 141:388–391
score of fetal maturation of newly born infants. J Mahle WT, Newburger JW, Matherne GP et al (2009) Role
Pediatr 95:769–774 of pulse oximetry in examining newborns for congen-
Ballard JL, Khoury JC, Wedig K et al (1991) New Ballard ital heart disease: a scientific statement from the AHA
score, expanded to include extremely premature and AAP. Pediatrics 124(2):823–836
infants. J Pediatr 119:417–423 Malessy MJ, Pondaag W (2009) Obstetric brachial plexus
Barlow TG (1962) Early diagnosis and treatment of con- injuries. Neurosurg Clin N Am 20(1):1–14
genital dislocation of the hip. J Bone Joint Surg Br 44: McCrindle BW, Shaffer KM, Kan JS et al (1996) Cardinal
B292–B301 clinical signs in the differentiation of hearth murmurs in
Brazelton TB (1973) Neonatal behavioural assessment children. Arch Pediatr Adolesc Med 150:169–174
scale. Spastics International Medical, London Medina LS, Crone K, Kuntz KM (2001) Newborns with
Cameron N (2004) Measuring techniques and instruments. suspected occult spinal dysraphism: a cost effectiveness
In: Nicoletti I, Benso L, Gilli G (eds) Physiological and analysis of diagnostic strategies. Pediatrics 108:e101
pathological auxology. Firenze, Edizioni Centro Studi Ortolani M (1937) Un segno poco noto e sua importanza
Auxologici, pp 117–159 precoce di prelussazione congenita dell’anca. Pediatrica
Centers for Disease Control and Prevention (CDC) (2013c) (Napoli) 45:129–136
Screening for critical congenital heart defects: morbid- Pondaag W, Malessy MJA, Thomeer RTWM (2004)
ity and mortality weekly report (MMWR) podcasts. Natural history of obstetric brachial plexus palsy:
Retrieved 3 Mar 2013, from http://www.cdc.gov/ a systematic review. Dev Med Child Neurol
nvbddd/pediatricgenetics/pulse.html 46:138–144
Chan A, McCaul KA, Cundy PJ et al (1997) Perinatal risk Riede FT, Worner C, Dahnert I et al (2010) Effectiveness of
of factors for developmental dysplasia of the hip. Arch neonatal pulse oximetry screening for detection of crit-
Dis Child Fetal Neonatal Ed 76:F94–F100 ical congenital heart disease in daily clinical routine –
Demott K, Bick D, Norman R, et al (2006) Clinical guide- results from a prospective multicenter study. Eur J
lines and evidence review for post natal care: routine Pediatr 169(8):975–981
post natal care of recently delivered women and their Royal College of Anaesthetists, Royal College of Midwives,
babies last updated: February 2015 Royal College of Obstetricians and Gynaecologists,
31 Physical Examination of the Newborn 469
Royal College of Paediatrics and Child Health (2007) congenital malformations: a meta-analysis. J Pediatr
Safer childbirth- minimum standards for the organisation Surg 33:580–585
and delivery of care in labour. RCOG Press, London Villar J, Cheikh Ismail L, Victora CG et al (2014)
Royal College of Obstetricians and Gynaecologists (2016) International standards for newborn weight, length, and
Providing quality care for women a framework for head circumference by gestational age and sex: the new-
maternity service standards, London born cross-sectional study of the INTERGROWTH-21st
Smythe JF, Teixeira OH, Vlad P et al (1990) Initial evalu- project. Lancet 384(9946):857–868
ation of heart murmurs: are laboratory tests necessary? Wolke D, Dave S, Hayes J et al (2002) Routine examina-
Pediatrics 86:497–500 tion of the newborn and maternal satisfaction: a
Swaiman KF (1999) Neurologic examination of the term randomised controlled trial. Arch Dis Child Fetal Neo-
and preterm infant. In: Swaiman KF, Ashwal A (eds) natal Ed 86:F155–F160
Pediatric neurology: principles and practice, 3rd edn. Wren C, Richmond S, Donaldson L (1999) Presentation of
Mosby, St Louis, p 69 congenital heart disease in infancy: implications for
Thummala MR, Raju TN, Langeberg P et al (1998) Iso- routine examination. Arch Dis Child Fetal Neonatal
lated single umbilical artery anomaly and the risk for Ed 80:F49–F53
Primary Investigations in the Term
and Preterm Newborn 32
Diego Gazzolo, Francesco Risso, and Andrea Sannia
Contents
32.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472
32.2 The Term Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472
32.2.1 Newborn Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472
32.2.2 Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473
32.3 The Preterm Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474
32.3.1 The Problem of Preterm Labor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474
32.3.2 Neonatal Assessment at Birth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
32.4 The Preterm Baby . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
32.4.1 Specific Risks for the Preterm Neonate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
32.4.2 Patent Ductus Arteriosus (PDA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477
32.4.3 Respiratory Distress Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477
32.4.4 Hyperbilirubinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478
32.4.5 Hypoglycemia and Hyperglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478
32.4.6 Intracranial Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
Abstract to gestational age at birth, the neonatal team
Admission to nursery or to neonatal intensive have to decide which clinical, laboratory and
care unit represents one of the topic moments diagnostic procedure need to be performed.
in newborn’s early post-natal life. Moving Some primary investigations such as metabolic
from adequate obstetrical history documenta- screening are generally regulated by national
tion according to maternal-fetal risk factors and governments, independently from clinical con-
ditions, whilst others depend from perinatal
risk factors and by clinical evaluation at birth.
This refers to the occurrence in term and
D. Gazzolo (*)
Neonatal Intensive Care Unit, Department of Maternal, preterm newborns of the main post-natal
Fetal and Neonatal Medicine, S. Arrigo Children’s complications such as infections, glucose
Hospital, Alessandria, Italy and bilirubinemia metabolism disturbances.
e-mail: [email protected]
F. Risso · A. Sannia
Neonatal Intensive Care Unit, Department of Emergency
Medicine, G. Gaslini Children’s Hospital, Genoa, Italy
# Springer International Publishing AG, part of Springer Nature 2018 471
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_182
472 D. Gazzolo et al.
Although respiratory, cardiovascular and cere- 32.2 The Term Newborn
bral complications account in the majority of
preterm infants, these clinical aspects have to 32.2.1 Newborn Screening
be taken into the due consideration also in term
newborns. In the present chapter on overview Newborn screening, started in 1960, is primarily
on new insight on neonatal laboratory tech- directed at disorders in which clinical complica-
nique and in non-invasive monitoring devices tions develop during the immediate postnatal
currently used in nursery and in intensive care period.
is provided.
32.2.1.1 Metabolic Screening
Metabolic diseases result from biochemical
32.1 Salient Points abnormalities that are manifest during the first
days after birth (Taeusch et al. 2005). Phenylke-
• Metabolic screening varies from country to tonuria (PKU) was the first metabolic disorder
country, and each nation applies its own pro- known to benefit from early diagnosis and imme-
gram of neonatal screening. A multi- diate dietary treatment. Infants with PKU were
disciplinary report by the ACMG, HRSA, and identified early, in large numbers, and developed
AAP recommended a panel of 29 tests. Uni- normal while receiving treatment (O’Flynn 1992).
versal newborn screening for metabolic disor- The success of such screening led to further pro-
ders is available in many developed countries. gress in the investigation of additional tests for
• Newborns at risk of sepsis need careful physi- metabolic diseases, such as galactosemia, maple
cal examination and standard laboratory inves- syrup disease (MSUD), and homocystinuria.
tigations such as WBC differential count, These tests could be applied to the same blood
immature-to-total neutrophil (I:T ratio), and C specimen obtained for PKU screening. In 1990,
reactive protein (CRP). tandem mass spectrometry (MS/MS) started a
• Based on potential multi-organ damage due to new era in newborn screening (Levy 1998). The
prematurity, close monitoring in the early technology allows for the detection of more than
phases after birth is essential. 30 biochemical genetic disorders with a single
• Temperature should be monitored and assay with high specificity and with a very low
recorded at 30 min intervals until thermostabil- of false positive rate. Currently, the disorders
ity is achieved. detected by most MS/MS newborn screening pro-
• Monitoring of blood pressure is essential for grams can be divided into three major categories:
the optimal management of premature infants. amino-acid disorders (including urea cycle
• RDS incidence is inversely proportional to gesta- defects), organic acid disorders and fatty acid
tional age and occurs most frequently in infants of oxidation defects (Levy 1998). In 1999, the Amer-
less than 1,200 g and 30 weeks’ gestation. ican Academy of Pediatrics (AAP) Newborn
• Transcutaneous (tc) measurements of PCO2 Screening Task Force recommended that Human
and PO2 are important monitoring parameters Resources and Services Administration (HRSA)
in the NICU allowing continuous and less developed and implemented nationally recog-
invasive monitoring of blood gas levels. nized newborn screening system standards and
• Recognition that preterm newborn are at risk policies in collaboration with the Maternal and
for disturbances of glucose homeostasis is the Child Health Bureau (MCHB) of HRSA and the
most important step for the prevention of both American College of Medical Genetics (ACMG)
hypoglycemia and hyperglycemia. (Maternal and Child Health Bureau 2006).
• Routine screening for GM-IVH is performed in Criteria included: (1) the current availability of
infants <30 weeks or <1250 g at birth. Hem- an effective and rapid screening test; (2) an effi-
orrhage occurs mostly within the first 3 days of cacious treatment and adequate understanding of
life. the natural history.
32 Primary Investigations in the Term and Preterm Newborn 473
Table 1 Newborn screening panel recommended by hyperplasia (cah), biotinidase deficiency, sickle
ACMG expert panel (Maternal and Child Health Bureau cell disease, cystic fibrosis are performed by
2006)
immunoassays, radioimmunoassay (RIA),
MS/MS detectable disorder fluoroimmunoassay (FIA), and enzyme-linked
Organic acids immunosorbent assay (ELISA) techniques. The
Isovaleric acidemia
topic is considered in more detail in ▶ Chap.
Glutaric aciduria 1
111, “Inborn Errors of Metabolism and
3-Hydroxy-3-methylglutaric aciduria
Newborns.”
Multiple carboxylase deficiency
Today the use of MS/MS for second-tier tests
Methylmalonic acidemia due to mutase deficiency
3-Methylcrotonyl CoA carboxylase deficiency
and confirmatory testing has been shown to pro-
Methylmalonic acidemia due to cobalamin A and B vide useful information especially in the early
defects detection of new disorders such as some lyso-
Propionic acidemia somal storage disorders, ADA and PNP SCIDs,
3-Ketothiolase X-adrenoleucodistrophy (X-ALD), Wilson dis-
Fatty acid oxidation ease, guanidinoacetate methyltransferase defi-
Medium chain acyl-CoA dehydrogenase ciency (GAMT), and Duchenne muscular
Very long chain acyl-CoA dehydrogenase dystrophy. The new bulk of investigation will be
Long chain 3-hydroxyacyl-CoA dehydrogenase focused to: (i) reduce the false positive rate by
Trifunctional protein deficiency using second-tier tests, (ii) avoid false negative
Carnitine uptake defect results by using new specific biomarkers, and
Amino acids/urea cycle
finally (iii) introduce new treatable disorders in
Phenylketonuria
NBS programs (Ombrone et al. 2016).
Maple syrup urine disease
Homocystinuria
Citrullinemia
Argininosuccinic aciduria
32.2.2 Infections
Tyrosinemia type
Disorders detected by other methods A wide variety of infectious agents may affect
Hemoglobinoathies newborn such as bacteria, viruses, fungi, proto-
Hb SS-Sickle cell anemia zoa, and mycoplasmas. This topic is considered in
Hb S/Beta-thalassemia more detail in ▶ Chaps. 103, “Fetal Infections:
Hb S/C disease Cytomegalovirus, Herpes Simplex, and Vari-
Others cella,” ▶ 104, “Fetal Infections: Rubella, HIV,
Congenital hypothyroidism HCV, HBV, and Human Parvovirus B19,”
Biotinidase deficiency ▶ 105, “Fetal Infections: Congenital Syphilis
Congenital adrenal hyperplasia and Tuberculosis,” ▶ 106, “Toxoplasmosis in the
Galactosemia due to GALT deficiency Fetus and Newborn,” ▶ 107, “Neonatal Bacterial
Congenital hearing loss and Fungal Infections,” ▶ 108, “Neonatal Septic
Cystic fibrosis Shock,” and ▶ 109, “Neonatal Viral Infections:
Enteroviruses and Respiratory Syncytial Virus.”
Metabolic screening varies from country to Several laboratory tests have been evaluated
country and each nation applies its own program for their ability to predict which at risk infants
of neonatal screening. A multidisciplinary report may develop symptomatic or culture-proven sep-
by the ACMG, HRSA and AAP recommended a sis, but there is at present no single test that is
panel of 29 tests and there is universal newborn sufficiently reliable. Investigators have proposed
screening for metabolic disorders in, many devel- different combinations of laboratory tests but
oped countries (Marsden et al. 2006) (Table 1). these various combinations were not more diag-
Conditions most commonly screened for are nostic than single laboratory tests although more
congenital hypothyroidism, galactosemia, adrenal predictive for negative cases (Kite et al. 1988).
474 D. Gazzolo et al.
Newborns at risk of sepsis need careful physical antibiotic therapy is started and before the results
examination and standard laboratory investigation of laboratory tests. The duration of therapy should
may be useful such as: WBC differential count, be guided by the baby’s clinical condition and the
immature-to-total neutrophil (I:T ratio) and C reac- results of the tests (Jeffrey and Gerdes 2004).
tive protein (CRP) (Kite et al. 1988). Although All together, future perspectives will regard
sensitivity/specificity is limited, total WBC count molecular biology improvement with the inclu-
and differential and I:T ratio can indicate bacterial sion in clinical guidelines of trustable, quick, and
infection. Taken together: (1) an elevated WBC is low-cost tests able to provide, for example, micro-
not predictive of infection in newborn infants; neu- biological diagnosis and to identify more micro-
tropenia is more common than neutrophilia in organisms than blood cultures (Suberviola et al.
severe neonatal sepsis, but also occurs in association 2016).
with maternal diseases (PIH, IUGR); (2) thrombocy-
topenia is a nonspecific indicator of infection;
(3) longitudinal WBC monitoring in the first 24 h 32.3 The Preterm Newborn
from birth is more predictive of infection than a
single determination (Schelonka et al. 1994; Preterm birth affects more than 500,000 babies in
Escobar et al. 2000; Rodwell et al. 1993). the United States each year (Green et al. 2005). In
CRP is an acute-phase reactant that increases in Italy the incidence of preterm birth is 6.7% at
the presence of inflammation caused by infection <36 weeks of gestation, 5.2% between 32 and
or tissue injury. Raised levels of CRP are found in 36 weeks of gestation and 0.9% <32 weeks
bacterial sepsis or meningitis. After inflammation (Campi and Bonati 2007). Preterm birth is one
onset, CRP synthesis increases within 4–6 h, dou- of the leading causes of infant mortality and mor-
bling every 8 h, and peaks at about 36–50 h. bidity (Challis et al. 2001). It accounts for more
Levels remain elevated with ongoing inflamma- than 70% of neonatal deaths and almost half the
tion, but with resolution they decline rapidly due children with long-term neurological disabilities
to a short half-life of 4–7 h. CRP demonstrates were born prematurely (Mathews et al. 2004).
high sensitivity and negative predictive value. A Since 1981, the US preterm birth rate has
single normal value of CRP at birth cannot rule increased from approximately 9% to 12% (Green
out infection because the sampling may have pre- et al. 2005; Institute of Medicine, Committee on
ceded the rise in CRP. Serial CRP measurements Understanding Premature Birth and Assuring
may be helpful (Benitz et al. 1998; Gabay and Healthy Outcomes 2007). Research indicates
Kushner 1999; DuClos 2000). Although CRP is that preterm birth is a multifactorial disease
widely used in neonatal intensive care unit caused by genetic, social and environmental fac-
(NICU), several biomarkers have been recently tors, which most likely interact to increase risk
proposed for early (2–12 h) and late (12–24 h) (Wilcox et al. 1995; Wang et al. 2002; Moore et al.
neonatal sepsis. The former refers to IL-6, IL-8, 2004; Macones et al. 2004; Kogan 1995; Johnson
nCD64, and TNF-α, while the latter point regards et al. 2005; Genc et al. 2004; Crider et al. 2005).
procalcitonin (Meem et al. 2011). Anyway, on the There are striking disparities in the rates and con-
basis of the aforementioned findings, it is reason- sequences of preterm birth across racial and ethnic
able to suggest that CRP combined with other groups in the US that are unexplained (Institute of
biomarkers will constitute the new perspective Medicine, Committee on Understanding Prema-
for the early diagnosis of neonatal sepsis ture Birth and Assuring Healthy Outcomes 2007).
(Delanghe and Speeckaert 2015).
For asymptomatic term infants with positive lab-
oratory tests, blood culture and antibiotic therapy are 32.3.1 The Problem of Preterm Labor
recommended until cultures are negative. Asymp-
tomatic infants born before 35 weeks with risk fac- The factor(s) controlling the spontaneous onset of
tors for sepsis should have blood cultures before labor are not known. This is frustrating from a
32 Primary Investigations in the Term and Preterm Newborn 475
physiological point of view, and also a major Table 2 Critical assessment findings for hypo- and
clinical problem. The last trimester of pregnancy hyperthermia
is necessary for the maturation of the fetal lungs Hypothermia
and other organs in preparation for extrauterine Pale, mottled skin that is cool to touch babies
life. If this process is interrupted by an early Acrocyanosis
delivery the chances of survival of the newborn Respiratory distress
are severely decreased. The mortality rate Apnea, bradycardia, central cyanosis
according to different countries still remains Irritability initially
Lethargy developing as hypothermia worsens
higher and constant, at lower gestational ages,
Hypotonia
with a wide range morbidity and disability in the
Weak, cry and suck
surviving infants (Morrison and Rennie 1997;
Gastric residuals, abdominal distension, emesis
Bibby and Stewart 2004). The factors responsible
Shivering in more mature
for parturition in women remain unknown and the Metabolic acidosis
endocrine paradigms described above do not fit Hypoglycemia
primates. Therefore, more research is necessary to And temperature measurement!!
identify the physiological trigger for parturition Hyperthermia
and to understand why the process may be acti- Reddened skin that is warm to touch
vated prematurely in some pregnancies. It is also Tachypnea
necessary to investigate the biochemical mecha- Tachycardia
nisms regulating uterine smooth muscle activity Irritability, lethargy, hypotonia, weak cry
in order to develop more effective and selective Poor feeding
therapy to control uterine contractions when this Apnea
is indicated. Critical clinical findings are reported Sweating in more mature babies
in Table 2. Dehydration
32.3.2 Neonatal Assessment at Birth core temperature simultaneously may be of help
differentiating between fever as a result of disease
Based on potential multiorgan damage due to and environmental overheating. Noting that the
prematurity, close monitoring, in the early phases baby’s servo-controlled skin temperature is rela-
after birth, is essential. Primary investigations tively stable but that the environmental tempera-
include vital signs recordings such as temperature ture has dropped also may be indicative of fever as
determination, heart and respiratory rates, oxygen the incubator responds to the high probe reading
saturation monitoring in parallel with blood pH by cooling the infant’s environment.
assessment.
32.3.2.2 Cardiorespiratory Monitoring
32.3.2.1 Temperature Determination The electrical activity of an infant’s heart is picked
Temperature determination is always required and up by chest leads (usually three), placed on the
might be recorded at 30 min intervals up to ther- infant and recorded by a cardiorespiratory moni-
mostability achievement. Furthermore, it is tor. The recording is displayed on a visual screen
suggested that temperature be recorded at 1–3 h as the infant’s electrocardiographic pattern. The
intervals by continuous monitoring with axillary infant’s respiratory pattern also is recorded,
determinations every 1–2 h (American Academy because the chest leads electronically detect
of Pediatrics and American College of Obstetri- movement of the infant’s chest with each respira-
cians and Gynecologist 2002). In this regard, tion. The oxygen saturation monitor relies on ade-
recordings should include environmental temper- quate perfusion to the site and the ability to detect
ature (i.e., air temperature in the incubator or arterial pulsation; thus if it is placed distal to a
radiant warmer settings). Measuring the skin and blood pressure cuff, there will be an inaccurate
476 D. Gazzolo et al.
reading while the cuff is inflated. Newer models of oxygen supply contribute to the subsequent devel-
pulse oximetry reduce the artefact that results opment of retinopathy of prematurity or
from motion and low perfusion (Goldstein et al. bronchopulmonary dysplasia. Hypocarbia has
1997; Sahni et al. 2003). These newer models also been associated with the subsequent development
are indifferent to ambient light whereas older of periventricular leukomalacia and cerebral palsy,
models were affected by light sources such as and may cause retardation of retinal vascularization
phototherapy. (Holmes et al. 1998). Transcutaneous measurement
of oxygen (PtcO2) and carbon dioxide (PtcCO2)
32.3.2.3 Blood Pressure Monitoring tension is a non-invasive method that has recently
Monitoring of blood pressure is essential for the offered some promise. Several studies have shown
optimal management of premature infants. Blood a good correlation between tc and arterial values
pressure is one of the most important physiologi- (Binder et al. 1994; Geven et al. 1987).
cal parameters to evaluate clinical stability in crit-
ical care. Several medical conditions in premature
infants determine changes in blood pressure (i.e., 32.4 The Preterm Baby
infections, drugs, dehydration, blood loss etc.).
The recognition and treatment of abnormal 32.4.1 Specific Risks for the Preterm
blood pressure states has significant prognostic Neonate
implications in neonatal intensive care
(Nuntnarumit et al. 1999). Blood pressure in the Preterm infants usually show multiorgan failure in
newborn is related to weight and gestational age. reverse proportion to the gestational age.
Blood pressure rises with postnatal age, The main target-organs are:
1–2 mmHg/day during the first week and
1 mmHg/week during next 6 weeks in the preterm • central nervous system (CNS): including apnea
infant, just as in the full-term infant. The measure- of prematurity, intracranial hemorrhage, devel-
ment of blood pressure can be obtained by opment disability, and cerebral palsy;
non-invasive or invasive methods. In stable • retinopathy of prematurity (ROP);
infants or when only intermittent blood pressure • cardiovascular complications may arise from
measurements are required, non-invasive the failure of the ductus arteriosus to close after
methods are preferred. Blood pressure invasive birth: Patent ductus arteriosus (PDA) is typical
monitoring is obtained via catheter that has been in preterm babies. Other congenital cardiac
introduced into an artery. This method is indicated malformations will further analyzed in
in very small or instable infants, especially those ▶ Chap. 68, “Early Diagnosis of Congenital
with severe hypotension. For more details, see Heart Disease: When and How to Treat”;
▶ Chap. 71, “Blood Pressure Disorders in the • respiratory problems that can range from lung
Neonate: Hypotension and Hypertension.” malformations (pulmonary hypoplasia, see
▶ Chap. 59, “Rare Lung Diseases of New-
32.3.2.4 Transcutaneous Blood Gas borns”) to wet lung and finally to chronic lung
Monitoring disease (see ▶ Chap. 57, “Bronchopulmonary
PCO2 and PO2 are important monitoring parame- Dysplasia/Chronic Lung Disease of the
ters in NICU. Compared to conventional blood gas Newborn”);
measurements that cause significant blood loss in • gastrointestinal and metabolic issues can arise
preterms, transcutaneous (tc) measurements allow from glycemia and ion disorders, feeding dif-
continuous, non-invasive monitoring of blood gas ficulties, and finally necrotizing enterocolitis
levels (Brouillette and Waxman 1997). Preterm (NEC). However of particular interest are kid-
infants are vulnerable to alterations in arterial oxy- ney diseases that are extensively described in
gen or carbon dioxide tension.Changes in ▶ Chaps. 114, “Pathophysiology of Fetal and
32 Primary Investigations in the Term and Preterm Newborn 477
Neonatal Kidneys,” and ▶ 115, “Acute and highly required according to RDS severity. Pro-
Chronic Renal Failure in the Newborn Infant”; phylactic and or rescue surfactant administration
• hematologic complications including anemia modalities are reported in ▶ Chap. 63, “Lung
of prematurity, thrombocytopenia, and hyper- Diseases: Surfactant Replacement Therapy in
bilirubinemia, and (jaundice) that can lead to Newborns.”
Kernicterus (for review see ▶ Chap. 75, In RDS respiratory drive recording is gener-
“Kernicterus, Bilirubin-Induced Neurological ally irregular in rate and depth, and is chiefly
Dysfunction, and New Treatments for abdominal, rather than thoracic, with a rate of
Unconjugated Hyperbilirubinemia in 30–60 breath/min. Tachypnea, a rate above
Neonates”); 60 breaths/min after the first hour of life, is the
• neonatal sepsis including viral and bacterial earliest symptom of respiratory diseases. Periodic
forms that can be characterized by general respirations are cyclic respirations of apnea
(septicemia) or localized sepsis (pneumonia, (5–10 s) and ventilation (10–15 s) (Holditch-
urinary tract infection, meningitis etc.). Davis et al. 2004). Apnea is a non-breathing
episode lasting longer than 20 s and accompanied
by physiologic alterations. Use of accessory mus-
32.4.2 Patent Ductus Arteriosus (PDA)
cle of respirations is indicative of a marked
increase in the work of breathing. Retractions
The ductus arteriosus’ function in the unborn baby
reflect the inward pull of the thin chest wall on
is to allow blood to bypass the lungs, because
inspiration. Retracting is best observed in relation
oxygen for the blood comes from the mother and
to the sternum (substernal and suprasternal) and
not from breathing air. In fullterm babies, the
the intercostals, supracostal, and subcostal
ductus arteriosus closes shortly after birth, but it
spaces. The increased negative intra-thoracic
frequently stays open in premature babies. When
pressure necessary to ventilate the stiff,
this happens, excess blood flows into the lungs
non-compliant lung causes the chest wall to
and can cause breathing difficulties and some-
retract. This further compromises the lung’s
times heart failure. More details about PDA and
expansion. The degree of retraction is directly
other congenital cardiac disorders are analyzed in
proportional to the severity of the disease. Nasal
▶ Chap. 69, “Patent Ductus Arteriosus.”
flaring is a compensatory mechanism that
attempts to take in more oxygen by increasing
32.4.3 Respiratory Distress Syndrome the size of the nostrils and thus decreasing the
resistance (by as much as 40) of the narrow air-
Clinical, diagnostic and therapeutic strategies in ways. Grunting is forced expiration through a
RDS management are described in ▶ Chap. 53, partially closed glottis.
“Respiratory Distress Syndrome: Predisposing Because the clinical presentation of many
Factors, Pathophysiology, and Diagnosis.” One respiratory and non-respiratory diseases is the
of the most common and immediate problems same, a chest X-ray examination may be the
facing premature infants is difficulty breathing. only way to differentiate cause and establish the
Although there are many causes of breathing dif- proper diagnosis. More recently, lung ultrasound
ficulties in premature infants, the most common is pattern has been recently proposed. In detail, an
called respiratory distress syndrome (RDS). Its ultrasound severity score has been shown to cor-
incidence is inversely proportional to gestational relate with oxygenation status in both term and
age and occurs most frequently in infants of less preterm neonates, and to be a good predictor of
than 1200 g and 30 weeks’ gestation. RDS affects surfactant need in preterm babies requiring respi-
male infants twice as frequently as in female ratory support (Brat et al. 2015).
infants (2:1) In RDS, the infant’s immature lungs Measurement of arterial blood gases is used to
fail to produce surfactant and its administration is demonstrate alterations in oxygenation and acid-
478 D. Gazzolo et al.
base balance and to differentiate between respira- Table 3 Indications for routine monitoring of blood glu-
tory and metabolic components. cose for prevention of neonatal hypoglycemia
Maternal conditions
Presence of diabetes or abnormal glucose tolerance test
32.4.4 Hyperbilirubinemia Preeclampsia and pregnancy-induced or essential
hypertension
A common treatable condition of premature babies Previous macrosomic infants
is hyperbilirubinemia, which affects 80% of prema- Substance abuse
ture infants. Although mild jaundice is fairly com- Treatment with beta-agonist tocolytics
mon in full-term babies (about 60%), it is much Treatment with oral hypoglycemic agents
more common in premature babies. In premature Neonatal conditions
infants, the bilirubin peak usually is on the fourth- Prematurity
Intrauterine growth restriction
fifth day of life and may be 10–12 mg/dL, possibly
Perinatal hypoxia-ischemia
rising to greater than 15 mg/dL without any specific
Sepsis
abnormality of bilirubin metabolism. Therefore for
Hypothermia
bilirubin screening it is enough to take sample blood
Polycythemia-hyperviscosity
on the fourth-fifth day of life. Neonatal jaundice is
Erythroblastosis fetalis
completely analyzed in ▶ Chaps. 73, “Bilirubin Iatrogenic administration of insulin
Metabolism, Unconjugated Hyperbilirubinemia, Congenital cardiac malformations
and Physiologic Neonatal Jaundice,” and ▶ 74, Persistent hyperinsulinemia
“Pathologic Unconjugated Hyperbilirubinemia– Endocrine disorders
Isoimmunization, Abnormalities of Red Blood Inborn errors of metabolism
Cells, and Infections.”
as the lower limit of “normal” plasma glucose
32.4.5 Hypoglycemia concentrations in the first 72 h of life (Cornblath
and Hyperglycemia and Schwartz 1993).
Recognition that preterm newborn are at risk for
disturbances in glucose homeostasis is the most 32.4.6 Intracranial Hemorrhage
important step in preventing both hypoglycemia
and hyperglycemia (Table 3). Maintenance of a Intracranial hemorrhage (ICH) can affect new-
neutral thermal environment is especially critical borns of all gestational ages and often is clinically
to minimize energy expenditure in those infants at “silent”. Among ICH, germinal matrix hemor-
risk for hyperglycemia. Other conditions associ- rhage and intraventricular hemorrhage
ated with hypoglycemia, such as asphyxia and (GM-IVH) are the most common in the premature
hypothermia, may be avoided through appropriate population (see ▶ Chap. 128, “Cerebral Hemor-
obstetric and neonatal intervention. When hypo- rhage in Newborns”). More recently, due to
glycemia is suspected, the plasma or blood increase in extreme prematurity survival rate, cer-
glucose concentration must be determined imme- ebellar hemorrhage constitutes a common pattern
diately. Ideally this determination should be made affecting 2–9% of preterm infants weighting less
with one of the laboratory enzymatic methods, that 750 g (de Vries et al. 2015). Routine screen-
such as the glucose oxidase or hexokinase ing for GM-IVH is performed in infants < 30
method, but even bedside reagent test strip glu- weeks or < 1250 g at birth. The timing of hem-
cose analyzers (i.e., glucometers) can be used if orrhage occurrence is mostly within the first three
the test is performed carefully with awareness of days of life. “Late” hemorrhage (i.e., after 3 days
the more limited accuracy of these devices. of age) may be associated with pneumothorax and
A number of current references use 40–45 mg/dL its restriction of venous return to the heart.
32 Primary Investigations in the Term and Preterm Newborn 479
Indications for cerebral ultrasound scan are Geven WB, Nagler E, deBoo T, Lemmens W (1987) Com-
discussed in ▶ Chap. 122, “Neuroimaging Studies.” bined transcutaneous oxygen, carbon dioxide tensions
and end-expired CO2 levels in severely ill newborns.
Adv Exp Med Biol 220:115–120
Goldstein MR, Martin GI, Sindel BD et al (1997) Novel
pulse oximetry technology resistant to noise artifact
References and low perfusion: “the neonatal model”. Am J Respir
Crit Care Med 155:A717
American Academy of Pediatrics, American College of Green NS, Damus K, Simpson JL et al (2005) Research
Obstetricians and Gynecologist (2002) Guidelines for agenda for preterm birth: Recommendations from the
perinatal care, 5th edn. American Academy of Pediat- March of Dimes. Am J Obstet Gynecol 193:626–635
rics, Elk Grove Village Holditch-Davis D, Scher M, Schwartz T (2004) Respira-
Benitz WE, Han MY, Madan A, Ramachandra P (1998) tory development in preterm infants. J Perinatol
Serial serum C-reactive protein levels in the diagnosis 24:631–639
of neonatal infection. Pediatrics 102:E41 Holmes JM, Zhang S, Leske DA, Lanier WL (1998) Car-
Bibby E, Stewart A (2004) The epidemiology of preterm bon dioxide-induced retinopathy in the neonatal rat.
birth. Neuro Endocrinol Lett 25(Suppl 1):43–47 Curr Eye Res 17:608–616
Binder N, Atherton H, Thorkelsson T, Hoath SB (1994) Institute of Medicine, Committee on Understanding Pre-
Measurement of transcutaneous carbon dioxide in low mature Birth and Assuring Healthy Outcomes (2007)
birthweight infants during the first two weeks of life. Preterm birth: causes, consequences, and prevention.
Am J Perinatol 11:237–241 National Academies Press, Washington, DC
Brat R, Yousef N, Klifa R, Reynaud S, Shankar Aguilera S, Jeffrey S, Gerdes MD (2004) Diagnosis and management
De Luca D (2015) Lung ultrasonography score to eval- of bacterial infections in the neonate. Pediatr Clin North
uate oxygenation and surfactant need in neonates Am 51:939–959
treated with continuous positive airway pressure. Johnson WG, Scholl TO, Spychala JR et al (2005) Com-
JAMA Pediatr 169(8):e151797. https://doi.org/10.100 mon di- hydrofolate reductase 19-base pair deletion
1/jamapediatrics.2015.1797. Epub 2015 Aug 3 allele: a novel risk factor for preterm delivery. Am J
Brouillette RT, Waxman DH (1997) Evaluation of the Clin Nutr 81:664–668
newborn’s blood gas status. Clin Chem 43:215–221 Kite P, Millar MR, Gorham P et al (1988) Comparison of
Campi R, Bonati M (2007) Italian child health statistic 5 tests in diagnosis of neonatal bacteraemia. Arch Dis
review: births and deaths. Ital J Pediatr 33:67–73 Child 63:639–643
Challis JR, Lye SJ, Gibb W (2001) Understanding preterm Kogan MD (1995) Social causes of low birth weight. J R
labor. Ann N Y Acad Sci 943:225–234 Soc Med 88:611–615
Cornblath M, Schwartz R (1993) Hypoglycemia in the Levy HL (1998) Newborn screening by tandem mass spec-
neonate. J Pediatr Endocrinol 6:113–129 trometry: a new era. Clin Chem 44:2401–2402
Crider KS, Whitehead N, Buus RM (2005) Genetic varia- Macones GA, Parry S, Elkousy M et al (2004) A polymor-
tion associated with preterm birth: a HuGE review. phism in the promoter region of TNF and bacterial
Genet Med 7:593–604 vaginosis: preliminary evidence of geneenvironment
de Vries LS, Benders MJ, Groenendaal F (2015) Progress in interaction in the etiology of spontaneous preterm
neonatal neurology with a focus on neuroimaging in the birth. Am J Obstet Gynecol 190:1504–1508
preterm infant. Neuropediatrics 46(4):234–241. https:// Marsden D, Larson C, Levy HL (2006) Newborn screening
doi.org/10.1055/s-0035-1554102. Epub 2015 Jun 29 for metabolic disorders. J Pediatr 148:577–584
Delanghe JR, Speeckaert MM (2015) Translational Maternal and Child Health Bureau (2006) Newborn
research and biomarkers in neonatal sepsis. Clin Chim Screening: Toward a Uniform Screening Panel and
Acta 451(Pt A):46–64. https://doi.org/10.1016/j. System. http://www.mchb.hrsa.gov/screening
cca.2015.01.031. Epub 2015 Feb 4. Review Mathews TJ, Menacker F, MacDorman MF (2004) Infant
DuClos T (2000) Function of C-reactive protein. Ann Med mortality statistics from the 2002 period: linked birth/
32:274–278 infant death data set. Natl Vital Stat Rep 53:1–29
Escobar GJ, Dekun L, Armstrong MA et al (2000) Neona- Meem M, Modak JK, Mortuza R, Morshed M, Islam MS,
tal sepsis workups in infants 2000 grams at birth: a Saha SK (2011) Biomarkers for diagnosis of neonatal
population-based study. Pediatrics 106:256–263 infections: a systematic analysis of their potential as a
Gabay C, Kushner I (1999) Mechanisms of disease: acute- point-of-care diagnostics. J Glob Health 1
phase proteins and other systemic responses to inflam- (2):201–209
mation. N Engl J Med 340:448–454 Moore S, Ide M, Randhawa M et al (2004) An investiga-
Genc MR, Onderdonk AB, Vardhana S et al (2004) Poly- tion into the association among preterm birth, cytokine
morphism in intron 2 of the interleukin-1 receptor gene polymorphisms and periodontal disease. BJOG
antagonist gene, local midtrimester cytokine response 111:125–132
to vaginal flora, and subsequent preterm birth. Am J Morrison JJ, Rennie JM (1997) Clinical, scientific and
Obstet Gynecol 191:1324–1330 ethical aspects of fetal and neonatal care at extremely
480 D. Gazzolo et al.
preterm periods of gestation. Br J Obstet Gynaecol Schelonka RL, Bradley YA, desJardins SE et al (1994)
104:1341 Peripheral leukocyte count and leukocyte indexes in
Nuntnarumit P, Yang W, Bada-Ellzey HS (1999) Blood healthy newborn term infants. J Pediatr 125:603–606
pressure measurements in the newborn. Clin Perinatol Suberviola B, Márquez-López A, Castellanos-Ortega A,
26:981–996 Fernández-Mazarrasa C, Santibáñez M, Martínez LM
O’Flynn ME (1992) Newborn screening for phenylketonuria: (2016) Microbiological diagnosis of sepsis: polymerase
thirty years of progress. Curr Probl Pediatr 22:159–165 chain reaction system versus blood cultures. Am J Crit
Ombrone D, Giocaliere E, Forni G, Malvagia S, la Marca G Care 25(1):68–75. https://doi.org/10.4037/ajcc2016728
(2016) Expanded newborn screening by mass spec- Taeusch HW, Ballard RA, Gleason CA (2005) Avery’s
trometry: new tests, future perspectives. Mass disease of the newborn, 8th edn. Elsevier Saunders,
Spectrom Rev 35(1):71–84. https://doi.org/10.1002/ Philadelphia
mas.21463. Epub 2015 May 7 Wang X, Zuckerman B, Pearson C et al (2002) Maternal
Rodwell RL, Taylor KM, Tudehope DI, Gray PH (1993) cigarette smoking, metabolic gene polymorphism, and
Hematologic scoring system in early diagnosis of sepsis infant birth weight. JAMA 287:195–202
in neutropenic newborns. Pediatr Infect Dis J 12:372–376 Wilcox MA, Smith SJ, Johnson IR (1995) The effect of
Sahni R, Gupta A, Ohira-Kist K et al (2003) Motion social deprivation on birthweight, excluding physio-
resistant pulse oximetry in neonates. Arch Dis Child logical and pathological effects. Br J Obstet Gynaecol
Fetal Neonat Ed 88:F505–F508 102:918–924
Oxygen Saturation Monitoring in
Neonatal Period 33
Augusto Sola and Sergio Golombek
Contents
33.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482
33.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482
33.3 Oxygen Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
33.4 Assessment of Oxygen in Blood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
33.5 Saturation and Assessment of Saturation with
SpO2 Monitors in Clinical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
33.5.1 SpO2 Monitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487
33.6 Physiology of Tissue Oxygenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489
33.7 Hazards of Hyperoxemia and Hyperoxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
33.8 Intention to Treat: SpO2 Target Ranges for
Preterm Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
33.9 Intention to Treat with SpO2 Target Ranges in the Delivery Room
and in Other Neonatal Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
33.10 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
A. Sola (*)
Ibero American Society of Neonatology (SIBEN),
Wellington, FL, USA
e-mail: [email protected]
S. Golombek (*)
New York Medical College, New York, USA
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 481
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_291
482 A. Sola and S. Golombek
Abstract • The most widely used tool to guide its admin-
Oxygen (O2) is a potent drug that is often used istration and dosage is noninvasive monitoring
inappropriately in the clinical environment. of O2 saturation by pulse oximetry (SpO2).
Its administration needs to be improved in • Cellular oxygenation is complex and not easy to
neonatal care. Healthcare providers never assess in clinical practice. Hypoxemia does not
induce hypoxemia, and the same is not true necessarily cause tissue hypoxia and there are
for hyperoxemia. Clinical signs (cyanosis and situations where there is tissue hypoxia without
tongue color) are of no value to detect hypox- hypoxemia.
emia and hyperoxemia. Pulse oximetry • The hazards of hyperoxemia and hyperoxia are
(SpO2) is the most important method for mon- many and should be avoided or minimized.
itoring O2 saturation. The hazards of Undesired effects of maternal and fetal oxida-
hyperoxemia and hyperoxia should be tive stress and short- and long-term O2 therapy
avoided or minimized. Undesired effects of involve every organ system and many genes.
maternal and fetal oxidative stress and short- • The SpO2 in normal newborns and in those who
and long-term O2 therapy involve every organ are being treated with CPAP or assisted ventila-
system and many genes. The SpO2 in normal tion breathing room air (FiO2 0.21) is 95–100%.
newborns and in those who are treated with • The intention to treat (“target SpO2”) in infants
CPAP or assisted ventilation breathing room breathing supplemental O2 should not include
air (FiO2 0.21) is 95–100%. The intention to SpO2 values associated with potential
“target SpO2” in infants breathing supplemen- hyperoxia nor possible hypoxia and also must
tal O2 should not include values associated aim to avoid recurring periods of hypoxemia-
with potential hyperoxia nor possible hypoxia hyperoxemia-reperfusion.
and also must aim to avoid recurring periods • It is impossible to maintain newborn infants
of hypoxemia-hyperoxemia-reperfusion. It within the desired intention to treat all the
is impossible to maintain newborn infants time. When tight or narrow SpO2 target ranges
within narrow SpO2 target ranges all the are intended, there is even more time spent
time. Choosing wider intermediate SpO2 outside of the desired intention to treat.
ranges for treatment allows for easier care • A narrow intention to treat in low ranges (i.e.,
and better compliance, and such ranges have SpO2 target 85–89%) should not be used clini-
been associated with a decreased rate of cally. On the other hand, there is no evidence
severe ROP, without an increased morbidity that a narrow SpO2 target of 91–95% or
or mortality. 90–95% should be universally used in clinical
practice for preterm infants in the initial periods
of life.
• Choosing wider intermediate SpO2 ranges for
33.1 Salient Points the intention to treat allows for easier care and
better compliance, and such ranges have been
• Oxygen (O2) is a very potent drug that is often associated with a decreased rate of severe ROP,
used inappropriately in the clinical environ- without an increased morbidity or mortality.
ment. Its administration needs to be improved
in neonatal care.
• Healthcare providers never induce hypoxemia 33.2 Introduction
and all measures are implemented clinically to
try to overcome it when present. The same is Many times clinical interventions in neonatal med-
not true for hyperoxemia. icine are not based on proven benefit but on
• Clinical signs, such as cyanosis and tongue anecdotal evidence, expert opinion, and tradition.
color, are of little or no value to detect hypox- The administration of oxygen (O2) is one of such
emia and hyperoxemia. clinical interventions. The history of the use of O2
33 Oxygen Saturation Monitoring in Neonatal Period 483
is fascinating and has been burdened with errors In this chapter we will cover several topics in
(Comroe et al. 1950; Van Den Brenk and Jamieson relation to O2 administration and SpO2, including
1962; Phibbs 1977; Silverman 1980) but its O2 administration, assessment of O2 in blood,
description escapes the content of this chapter. arterial saturation (SaO2) and SaO2 monitors,
Perinatal interest about O2 and noninvasive moni- physiology of tissue oxygenation, and the hazards
toring of O2 saturation by pulse oximetry (SpO2) of hyperoxia, to end with the clinical concepts of
has increased markedly in this century (Askie intention to treat and SpO2 targets in neonatal
et al. 2003; Chow et al. 2003; Deulofeut care, emphasizing on the importance of avoiding
et al. 2006, 2007; Hagadorn et al. 2006; Saugstad abnormal amounts of O2 in the blood (i.e.,
2007; Sola et al. 2007, 2008, 2014; Sola 2008; hyperoxemia or hypoxemia).
Castillo et al. 2008, 2011; Lim et al. 2014; Bizzarro
et al. 2014; Rabi et al. 2007; Dawson et al. 2010,
2012; Vento et al. 2013; Saugstad et al. 2014; Sola 33.3 Oxygen Administration
and Zuluaga 2013; Saugstad and Aune 2014;
Schmidt et al. 2013, 2014a, b; Vento 2014; Noh The administration of supplemental O2 should be
et al. 2014; Yalcin et al. 2013; Hamel et al. 2014; considered in the same meticulous way as it is
Lye et al. 2013; Klimova et al. 2013; Klingel and done when any drug is given to a newborn infant.
Patel 2013; Thomson and Paton 2014; Carlo Therefore, the dose or fraction of inspired O2
et al. 2010; Stenson et al. 2013; Darlow (FiO2) should be clearly indicated and the pre-
et al. 2014; Kaindl et al. 2006; Wollen et al. 2014; scription should be carefully followed and moni-
Farrow et al. 2012; Spector et al. 2005; Wellmann tored. Basic issues need to be taken into
et al. 2014; Hay et al. 2002; Baquero et al. 2011; consideration at all times when supplemental O2
Polin et al. 2014; Ahmed et al. 2010; Vagedes is provided in order to avoid risks and potential
et al. 2013; Zhang et al. 2011; Niermeyer damage. They are summarized in Table 1.
et al. 1995; Laman et al. 2005; de Wahl Granelli In clinical practice we must provide supple-
et al. 2009; Ewer et al. 2011; Zapata et al. 2014; mental O2 and any adjustment of FiO2 based
Bancalari and Claure 2012; Claure and Bancalari only on the objective assessment of O2 in blood,
2013, 2015); only in 2015 there have been which is described below.
more than 16 publications on the topic
(Sola 2015; Lakshminrusimha et al. 2015;
Manja et al. 2015; Synnes and Miller 2015; 33.4 Assessment of Oxygen in Blood
Suwattanaphim et al. 2015; Ketko et al. 2015; van
Kaam et al. 2015; Lim et al. 2015; Paul 2015; The first premise we must keep in mind is that the
Narayen et al. 2015; Rawat et al. 2015; Clarke amount of O2 in arterial blood does not equate
et al. 2015; Hassan et al. 2015; Eghbalian 2014; with tissue oxygenation because there are many
Samiee-Zafarghandy et al. 2015; Arawiran other factors that contribute to tissue oxygenation,
et al. 2015; Terrill et al. 2015). as it will be shown later. Be this as it may, the most
When an infant is hypoxemic or suspected of common method to assess O2 in blood is the
being hypoxemic, healthcare professionals noninvasive continuous estimate of SaO2 by
become appropriately concerned. However, the SpO2, currently being considered as the fifth
same has not been the case with hyperoxemia, vital sign.
which is frequent, and it is induced by excess O2 Table 2 provides a summarized description of
administration. Because of the association of various methods of O2 assessment. Clinical signs,
hyperoxemia with brain damage, gene changes, such as cyanosis and tongue color, are of little or
and cancer, there is a need for education about the no value (Zhang et al. 2011; Niermeyer
judicious use of O2 supplementation, SpO2 man- et al. 1995; Laman et al. 2005; de Wahl Granelli
agement, and the potential damaging effects of et al. 2009; Ewer et al. 2011). Intermittent inva-
hyperoxemia. sive arterial or venous samples can be obtained to
484 A. Sola and S. Golombek
Table 1 Guidelines in relation to administration of the infant is clinically ill. Finally, noninvasive
supplemental O2 continuous monitoring can assess the amount of
Do not provide FiO2 > 0.21 based on previous maternal O2 in blood. Continuous transcutaneous PO2
or neonatal history, gestational age, color, apnea, (TcPO2) monitors had been widely used before
tachypnea, grunting, or any other clinical symptom
SpO2 became available, but they are almost never
Provide FiO2 > 0.21 only if the need is objectively
demonstrated by low O2 in blood as measured by SpO2 used currently. With TcPO2, high PaO2 had been
monitor or others more easily detected. Nonetheless, currently SpO2
O2 should be blended with air and the FiO2 clearly is the method used for continuous monitoring of
prescribed and measured O2 in blood. Its advantages and disadvantages are
The gas delivered should be heated and humidified at all discussed next.
times
FiO21.0 (pure O2) is very rarely truly necessary in
neonatal care and less so in the delivery room
Avoid as much as possible making large increases of 33.5 Saturation and Assessment
FiO2 when an infant has an episode of acute decrease of of Saturation with SpO2
SpO2 Monitors in Clinical Care
The practice of “preoxygenation” for endotracheal tube
suctioning, before or during anesthesia and before
O2 is a very insoluble molecule, and the main
extubation, is very risky and potentially dangerous and is
not supported by any (current) evidence function of hemoglobin (Hb) is to solubilize O2
The use of manual ventilation with non-blended high and transport it from the lungs to the tissues. Hb is
FiO2 and with dry and cold gas should be eradicated from composed of four polypeptide chains, and each
clinical practice chain contains one heme group. Saturation is
The treatment of apnea is not to provide supplemental O2, derived from the Latin word “saturare,” which
but to ventilate
means to fill, and it refers to reaching a maximum
In any case that there is cardiorespiratory arrest,
resuscitative measures call for ventilation and circulation capacity. The standard unit of O2 saturation is
Hyperoxygenation could be potentially dangerous due percent; when all available hemoglobin-binding
to the hypoxemia-hyperoxemia-reperfusion injury that sites are completely occupied by O2 molecules,
can occur to many organs the arterial O2 saturation (SaO2) is 100%. There-
Ventilation and cardiac massage can (and should) be fore, SaO2 can never be higher than 100%, regard-
provided with the same FiO2 the infant was receiving
less of the FiO2 the infant breathes. One gram of
hemoglobin can carry approximately 1.34 ml of
O2 when fully saturated, a concept known as the
directly measure PaO2 or PvO2 and/or arterial or maximum oxygen-carrying capacity.
venous saturation (SaO2 or SvO2). Nevertheless, SaO2 and Hb are the key factors that determine
they are not ideal to closely monitor an unstable the arterial oxygen content (CaO2), whereas the
neonate as these measurements are only obtained contribution of O2 dissolved in plasma is minimal
at one point in time and therefore are not fully (0.003 ml of O2 per millimeter of mercury of PaO2
representative of the whole clinical picture. Addi- which is to say 0.3 ml of O2 per deciliter of plasma
tionally, the only way to measure SaO2 is with a when the PaO2 is 100 mmHg). The following two
co-oximeter, ideally a last generation one, with examples reveal the significance of the Hb con-
multiple wavelengths. Therefore, the SaO2 centration in determining CaO2:
reported from a “regular” arterial blood gas deter-
mination should not be used for clinical manage- 1. With SaO2 of 100% and Hb of 8 g/dl, CaO2 is
ment. The reason is that this value of Sa O2 is not a 10.72 ml/dl calculated by multiplying the 8 g/
measured SaO2 but a calculated one. As shown in dl of Hb by 1.34 (and the amount of dissolved
Table 2, such calculation is done using formulas O2 is minimal).
or algorithms that are based on multiple factors, 2. With SaO2 of 100% and Hb of 20 g/dl, the
none truly applicable to a neonate and worse so if CaO2 is 26.8 ml/dl, using the same calculation.
33 Oxygen Saturation Monitoring in Neonatal Period 485
Table 2 Oxygen in blood
Method Comments
Cyanosis: a clinical sign that has been used to assess O2 Bluish discoloration of skin and membranes
needs and to try to tailor O2 administration Many studies have shown the poor predictive value of this
clinical sign
It could be due to an increased concentration of reduced
(not saturated) Hb but may be due to several other factors
It is unreliable because human beings perceive color with
variability
It depends on total Hb concentration, race, skin thickness,
and illumination
Unreliable because of “blind spot” for detecting cyanosis
on the face of even significant Hb desaturation; such
“spot” is accentuated in cases of low total Hb
concentration
Many infants who do not show cyanosis are hypoxemic
and with a need for some evaluation and consideration of
therapy
Some infants who show what appears to be cyanosis do
not need supplemental O2
Tongue color (in the delivery room) Specific but insensitive sign. When the tongue is pink, it is
likely that an infant has SpO2 > 70 % and may not
require supplemental O2
Measurements of PaO2 in arterial (or venous) blood Frequent blood samples may lead to anemia and/or
hypovolemia
Not fully representative, as these measurements are only
at one point in time
Co-oximeters for intermittent direct measurements of Modern co-oximetry: spectrophotometers measuring light
SaO2 (gold standard for measuring SaO2) absorbance at 100–130 wavelengths
Expensive, require blood sampling and provide only
intermittent monitoring
Not ideal to closely monitor an unstable neonate
Calculation of SaO2 from an arterial blood gas by Is of no value in newborns
means of formulas or algorithms (based on PaO2 Assumes a normal adult O2 dissociation curve and O2
measured and other factors) (should not be used for affinity
clinical management) Assumes normal adult 2–3 DPG, hemoglobin
(Hb) concentration, temperature, pH, and PaCO2 and that
the patient has no dyshemoglobinemia and is without fetal
Hb
In newborns: Hb concentration is variable and a large and
variable proportion of Hb is Hb F (not A), and 2–3 DPG is
low and variable in relation to transfusions
In ill newborns pH, PaCO2, and temperature are variable,
with frequent changes
It is incorrect to base clinical decisions on the reported
(calculated) SaO2 derived from the PaO2 measured in an
arterial blood gas
Many places customize the output of blood gas analyzers
so they do not report SaO2
The monitor, which measures Hb-O2 saturation, does not
measure the same thing as a calculated SaO2 from an
arterial blood gas
A SaO2 value calculated from a blood gas must never be
compared to continuous SpO2
Noninvasive pulse oximetry (SpO2) Please see description in text
Transcutaneous PO2 was routinely monitored in the
past, but not currently
486 A. Sola and S. Golombek
If, in the second case, only 90% of the shown in Fig. 1, other conditions also affect
hemoglobin-binding sites were occupied with O2 shifts of the Hb-O2 dissociation curve.
molecules, then CaO2 would be 24.12 ml/dl, still When a healthy neonate is breathing room air
much higher than in the first example with 100% (FiO2 0.21), the normal room air SaO2 is
SaO2. Thus, even if all binding sites are occupied 95–100%, except during the transition to extra
(as in the first example above), there can still be uterine life when it is lower since, as described
tissue hypoxia because the CaO2 may be low later, the newborn may take 15–20 min to
because of anemia. achieve this normal SaO2. Figure 2 shows an
The hemoglobin-oxygen (Hb-O2) dissocia- example of the Hb-O2 dissociation curve in an
tion curve is an italic sigmoid curve that shows infant receiving supplemental O2. When the
a predictable relation between PaO2 and SaO2 SaO2 is about 86–93%, the corresponding PaO2
when the curve is more verticalized, which hap- will be about 50–68 mmHg based on the Hb-O2
pens at levels of SaO2 of about 50–93% and curve (Fig. 2). However, when the SaO2 is
SaO2 of about 30–75 mmHg (Fig. 1). However, 95–100%, the PaO2 is unpredictable, as the rela-
at higher SaO2 levels, the Hb-O2 is more hori- tion between SaO2 and PaO2 is lost. In this case,
zontal and the predictability is lost. In addition, if an infant is receiving 100% O2 (FiO2 1.0), the
the curve can move to the right and to the left PaO2 can be anywhere between 85 and up to
depending on several factors, shown in Fig. 1. As 400 mmHg (Fig. 2), depending on the presence
shown in the example in this figure, when the of lung disease and shunting and their severity.
curve is shifted to the right, a PaO2 of 52 mmHg This is an important reason not to allow SaO2
will be associated with a SaO2 of about 80%. higher than about 95% when an infant is breath-
With the curve shifted to the left, the SaO2 will ing FiO2 > 0.21. In such cases there is a high
be about 91% with the same PaO2. This means probability of elevation of O2 in blood or
that with a larger amount of fetal hemoglobin hyperoxemia, which could be associated with
(HbF), there is greater affinity for O2 (higher more dissolved free O2 in plasma, potentially
SaO2 at the same PaO2) and that there is less O2 damaging tissues, cells, and genes.
release to the tissues. The reverse happens when A normal or even high PaO2 and a normal
the Hb is mostly of the adult type (HbA). As SpO2 (normoxemia or hyperoxemia) do not
Fig. 1 Hemoglobin-
oxygen (Hb-O2)
dissociation curve. With
HbF the curve is shifted to
the left (see description in
text)
33 Oxygen Saturation Monitoring in Neonatal Period 487
100
> 21% FiO2 100%
% 90
95%
O2 O2
O2 OH
Oxyhemoglobin (% Saturation)
80
70
60
50
40
O2
30
20
10
0 10 20 30 40 50 60 70 80 90 100 ... ... ... 600
PaO2 (mm Hg)
Fig. 2 Hb-O2 relationship when breathing supplemental O2 (FiO2 > 0.21). With SaO2 95–100 % (measured by
pulse oximetry), PaO2 could be > 80 mmHg and free dissolved O2 will be circulating
guarantee that the tissues are receiving enough O2. Table 3 Factors associated with tissue hypoxia on the
Insufficient tissue oxygenation is called hypoxia face of normal or high PaO2
and can exist in various circumstances on the face 1. Anemia
of normal or high PaO2 as shown in Table 3. On 2. Altered affinity of Hb for binding O2 (i.e., in cases of
the other hand, a low PaO2 in blood (i.e., hypox- methemoglobinemia or when Hb-O2 curve shifts
markedly to the right)
emia) is not necessarily associated with hypoxia
3. Poor perfusion (altered cardiac output and vascular
because tissue oxygenation is a complex phenom- resistance)
enon, as described later. Several factors, such as 4. Decreased O2 delivery
an increase in cardiac output, can help to prevent 5. Altered microcirculation and related factors
hypoxia.
33.5.1 SpO2 Monitors this ratio as a percentage of Hb saturated with O2.
These devices are very useful in the diagnosis of
The most common method to assess oxygenation desaturation (i.e., hypoxemia) and evaluation of
is the noninvasive continuous measurement of pulse rate, but they are of little or no value in diag-
arterial oxygen saturation by pulse oximetry nosing hyperoxemia unless some important physio-
(SpO2), currently being considered as a fifth vital logical factors are entered into the assessment.
sign. However, SpO2 does not equate with tissue The following concepts are based on more than
oxygenation because there are many other factors 200 peer-reviewed publications on the subject
that contribute to tissue oxygenation as shown in a since the late 1990s; a few of them are listed in
later section. the bibliography (Sola et al. 2008, 2014; Castillo
SpO2 monitors work by establishing the ratio et al. 2011; Carlo et al. 2010; Stenson et al. 2013;
between red and infrared wavelengths and display Schmidt et al. 2013; Darlow et al. 2014; Hay
488 A. Sola and S. Golombek
et al. 2002; Baquero et al. 2011; Ahmed between different SpO2 monitors. Finally, they
et al. 2010; Vagedes et al. 2013; Zapata also differ in their ability to provide accurate mea-
et al. 2014; Sola 2015; Lakshminrusimha surements through motion and low perfusion. In
et al. 2015; Manja et al. 2015; Synnes and summary, the function, strengths, limitations, and
Miller 2015). Similar to most other pieces of differences of oximetry monitors are well studied.
medical equipment, all SpO2 monitors available The SpO2 monitor with Signal Extraction Tech-
in the market have an inherent bias (equipment nology (SET ®), (Masimo Corporation, Irvine,
error). The bias (or SD) is not the same for mon- CA, USA) functions more accurately and pre-
itors of different manufacturing companies and is cisely than any other SpO2 monitor in the market.
as low as 2% or a bit lower in some and as high as It has been proven to have better specificity and
5% or higher in others. Due to equipment bias and sensitivity and fewer false alarms and missed
in line with the Gaussian curve of normal distri- events and to function best during critical illness
bution, the SpO2 readout is within one standard and is approved by the FDA to measure through
deviation (SD) of the true arterial saturation 68% motion and low perfusion states. In addition, it can
of the time. This means that when an SpO2 with use more than the classic 2 wavelengths (red and
equipment bias of 1% displays a value of 90%, it infrared) and can therefore measure hemoglobin,
does not mean that the true arterial saturation is methemoglobin, and carboxyhemoglobin in addi-
90%, but that 68% of the time the true arterial tion to SpO2. Based on all these concepts, the
saturation will be either 89%, 90%, or 91%. If, on SpO2 monitor was chosen by different investiga-
the other hand, the monitor from another company tors in the important neonatal randomized clinical
has a bias of 3%, then when the monitor reads an trials published in the last few years (Carlo
SpO2 of 90%, the true arterial saturation will be et al. 2010; Stenson et al. 2013; Schmidt
between 87% and 93% for 68% of the time. Of et al. 2013; Darlow et al. 2014) features SET ®.
course, based on simple statistics, the spread is
more with two standard deviations. According to 33.5.1.1 Alarms in SpO2 Monitors
the Gaussian curve of normal distribution or bell- There are many alarms in the NICU over the
shaped curve, 95% of the time, the SpO2 reported course of a day, and this has been identified as a
will be within two standard deviations of the true safety issue. It is therefore important to choose
arterial saturation. This explains why with the monitors and other equipment that provide very
same monitor in the same individual the SpO2 few or no false alarms. This is also important for
readout could be different by 1–3% or SpO2 monitors, and as mentioned before, the
more, depending on the bias of the equipment. amount of false alarms is different among differ-
Additionally, the true arterial saturation is not ent monitors. With SpO2 there are also alarms that
necessarily the same in two different individuals are true alarms but do not require any clinical
who have exactly the same SpO2 readout. The intervention.
difference could be as high as 3–4% or more. It cannot be overemphasized that it is clinically
This clearly explains why it is nonsensical to mandatory to choose and set alarms appropriately
emphasize differences in SpO2 values of 1–2% and to ensure the alarm system is always opera-
in clinical care tive. The low alarm limit for SpO2 monitors
The specificity and sensitivity to provide accu- should always be 85%, to avoid hypoxemia.
rate readings also varies between SpO2 monitors. When the low alarm sounds, all clinicians pay
Different monitors offer different accuracy levels attention to the potential problem of the infant.
and precision and they differ in the time they take Unfortunately there is less response and much
to respond and in the number of false alarms, more frequent violations to high alarms in clinical
missed events, and detection of true events. care. The high alarm value to be chosen varies
False-positives and false-negatives, and therefore according to whether the infant is breathing room
receiver operating curves, are also different air or receiving any amount of supplemental O2
33 Oxygen Saturation Monitoring in Neonatal Period 489
(FiO2 > 0.21). In room air the normal SpO2 is cluster of shorter events as a single, prolonged
95–100% and therefore the high alarm should not episode and, as a result, potentially overestimate
be on. However, in infants breathing supplemen- the frequency of long events (Ahmed et al. 2010).
tal O2, the high alarm should be set at 95% to One study recorded 339 desaturations of SpO2
avoid hyperoxemia. The high alarm should < 80% when using an average time of 16 s and
always be operative and responded to when an 1958 when the average time was set at 3 s
infant is breathing FiO2 > 0.21. (Vagedes et al. 2013). Careful attention should
In clinical care it is not only important to detect therefore be paid to averaging time and sensitivity
and prevent significant periods of hypoxemia and in the monitors used for clinical care. The perfor-
hyperoxemia of prolonged duration (>20 s). It is mances of monitors manufactured by different
also important to detect repeated shorter frequent companies vary, and some have default settings
episodes of desaturation, as they may not be that cannot be modified. In the delivery room,
inconsequential. A feature available in some mon- when changes may occur rapidly during resusci-
itors is the so-called alarm delay, which could be tation, maximum sensitivity and an average time
set by the clinician, just as the averaging time and of 2 s are recommended. However, this is not the
sensitivity discussed below. These three variables case for a critically ill infant in the NICU, as these
impact when will an episode provide an audible settings could alarm the clinician by alerting him
alarm or not. If the delay is set at 10 s, the alarm or her to very brief and clinically insignificant
will sound 10 s after the SpO2 has been below episodes. In the NICU setting, an average time
(or above) the limits chosen. This may be neces- of 8–12 s with intermediate sensitivity may be
sary for some infants, as repeated and frequent adequate (Sola et al. 2014; Sola 2015).
brief periods of hypoxemia may have undesired
long-term effects, but the alarms will sound more
frequently. A delay time at 20 s means that if an 33.6 Physiology of Tissue
infant has repeated episodes of 15 s of hypoxemia Oxygenation
the alarms will not sound. Usually the delay
should not be longer than 20 s, to ensure that The PaO2 depends on the amount of O2 within
significant hypoxemic events are not missed. In alveoli (i.e., alveolar partial pressure of oxygen
some babies this may need to be adjusted [PAO2]), the ability of O2 to enter adjacent pul-
according to individualize care and infant’s needs. monary capillaries (i.e., O2 diffusion), and the
degree of intrapulmonary and extrapulmonary
33.5.1.2 Averaging Time and Sensitivity shunts. Of course the PAO2 depends on the alve-
in SpO2 Monitors olar gas equation, which is related to the atmo-
Pulse oximeter saturation values are not really spheric pressure, the alveolar CO2, and the
beat-to-beat and are usually obtained by averag- relative humidity or water vapor pressure. At
ing preceding measurements. Some SpO2 moni- sea level the PAO2 is about 110 mmHg in new-
tors allow clinicians to modify the averaging time borns and adults. The PaO2 in healthy children
and sensitivity or both at the same time. This has and adults is approximately 100 mmHg at sea
an impact on the monitor’s response and therefore level; in neonates, however, the PaO2 is lower
on what the clinicians observe in the digital dis- (45–75 mmHg and rarely >80 mmHg) because
play in the same infant at the same time. With of intrapulmonary and extrapulmonary shunting.
monitors that provide this function, the number of When healthy adults are breathing 100% oxygen
desaturations, and therefore alarms, is greater and the SaO2 is 95–100%, the PaO2 is > 600
using short, 2-s averaging time. On the other mmHg, but it is lower, approximately
hand, a long averaging time of 16 s reduces the 280–400 mmHg in healthy newborn infants
detection of brief periodic desaturation events and because of the neonatal intrapulmonary and
of those of greater severity. It may also interpret a extrapulmonary shunts.
490 A. Sola and S. Golombek
There are many factors involved in tissue oxy- the potential damage of ROS, peroxides, and free
genation, which are summarized in Table 4. As radicals to all components of the cell (proteins,
mentioned previously, hypoxemia does not neces- lipids, and DNA). Suffice to say here that oxida-
sarily cause tissue hypoxia and there are situations tive damage is less controlled in infants and
where there is tissue hypoxia without hypoxemia. therefore oxidative damage and possible cell
Some of the factors involved in tissue oxygenation death occur more easily with excess O2 adminis-
mentioned in Table 4, like peripheral vascular resis- tration (Kaindl et al. 2006; Wollen et al. 2014;
tance, O2 delivery and consumption, microcircula- Farrow et al. 2012; Spector et al. 2005;
tory changes, and the function of precapillary Wellmann et al. 2014). Thus, we must change
sphincters and post capillary venules, cannot be the way we administer supplemental O2 when a
well evaluated in clinical care. Thus, it becomes newborn infant is not hypoxemic and stop using
of great significance to make an effort to avoid pure free-flowing O2 in order to avoid causing
practices that lead to hyperoxemia that may induce conditions associated with hyperoxia, oxidative
unnecessary oxidative stress and oxidant injury. stress, and damage.
A summary of undesired effects of maternal
and fetal oxidative stress and short- and long-term
33.7 Hazards of Hyperoxemia O2 therapy is presented in Tables 5, 6, 7, and 8.
and Hyperoxia During normal birth without supplemental O2
administration, there is already altered lipid per-
Oxygen is a very potent drug that is often used oxidation levels and antioxidant capacity, which is
inappropriately in the clinical environment. At worsened if the delivery is by cesarean section
high level of arterial O2, there will be an increase (Noh et al. 2014). Excess O2 during labor and in
in both free dissolved oxygen and reactive oxygen cesarean deliveries induces much more damage
species (ROS). Measurements of PaO2, when pro- and is potentially dangerous for the pregnant
viding supplemental oxygen, help avoid unneces- woman and the fetus, as shown in Table 5 (Yalcin
sary hyperoxemia and hyperoxia, but it is more et al. 2013; Hamel et al. 2014; Lye et al. 2013;
important to monitor SpO2 continuously when an Klimova et al. 2013; Klingel and Patel 2013).
infant is breathing supplemental O2. Therefore, the practice of providing supplemental
Excessive O2 administration can lead to O2 to pregnant women should be reserved only for
overproduction of ROS. Other chapters of this documented maternal hypoxemia.
text discuss in detail the antioxidant system and Table 6 summarizes undesired effects of acute
O2 therapy and Table 7 several clinical conditions
associated with hyperoxia, oxidative stress, and
Table 4 Factors related to tissue oxygenation
damage. In the neonatal and pediatric populations,
PaO2 (mmHg) O2 Consumption excess O2 is potentially very damaging. Our cur-
Hb concentration (anemia) and Pulmonary
quality vascular resistance rent understanding of its potentially injurious
(Hb F; Hb A; dyshemoglobins) Pulmonary blood effects is summarized in Table 8, and they include
Hb-O2relationship (saturation flow increase in cancer risk, retinopathy of prematurity
in %) Hematocrit (ROP), bronchopulmonary dysplasia (BPD),
Oxygen content (CaO2; in ml of (hyperviscosity)
O2/dl) pH injury to the developing brain, disruption of the
[(SaO2 x Hb x 1.34) + .003 ml CO2 (local and circadian rhythm, and alteration of enzymes, pro-
O2/mmHg PaO2] systemic) teins, and genes by hyperoxia (Lye et al. 2013;
Cardiac output Temperature Klimova et al. 2013; Klingel and Patel 2013;
(Heart rate, stroke volume, Glycemia
minute volume) Local PO2 Kaindl et al. 2006; Wollen et al. 2014; Farrow
Peripheral vascular resistance (4–20 mmHg) et al. 2012; Spector et al. 2005; Wellmann
Systemic blood flow Distance to et al. 2014) (Table 8). O2 excess is a concern at
O2 delivery mitochondria any time and this includes anesthesia and recovery
Microcirculation
after surgery (Table 8). Some anesthetic and
33 Oxygen Saturation Monitoring in Neonatal Period 491
Table 5 Hyperoxemia and hyperoxia in the prenatal Table 6 Undesired effects of acute O2 therapy
period
Altered respiratory control and chemo- and baroreceptors
Cesarean section: higher oxidative stress and alteration responses
of the oxidant and antioxidant system compared to Raised blood pressure
vaginal deliveries (additional risk associated with Redistribution of blood in the microcirculation
planned elective cesarean sections)
Decrease blood flow in the cerebral and renal beds
Unnecessary use of O2 during C-sections and labor
Decrease cardiac index
and delivery
Decrease heart rate
1. Increases markedly the potential damage being caused
to mothers, placenta, and fetus Decrease myocardial contractility
2. FiO2 0.4 in elective cesarean sections under spinal Decrease cardiac oxygen consumption
anesthesia: significantly worse fetal and maternal total Lower capillary density
antioxidant capacity, total oxidant status, and oxidative
stress index than with room air
3. Significant differences in healthy pregnant women
who received supplemental O2 during C-S with regional
anesthesia (higher PaO2, free O2 radicals, and ROS in Table 7 Conditions associated with hyperoxia, oxidative
both mother and neonate) stress, and damage
4. Supplemental O2 in intrauterine resuscitation: this Aging Other
practice should not be considered an indicated
DNA impact – cancer Fragile X syndrome
intervention for nonreassuring fetal status since it is of
Alteration of gene Sickle cell disease
unproven benefit and is potentially harmful due to
expression Lichen planus
increase free radical activity
Central nervous Vitiligo
Effects of hyperoxia on placental functions: system Infection
1. In explants of villi of human placentas: a protein of Parkinson’s disease Inflammation – fibrosis
resistance to breast cancer (ABCG2 mRNA), which also Alzheimer’s disease Chronic fatigue syndrome
protects the fetus against maternally derived toxins, Neuronal Altered renal function
drugs, chemical substances, and pollutants (i.e., degeneration Perinatal: specific to mother,
xenobiotics), increases after hours of hyperoxia. It is Autism fetus, and neonate
possible, therefore, that placental changes in O2 tension Altered blood flow Placental defenses and
and delivery may alter resistance to drugs and toxins Cardiovascular genes
during fetal life Atherosclerosis ROP
2. Increased PaO2 reduces the cellular pro-inflammatory Heart failure BPD – lung injury
response to E. coli and promotes an abnormal anti- Myocardial Developing brain
inflammatory cytokine profile in the membranes. infarction Increased PVR
Therefore, tissue injury may occur as a result of injurious Decreased Abnormal response to iNO
O2 by-products secondary to hyperoxia in utero contractility Altered clock genes
Altered chemo- and Altered ocular genes
baroreceptors Thymus (T cells)
Endocrine
sedative drugs have been associated with
Insulin
hyperoxia-induced oxidative stress and therefore Glucagon
should be used judiciously. Worse even is the Lung
combination of these drugs with hyperoxemia. Atelectasis
Alveolar collapse
The practice of preoxygenation must be carefully
evaluated and not used routinely (Sola 2008). ROP retinopathy of prematurity, BPD bronchopulmonary
dysplasia, PVR pulmonary vascular resistance, iNO
Benefits of changing clinical practice to try to inhaled nitric oxide
reduce PAO2 and/or maintain SpO2 values to
decrease hyperoxemia have been proven (Chow
et al. 2003; Deulofeut et al. 2006; Bizzarro damaging in newborn infants. O2 should never
et al. 2014; Castillo et al. 2011). Using excess be denied when necessary, but providing unnec-
O2 for the treatment of non-hypoxemic humans essary O2 should be avoided at all times during the
is definitely a health hazard (Sola et al. 2007). birthing process and after birth, including in the
More so, periods of fluctuating hypoxemia- delivery room, during resuscitation, and in the
hyperoxemia-reperfusion are potentially very neonatal intensive care unit, as well as before,
492 A. Sola and S. Golombek
Table 8 Undesired effects of pediatric and neonatal O2 Table 8 (continued)
excess
outcome, alter NMDA receptors, and enhance human
ROP and BPD neural stem cell proliferation and neuronal apoptosis
Cell death in the developing brain High FiO2 worsens compliance and lung units with
Worse long-term neurodevelopment outcomes; low ventilation to perfusion ratios become more unstable
contributing factor to the pathogenesis of cerebral palsy when breathing O2
(Study of 1105 preterm infants; risk of disabling cerebral Pure O2 results in reabsorption atelectasis shortly after
palsy was double in those exposed to hyperoxia and it its application; rapid recurrence of the atelectasis,
was eightfold in the highest quintiles of O2 exposure) together with decreased FRC and alteration of ventilation
Enzyme and gene alteration homogeneity, occurs more frequently
Proteome changes induced by oxidative stress have Pure O2 aggravates central hypoventilation and apnea,
been described can induce mental changes, and increases the risk for
In models of persistent pulmonary hypertension postoperative atelectasis
(PPHN): Rev-erbα is degraded in hyperoxia; its disruption
100 % O2 increases ROS in the mitochondrial matrix exacerbates hyperoxic lung injury, which is associated
prior to the cytosol and can produce significant changes with decreased cell proliferation and distorted alveolar
in critical cellular signaling pathways architecture
100 % O2 increases PDE5 activity and decreases Diagnostic hyperoxic challenge test, nitrogen washout
NO-mediated cGMP-dependent vasorelaxation for pneumothorax:
100 % O2 decreases the response to iNO, produces Please see text. Both practices should be eradicated
oxidative stress in the lung and vessels, and alters from clinical care
pulmonary artery contractility Pure O2 (i.e., 100 % O2, FiO2 1.0) is almost never
Some of these alterations are prevented with the use of indicated in neonatal care. In the few cases when it is
antioxidants such as superoxide dismutase and catalase, really necessary, it should be weaned as soon as possible
confirming the role of oxidative stress in these responses
Two minutes of 100 % O2 in children ages 8–15:
abnormal activation of hippocampus, hypothalamus, and
insula, areas that regulate blood pressure, heart rate, and during, and after neonatal anesthesia and other
response to stress
procedures.
Risk of leukemia and cancer in childhood: threefold
increase with exposure to 100 % O2 in the delivery room
for 3 min or more
Newborn eyes of experimental animals: hyperoxia at 33.8 Intention to Treat: SpO2 Target
birth alters whole-genome expression (If this were to Ranges for Preterm Infants
occur during induced hyperoxia after birth of preterm
infants, predisposition for ROP could be markedly
increased at that time) The SpO2 in normal newborns breathing room air
Circadian rhythm disruption (FiO2 0.21) is 95–100%. The same is true for
Key circadian genes are Rev-erbα, Per, and Bmal neonates who are being treated with CPAP or
Rev-erbα is degraded in hyperoxia; its disruption assisted ventilation when they are breathing room
exacerbates hyperoxic lung injury, which is associated air. However, this is not the case for infants breath-
with decreased cell proliferation and distorted alveolar ing supplemental O2 in whom the most prudent
architecture. Stabilizing lung Rev-erbα prevents the loss
of cell proliferation approach is not to tolerate possible hypoxia and at
Combined effect of O2 and phototherapy: potential the same time not to accept SpO2 values associated
cytotoxicity and disruption of circadian gene expression with potential hyperoxia to avoid issues mentioned
is concerning. This cytotoxic effect can be partly reversed in Table 8. This is not easy to accomplish all of the
in animals by stabilizing Rev-erbα and this improves time in clinical practice, and some recommenda-
mitochondrial efficiency conferring a survival advantage
tion are described below and summarized in
Hyperoxia during anesthesia or recovery post-
surgery: Table 9, based on current available evidence.
Potentiation of brain damage and ROP First and foremost, we must take into consid-
Negative impact of sedatives like midazolam and eration three important factors when we make
ketamine; both affect long-term neurodevelopmental decisions on the intention to treat for SpO2
(continued) targeting. As discussed in a previous section,
33 Oxygen Saturation Monitoring in Neonatal Period 493
Table 9 What to do with SpO2 in clinical practice in 2016 sample size were performed with one SpO2 mon-
in tiny preterm infants who are breathing supplemental itor which has SET ®, and therefore, it is not clear
oxygen?
if the same planned intention to treat based on
Try to avoid SpO2 > 94 % to avoid high PaO2 values these monitors would be valid in centers using
Avoid inducing significant fluctuations in SpO2 because a different SpO2 monitors. Thirdly, the clinically
higher incidence of intermittent hypoxemic-hyperoxemic
episodes is associated with severe ROP optimal or ideal SpO2 range for extremely preterm
Evaluate in detail the infant who has frequent wide infants breathing supplemental O2 is currently
swings in SpO2 and consider modifying other aspects of unknown and likely varies with advancing gesta-
care (i.e., PEEP, position, other) and not just adjustments tional and postnatal age and clinical condition.
of FiO2, which actually could be part of the cause of the
However, in more than a decade of many publi-
significant fluctuations
When FiO2 is increased, return it gradually to baseline
cations, prevention of severe ROP in preterm
levels without leaving the infant with high SpO2 infants through changes in clinical practice and
Choose an intention to treat which is wide and not with SpO2 technology has been established (Chow
narrow SpO2 ranges and oximetry alarm settings, with et al. 2003; Deulofeut et al. 2006; Bizzarro
enforcement of adherence to those alarm settings, with et al. 2014; Castillo et al. 2011; Sola et al. 2014).
frequent audits and feedbacks. For example, intention to
treat not less than 86 %and not more than 94 %, with low For these preterm infants when they are receiving
alarm at 85% and high alarm at 95% supplemental O2, a prudent clinical approach is
The intention to treat for SpO2 ranges could be, for presented in Table 9, based on available publica-
example, between 86 % and 94 % (high alarms at 85 % tions to date.
and 95 %, respectively), according to the patient and the It may be sensible to consider a lower SpO2
diagnosis. Of course, if somebody chooses to set alarms
at 86 % and 94 % (with SpO2 range 87–93 %), there is limit of >85% and a higher limit of 95% when a
no supporting evidence against such practice preterm infant is breathing FiO2 > 0.21 (Schmidt
On the basis of evidence to date, do not use intention to et al. 2014a, b; Sola et al. 2014; Lakshminrusimha
treat with SpO2 ranges as narrow as 85–89 % or et al. 2015; Manja et al. 2015). This is an intended
91–95 %
range of SpO2, which is very different to saying
If the SpO2 levels remain steadily (“stable”) in the low
end (85–87 %), it may also be prudent to evaluate
that an SpO2 of 85% or 95% is normal. If one so
carefully and modify settings if necessary chooses, the low and high alarm limits should be
The intention to treat may not be the same for each NICU: set at 85% and 95%, respectively. The alarms
In a NICU with low rates of mortality and necrotizing should be operative at all times and a clinical
enterocolitis (NEC) but high rates of severe ROP, it has response would be initiated when the low or
been suggested that consideration is given to set the lower high alarm sounds.
alarm at 85–86 % (or even lower in the tiniest of infants)
and the upper alarm at 93 % or 94 % It is a challenge to maintain infants within the
In a NICU that has high rates of mortality and intention to treat chosen. It is well known that
necrotizing enterocolitis but low rates of severe ROP, the some preterm infants breathing O2 have more
lower alarm could be at 88 % and the upper alarm at oscillation in SpO2 than others, and it is impossi-
95 %
ble to maintain the SpO2 within the intended
SpO2 alarms must always be operative when a neonate is
receiving supplemental O2; the low alarm should be 1 %
target all the time. It has been shown that adher-
below the intended low SpO2, and the high alarm at the ence to planned SpO2 targets varies between
same 1 % above the intended high SpO2 shifts and centers, mainly due to the SpO2 targets
chosen, differences in education, staff commit-
ment to this issue, workload, and accuracy and
SpO2 monitors have a bias or error and therefore it precision of monitors used. This means that
does not make much sense to spend much time actual versus intended SpO2 levels are very var-
arguing if an SpO2 of 89% is significantly worse iable (Dawson et al. 2010; Saugstad and Aune
than an SpO2 of 91% for an individual baby at any 2014; Schmidt et al. 2014a; Noh et al. 2014;
given time. Secondly, one SpO2 monitor is not the Yalcin et al. 2013). In some places of the world,
same as another SpO2 monitor. All the random- there are now equipments that provide automated
ized trials and descriptive studies with large control of FiO2 for infants on noninvasive and
494 A. Sola and S. Golombek
invasive respiratory support (Zapata et al. 2014; lead to increased tolerance of an SpO2 level
Bancalari and Claure 2012; Claure and Bancalari >95%. In a study of 1000 samples, we found
2013, 2015; van Kaam et al. 2015). Even though that when SpO2 is > 94%, hyperoxemia (PaO2
these methods reduce the percent time spent out- i > 80 mmHg) occurs in 60% of the samples
side of the limits of the intention to treat, babies (Castillo et al. 2008). Therefore, with narrow
are still off target between 40% and 50% of the SpO2 ranges, the % time with hyperoxemia
time. The percent time spent below the lower increases much more than the one spent in hyp-
SpO2 value chosen in the intention to treat or in oxemia (Sola et al. 2014).
hypoxemia with SpO2 < 80% is reduced but not Based on these considerations, a narrow low
eliminated. The time spent above the maximum SpO2 target of 85–89% should not be used clin-
SpO2 chosen or at extreme hypoxemia with SpO2 ically. Even though this may not be associated
> 98% is also reduced during automated FiO2 with increased mortality (Schmidt et al. 2013;
but these episodes are not eliminated (Zapata Darlow et al. 2014; Manja et al. 2015), it may
et al. 2014; van Kaam et al. 2015). When tight potentially lead to more periods of hypoxemia-
or narrow SpO2 target ranges are intended, there hyperoxemia-reperfusion damage. On the other
is more time spent outside of the desired range hand, at the high end of SpO2, there is no evi-
whether, with manual or automated control of the dence that a narrow SpO2 target of 91–95% or
FiO2 (Hagadorn et al. 2006; Deulofeut 90–95% should be universally used in clinical
et al. 2007; Sola et al. 2007, 2008, 2014; Castillo practice for preterm infants in the initial periods
et al. 2008; Lim et al. 2014; Bizzarro et al. 2014; of life, since they may increase the time in
Schmidt et al. 2013, 2014a, b; Carlo et al. 2010; hyperoxemia, which may be associated with
Stenson et al. 2013; Darlow et al. 2014; Zapata severe ROP and other damaging effects. In one
et al. 2014; van Kaam et al. 2015), there are more study, when the intended target SpO2 was
fluctuations in SpO2. If the narrow SpO2 range is 91–95%, the actual SpO2 was 85–95% 54% of
on the low end (SpO2 85–89%), there are more the time, > 95% for 36% of the time and <85%
periods of hypoxemia, which are followed by for only 10% of the time. One study of random
hyperoxemia by the clinical response of increas- observations, after clinical practice was changed
ing the FiO2. Also, the narrower the SpO2 to aiming for SpO2 in the 88–93% range,
targeting range and alarm limits chosen, the showed that the target was achieved 72% of the
greater will be the number of alarms. An intended time; SpO2 was 96–100% in 18% of the time and
narrow SpO2 target, for example, 90–93%, is it was <85% for 10% of the time. Wider inter-
almost never the actual SpO2 values, even when mediate targets allow for easier care and better
the nurse to patient ratio is one-to-one, which compliance and, with an SpO2 monitor with SET
®
very rarely happens. In addition, the education as the one used in the large clinical studies,
programs in most nursing and medical schools such ranges have been associated with a
emphasize the problems of hypoxia and the need decreased rate of severe ROP, without an
to correct it, much more than what they do about increased morbidity or mortality (Chow
the complications of hyperoxia. This is another et al. 2003; Deulofeut et al. 2006, 2007; Bizzarro
reason why infants are outside the desired range et al. 2014; Schmidt et al. 2014a). Therefore, in
and explains why the % time in hyperoxemia is the early periods of care of small preterm infants,
much higher than the % time with hypoxemia. rather than using narrower intended targets, like
Therefore, in clinical care there are more viola- 85–89%, 90–93%, or 91–95%, it may be safer to
tions and less response to high alarms with and an use wider intermediate SpO2 targets such as
increased tolerance of SpO2 95% as compared 86%, 87%, or 88% for the lower value and
to the responses to low alarms and to SpO2 93% or 94% for the higher one. However, these
< 85%. Therefore, a narrow high target like intermediate target ranges may be not very dif-
91–95% is not only difficult to achieve but can ferent from one another, due to the inherent bias
33 Oxygen Saturation Monitoring in Neonatal Period 495
of SpO2 monitors and the significant difference Table 10 SpO2 targeting in the delivery room during
between monitors described previously. neonatal resuscitation
In summary, in any infant breathing supple- SpO2 increases steadily over time during the normal
mental O2, it is of clinical significance to avoid neonatal transition, reaching >90 % in approximately
8 min in term infants and requiring a little more time in
hypoxemia, hyperoxemia, and recurring episodes preterm infants and after cesarean deliveries
of hypoxemia-hyperoxemia-reperfusion. A sum- As a general concept, if a term or preterm infant breathing
mary of important issues for clinical care of tiny room air has an SpO2 < 90 % at or after age 10 min,
preterm babies breathing supplemental O2 early in detailed evaluation should be performed
In term or near-term infants:
life and until the retina is mature is presented in When there is an absence of lung disease, there is no
Table 9. The challenges to try to keep actual SpO2 need to provide any supplemental O2
within the intended range most of the time must be It is recommended to start resuscitation with room air
overcome to improve infant safety. For this If significant lung disease is anticipated, use higher
FiO2 (i.e., 0.30–0.40)
to happen, it is necessary to ensure teamwork In tiny preterm infants: start with SpO2 of 0.21–0.30
among all neonatal healthcare providers and to Subsequently, in both term and preterm infants, adjust
include parents in the objective of avoiding FiO2 aiming to maintain preductal SpO2 within published
hyperoxemia in these tiny fragile infants. nomograms, as below:
1 min of age: 10th and 90th percentiles of SpO2 are
40–85 %
2 min of age: 10th and 90th percentiles of SpO2 are
33.9 Intention to Treat with SpO2 46–91 %
Target Ranges in the Delivery 3 min of age: 10th and 90th percentiles of SpO2 are
55–92 %
Room and in Other Neonatal 5 min of age: 10th percentile 73 % (90th percentile is
Conditions 97 %)
Age Preductal SpO2 in Preductal SpO2 in
All the measures to try to avoid both hypoxemia term newborns preterm newborns
and hyperoxemia are just as important as in 3 min 55–80 % 55–80 %
the delivery room during neonatal resuscitation, 5 min 75–90 % 75–85 %
in other neonatal conditions, and during endotra- 10 min 90–97 % 85–90 %
cheal tube suctioning, transport, anesthesia, sur- If CPAP is used in tiny infants breathing room air, the
increase in SpO2 occurs more rapidly than those
gery, and other procedures (Sola 2008). described above. No one knows whether this is of any
Indeed, specific guidelines for targeting SpO2 in benefit or whether it is actually risky because of faster
newborns soon after birth have recently been exposure to potential oxidation
recommended and are based on normal fetal oxy- Always decrease FiO2 if SpO2 > 93–95 %
gen physiology and the expected physiologic
changes during transition from intrauterine to extra-
uterine life. A summary is presented in Table 10. in both the preductal and postductal regions
During gestation, human fetuses have an extremely (Table 10). Infants born by elective cesarean deliv-
low SpO2, with the highest SpO2 in the umbilical ery take a bit longer to attain an SpO2 above 94%
vein (70–75%). Despite this relatively hypoxemic (Dawson et al. 2010, 2012; Vento et al. 2013;
environment, fetal tissues are not affected in this Saugstad et al. 2014).
state and are not hypoxic. Just before birth, the It is clear that in many cases there is no need to
SpO2 in the fetus is 60% and can decrease to 30% provide supplemental O2 during neonatal resuscita-
during labor. Healthy newborns cannot be expected tion, and less so 100% O2. A similar situation
to transition from fetal to neonatal life in a few occurs in periods of apnea, when the treatment is
seconds or minutes. In the postnatal transition to ventilate the alveoli (breathe) and circulate, but
period, the SpO2 to preductal tissues (brain, right not to give supplemental O2. Undeniably, many
arm, coronary arteries) is higher than postductal adult human beings have been successfully resus-
tissues. Then the SpO2 increases steadily but slowly citated by mouth-to-mouth resuscitation. In such
496 A. Sola and S. Golombek
cases the FiO2 is approximately 17% as a result of Table 11 Clinical recommendations for SpO2 targeting in
the CO2 in exhaled gas. Similarly, studies have found various neonatal conditions (without any published solid or
definitive evidence)
that O2 is not necessary in many cases of newborn
resuscitation (Rabi et al. 2007; Dawson et al. 2010, Apnea
2012; Vento et al. 2013; Saugstad et al. 2014). Start ventilation with the same FiO2 the infant was
receiving, even if it was room air
Several publications describe nomograms
CPAP and room air (FiO2 0.21)
for what is considered normal SpO2 during the SpO2 of 95–100 % is normal. If SpO2 < 94 %:
first minutes of life or transitional period from evaluate and decide if more pressure or supplemental
fetal to neonatal life (Table 10). Values were FiO2 or both are needed
obtained from preductal territory and are not Nasal cannula (high or low flow):
the same for term and preterm infants and vary As for CPAP, SpO2 of 95–100 % is normal in room air
according to mode of delivery and maybe even The FiO2 from the wall or from a blender does not match
the PiO2 in the airways and alveoli
sex (Rabi et al. 2007; Dawson et al. 2010, 2012;
When an infant is in the hospital and not close to
Vento et al. 2013; Saugstad et al. 2014). discharge, it is safer to use a blender and wean the FiO2
Because of study design issues and changes all the way to room air if the SpO2 > 95 %
that have occurred in the physiology of transi- If 100 % FiO2 is used, then the only alternative is to
tion by modifications in the time of cord decrease flow if SpO2 > 95 %, but this is more
clamping, the SpO2 values in the nomograms unpredictable
may change in the near future. However, hyp- Persistent pulmonary hypertension of the newborn and
congenital diaphragmatic hernia
oxemia should not be accepted during neonatal
SpO2 in the preductal territory (right hand) should be
resuscitation, and it is as important to avoid 91–96 %
hyperoxemia. For this reason, in all hospital Wean respiratory pressures and FiO2when the
settings, including birthing centers, a heater preductal SpO2 is >96 %
humidifier (to provide adequately conditioned Avoid using 100 % oxygen as much as possible
inhaled gas) and a blender (to accurately mea- Established BPD:
sure the dose of O2) are mandatory. In addition, Persistent hypoxia must be avoided because it can lead to
right ventricular hypertrophy, pulmonary
an adequate SpO2 monitor that can rapidly mea-
vasoconstriction and hypertension, cor pulmonale, and
sure SpO2 despite poor perfusion and motion is bronchoconstriction. When breathing supplemental
necessary to more accurately adjust the amount oxygen, it may be prudent to adjust the FiO2 to try
of supplemental O2. maintain SpO2 at approximately 91–96 %, cautiously
weaning the FiO2 when SpO2 > 95 %
Table 11 summarizes issues related to other
Suction of endotracheal tube:
neonatal practices and conditions in which careful
Do not “pre-oxygenate”
attention to FiO2 and SpO2 also needs to be con-
Avoid hypoxemia and hyperoxemia
sidered. Included are apnea, persistent pulmonary If SpO2 decreases do not increase FiO2 abruptly or
hypertension, BPD, and others. Currently, there is unnecessarily for recovery
no published solid definitive research that pro- Surgery and anesthesia:
vides concrete evidence for targeted SpO2 in Do not use preoxygenation
these clinical disorders. In general, in infants Avoid hypoxemia and hyperoxemia
beyond the immediate newborn period, supple- If SpO2 is 96–100 %, the FiO2 should be weaned
mental O2 should be decreased when SpO2
> 95%. Indeed, targeting a higher SpO2 range
>95% in preterm infants who were O2 dependent Hyperoxemia should not be induced in any neo-
with BPD conferred no significant benefit with nate before, during, and after endotracheal tube
respect to prevention of worsening ROP or suction or invasive procedures, including surgery,
improved growth and development. Worse so, it and it should not be caused in periods before and
resulted in worse pulmonary outcomes, increased after extubation. Preoxygenation is a dangerous and
burden on health services, and a greater need for ineffective practice for endotracheal tube suction,
medications (Askie et al. 2003) before or during anesthesia and before extubation,
33 Oxygen Saturation Monitoring in Neonatal Period 497
that should be eradicated in newborns of any ges- the avoidance and rapid treatment of hypoxemia
tational age, and this has been summarized else- but being extremely vigilant to avoid inducing or
where (Sola 2008). Lastly, as shown in Table 8, causing hyperoxemia and not allowing SpO2 to
practices that can lead to severe and prolonged be > 95% when supplemental O2 is used.
hyperoxemia, like nitrogen washout without any Most of the available evidence derived from
proven benefit in important outcomes of randomized clinical trials, physiology, and large
pneumothoraces and the hyperoxic challenge test descriptive studies have been the foundation for
to try to differentiate heart versus lung disease, what is included in this chapter with the aim to
should also be eliminated from clinical practice. provide tools for clinical practice. Based on the
Some recommendations for SpO2 targeting in var- available evidence and on thorough review of
ious neonatal conditions are shown in Table 11. each center’s own data, infant safety and out-
As much as the ideal and best SpO2 targets for comes can be improved. We cannot disregard
tiny preterm infants breathing O2 during the first that changes in clinical practice in O2 administra-
weeks after birth is still a matter of controversy, it tion and monitoring can improve outcomes, like
has been studied in much more detail than for any lower rates of severe ROP without an increase in
of the conditions mentioned in Tables 10 and 11. mortality or long-term morbidity. Decreasing
Therefore, we must be vigilant of future studies hyperoxemia and episodes of hypoxemia
that may find that some of these recommendations followed by hyperoxemia reperfusion from the
need to be modified. Additionally, five similarly time of birth will prevent many if not all of the
designed randomized controlled trials compared problems mentioned in the various sections and
only two SpO2 target ranges (intention to treat tables of this chapter.
85–89% versus 9–95%). The different results The limitations in the existing evidence (Sola and
reported partially or completely to date, and the Zuluaga 2013; Saugstad and Aune 2014; Schmidt
various publications that have analyzed such stud- et al. 2013, 2014a, b; Sola et al. 2014; Carlo
ies in detail, suggest that none of those SpO2 et al. 2010; Stenson et al. 2013; Darlow et al. 2014;
ranges of intention to treat should be chosen in Sola 2015; Lakshminrusimha et al. 2015; Manja
clinical practice. There are many more than these et al. 2015), and the fact that the “magic” SpO2
two possible SpO2targets and we should not keep range for all infants at all times is not truly known,
repeating the same mistakes of the past due to and it is likely that it will never be known, make it
simplification and immoderation. The observed essential that all recommendations in regard to FiO2
limitations in the existing evidence about optimal and SpO2 are meticulously reviewed. When infants
SpO2 in the premature infant early in life make it breathe supplemental O2, we must know the dose of
essential to avoid any firm recommendation. O2; avoid the use of pure, dry, and cold O2; and
Therefore the paragraphs in the section of “Inten- continuously monitor SpO2 with the best monitors
tion to Treat: SpO2 Target Ranges for Preterm available in the market. With this and a concerted
Infant” and the concepts in Table 9 should be team effort to try to avoid tissue hypoxia, significant
read and analyzed with great caution. fluctuations in SpO2, and hyperoxemia, many infants
will be healthier and safer.
33.10 Summary
References
Cellular oxygenation is complex and not easy to
assess in clinical practice. Hopefully, in the future Ahmed SJ, Rich W, Finer NN (2010) The effect of averag-
we will be able to do this better at the bedside. In ing time on oximetry values in the premature infant.
Pediatrics 125:e115–e121
the meantime, we must do everything possible to
Arawiran J, Curry J, Welde L, Alpan G (2015) Sojourn in
ensure sufficient O2 delivery to the tissues while excessively high oxygen saturation ranges in individ-
minimizing O2 toxicity and oxidative stress. There- ual, very low-birthweight neonates. Acta Paediatr 104
fore, the intention to treat should include not only (2):e51–e56
498 A. Sola and S. Golombek
Askie LM, Henderson-Smart DJ, Irwig L, Simpson JM de Wahl Granelli A, Wennergren M, Sandberg K,
(2003) Oxygen-saturation targets and outcomes in Mellander M, Bejlum C, Ingana L et al (2009) Impact
extremely preterm infants. N Engl J Med 349 of pulse oximetry screening on the detection of duct
(10):959–967 dependent congenital heart disease: a Swedish prospec-
Bancalari E, Claure N (2012) Control of oxygenation dur- tive screening study in 39,821 newborns. BMJ 338:
ing mechanical ventilation in the premature infant. Clin a3037
Perinatol 39:563–572 Deulofeut R, Critz A, Adams-Chapman I, Sola A (2006)
Baquero H, Alviz R, Castillo A, Neira F, Sola A (2011) Avoiding hyperoxia in infants < or 1⁄4 1250 g is asso-
Avoiding hyperoxemia during neonatal resuscitation: ciated with improved short- and long-term outcomes. J
time to response of different SpO2 monitors. Acta Perinatol 26(11):700–705
Paediatr 100(4):515–518 Deulofeut R, Dudell G, Sola A (2007) Treatment-by-gen-
Bizzarro MJ, Li FY, Katz K, Shabanova V, Ehrenkranz RA, der effect when aiming to avoid hyperoxia in preterm
Bhandari V (2014) Temporal quantification of oxygen infants in the NICU. Acta Paediatr 96(7):990–994
saturation ranges: an effort to reduce hyperoxia in the Eghbalian F (2014) A comparison of supine and prone
neonatal intensive care unit. J Perinatol 34(1):33–38 positioning on improves arterial oxygenation in pre-
Carlo WA, Finer NN, Walsh MC, SUPPORT Study Group mature neonates. J Neonatal Perinatal Med 7
of the Eunice Kennedy Shriver NICHD Neonatal (4):273–277
Research Network et al (2010) Target ranges of oxygen Ewer AK, Middleton LJ, Furmston AT, Bhoyar A, Daniels
saturation in extremely preterm infants. N Engl J Med JP, Thangaratinam S et al (2011) Pulse oximetry screen-
362(21):1959–1969 ing for congenital heart defects in newborn infants
Castillo A, Sola A, Baquero H et al (2008) Pulse oxygen (PulseOx): a test accuracy study. Lancet 378:785–794
saturation levels and arterial oxygen tension values in Farrow KN, Lee KJ, Perez M et al (2012) Brief hyperoxia
newborns receiving oxygen therapy in the neonatal increases mitochondrial oxidation and increases phos-
intensive care unit: is 85% to 93% an acceptable phodiesterase 5 activity in fetal pulmonary artery
range? Pediatrics 121(5):882–889 smooth muscle cells. Antioxid Redox Signal 17
Castillo A, Deulofeut R, Critz A, Sola A (2011) Prevention (3):460–470
of retinopathy of prematurity in preterm infants through Hagadorn JI, Furey AM, Nghiem TH, AVIOx Study Group
changes in clinical practice and SpO2 technology. Acta et al (2006) Achieved versus intended pulse oximeter
Paediatr 100(2):188–192 saturation in infants born less than 28 weeks’ gestation:
Chow LC, Wright KW, Sola A, CSMC Oxygen Adminis- the AVIOx study. Pediatrics 118(4):1574–1582
tration Study Group (2003) Can changes in clinical Hamel MS, Anderson BL, Rouse DJ (2014) Oxygen for
practice decrease the incidence of severe retinopathy intrauterine resuscitation: of unproved benefit and
of prematurity in very low birth weight infants? Pedi- potentially harmful. Am J Obstet Gynecol 211
atrics 111(2):339–345 (2):124–127
Clarke A, Yeomans E, Elsayed K, Medhurst A, Berger P, Hassan MA, Mendler M, Maurer M, Waitz M, Huang L,
Skuza E, Tan K (2015) A randomised crossover trial of Hummler HD (2015) Reliability of pulse oximetry
clinical algorithm for oxygen saturation targeting in during cardiopulmonary resuscitation in a piglet
preterm infants with frequent desaturation episodes. model of neonatal cardiac arrest. Neonatology 107
Neonatology 107(2):130–136 (2):113–119
Claure N, Bancalari E (2013) Role of automation in neo- Hay WW Jr, Rodden DJ, Collins SM, Melara DL, Hale
natal respiratory support. J Perinat Med 41(1):115–118 KA, Fashaw LM (2002) Reliability of conventional and
Claure N, Bancalari E (2015) Closed-loop control of new pulse oximetry in neonatal patients. J Perinatol 22
inspired oxygen in premature infants. Semin Fetal Neo- (5):360–366
natal Med 20(3):198–204 Kaindl AM, Sifringer M, Zabel C et al (2006) Acute and
Comroe JH Jr, Bahnson ER, Coates EO Jr (1950) Mental long-term proteome changes induced by oxidative
changes occurring in chronically anoxemic patients during stress in the developing brain. Cell Death Differ 13
oxygen therapy. J Am Med Assoc 143(12):1044–1048 (7):1097–1109
Darlow BA, Marschner SL, Donoghoe M, Benefits Of Ketko AK, Martin CM, Nemshak MA, Niedner M,
Oxygen Saturation Targeting-New Zealand (BOOST- Vartanian RJ (2015) Balancing the tension between
NZ) Collaborative Group et al (2014) Randomized hyperoxia prevention and alarm fatigue in the NICU.
controlled trial of oxygen saturation targets in very Pediatrics 136(2):e496–e504
preterm infants: two year outcomes. J Pediatr 165 Klimova NG, Hanna N, Peltier MR (2013) Effect of
(1):30–35, e2 oxygen tension on bacteria-stimulated cytokine pro-
Dawson JA, Kamlin CO, Vento M et al (2010) Defining the duction by fetal membranes. J Perinat Med 41
reference range for oxygen saturation for infants after (5):595–603
birth. Pediatrics 125(6):e1340–e1347 Klingel ML, Patel SV (2013) A meta-analysis of the effect
Dawson JA, Vento M, Finer NN et al (2012) Managing of inspired oxygen concentration on the incidence of
oxygen therapy during delivery room stabilization of surgical site infection following cesarean section. Int J
preterm infants. J Pediatr 160(1):158–161 Obstet Anesth 22(2):104–112
33 Oxygen Saturation Monitoring in Neonatal Period 499
Lakshminrusimha S, Manja V, Mathew B, Suresh GK and systematic review of the oxygen saturation target
(2015) Oxygen targeting in preterm infants: a physio- studies. Neonatology 105(1):55–63
logical interpretation. J Perinatol 35(1):8–15 Saugstad OD, Aune D, Aguar M, Kapadia V, Finer N,
Laman M, Ripa P, Vince J, Tefuarani N (2005) Can clinical Vento M (2014) Systematic review and meta-analysis
signs predict hypoxaemia in Papua New Guinean chil- of optimal initial fraction of oxygen levels in the
dren with moderate and severe pneumonia? Ann Trop delivery room at <32 weeks. Acta Paediatr 103
Paediatr 25:23–27 (7):744–751
Lim K, Wheeler KI, Gale TJ et al (2014) Oxygen satu- Schmidt B, Whyte RK, Asztalos EV, Canadian Oxygen
ration targeting in preterm infants receiving contin- Trial (COT) Group et al (2013) Effects of targeting
uous positive airway pressure. J Pediatr 164 higher vs lower arterial oxygen saturations on death
(4):730–736.e1 or disability in extremely preterm infants: a randomized
Lim K, Wheeler KI, Jackson HD, Sadeghi Fathabadi O, clinical trial. JAMA 309(20):2111–2120
Gale TJ, Dargaville PA (2015) Lost without trace: Schmidt B, Whyte RK, Roberts RS (2014a) Trade-off
oximetry signal dropout in preterm infants. Arch Dis between lower or higher oxygen saturations for
Child Fetal Neonatal Ed 100(5):F436–F438 extremely preterm infants: the first benefits of oxygen
Lye P, Bloise E, Dunk C et al (2013) Effect of oxygen on saturation targeting (BOOST) II trial reports its primary
multidrug resistance in the first trimester human pla- outcome. J Pediatr 165(1):6–8
centa. Placenta 34(9):817–823 Schmidt B, Roberts RS, Whyte RK, Canadian Oxygen
Manja V, Lakshminrusimha S, Cook DJ (2015) Oxygen Trial Group et al (2014b) Impact of study oximeter
saturation target range for extremely preterm infants: a masking algorithm on titration of oxygen therapy in
systematic review and meta-analysis. JAMA Pediatr the Canadian oxygen trial. J Pediatr 165
169(4):332–340 (4):666–671, e2
Narayen IC, Smit M, van Zwet EW, Dawson JA, Blom NA, Silverman WA (1980) Retrolental fibroplasia: a modern
te Pas AB (2015) Low signal quality pulse oximetry parable. Grune & Stratton, New York
measurements in newborn infants are reliable for oxy- Sola A (2008) Oxygen in neonatal anesthesia: friend or
gen saturation but underestimate heart rate. Acta foe? Curr Opin Anaesthesiol 21(3):332–339
Paediatr 104(4):e158–e163 Sola A (2015) Oxygen saturation in the newborn and the
Niermeyer S, Yang P, Shanmina D, Zhuang J, Moore LG importance of avoiding hyperoxia-induced damage.
(1995) Arterial oxygen saturation in Tibetan and Han NeoReviews 16:e393. https://doi.org/10.1542/neo.16-
infants born in Lhasa, Tibet. N Engl J Med 7-e393
333:1248–1252 Sola A, Zuluaga C (2013) Oxygen saturation targets and
Noh EJ, Kim YH, Cho MK et al (2014) Comparison of retinopathy of prematurity. J AAPOS 17:650–652
oxidative stress markers in umbilical cord blood after Sola A, Rogido MR, Deulofeut R (2007) Oxygen as a
vaginal and cesarean delivery. Obstet Gynecol Sci 57 neonatal health hazard: call for détente in clinical prac-
(2):109–114 tice. Acta Paediatr 96(6):801–812
Paul M (2015) Oxygen administration to preterm neonates Sola A, Saldeño YP, Favareto V (2008) Clinical practices
in the delivery room: minimizing oxidative stress. Adv in neonatal oxygenation: where have we failed? what
Neonatal Care 15(2):94–103 can we do? J Perinatol 28(Suppl 1):S28–S34
Phibbs RH (1977) Oxygen therapy: a continuing hazard to Sola A, Golombek SG, Montes Bueno MT et al (2014) Safe
the premature infant. Anesthesiology 47(6):486–487 oxygen saturation targeting and monitoring in preterm
Polin RA, Bateman DA, Sahni R (2014) Pulse oximetry in infants: can we avoid hypoxia and hyperoxia? Acta
very low birth weight infants. Clin Perinatol 41 Paediatr 103(10):1009–1018
(4):1017–1032 Spector LG, Klebanoff MA, Feusner JH, Georgieff MK,
Rabi Y, Rabi D, Yee W (2007) Room air resuscitation of Ross JA (2005) Childhood cancer following neonatal
the depressed newborn: a systematic review and meta- oxygen supplementation. J Pediatr 147(1):27–31
analysis. Resuscitation 72(3):353–363 Stenson BJ, Tarnow-Mordi WO, Darlow BA, BOOST II
Rawat M, Chandrasekharan PK, Williams A, Gugino S, United Kingdom Collaborative Group; BOOST II
Koenigsknecht C, Swartz D, Ma CX, Mathew B, Australia Collaborative Group; BOOST II
Nair J, Lakshminrusimha S (2015) Oxygen saturation New Zealand Collaborative Group et al (2013) Oxygen
index and severity of hypoxic respiratory failure. Neo- saturation and outcomes in preterm infants. N Engl J
natology 107(3):161–166 Med 368(22):2094–2104
Samiee-Zafarghandy S, Saugstad OD, Fusch C (2015) Do Suwattanaphim S, Yodavuhd S, Puangsa-art SJ (2015)
we have an answer when it comes to providing Time duration of oxygen adaptation immediately after
extremely preterm infants with optimal target oxygen birth; monitoring by pulse oximeter in perinatal period
saturation? Acta Paediatr 104(3):e130–e133 of the infants at Charoenkrung Pracharak Hospital. J
Saugstad OD (2007) Take a breath—but do not add oxygen Med Assoc Thai 98(7):656–663
(if not needed). Acta Paediatr 96(6):798–800 Synnes A, Miller SP (2015) Oxygen therapy for preterm
Saugstad OD, Aune D (2014) Optimal oxygenation of neonates: the elusive optimal target. JAMA Pediatr
extremely low birth weight infants: a meta-analysis 169(4):311–313
500 A. Sola and S. Golombek
Terrill PI, Dakin C, Hughes I, Yuill M, Parsley C (2015) published nomogram. Arch Dis Child Fetal Neonatal
Nocturnal oxygen saturation profiles of healthy term Ed 98(3):F228–F232
infants. Arch Dis Child 100(1):18–23 Wellmann S, Bührer C, Schmitz T (2014) Focal necrosis
Thomson L, Paton J (2014) Oxygen toxicity. Paediatr and disturbed myelination in the white matter of new-
Respir Rev 15(2):120–123 born infants: a tale of too much or too little oxygen.
Vagedes J, Poets CF, Dietz K (2013) Averaging time, Front Pediatr 2(14):143
desaturation level, duration and extent. Arch Dis Wollen EJ, Kwinta P, Bik-Multanowski M, Madetko-
Child Fetal Neonatal Ed 98:F265–6 Talowska A, Sejersted Y, Wright MS et al (2014)
Van Den Brenk HA, Jamieson D (1962) Potentiation Hypoxia-reoxygenation affects whole-genome expres-
by anaesthetics of brain damage due to breathing sion in the newborn eye. Invest Ophthalmol Vis Sci
high-pressure oxygen in mammals. Nature 55(3):1393–1401
194:777–778 Yalcin S, Aydoğan H, Kucuk A et al (2013) Supplemental
van Kaam AH, Hummler HD, Wilinska M, Swietlinski J, oxygen in elective cesarean section under spinal anes-
Lal MK, te Pas AB, Lista G, Gupta S et al (2015) thesia: handle the sword with care [in Spanish]. Rev
Automated versus manual oxygen control with dif- Bras Anestesiol 63(5):393–397
ferent saturation targets and modes of respiratory Zapata J, Gómez JJ, Araque Campo R, Matiz Rubio A,
support in preterm infants. J Pediatr 167 Sola A (2014) A randomised controlled trial of an
(3):545–550.e1-2 automated oxygen delivery algorithm for preterm neo-
Vento M (2014) Oxygen supplementation in the nates receiving supplemental oxygen without mechan-
neonatal period: changing the paradigm. Neonatology ical ventilation. Acta Paediatr 103(9):928–33
105(4):323–331 Zhang L, Mendoza-Sassi R, Santos JC, Lau J (2011)
Vento M, Cubells E, Escobar JJ et al (2013) Oxygen Accuracy of symptoms and signs in predicting
saturation after birth in preterm infants treated with hypoxaemia among young children with acute respi-
continuous positive airway pressure and air: assess- ratory infection: a meta-analysis. Int J Tuberc Lung
ment of gender differences and comparison with a Dis 15:317–325
Part III
Nutrition
Physiology of the Gastrointestinal
Tract in Newborns 34
Arieh Riskin, Carlo Agostoni, and Raanan Shamir
Contents
34.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504
34.2 Development of the Gastrointestinal Tract: Organogenesis and
Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
34.3 Vascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
34.4 Neural Control of Motor Function and
Gastrointestinal Motility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509
34.4.1 Myogenic Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509
34.4.2 Enteral Nervous System (ENS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 510
34.4.3 Central Nervous System (CNS) Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511
34.4.4 Gastrointestinal Motility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511
34.5 Digestion and Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
34.5.1 Fat Digestion and Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
34.5.2 Protein Digestion and Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517
34.5.3 Carbohydrate Digestion and Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518
A. Riskin (*)
Department of Neonatology, Bnai Zion Medical Center,
Rappaport Faculty of Medicine, Technion, Israel Institute
of Technology, Haifa, Israel
e-mail: [email protected]; [email protected]
C. Agostoni
Pediatric Clinic, Department of Clinical Sciences and
Community Health, University of Milan Fondazione,
IRCCS Ca Granda, Ospedale Maggiore Policlinico,
Milano, Italy
e-mail: [email protected]
R. Shamir
Institute of Gastroenterology Nutrition and Liver Diseases,
Schneider Children’s Medical Center, Sackler Faculty of
Medicine, Tel-Aviv University, Petach-Tikva, Israel
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 503
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_183
504 A. Riskin et al.
34.5.4 Micronutrient Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519
34.6 Host Defense . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 528
Abstract followed by folding that forms the villi and
The chapter will discuss the different elements microvilli. However, functional maturation,
of the developmental physiology of the gastro- including the appearance of digestive enzymes
intestinal tract, including organogenesis, vas- in the villi and the development of swallowing
cularization, neural control, and host defense and mature motility patterns, occurs much later
mechanisms. The development of gastrointes- than structural development; some functions
tinal motility and of the digestive and absorp- are not fully established until 2–4 years of age.
tive functions and how they relate to feeding • Mechanisms regulating intestinal vascular
and nutrition of the preterm and term neonates resistance in the neonate are nitric oxide,
will be outlined. Aspects of morphology, phys- endothelin, and calcium-induced phosphoryla-
iology, and biochemistry of the developing tion of myosin light chain kinase.
gastrointestinal tract as well as more recent • Mesenteric blood flow is regulated by changes
findings at the molecular biology level will be in the tone of the arteriole and the precapillary
discussed. Application of this basic knowledge sphincter.
on intestinal functional development should be • Peristaltic activity allows intestinal contents to
used in order to improve nutrition for preterm move along the intestine and can occur through
infants and prevent short- and long-term mor- a variety of mechanisms regulated by enteric
bidities that may be related to inadequate or nervous system, a subsystem of the autonomic
poor feeding and nutrition: system that includes two major nerve plexuses
situated in the bowel wall.
(A) Development of the gastrointestinal tract – • Gastrointestinal motility, secretion, and vascu-
organogenesis and function lar flow are controlled by the central nervous
(B) Vascularization and enteric nervous systems, comprising affer-
(C) Neural control of motor function and gas- ent sensory neurons, efferent motor neurons,
trointestinal motility synapses to the effector (e.g., muscle) cells,
(D) Digestion and absorption and interneurons that integrate the messages.
(E) Host defense • Between 24 and 28 weeks’ gestation, only
(F) Gastrointestinal hormones and peptides unorganized irregular contractions are
(These are discussed in ▶ Chap. 35, “Hor- recorded with few quiescent intervals. By
mones and Gastrointestinal Function of 28–32 weeks, periods of quiescence appear,
Newborns”) alternating with short bursts of phasic activity
called clusters. Between 32 and 36 weeks,
motor patterns become more organized and
34.1 Salient Points the periods of quiescence and clusters
lengthen. Migratory-motor complexes are first
• The gastrointestinal tract develops from the seen around 33 weeks.
primitive digestive tube that originates from • Lingual and gastric lipases are essential for the
the dorsal part of the yolk sac. By the second digestion of milk fat in the newborns. They are
trimester, all anatomic structures of the gastro- present from as early as 26 weeks’ gestation
intestinal tract are well formed and recogniz- and compensate for the limited action of bile
able. The process of maturation involves a acids and pancreatic lipases that are found in
rapid increase in the mucosal surface area low amounts, especially in preterm infants.
34 Physiology of the Gastrointestinal Tract in Newborns 505
The contribution of lingual lipase declines sig- attached to the midgut of the digestive tube, but
nificantly later in life. as early as the fourth week of gestation, the gut
• Proteolysis in the stomach is affected by gastric becomes distinct from the yolk sac. The yolk sac
content and motility and most importantly by is connected to the digestive tube through the
gastric acidity. The pH of gastric juice is neu- omphalomesenteric (vitelline) duct. The dorsal
tral or slightly acid at birth and decreases mesentery separates the digestive tube from the
within hours. Gastric acid flow doubles during dorsal wall of the embryo, and at this stage there is
the next 2 months. also a ventral mesentery that separates the anterior
• Lactase activity appears in the differentiating part from the ventral embryonic wall. Continuity
brush border of the fetal small intestine along with the exterior environment is formed only after
with other disaccharidases as from early as 12 the rupture of the buccopharyngeal and cloacal
weeks of gestation, although in low levels. membranes. The anatomic formation of the
Lactase activity exhibits relatively higher esophagus, stomach, intestine, pancreas, and
levels from 37 weeks of gestation. However, liver is achieved by the fourth week through a
lactase activity remains decreased during the series of evaginations, elongations, and dilata-
first weeks after birth, and this is reflected by tions. Further development through cell prolifera-
the limited capacity of term and especially tion, growth, and morphogenesis then follows.
preterm infants to digest and absorb lactose in The pharynx, esophagus, stomach, liver, gall-
the small intestine. bladder, pancreas, and upper duodenum originate
• Prenatal exposure of the gut to bacteria may from the foregut. The distal portion of the duode-
modulate postnatal adaptations inducing toler- num, jejunum, ileum, cecum, appendix, and
ance toward colonization of certain bacteria. ascending colon and two-thirds of the transverse
Aberrant bacterial colonization immediately colon arise from the midgut. The hindgut differen-
after birth may lead to feeding intolerance in tiates into the third distal part of the transverse
a newborn. colon, the descending colon, the sigmoid colon,
• Defense factors in human milk include antimi- the upper two-thirds of the rectum, and the urogen-
crobial agents, anti-inflammatory factors, ital sinus (Beck 2002). Arterial supply delineates
immunomodulators, and leukocytes. Gastric the boundaries: the celiac axis supplies the foregut,
acidity and pancreato-biliary secretions and the superior and inferior mesenteric arteries
decrease the load of viable microorganisms supply the midgut and hindgut, respectively.
and intact dietary protein antigens. The rapid elongation of the gut during the first
• The use of probiotics significantly reduces the trimester leads to its herniation into the umbilical
occurrence of NEC and death in VLBW pre- cord. The gut reenters into the abdominal cavity
mature infants. and rotates counterclockwise around the superior
• More randomized trials on preterm infants are mesenteric artery to reach its final position by
needed to support the potential beneficial 20 weeks of gestation (Fig. 1). Failure of this
effects of prebiotics on feeding tolerance and process results in malrotation.
the reduced incidence of NEC and hospital- By the second trimester, all the anatomic struc-
acquired infections. tures of the gastrointestinal tract are well formed
and recognizable. The process of maturation
involves rapid increase in the mucosal surface
34.2 Development area followed by folding forming the villi and
of the Gastrointestinal Tract: microvilli. However, functional maturation,
Organogenesis and Function including the appearance of digestive enzymes
in the villi and the development of swallowing
The gastrointestinal tract develops from the prim- and mature motility patterns, occurs much later
itive digestive tube that originates from the dorsal than structural development; some functions are
part of the yolk sac. Initially the yolk sac is not fully established until 2–4 years of age.
506 A. Riskin et al.
a Aorta b Aorta
Foregut
Celiac Axis Celiac Axis
Umbilical Orifice
Prearterial Mesentery Superior Mesenteric Artery
Superior Mesenteric Artery
Midgut Duodeno-Colic
Vitelline Duct Boundaries of Midgut Isthmus Umbilical Orifice
and Artery Inferior Mesenteric Artery
Inferior Mesenteric Artery Prearterial
Postarterial Mesentery Hindgut Mesentery
Hindgut
(Stippled)
Postarterial
Mesentery
c d Aorta
Aorta
Superior Mesenteric
Artery Umbilical Orifice Superior Mesenteric
Artery
Postarterial
Mesentery
Small Intestine
Re-Entering Abdomen
Behind Mesenteric
Artery Prearterial
Mesentery
Cecum Retained in
Umbilical Sac
Fig. 1 Diagram showing normal rotation of alimentary temporary umbilical hernia is in the process of reduction;
tract. (a) Fifth week of intrauterine life (lateral view). The the most proximal part of the prearterial segment entering
foregut, midgut, and hindgut are shown with their individ- the abdomen to the right of the superior mesenteric artery is
ual blood supply supported by the common dorsal mesen- held forward close to the cecum and ascending colon,
tery in the sagittal plane. The midgut loop has been permitting the bowel to pass under it. As the coils of
extruded into the umbilical cord. (b) Eighth week of intra- small intestine collect within the abdomen, the hindgut is
uterine life (anteroposterior view). The first stage of rota- displaced to the left and upward. (d) Eleventh week of
tion is being completed. Note the narrow duodenocolic intrauterine life at the end of the second stage of rotation.
isthmus from which the midgut loop depends and the From its original sagittal position, the midgut has rotated
right-sided position of the small intestine and left-sided 270 degrees in a counterclockwise direction about the
position of the colon. Maintenance of this position within origin of the superior mesenteric artery. The essentials of
the abdomen after birth is termed nonrotation. (c) About the permanent disposition of the viscera have been
the 10th week of intrauterine life, during the second stage attained. (Originally from Gardner and Hart (1934), Copy-
of rotation (anteroposterior view). The bowel in the right American Medical Association)
Maturation tends to follow a cephalocaudal pro- the advantages of breast milk with its immuno-
gression from the proximal to the distal part of the logic and trophic growth factors to the newborn
gastrointestinal tract (Table 1). (Calder et al. 2006). At the cellular level, regula-
The regulation of timing and nature of growth tion occurs by homeodomain transcription factor
and maturation of the gastrointestinal tract is genes (Beck 2002) and cell to cell interactions,
complex and involves many factors. These especially epithelial-mesenchymal interactions
include not only intrinsic factors like signals (de Santa et al. 2003). The pluripotent stem cell
arising from gene expression (Montgomery located in the crypt of the villus continuously
et al. 1999), biologic clock or regulatory hor- differentiates into the four gut cell lineages:
mones, and peptide growth factors but also absorptive enterocytes, mucous (goblet), Paneth,
extrinsic environmental factors acting also at and endocrine cells (Simon-Assmann
the molecular level. The gastrointestinal tract is et al. 2007). This process that involves continu-
in continuity with the environment; the fetal gut ous proliferation, migration, and loss of epithe-
is thus exposed to the amniotic fluid content as lial cells along the mucosal surface is also
the neonatal gut is exposed to enteral feedings, regulated genetically by homeodomain tran-
nutrients, and even microbes. This is related to scription factors (Beck 2002).
34 Physiology of the Gastrointestinal Tract in Newborns 507
Table 1 Anatomic and functional maturation of the gastrointestinal tract (Originally Table 70.1 page 1073 from Berseth
(2005), now Copyright Elsevier
Postconceptional age (weeks)
15 20 25 30 35 40
Mouth Salivary glands Swallow Lingual lipase Sucking
Esophagus Muscle layers present Striated Poor lower esophageal
epithelium sphincter tone
present
a
Stomach Gastric glands present G cells appear Gastric secretions present Slow gastric
emptying
a
Pancreas Exocrine and endocrine Zymogen present Reduced trypsin lipase
tissue differentiate
a
Liver Lobules form Bile secreted Fatty acids absorbed
Intestine Crypt and villus form Glucose Dipeptidase, sucrase, and Lactase active
transport present maltase active
Colon Crypts and villi Meconium
recede passed
Reproduced with permission from Berseth, CL. Developmental anatomy and physiology of the gastrointestinal tract. In:
Taeusch HW, Ballard RA (eds) Avery’s diseases of the newborn, 8th edn. W.B. Saunders Company. Philadelphia,
Copyright W.B. Saunders
Italics indicate functional maturation
a
Full functional maturation occurs postnatally
For detailed aspects on structural anatomic it is still the most sensitive layer to any derange-
development of the different parts and organs ments in blood supply.
along the gastrointestinal tract, refer to the first Based on animal studies, it is assumed that
chapters in section on the gastrointestinal tract, intestinal basal vascular resistance decreases in
where congenital malformations are discussed. the immediate postnatal period, thus doubling
blood flow and oxygen delivery in the neonate to
compensate for the higher metabolic activity
34.3 Vascularization related to nutrient absorption that was not needed
in fetal life. However, later on between postnatal
Vascular supply to the intestine develops concur- days 12–30 vascular resistance increases again
rently with its anatomic development. The arterial due to maturation of the intestinal extrinsic adren-
supply develops as three ventral out-buddings of ergic innervation, as well as changes in the geom-
vessels from the aorta: The celiac trunk supplies etry of the intestinal vasculature in response to the
the stomach, pancreas, and duodenum via its rapid increase in size (length and surface area) of
splenic, left gastric, and hepatic branches; the the gut that happens concomitantly (Reber
superior mesenteric artery supplies the jejunum et al. 2002).
and ileum; and the inferior mesenteric artery sup- Basal vascular resistance is mediated by nitric
plies the colon and rectum. Smaller branches of oxide (NO) that is continuously produced by the
the superior mesenteric artery form arcades before endothelial cell NO synthase isoform (ecNOS) or
entering the intestinal wall that along with anas- is increased in response to mechanical or chem-
tomoses with branches of the inferior mesenteric ical stimuli. NO causes vasodilatation of the
artery provide rich collateral flow. Watershed adjacent vascular smooth muscle via production
areas of marginal blood supply however exist in of cGMP by activated guanylate cyclase. Rates
the distal transverse colon and upper rectum. of NO production and its relaxation effect on the
Since there is high metabolic activity in the intes- mesenteric artery bed are maximal immediately
tinal mucosal layer, it has rich vascular supply, yet after birth. Its role in determining vascular tone
508 A. Riskin et al.
lessens over the first month of life. The essential precapillary sphincter. Control of blood flow is
role of endothelial production of NO in intrinsic and extrinsic (Reber et al. 2002). Intrin-
maintaining newborn intestinal hemodynamics sic control is achieved by local factors that react
may be important in the pathogenesis of necro- to changes in arterial pressure (pressure-flow
tizing enterocolitis (NEC), because endothelial autoregulation) and tissue oxygenation, such as
dysfunction that would limit NO production may functional postprandial hyperemia in response to
lead to vasoconstriction and substantial intestinal feeding or reactive hyperemia in response to
ischemia (Reber et al. 2002). vessel occlusion. Modest arterial hypoxemia
Individual vascular smooth muscle cells (PO2 around 50 mmHg) causes vasodilatation
respond to stretch stimulus by contracting via and increased perfusion to the gut, yet profound
stimulation of calcium-induced phosphorylation hypoxemia (PO2 < 40 mmHg) causes vasocon-
of myosin light chain kinase (Davis and Hill striction and gut ischemia. These different
1999). This intrinsic myogenic response is the responses probably reflect NO regulation of vas-
second mechanism mediating vascular response cular tone (Reber et al. 2002). Extrinsic regula-
in the neonatal intestine, and it has important role tion is mediated by sympathetic input from the
in setting basal intestinal vascular resistance in the splanchnic nerves. However, the vasoconstric-
first days of life (Reber et al. 2002). It causes tion response to adrenergic nerve stimulation is
vasoconstriction in response to increase in intra- short-lived, and gut blood flow is slowly restored
vascular pressure in some of the blood vessels. to its baseline by a process termed autoregulatory
Endothelin, the third mediator of vascular escape.
resistance, is a vasoactive peptide mainly pro- Circulating endogenous and exogenous fac-
duced by the vascular endothelium. ET-1, the tors (e.g., hormones, histamine, and prostaglan-
intestinal form, is continuously produced by the dins) can also modulate vascular tone. The
intestinal vascular endothelium in an age-specific presence of nutrients in the gut triggers the post-
manner. Its production is greater in young sub- prandial hyperemic response with brisk vasodi-
jects, especially in newborns, probably reflecting latation and increased blood flow and oxygen
its essential role in angiogenesis at this time of delivery. Postprandial hyperemia in the newborn
exceptionally rapid growth of the intestine. is mediated by dilatation of the intestinal circu-
Endothelin binding to ETA receptors on vascular lation in response to substance P, which is a
smooth muscle induces potent sustained contrac- peptide neurotransmitter in the enteric nervous
tion, while its binding to ETB receptors causes system (Nowicki 1998). Both postprandial
NO-mediated vasodilatation. The force of ETA- hyperemia and autoregulatory escape phenom-
induced vasoconstriction exceeds the modest ena are present in newborns. However, unlike
ETB-induced NO-dependent vasodilatation; thus, term infants, healthy preterm infants require
the net effect of constitutive ET-1 production is compensatory systemic hemodynamic changes
vasoconstriction (Nankervis and Nowicki 2000). in response to feeding and postprandial hyper-
The significance of these three mechanisms emic response because the increased mesenteric
regulating intestinal vascular resistance in the flow causes cardiac output increase and systemic
neonate is markedly diminished after the first blood pressure decrease (Martinussen
postnatal month of life. Thereafter, the greater et al. 1996). Drugs used in neonatal care such
degree of extrinsic adrenergic innervation as indomethacin (Gork et al. 2008), dopamine,
causes increased basal vascular resistance and caffeine (Hoecker et al. 2002) as well as
with more robust responses to baro- and other treatments (e.g., hyperalimentation and
chemoreflexes. CPAP) (Havranek et al. 2006) may diminish
Mesenteric blood flow is regulated by intestinal mesenteric blood flow, thus disrupting
changes in the tone of the arteriole and the compensatory mechanisms.
34 Physiology of the Gastrointestinal Tract in Newborns 509
34.4 Neural Control of Motor 34.4.1 Myogenic Control
Function and Gastrointestinal
Motility Contractile activity can also propagate toward the
anus in association with propagating slow-wave
A major function of the gut is motor activity that activity (Siegle et al. 1990), expressing myogenic
moves the content forward along the gastrointesti- control. Muscle cells generate this spontaneous
nal tract. This includes sucking, swallowing, gastric electrical activity through fluctuations in resting
emptying, propagation of the food along the small membrane potential, and these periodic depolar-
intestine, and evacuation of wastes from the colon. izations are called slow waves, electrical control
Neural crest cells migrate into the developing gut activity, basic electrical rhythm, or pacemaker
and with muscle cells differentiate to form three activity. This myogenic pacemaker slow-wave
layers of muscle that surround the mucosa (by activity originates from specialized smooth mus-
14 weeks of gestation) and a neural network that cle cells, the interstitial cells of Cajal (ICC)
control motor activity (by 20–24 weeks of gesta- (Lecoin et al. 1996), that form an electrical syn-
tion). This neural network comprises the enteric cytium with the smooth muscle layers. The net-
nervous system (ENS). The phasic contractions of work of ICC is also associated with Auerbach’s
the gastrointestinal tract are regulated by a complex plexus (Huizinga et al. 1995). There is evidence
interplay between the myogenic, neural, and chem- that the absence of ICC network may contribute to
ical control mechanisms (Sarna and Otterson 1988). abnormalities in intestinal transit in humans,
Peristaltic activity allows intestinal contents to including infantile hypertrophic pyloric stenosis
move along the intestine and can occur through a and Hirschsprung’s disease (Vanderwinden
variety of mechanisms. Phasic contractions are et al. 1996a, b). The fact that ICC are always
responsible for the mixing and propulsive move- very intimately associated with neural structures
ments of the gut after a meal. These are called suggests a close cooperation between myogenic
migrating action potential complexes (MAPCs), and neural control. Contractions occur when a
and they are prominent postprandially (Sarna and slow wave under the influence of a neural or
Otterson 1988; Huizinga et al. 1998). During chemical stimulation exceeds the excitation
fasting, organized groups of contractions called threshold necessary for an action potential called
cyclic motor activity and migrating motor complex electrical response activity or spike potential.
(MMC) keep the upper digestive tract clean of Following this depolarization of the smooth
residual food and debris (Sarna and Otterson 1988; muscle cell, intracellular calcium levels increase,
Huizinga et al. 1998). MMC cyclic motor contrac- calcium binds to the regulatory protein calmod-
tions originate from the antrum and progress to the ulin, and this permits the binding of the contrac-
ileum. They are characterized by periods of quies- tile proteins actin and myosin, resulting in a
cence followed by irregular contractions and then a contraction. It can be seen that the contraction
period of regular contractions and return to the caused by the electrical response activity occurs
quiescent state. In addition, the small intestine and on the background of the electrical control activ-
the colon generate giant migrating contractions ity, i.e., the slow waves of myogenic control
which are several-fold stronger than the postprandial (Sarna and Otterson 1989). This background
phasic contractions and migrate uninterrupted over slow-wave activity controls timing, speed, and
long distances. The giant migrating contractions are direction of the intestinal contractions. There is
effective in rapid propulsion. The upper small intes- probably cooperation between the neural and
tine and the gastric antrum may also generate retro- myogenic control of intestinal motility to ensure
grade giant contractions that generally precede proper transit (Huizinga et al. 1998). Denervated
vomiting (Sarna and Otterson 1988). Movements gut muscle cell has thus basal contraction rate
of MMCs and MAPCs are orchestrated by the ENS. like cardiac muscle cell.
510 A. Riskin et al.
34.4.2 Enteral Nervous System (ENS) is a main inhibitory neurotransmitter. Nitric oxide
(NO) mediates non-adrenergic non-cholinergic
The ENS is a subsystem of the autonomic system (NANC) relaxation of gastrointestinal smooth
that includes two major nerve plexuses situated in muscle (Stark et al. 1993). NO synthase (NOS)
the bowel wall. The myenteric (Auerbach) plexus and NO-containing enteric neurons have been
lies between the external circular and longitudinal demonstrated in the ENS (Vanneste et al. 2008).
muscle layers, and the submucosal (Meissner) Vasoactive intestinal peptide (VIP), another inhib-
plexus lies between the circular muscle layer and itory neurotransmitter, may mediate NO effects
the muscularis mucosa. The ENS also includes six (Grider and Murthy 2008). The absence of NO
minor plexuses located in the different layers of the has been implicated in the pathogenesis of infantile
bowel wall (Fig. 2). The ENS is integrated within hypertrophic pyloric stenosis (Saur et al. 2004) and
the central nervous system (CNS) control of the gut, Hirschsprung’s disease (VanderWall et al. 1995).
but it also provides the final regulation and is even Enteric neurons and glial cells of the ENS orig-
able to regulate gut motility, secretion, and vascular inate from the neural crest (Anderson et al. 2006).
flow independent of the CNS and spinal nervous Cells from the vagal region migrate to the whole
control. The ENS with its large number of neurons length of the gastrointestinal tract, but cells from
compared to the relatively sparse central innerva- the truncal and sacral regions populate only the
tion of the gut is thus termed the “little brain of the foregut and the post-umbilical hindgut, respec-
gut,” stressing its uniqueness compared to other tively (Gershon et al. 1993). Like intestinal smooth
peripheral nerve systems (Holle and Forth 1990). muscle development, neural cells from the vagal
The basic unit of the ENS is the nerve region develop in a craniocaudal direction, as
cell. Neurotransmitters are released to other opposed to neural cells originating from the sacral
neurons or directly act upon striated or smooth region that migrate into the distal bowel in a caudo-
muscle cells. Acetylcholine is the main excitatory cranial direction. Neural cells that migrate from the
neurotransmitter mediating smooth muscle con- outer mesenchyme of the gut to the inner mucosa
tractions (Vanneste et al. 2008). Glutamate is also proliferate. At this stage, the cells are pluripotent and
an excitatory neurotransmitter acting on N-methyl- transiently express catecholamines (Baetge
D-aspartate (NMDA)-type receptors in the et al. 1990). Later in gestation, the neural cells in
myenteric plexus in conjunction with cholinergic the gut wall mature and differentiate into enteral
stimuli (Wiley et al. 1991). Glutamate can be syn- neurons that do not express catecholamines anymore.
thesized from exogenous L-glutamine in myenteric Differentiated neurons express serotoninergic and
neurons and be released in response to neuronal peptidergic (e.g., substance P and neuropeptide Y)
depolarization (Wiley et al. 1991). Norepinephrine neurotransmitters. Some of the neural crest-
Fig. 2 Arrangement of
enteric plexuses in whole Paravascular Nerve Perivascular Nerves
mounts of intestine. In
addition to the large
myenteric and submucosal Mesentery
plexuses, several smaller Subserous Nerve
plexuses are shown.
(originally from Furness Myenteric
and Costa (1987), now Plexus
Copyright Elsevier) Submucous
Plexus
Deep Muscular
Mucosal Plexus
Plexus
34 Physiology of the Gastrointestinal Tract in Newborns 511
derived cells that colonize the fetal bowel cluster (Altschuler et al. 1989). They reach the liver,
and form ganglion cells that form the two gangli- gallbladder, and pancreas too. Splanchnic affer-
onated plexuses described above (Faure ents innervate the mucosal and muscular layers,
et al. 2007). These ganglion cells are distributed the serosa, and the bowel mesenterium. Motor
normally by 24 weeks gestation, although their innervation is made of sympathetic and parasym-
density continues to change over the first years of pathetic components of the autonomic nervous
life (Wester et al. 1999). In the human fetus by the system. Preganglionic sympathetic neurons are
tenth week of gestation, the circular muscle layer found in segments T2-L2 of the spinal cord. Post-
is formed, followed by the appearance of a prim- ganglionic sympathetic neurons are found in the
itive myenteric plexus and the longitudinal prevertebral sympathetic trunk (celiac, superior,
smooth muscle layer in the 12th week of gesta- and inferior mesenteric ganglia). Preganglionic
tion. Most neurons in the myenteric ganglia at the parasympathetic neurons are present in the
tenth week of gestation are undifferentiated medulla and in the sacral region of the spinal
neuroblasts. The time between the 10th and 18th cord. Postganglionic parasympathetic neurons
week of gestation is important for both morpho- are located within the gastrointestinal tract. Most
logical and functional maturation of the ENS. In of the parasympathetic innervation of the gut
the 18-week-old human fetus, most neurons in the comes from the vagus. Vagal efferents end up in
myenteric ganglia are already differentiated and the enteric ganglia of the ENS (Kirchgessner and
mature, and the organization of smooth muscle Gershon 1989). Sacral nerves innervate only the
cells and the primary strands of the myenteric distal colon from the middle of the transverse
plexus provide a satisfactory basis for an inte- colon. Since the vagus innervates most of the gut
grated peristaltic movement that is already seen and has both afferent and efferent fibers, it needs
in the gut (Fekete et al. 1996). Neurotransmitters precise central viscerotropic organization of
are evident by 24–26 weeks, although their distri- inputs and outputs. Afferent fibers reach the
bution along the gut may change and reach adult nucleus tractus solitarius and the vagal sensory
pattern only close to term. nucleus. Efferent fibers originate from the motor
Abnormalities in migration and differentiation nuclei and dorsal motor nucleus of the vagus and
of neural crest cells may cause a number of gas- the nucleus ambiguous (Altschuler et al. 1989;
trointestinal disorders (Newgreen and Young Berthoud et al. 1990). The nucleus tractus
2002a, b), and the main one is Hirschsprung’s solitarius is an important synaptic site where inter-
disease that results from the absence of enteric neurons coordinate afferent inputs with efferent
ganglia in the distal hindgut. outputs delivered to the nucleus ambiguous and
the dorsal motor nucleus of the vagus in order to
control esophageal and gastrointestinal motility.
34.4.3 Central Nervous System (CNS) Glutamate, an excitatory amino acid, is consid-
Control ered one of the neurotransmitters involved in this
brain-stem synaptic transmission via NMDA
CNS and ENS that control gastrointestinal motil- receptors, specifically involved in esophageal
ity, secretion, and vascular flow consist of afferent motor activity in response to swallowing (Kessler
sensory neurons, efferent motor neurons, synap- 1993).
ses to the effector (e.g., muscle) cells, and inter-
neurons that integrate the messages. Sensory
afferent fibers travel with parasympathetic pre- 34.4.4 Gastrointestinal Motility
ganglionic fibers in the vagus nerve and sympa-
thetic postganglionic fibers in the splanchnic The motor activity of the gastrointestinal tract is
nerves. Vagal afferents conduct impulses from critical for feeding, digestion, and absorption of
the mucosal and muscular layers of the whole nutrients. It is responsible for the transit of food
gut, from the soft palate to the distal colon from the esophagus, the stomach, and then
512 A. Riskin et al.
throughout the intestine and promotes mixing of maturation of gastric emptying, gastric antral and
the nutrients with pancreatic, biliary, and intesti- small intestinal motility, and stimulation of secre-
nal secretions. Smooth muscles of the intestine are tion of gastrointestinal enzymes and peptides that
arranged in outer longitudinal and inner circular enhance weight gain as well. Early introduction of
layers. They develop in a craniocaudal direction oral feeding to preterm infants accelerates matu-
that resembles the development of the vagal neu- ration of nutritive sucking and the transition time
ral crest-derived ENS. By the end of the first from tube to full oral feeding (Simpson
trimester, longitudinal and circular muscles are et al. 2002). Maturation of sucking skills corre-
detectable in the ileum. During the rest of gesta- lates better with postmenstrual gestational age
tion, muscle thickness increases. By 28 weeks than with postnatal age in preterm infants
gestation, contraction of the gut can produce (Gewolb et al. 2001). Lau et al. characterized
60% of the intraluminal pressures measured at five developmental stages of sucking in preterm
term. These pressures are sufficient for preterm infants that were found to be in correlation with
infants to be able to move intestinal content for- postmenstrual age, feeding progress, and the num-
ward. There is a gradual maturation of gut motility ber of daily oral feedings. Rhythmicity of sucking
during fetal life that continues in the first years of and rate of transfer of milk into the posterior
postnatal life (Berseth 1996). The gradual matu- pharynx were enhanced when infants reached
ration of gut motility is the result of muscular and the more mature stages of sucking, and general
neural maturation. Motor activity is immature in oral feeding performance improved as infants’
preterm infants. Normal propulsive motility of the sucking skills matured (Lau et al. 2000). The
gut is evident by 30 weeks gestation. The classical first stage of swallowing is an involuntary reflex
MMC (migrating motor complexes) are demon- in preterm and term infants induced by the pres-
strated by 33 weeks but at slower propagation ence of milk in the posterior pharynx. At term,
rates and without being abolished by feeding as sucking is followed in an orderly manner by
happens in older children and adults. swallowing, esophageal peristalsis, relaxation of
Sucking and swallowing involve skeletal and the lower esophageal sphincter (LES), and relax-
smooth muscles. Although sucking and ation of the gastric fundus.
swallowing reflexes appear early in gestation, The esophagus serves as a connecting tube
their maturation is not complete until after birth. between the oropharynx and the stomach, but its
Fetuses can swallow amniotic fluid by peristaltic activity is essential for adequate pas-
15–17 weeks gestation. Exposure to swallowed sage of nutrients and for adequate clearing of
amniotic fluid including its growth factors such as refluxed materials. Coordinated esophageal peri-
the epidermal growth factor (EGF) is important stalsis is present by 32 weeks of gestation, and by
for gastrointestinal development (Kelly that time upper esophageal sphincter (UES) tone
et al. 1997). Close to term, the fetus swallows is already present. Esophageal sphincters are not
450–750 ml of amniotic fluid each day. Esopha- anatomic but rather functional. The LES is an area
geal or intestinal atresia results in of increased muscular tone in the distal esopha-
polyhydramnios. Nonnutritive sucking appears gus. Its main functions are to prevent gastric acid
between 18 and 20 weeks, but nutritive sucking reflux and to propel food into the stomach. In term
that involves coordinated mechanisms of sucking, infants, LES tone is 20–40 mmHg. However, con-
swallowing, and breathing develops only by traction amplitudes, propagation of pressure
34–35 weeks of gestation (Lau et al. 2003), but waves, and LES tone are lower in preterm com-
has been described earlier (as early as pared to term infants. LES tone in a preterm infant
30–32 weeks) in preterm infants after early less than 29 weeks gestation is lower than 5 mmHg
oromotor stimulation of nonnutritive sucking (Newell et al. 1988). Gastroesophageal reflux
and use of pacifiers in preterm infants (Simpson (GER) that is more common in preterm infants is
et al. 2002). The maturation of nutritive sucking is probably related to low LES tone and poor regula-
parallel to the rapid growth in gastric size and tion of its relaxation (Omari et al. 1999). Using
34 Physiology of the Gastrointestinal Tract in Newborns 513
impedance pH monitoring nonacid as well as acid pylorus where mixing is taking place. Gastric
GER has been demonstrated (Wenzl et al. 2002) emptying requires adequate and coordinated
though norms for premature as well as term infants antral and duodenal motor activities. As opposed
are yet to be established. The esophagus also pro- to antral motor activity that seems to be mature as
vides aerodigestive defenses that exist in the healthy early as 24 weeks gestation (Ittmann et al. 1992),
term infant and prevents aspiration of bolus feed or the coordination and the level of duodenal motor
secretions. These mechanisms include: basal UES activity are decreased in preterm infants. In half of
and LES tonic contractions, primary peristalsis of the preterm infants, duodenal contractions cease
the esophagus triggered by swallowing, and second- in response to feeding resulting in delayed gastric
ary peristalsis with increase in UES tone in response emptying (Al-Tawil et al. 2002). Reduced osmo-
to esophageal provocation. These defenses may not lality and increased volumes of feeding seem to
function in infants with neurodevelopmental abnor- increase gastric emptying, but gastric emptying
malities or maldevelopment of the foregut. Also, remains strongly related to gestational age at
these defenses may not be fully mature in preterm birth even at the age of 1 month (Ramirez
infants, especially those with chronic lung disease et al. 2006).
(Gupta et al. 2009). Maturation of gastrointestinal motility with
Gastric emptying of liquid feeds is regulated increasing gestational age is most evident in the
by the fundus and proximal third of the stomach small intestine. This is shown by longer transit
that dilate to accommodate the milk volume and is times as infants are more immature, especially
dependent on the pressure gradient between the before 30 weeks when ineffective gut motility
proximal stomach and the duodenum. Accommo- may interfere with enteral feeding. The migratory
dation of large volumes of milk in the fundus is motor complexes (MMCs), described above, act as
poor immediately after birth. During the first three “housekeepers” that propel luminal content cau-
postnatal days, the newborn stomach becomes dally along the small intestine. Term and late pre-
more compliant and develops more receptive term infants born after 36 weeks gestation present
relaxation, associated with a larger volume capac- organized MMC pattern (Ittmann et al. 1992) with
ity. This is in accordance with the small feedings periods of quiescence followed by irregular con-
that neonates ingest in the first days of life tractions and then regular contractions and return to
(Zangen et al. 2001). Gastric emptying of more the quiescent baseline (Fig. 3). This pattern is rarely
solid contents is regulated by the distal portion of found in preterm infants. Between 24 and 28 weeks
the body of the stomach, the antrum, and the gestation, only unorganized irregular contractions
Fig. 3 Migrating motor
complex in a term infant.
Upper tracing: motor
contractions recorded from
the antrum. Lower three
tracings: motor contractions
recorded from the
duodenum. Phasic activity
present in the antrum is
temporally associated with
the appearance of intense
phasic activity that migrates
distally to the three
duodenal leads. (originally
from Ittmann et al. (1992),
now copyright Springer)
514 A. Riskin et al.
are recorded with little quiescence intervals suggested that early feeding may accelerate the
(Berseth 1996; Ittmann et al. 1992). By maturation of gut motility in preterm infants
28–32 weeks, periods of quiescence appear alter- (Berseth 1992). Composition and caloric content
nating with short bursts of phasic activity called of the food, but not its volume, also has an effect on
clusters. Between 32 and 36 weeks, motor patterns the maturation and intensity of the gut motor
become more organized and the periods of quies- response, suggesting that diluted formula may not
cence and clusters lengthen. MMCs are first seen provide an optimal stimulant for the preterm intes-
around 33 weeks (Berseth 1996; Ittmann tinal functional responses to feeding (Koenig
et al. 1992) (Fig. 4). Feeding should normally et al. 1995).
disrupt MMC pattern by creating strong contrac- Ninety-four percent of term newborn infants
tions originating from the gastric antrum and pylo- pass meconium within the first 24 h and close to
rus that mix gastric content and propagate it 100% do so within the first 48 h. Passage of
through the pylorus and along the small intestine. meconium may be delayed in preterm infants, up
These contractions are the migrating action poten- to 10 days and more in the very-low-birth-weight
tial complexes (MAPCs) discussed above. Berseth preterm infants (Wang and Huang 1994). Normal
Fig. 4 Motor activity in the
small intestine of preterm
infants at different
gestational ages.
Representative serial
tracings from an individual
subject, at postconceptional
age of (a) 32 weeks, (b) 34
and (c) 36 weeks,
demonstrating increasing
cluster duration and
decreasing cluster
frequency (Fig. 3 page 649
from Berseth (1989), now
Copyright Elsevier)
34 Physiology of the Gastrointestinal Tract in Newborns 515
colonic function is necessary for successful defe- could not have been related to the absence of a
cation. However, not many studies were done on recto anal inhibitory reflex (Lorijn et al. 2005).
colonic motility, especially in preterm infants. The
colon transports nonabsorbable substances for
excretion and facilitates exchange of water and 34.5 Digestion and Absorption
electrolytes. Transit is slow and is achieved by
mass movements that sweep the colon. Colonic Three steps can be defined in the process of nutri-
motility is characterized by irregular alterations of ent absorption: digestion, which is the processing
quiescence with non-propagating and propagating of nutrients within the intestinal lumen and at the
contractions (Nurko 2005). Colonic propagated terminal digestive sites of the brush border mem-
events are defined as low- and high-amplitude brane of the mucosal epithelial cells; absorption in
propagated contractions (LAPCs and HAPCs), the epithelial absorptive surfaces, which involves
and HAPCs are responsible for the mass move- the membrane transport systems of the small
ments. A colonic motor response to a meal is intestinal epithelium; and transport of nutrients
comprised of segmental contractions, increased into the circulation (Phillips 1997).
colonic smooth muscle tone, and possibly also
HAPCs. These were described in children as
well, HAPCs being more frequent 34.5.1 Fat Digestion and Absorption
(Di et al. 1995). The only colonic cyclic activity
is distal to the rectosigmoid junction. It is called Fat is the major source for energy (provides half of
recto motor complex and it is not synchronous the caloric intake) (Hamosh 1995) and polyunsatu-
with the small bowel MMCs. It keeps the rectum rated fatty acids in newborns (Koletzko et al. 1998).
empty, especially at night, and thus helps It is an essential cell membrane component
maintaining continence (Rao and Welcher 1996). (Koletzko et al. 1998), and it facilitates the absorp-
It seems that colonic motility in term neonates is tion of fat-soluble vitamins. Most of the lipids are
similar to that found in older children. However, absorbed in the proximal two-thirds of the jejunum.
colonic motility is immature in preterm infants. Digestion and transport of fat in the lumen of
This is supported by the fact that term newborns the gastrointestinal tract requires solubilization of
that develop hypoxemia pass meconium in utero, the dietary lipids, mostly triglycerides, in the
while preterm infants rarely do so, suggesting the aqueous medium of the gut content, i.e., emulsi-
production of contractions that create mass stool fication. This involves mechanical actions of mas-
movements is immature in preterm babies. tication and gastric mixing to form fat droplets, as
Hirschsprung’s disease is the most common well as coating by phospholipids (mostly phos-
motility disorder affecting the colon. Neuronal phatidylcholine in food with the addition of bile
intestinal dysplasia (NID) of the colonic phospholipids in the duodenum) to stabilize the
submucous plexus is considered a congenital mal- emulsion. Emulsification allows exposure of large
formation of the enteric nervous system causing surface area to the action of the lipolytic enzymes.
symptoms resembling those of Hirschsprung’s Hydrolysis of fat to form mono- or diglycerides
disease. It is a poorly understood colonic motility and free fatty acids begins, especially in new-
disorder that is often associated with borns, in the stomach by lingual lipase secreted
Hirschsprung’s disease and is also associated from Ebner’s glands near the circumvallate papil-
with chronic intestinal pseudo-obstruction, lae (Kawai and Fushiki 2003) and by gastric lipase
anorectal malformations, and the multiple endo- secreted by gastric glands. Lingual and gastric
crine neoplasia (MEN) II syndrome (Koletzko lipases are essential for the digestion of milk fat
et al. 1999). Anal sphincter function is mature in in the newborns because they can penetrate into
term infants, but may be immature in less than the milk fat globule and initiate the digestive
30 weeks gestation premature infants. However, process, contrary to the pancreatic or milk diges-
delayed meconium passage in preterm infants tive lipases (Hamosh 1990). In newborns, lingual
516 A. Riskin et al.
lipase contributes significantly to lipid hydrolysis, adequate amounts. BSSL is not destroyed and
and nonnutritive sucking stimulates its release does not lose its activity in the stomach; thus, it
from the posterior part of the tongue. Lingual can reach the duodenum and be activated by the
and gastric lipases that are present as early as concentrations of bile acids as found in the
26 weeks gestation compensate for the limited infant’s duodenum. Breast milk also contains lipo-
action of bile acids and pancreatic lipases that protein lipase (LPL) that has been described as
are found in low amounts, especially in preterm related to the prolonged neonatal jaundice in
infants (Hamosh 1987). The contribution of lin- breastfed infants. Lingual, gastric, and milk
gual lipase significantly declines later in life. lipases compensate for the low pancreatic lipase
Gastric hydrogen ions enter the duodenum and activity in term and preterm newborns (Hamosh
stimulate the release of secretin that enhances 1987), and since they all function well also in the
bicarbonate secretion from the pancreas. This pro- presence of low bile acid concentrations, they can
cess that raises the intraluminal pH to 6.5, which is also function well in preterm infants where bile
more suitable for further fat digestion, is less acid synthesis in the liver is decreased and their
effective in newborns. The optimum pH of lingual intraluminal concentration is half of the critical
lipase which is 3.5–6.0 is compatible with its micellar concentration required for fat absorption
continued activity in the upper small intestine, (Hamosh 1987).
especially in newborns, where the luminal pH is The source of dietary fat influences absorption
under 6.5 (Hamosh 1987). The initial gastric (Ramirez et al. 2001), human milk being the best
phase of lipolysis generates modest amounts of source for term and preterm newborns (Schanler
diglycerides, monoglycerides, and free fatty acids 1995). Unsaturated fatty acids are absorbed better
that are required with bile salts for optimal activity than saturated ones, and short- and medium-chain
of the intestinal phase of lipolysis. The bile salts triglycerides are absorbed better than long-chain
further enhance fat emulsification rendering it triglycerides (Ramirez et al. 2001). Yet, long-
more susceptible to the action pancreatic lipase chain fatty acids (>16C) may have a growth-
that degrades it to monoglycerides and fatty acids. promoting effect on intestinal cells, as can be
The coactivity of the enzyme colipase is critical to seen in short bowel syndrome (Niot et al. 2009).
facilitate its attachment to the triglyceride droplets Intraluminal calcium concentration also influ-
and to prevent bile salts from deactivating pancre- ences fat absorption. High calcium intake, as
atic lipase. All pancreatic lipase levels are low found in cow’s milk, can impair fat absorption in
after birth, especially in preterm low-birth-weight term and preterm newborns. In human milk,
infants (Hamosh 1987), and increase to adult palmitic acid esterified at the sn-2 position of the
levels only by 6 months of age. The colipase- triacylglycerol molecule is well absorbed as
dependent pancreatic lipase catalyzes the 2-monopalmitin (Kennedy et al. 1999). Lower
intraduodenal phase of triglyceride digestion in digestibility of fat in bovine milk-based infant
formula-fed infants. However, in breastfed formulas compared to human milk is related to
infants, this process is also mediated by the bile the different position of palmitic acid in both fat
salt-stimulated lipase (BSSL), the main lipase in sources (Bracco 1994).
breast milk that is capable of hydrolyzing all three After the luminal phase of digestion and
ester bonds of triglycerides, thus shifting the final processing of the lipids is completed, the mixture
products of triglyceride digestion to glycerol and of all lipolytic products in the lumen is mixed
free fatty acid that promote efficient fat absorption with bile salts to form small aggregates of mixed
(Hernell and Blackberg 1994). BSSL is identical micelles or liposomes, which are larger aggre-
to the pancreatic bile salt-stimulated lipase that is gates that are ready for the next mucosal phase of
responsible also for hydrolyzing intestinal absorption. The bile salts that have both lipid-
cholesteryl esters and phospholipids (Shamir and water-soluble domains allow the passage of
et al. 1995), and its presence in human milk may micelles through the water layer at the mucosal
serve as a bridge until the pancreas secretes it in cell surface and the lipid-rich microvillus
34 Physiology of the Gastrointestinal Tract in Newborns 517
membrane. The bile salts that are not absorbed the proenzymes of pepsin that are activated in low
remain in the intestinal lumen and are actively pH. Proteolysis in the stomach is affected by gastric
reabsorbed at the terminal ileum and into the content and motility and most importantly by gas-
portal system to be resecreted into the bile. This tric acidity. The pH of gastric juice is neutral or
enterohepatic circulation plays an important role slightly acid at birth and decreases within hours.
in the pathogenesis of neonatal hyperbilir- Gastric acid flow doubles within the next 2 months
ubinemia. Monoglycerides and free fatty acids (Mouterde et al. 1992). Parietal cell activity is
diffuse into the cells. A significant proportion of noted in the body, antrum, and pyloric regions of
this phase of lipid absorption is not by passive the fetal stomach as early as 13 weeks (Kelly
diffusion, but involves active, protein-mediated et al. 1993a). However, although the fetus has the
transport (Thomson et al. 2001; Iqbal and capacity to produce gastric acid from the middle of
Hussain 2009). The major fatty acid protein the second trimester, gastric acid secretion is sig-
transporter so far identified is FATP4 that is nificantly reduced in preterm infants (Kelly
mainly involved in long-chain fatty acid absorp- et al. 1993b) and increases with growing postnatal
tion (Stahl et al. 1999). These fatty acid trans- and gestational age. Parietal cells disappear from
porter proteins are located on the apical side of the antrum of the stomach in the third trimester of
the enterocyte (Thomson et al. 2001). Inside the pregnancy, but this process fails to occur in approx-
absorptive cells of the villus, fatty acids are imately 20% of the population (Kelly et al. 1993a).
transported to the smooth endoplasmic reticulum Milk entry into the infant’s stomach sharply raises
where the triglycerides are resynthesized. The gastric pH followed by slower return to lower pH
triglycerides along with cholesteryl esters, phos- compared to older children (Lopez-Alonso
pholipids, and apoproteins are packed together as et al. 2006). The outflow of pepsin is also dimin-
chylomicrons that bind to the basolateral mem- ished in the newborn infant and increases until
brane and are transported via the intestinal lym- 3 months of age (Mouterde et al. 1992). Thus,
phatics into the circulation (Iqbal and Hussain gastric proteolysis is limited in term and especially
2009). Fat absorption seems to be fully devel- in preterm infants because of low pepsin levels
oped at birth to suit the high fat intake of new- combined with low gastric acidity. However, gas-
born infants (Hamosh 1995). This seems to be tric proteolysis does not seem to be critical for
true for preterm infants too, thus suggesting that further digestion and absorption of proteins.
the relative inefficiency of fat absorption in pre- In the duodenum, several proteases act
term infants (40–90%) is mostly attributed to together to digest proteins into amino acids and
immaturity of the intraluminal digestive mecha- oligopeptides (di- or tripeptides). Pancreatic
nisms, as described above. enzymes are secreted as inactive proenzymes
that are activated by hydrolysis of a peptide
bond. Bile salts in the duodenum induce entero-
34.5.2 Protein Digestion kinase release from the microvillus membrane of
and Absorption the absorptive cells. Enterokinase converts tryp-
sinogen to trypsin that in turn activates all the
Although proteins encompass 10–15% of the other pancreatic proteases and the release of
caloric intake, they are important for somatic more trypsinogen. The concentrations of the pro-
growth and synthesis of intracellular structures teolytic enzymes (e.g., trypsin, chymotrypsin)
and enzymes. Adequate protein intake is critical excreted from the exocrine pancreas only mod-
for the premature infant, especially for brain estly increase during the first hours to months after
development (Thureen and Heird 2005). The ini- delivery, and they are fairly efficient in proteolysis
tial step of protein digestion takes place in the from birth on. This is true for premature infants as
stomach and includes denaturation by gastric early as 23 weeks gestation (Kolacek et al. 1990).
acidity and proteolysis mostly into large polypep- However, feeding preterm infants with high-
tides by gastric pepsins. Pepsinogens 1 and 2 are protein diet stimulates increased trypsin secretion
518 A. Riskin et al.
into the duodenum. Lower chymotrypsin concen- 34.5.3 Carbohydrate Digestion
tration are found in infants who are small for and Absorption
gestational age (SGA) (Kolacek et al. 1990)
suggesting a deleterious effect of intrauterine Carbohydrates provide about 40% of the caloric
growth retardation on pancreatic exocrine func- intake of the newborn. Lactose is the major
tion, which may limit postnatal catch-up growth. source of carbohydrates in human milk. Lactase
Concerns regarding protease inhibitors in human activity appears in the differentiating brush bor-
milk and colostrum that may interfere with the der of the fetal small intestine along with other
digestion of proteins in the intestine of breastfed disaccharidases (mainly sucrase) as early as
babies (Chowanadisai and Lonnerdal 2002) were 12 weeks of gestation (Lichnovsky and Lojda
disputed by others (Henderson et al. 2001). 1992), although in low levels. Lactase activity
Following the digestion by pancreatic prote- exhibits relatively higher levels at 37 weeks of
ases, amino acids and oligopeptides are passively gestation (Villa et al. 1992). Lactase activity is
absorbed at the brush border membrane by sec- still decreased during the first weeks of life, and
ondary active transport via sodium-dependent this is reflected by the limited capacity of term
amino acid cotransporters (Stevens and Preston and especially preterm infants to digest and
1998). The low intracellular sodium concentration absorb lactose in the small intestine (Shulman
creates gradient for sodium entry that drives the et al. 2005). Nevertheless, preterm infants fed
absorption of the coupled amino acid. The energy lactose-containing milk or formulas grow well
is indirectly provided by the sodium-potassium and have no diarrhea. The elevation of breath
ATPase pump. There are different classes of hydrogen in these infants apparently represents
amino acid transporters as well as transporters a successful adaptation of the colonic microflora
for oligopeptides. There are also peptidases on that converts malabsorbed lactose to volatile
the brush border membrane, as well as in the organic acids that are subsequently absorbed
cytoplasm of the absorptive cell. In the embryonic (Kien et al. 1989). Glucose polymers are poly-
period (4–8 weeks), the activity of proteases is saccharides that require hydrolysis by amylase.
mainly detected on the luminal surface of the Since pancreatic alpha-amylase levels are low in
fetal intestine. Later on, villi are formed from the young infants and increase only later during
duodenum up to the ileum. After 9 weeks of postnatal life, glucose polymers are either hydro-
gestation, differentiation of Lieberkuhn crypts lyzed by salivary alpha-amylase whose activity
can be observed. The activity of proteases is increases earlier or by the intestinal brush border
high in the differentiating microvillous zone of enzyme, glucoamylase. Alpha-amylase in breast
the primitive enterocytes (Lichnovsky and Lojda milk probably also participates in digestion,
1992). Thus, the peptide transport system and the because it can survive the mild acidity (Lindberg
brush border and cytosolic peptidases are well and Skude 1982) and low pepsin levels in the
developed and functional in preterm infants. In stomach of newborn babies.
addition, preterm and term newborns have Glucose and other monosaccharide products
increased small intestinal permeability that allows of hydrolysis are then absorbed from the jejunum
them to absorb intact macromolecules by active and ileum either by active sodium-dependent D-
pinocytosis (Walker 2002). Amniotic fluid pro- glucose cotransport carrier system (SGLT1) or
teins are swallowed in utero and food and other by the GLUT family of facilitative glucose trans-
proteins are ingested during the neonatal period. porters (Davidson et al. 1992). The sodium-
These include albumin, beta-lactoglobulin, immu- dependent D-glucose cotransport carrier systems
noglobulins (A and G) and other immunologic demonstrate early differentiation of a functional
factors, hormones (chorionic gonadotropin and heterogeneity in glucose transport capacity along
growth hormone), and even intact lactoferrin of the human fetal small intestine (Malo and
maternal origin. Berteloot 1991). These brush border cotransport
34 Physiology of the Gastrointestinal Tract in Newborns 519
systems develop in the jejunum and ileum of the 34.5.4 Micronutrient Absorption
fetus as early as 17–20 weeks gestation and can
be differentiated not only by their kinetic prop- The absorption of the different micronutrients
erties but also by their differences in both sub- matures at varying rates during infancy.
strate and inhibitor specificities (Malo 1990). Water and electrolytes: Water is absorbed
The facilitative glucose transporter isoforms passively following the gradients of sodium and
GLUT2 and GLUT5 are also developmentally other electrolytes. Stimulation of intestinal
modulated with highest levels in adult small sodium absorption by adding solutes (sugars or
intestine. By contrast, GLUT1 expression is amino acids) that are absorbed by sodium-coupled
higher in the fetal small intestine. In the adult mechanisms increase net fluid absorption (Schultz
small intestine, GLUT5 is localized to the lumi- 2007).
nal brush border surface of mature enterocytes. The intestinal epithelium is more susceptible to
Yet, in the fetal small intestine, GLUT5 is local- diarrhea in young infants. Protracted diarrhea of
ized along the intercellular junctions of the infancy (PDI) describes infants with loose and
developing villus. Thus, both the expression frequent stools of sufficient severity to require
and localization of GLUT 5 are developmentally nutritional support, often in the form of parenteral
regulated. In a mature absorptive epithelial cell, alimentation (Sherman et al. 2004). The most
GLUT5 is localized to the luminal surface common cause for PDI is postinfectious diarrhea
(Davidson et al. 1992). Postnatal glucose absorp- with failure of the injured gut to recover rapidly.
tion in infants is less efficient than in adults, and The causes of PDI can be classified into two
the kinetics of glucose absorption is related to categories based on the findings of intestinal
gestational and postnatal ages, as well as to the biopsy: PDI with normal villi and PDI with villus
diet and exposure to glucocorticoids (Murray atrophy. The most common cause of protracted
et al. 1990). diarrhea with villous atrophy is microvillus inclu-
Carbohydrates that are not digested and sion disease, an autosomal recessive disorder that is
absorbed in the small intestine reach the colon present upon birth with striking secretory diarrhea.
where they are degraded by colonic bacteria. The Diagnosis is based on typical electron microscopy
last step of this degradation is fermentation that findings including the diagnostic finding of micro-
results in the formation of short-chain fatty acids, villi inside involutions of the apical membrane (Bar
methane, carbon dioxide, and hydrogen. These et al. 2007). During pregnancy, ultrasound demon-
short-chain fatty acids, particularly butyrate strates multiple fluid-filled dilated intestinal loops
(Wong et al. 2006), are the preferred energy and polyhydramnios. Other causes of congenital
source for the colonic epithelial cells. In the diarrhea with villus destruction include tufting
premature infant, colonic fermentation serves as enteropathy, autoimmune enteropathy, and IPEX
a major important route for lactose carbon syndrome (Sherman et al. 2004), as well as
absorption (as discussed above) (Kien carbohydrate-deficient glycoprotein syndrome
et al. 1989). Developmental aspects of colonic (Sparks 2006) and enterocyte heparin sulfate defi-
fermentative activity; effects of systemic antibi- ciency (Murch et al. 1996).
otic treatment on colonic microflora; the effects In the category of normal villous PDI, congen-
of various fermentation pathways on energy bal- ital ion transport defects cause secretory diarrhea
ance; the capacity for absorption of sugars, short- presenting at birth. The most common congenital
chain fatty acids, and electrolytes by colonic ion transport defect is in the chloride-bicarbonate
epithelia; and the effects of fermentation prod- anion exchanger that is located in the distal ileum
ucts on metabolism and on the mucosal cells are and colon. This transmembrane protein belongs to
all important to premature infants especially in the sulfate transporter family that has three known
relation to colonic disease or surgical resection members in humans, all associated with a distinct
(Kien et al. 1989). genetic disease (Kere et al. 1999). Members of the
520 A. Riskin et al.
gene family can transport other anions as well Vitamins: Human milk is a good source for
(chloride, sulfate, and oxalate) (Lohi et al. 2002). most vitamins. In healthy breastfed infants of
In these cases of congenital chloride diarrhea, well-nourished mothers, there is little risk for vita-
HCO3 is not secreted into the gastrointestinal min deficiencies, and the need for vitamin supple-
tract lumen, leading to alkalosis. Fecal chloride mentation is rare. The exceptions to this, to avoid
concentration exceeds the sum of fecal sodium deficiencies, are a need for vitamin K supplemen-
and potassium levels, establishing the diagnosis tation in the immediate newborn period and the
(Kere et al. 1999). Congenital sodium diarrhea, a need to supplement vitamin D in breastfed infants
disorder of the intestinal H+/Na+ exchanger with dark skin or inadequate sunlight exposure
located in the small intestine and colon, is charac- (Greer 2001; Mimouni and Shamir 2009). Most
terized by hyponatremia, alkaline diarrhea, and vitamins appear to be absorbed adequately in term
high concentration of stool sodium (Keller and preterm infants.
et al. 1990). In the other congenital ion transport Fat-soluble vitamins: Fat-soluble vitamins
defects (sodium cotransporters), abnormal include vitamins A, D, E, and K. Vitamins A
reabsorption of sodium is involved, which usually (retinoids) and E (tocopherols) are two potent
results in hyponatremia (Sherman et al. 2004). antioxidant nutrients that also play a significant
The colon has an important role in absorbing role in immune function.
sodium and water from the intestinal lumen. Vitamin D (calciferol) plays a major role in
Active absorption of sodium ion can be increased intestinal calcium absorption and bone mineral-
three- to fourfold by the presence of aldosterone ization (Mimouni and Shamir 2009).
(Harvey et al. 2008), suggesting that colonic Cholesterol-derived precursor uses UV sunlight
absorption of sodium is central to maintaining to convert to previtamin D3, which is then
salt and water homeostasis. Colonic mucosa in converted to inactive form of vitamin D3. Vita-
the fetus has well-developed villi that allows it to min D3 is then hydroxylated in the liver
be involved in nutrient absorption in contrast to (25-(OH)D) and in the kidneys to make active
the adult (Menard et al. 1994). Thus, in addition to vitamin D (1,25-(OH)2D). Vitamin D crosses the
its role in salt and water homeostasis, it can also placenta mainly in the form of 25-(OH)D. The
absorb essential nutrients by active (sodium- transport is passive or facilitated, with lower
coupled) transport of glucose and amino acids values in the fetus, and therefore fetal 25-(OH)
that may also compensate for decreased absorp- D concentrations correlate with those of the
tion in the developing small intestine. mother. Exogenous vitamin D3 (from animal
Minerals and trace elements: Trace elements source) or D2 (ergocalciferol, synthesized by
and mineral absorption depends on the milieu in plants) can also be absorbed in the duodenum
which they are presented to the intestine. The and the jejunum, although vitamin D2 appears to
bioavailability of iron, calcium, and other min- be absorbed to a much lesser extent than vitamin
erals for absorption is better from human breast D3 (Houghton and Vieth 2006).
milk (Bosscher et al. 2001). Preterm infants may Vitamin K intervenes in the synthesis of coag-
absorb as much as 50% of the iron in breast milk, ulation factors particularly in prothrombin synthe-
as opposed to formulas. This is true for other sis. Fat-soluble vitamins are totally dependent on
minerals that are more bioavailable for preterm micelles in order to be presented to the brush
infants in human milk. This does not alter the need border membrane. Absorption is also dependent
to supplement some of these nutrients (mainly on the presence of bile salts in the small intestine
calcium and phosphorus) to preterm infants to (Greer 2000). Ingested carotene and dietary
compensate for their increased demands (Schanler retinyl esters are converted to free retinol in the
and Rifka 1994). proximal small intestine by pancreatic hydrolases
Calcium and phosphorus absorption and require- and are the dietary sources for vitamin A. Retinol
ments are discussed in ▶ Chap. 41, “Calcium and absorption into the intestinal cells is facilitated by
Phosphorus Homeostasis: Pathophysiology.” retinol-binding protein, RBP II, which is found
34 Physiology of the Gastrointestinal Tract in Newborns 521
almost exclusively in absorptive cells. In the requiring multiple steps from the stomach to the
enterocyte, fat-soluble vitamins are re-esterified ileum and the involvement of at least four differ-
and incorporated into the developing chylomi- ent binding proteins (Halsted 2003). Its absorp-
cron. Chylomicrons travel through the lymphatic tion is complex. In the gastric acidic environment,
system and then enter the bloodstream. Some of it is released from the food to form complexes
the vitamins use protein carrier for transport in the with R-binders that are proteins found in the
bloodstream (retinol-binding protein, RBP I, for saliva, gastric juice, bile, and milk and have high
carrying retinol to target tissue and D-binding affinity for vitamin B12. At the alkaline environ-
protein to take hydroxylated vitamin D from the ment of the duodenum, pancreatic proteases
liver to the kidney for further hydroxylation). degrade R-binders allowing vitamin B12 to bind
Excess is stored in liver and adipose tissue and to the intrinsic factor that is produced by the
released as needed by the body. The risk of toxic- parietal cells of the stomach. The complex of
ity may be relevant for high doses of vitamins D, vitamin B12 and intrinsic factor is absorbed intact
A, and E and is less relevant for vitamin in the distal ileum. Inside the ileal mucosal cells,
K. Disorders affecting fat absorption, such as vitamin B12 is released from the intrinsic factor
short bowel syndrome, cholestasis, and other dis- and binds to a specific transport protein,
eases associated with bile acid deficiency, may transcobalamin II, to be delivered to the liver via
cause fat-soluble vitamin deficiency. Vitamin K2 circulation. It is excreted mainly in the bile, but
(menaquinones) is synthesized by bacteria in the has a very long half-life due to very effective
large intestine. Because the transfer of the vitamin enterohepatic circulation. It is actively transported
K across the placenta during pregnancy is poor across the placenta so that newborns have concen-
and the sterile gut of the infant is unable to pro- trations twice as high as mothers (Greer 2000).
duce menaquinones, newborn babies are routinely Hepatic stores correlate with the duration of preg-
given supplements of vitamin K (Greer 2000). nancy and are thus large in full-term newborns,
Water-soluble vitamins: Water-soluble vita- but lower in preterm infants. Clinical manifesta-
mins are required as enzyme cofactors in a wide tions of vitamin B12 deficiency appear only in late
variety of metabolic reactions. Riboflavin (vita- infancy, because of the hepatic stores and the long
min B2), niacin, and vitamin C (ascorbic acid) are half-life (Greer 2000). There are several congenital
essential for oxidation-reduction reactions. Thia- defects that can affect the complex absorption of
mine (vitamin B1) and biotin are involved in vitamin B12, but they are rare compared to dietary
macronutrient metabolism. Folate, vitamin B12, deficiency that is not evident in neonatal period.
pyridoxine (vitamin B6), and riboflavin play
important roles in the regulation of
S-adenosylmethionine production and DNA syn- 34.6 Host Defense
thesis. Each of these water-soluble vitamins
requires its own membrane transport process for The microbiota is a large and diverse community
absorption across the enterocyte. Most of the of microorganism that resides in the human gut. It
water-soluble vitamins are absorbed from the is dominated by bacteria and is known to have a
proximal small intestine (Greer 2000; Halsted critical role in the evolution of intestinal functions
2003). Folate, biotin, and riboflavin can be and overall health of the host. The bacterial cells
transported across colonic epithelial cells as outnumber human cells of the host, and their total
well, although the clinical significance of this is amount of genes, which is called the microbiome,
uncertain (Halsted 2003). Riboflavin is light sen- estimated to be about two to four million genes,
sitive and is rapidly photodegraded. Phototherapy exceed the number of human genes by more than
is a possible cause for riboflavin deficiency in 100-fold. The microbiota is considered as an
neonates (Bohles 1997). This may affect antioxi- “organ within an organ,” because through expres-
dant mechanisms in preterm infants. The absorp- sion of the microbiome, these intestinal bacteria
tion of vitamin B12 (cobalamin) is unique in can execute numerous enzymatic reactions that
522 A. Riskin et al.
mammalian host is not able to catalyze. Microbes may lead to feeding intolerance in a newborn
of the intestinal tract are important in nutrient (Di Mauro et al. 2013).
processing and absorption, may play a role in The immune system of preterm infants is
growth and is important in the development of immature. Thus, preterm infants are prone to a
the immune system and maintaining its integrity. delayed gastrointestinal colonization, reduced
The microbiota functions include modulating the microbial diversity in the bowel, acquisition of
expression of genes involved in strengthening antibiotic-resistant strains, loss of strains associ-
mucosal barrier, angiogenesis and postnatal intes- ated with antibiotic treatment, and increased intes-
tinal maturation, support of normal digestion, and tinal bacterial translocation (Caicedo et al. 2005).
consumption and storage of energy from the diet, The gut of extremely low-birth-weight infants is
usually by fermenting unused energy substrates to colonized by a paucity of bacterial species
short-chain fatty acids (SCFAs) (Di Mauro (Gewolb et al. 1999). This can favor the over-
et al. 2013). growth of microorganisms such as Enterobac-
Fetal gastrointestinal tract was originally teriaceae and coagulase-negative staphylococci,
thought to be sterile. However, recent studies which are the most frequent pathogens of nosoco-
using molecular techniques suggest that the fetal mial infection in neonatal intensive care units
intestine may be exposed to microbes via (Gaynes et al. 1996). These factors also make
swallowing of colonized amniotic fluid, which the preterm infant more susceptible to antibiotic-
can be associated with preterm delivery, the resistant infections, systemic inflammatory
so-called fetal inflammatory response syndrome response syndrome, and necrotizing enterocolitis
(FIRS) (Park et al. 2009). Prenatal exposure of the (NEC) (Neu and Caicedo 2005). Breast milk and
mother to bacterial components can influence reduction of antibiotic exposure have been found
intestinal epithelial development and function in to be important in increasing fecal microbial
newborn, as well as sensitivity to inflammatory diversity in these premature infants (Gewolb
diseases such as NEC. Prenatal exposure of the et al. 1999). Microbes of the intestinal tract serve
gut to bacteria may modulate postnatal adapta- several roles, including nutrition, growth, and
tions inducing tolerance toward colonization of maintenance of function and development of the
certain bacteria. During birth the intestinal immune system (Hooper et al. 2002).
mucosa undergoes a dramatic transition to a The gut is in continuity with the environment
densely colonized environment. This heavy colo- and thus exposed to bacteria and antigens. The
nization of the gastrointestinal tract of newborn gastrointestinal tract presents the largest surface
infants occurs within a few days but starts imme- area in the body exposed to microbes and other
diately after birth. Initially, the type of delivery antigens. On the other hand, it needs to allow the
(passage through the birth canal versus cesarean entrance of nutrients and other beneficial mole-
section) and the type of diet (breast versus formula cules. Host defenses include nonspecific and spe-
feeding) affect the colonization pattern (Salminen cific components. The innate immune system
and Isolauri 2006). Other environmental factors responds in a nonspecific way, and the adaptive
such as developed versus developing countries immune system responds specifically by humoral
and the use of antibiotics in the neonatal period and cellular components that specifically react to
may also affect the microflora composition particular antigens.
(Guarner and Malagelada 2003). The gut interacts Defense factors in human milk include antimi-
with intestinal bacteria to develop and mature the crobial agents (secretory IgA, lactoferrin, lyso-
intestinal barrier protective mechanisms against zyme, glycoconjugates, oligosaccharides, and
foreign harmful molecules while maintaining digestive products of milk lipids), anti-
appropriate responses toward commensal bacteria inflammatory factors (antioxidants, epithelial
and nutrients by means of immune modulation growth factors, cellular protective agents, and
and immune tolerance (Di Mauro et al. 2013) enzymes that degrade mediators of inflammation),
(Fig. 5). Thus, aberrant bacterial colonization immunomodulators (nucleotides, cytokines, and
34 Physiology of the Gastrointestinal Tract in Newborns 523
Fig. 5 Intestinal function and microbiota – cells involved activity related to the contraction and indirectly influencing
in antigen sampling at the gastrointestinal barrier: Com- the cells of the gut immune system. The functional bidi-
mensal bacteria inhabiting the human intestine participate rectional interaction act via neuroimmune peptide receptor
in the development and maintenance of gut immunologic, on immune cells and on several receptors for immune
sensory, and motor functions. Under normal conditions, mediators expressed on enteric nerves. Immune cells
the gastrointestinal tract provides a stable habitat for com- release mediators in response to neural stimuli – Fig. 1
mensal bacteria that supports its structural and functional page 3 from: Di Mauro et al. (2013) (http://www.ijponline.
integrity. The ENS influences the gut directly with the net/content/39/1/15)
anti-idiotypic antibodies), and leukocytes (neutro- of the evolution of the mammary gland from the
phils, macrophages, and lymphocytes). The pres- immune system (Vorbach et al. 2006). In addition
ence and function of immunomodulatory and anti- to the well-known passive protection against
inflammatory factors present in human milk help infections during lactation (mainly via secretory
protecting the mature newborn as well as the IgA antibodies and also via several other factors
premature infant against infections. Some of like bactericidal lactoferrin), breastfeeding may
these factors present in human milk may actively also actively stimulate the immune system of the
modulate the synthesis and maturation of the infant (via anti-idiotypic antibodies, cytokines,
recipient immune system. This complex interac- growth factors, T and B lymphocytes, and macro-
tive system of bioactive substances in human milk phages) with other long-term positive effects
seems to be designed to operate in a complemen- (e.g., better immunological response to infections
tary manner with other noninflammatory mecha- and vaccines) (Garofalo and Goldman 1999;
nisms in order to resist digestion of these factors in Chirico et al. 2008).
the recipient gastrointestinal tract and to supple- Gastric acidity and pancreatobiliary secretions
ment the infant with developmentally delayed also decrease the load of viable microorganisms
immune factors. This is consistent with the theory and intact dietary protein antigens. These defenses
524 A. Riskin et al.
are all decreased in the newborn, especially the connections are dynamic structures that closely
preterm infant, as described above. The use of regulate the flow of fluids, electrolytes ions,
H2-blocking agents or proton pump inhibitors and even small molecules between the cells
that further decrease gastric acidity contributes to but prevent passage of larger molecules (Nusrat
a decreased defense and may result in higher rates et al. 2000). Epithelial cells also regulate
of infections (Beck-Sague et al. 1994). transcellular permeability to ions and small
Mechanical factors that appear early in gesta- molecules through alterations in the expression
tion are also involved in host defense by creating of selective membrane ion channels and pores.
physical barrier of mucous secretion and by gas- Control of water and chloride secretion through
tric emptying and intestinal peristalsis that prevent the channels can result in secretory diarrhea
stasis and bacterial overgrowth. In preterm infant that can flush away toxins and pathogens from
gastric emptying, MMCs and peristalsis may be the lumen (Hecht 1999).
delayed, as discussed above. Intestinal mucus In addition to mechanical barriers, and in addi-
secreted into the lumen from storage vacuoles in tion to mucin secretion, the gut elaborates chem-
the goblet cells, found throughout the small and ical defenses secreted by the absorptive
large intestine, plays a significant role in intestinal enterocytes and Paneth cells. Paneth cells are spe-
defense. It contains mucins, glycoproteins, immu- cialized secretory enterocytes located at the base
noglobulins, glycolipids, and albumin that form a of the small intestinal crypts, where they can
slippery gel over the intestinal surface that control microbial populations and protect neigh-
enhances forward propulsion. Mucous gel can boring stem cells. Paneth cells secrete lysozyme,
also trap large foreign antigenic molecules, thus phospholipase A2, and antimicrobial peptides.
preventing their diffusion into the gut wall. Mucin Antimicrobial peptides are divided into defensins
secretion changes in amount and composition (alpha and beta), which are the predominant class,
during development and maturation of the new- and cathelicidins. These small cationic peptides
born infant and in response to stress and hypoxia are able to insert into the membranes of a broad
(Louis et al. 2006). Microvilli also constitute a range of microbes (including bacteria, fungi, and
significant barrier because of their size and nega- enveloped viruses), where they play an active role
tive charge that prevent large macromolecules in oxygen-independent killing. It is possible that
from penetrating. low levels of Paneth cell defensins, characteristic
The intestinal single-cell layer of columnar of normal intestinal development, may predispose
epithelial cells is present by the end of the first preterm infants to necrotizing enterocolitis (NEC)
trimester. It is the cellular site of innate immu- (Salzman et al. 2007).
nity of the intestine separating the host from the An important non-constitutive defense com-
intestinal lumen. It is arranged in crypts and ponent of the gut innate immunity is the carefully
villi. Stem cells at the base of the crypts prolif- programmed and regulated inflammatory
erate and differentiate into enterocytes that response that is activated when potentially inju-
migrate to the villus tip. They eventually rious stimuli cross the barrier of the intestinal
slough into the lumen by physiologic apoptosis epithelium. This activated inflammatory
(anoikis), thus allowing reconstitution of the response induces recruitment of leukocytes
epithelium every 5 days (Pinto and Clevers (polymorphonuclear and macrophages) as well
2005). This renewal mechanism serves as a as complement, defensins, and cytokines to aid
defense mechanism against epithelial injury. in defense. Multiple endogenous or exogenous
Epithelial integrity is further protected by intra- signals can start the inflammatory process by
cellular contacts of membrane proteins and inducing the local release of soluble inflamma-
cytoskeletal anchor proteins that form the api- tory mediators and chemotactic agents that
cal junction complexes (AJCs) that are the basis increase vascular permeability and attract inflam-
for the series of tight junctions between the matory cells, resulting in edema and inflamma-
cells. The AJCs and their cytoskeletal tion (Medzhitov 2007).
34 Physiology of the Gastrointestinal Tract in Newborns 525
The human genome contains evolutionary results in induction of the expression of enzymes
ancient components of innate immunity that are important for bacterial killing and wound healing,
transmitted in the germ cells without exposure to as well as antibacterial peptides, cytokines, adhe-
the microbes and encode at least ten toll-like sion molecules, chemotactic messengers, and
receptors (TLRs). TLRs are transmembrane antiapoptotic proteins (Neish 2009). The sterile
receptors that recognize pathogen-associated fetal gut is naïve to MAMPs in utero. Within the
molecular patterns (PAMPs) or microbial associ- first days, the neonatal gut is challenged by mul-
ated molecular patterns (MAMPs) that are found tiple MAMPs as the luminal flora is introduced.
only on microbes, like lipopolysaccharides, pep- TLRs are expressed at the basolateral aspects of
tidoglycans, and lipoproteins. The binding of fetal intestinal crypts as early as 20 weeks of
MAMPs to TLRs or intracytoplasmic NOD pro- gestation (Fusunyan et al. 2001).
teins results in the activation of cytoplasmic sig- Membranous or microfold cells, commonly
naling circuits. These pathways include the classic referred to as M cells, are specialized epithelial
nuclear factor kappa-B (NF-kappa-B), the mito- cells of the gut-associated lymphoid tissues
gen-activated protein kinase (MAPK), and the (GALT) that play a major role in the intestinal
interferon regulatory factor (IRF) pathways. Dur- immune system by delivering luminal antigens
ing the initial events of bacterial perception by the to the underlying immune cells. M cells in the
intestinal epithelial cells, all these three pathways intestine lack well-developed microvilli and
are activated within minutes. Modulation of these allow macromolecular transport, as opposed to
pathways involves a regulated series of phosphor- the absorptive enterocytes with their developed
ylation and ubiquitination, leading to nuclear villi. M cells are present only in follicles overlying
translocation of these three transcription factors lymphoid tissue to which they can immediately
and transcriptional activation of a battery of effec- present foreign antigens and microorganisms that
tor inflammatory molecules (Louis and Lin 2009; they transport as macromolecules (Miller
(Sharma and Tepas 2010) (Figs. 6 and 7). This et al. 2007) (Fig. 5).
Fig. 6 Microbial associated molecular pattern (MAMP) domain-like receptors (NODs). Integration of these signals
activation and signaling in the cells of the gastrointestinal evokes cellular outputs based on the initial perception of
barrier: Microbial components such as lipopolysaccharides the triggering organism. Output can be a protective
(LPS), lipoteichoic acid (LTA), formylated peptides, and response to commensal microbiota, an inflammatory
flagellin serve as microbial associated molecular patterns response to pathogenic organism(s), or it can trigger apo-
(MAMPs) and signal pattern recognition receptors (PRRs) ptosis (Fig. 1 page 13 from: Sharma et al. (2010), copyright
including toll-like receptors (TLRs), formylated peptide Springer)
receptors (FPRs), or nucleotide-binding oligomerization
526 A. Riskin et al.
Microbes modulate expression of TLRs and NOD/CARD mediated responses
TLR4 TLR4 TLR4
LBP LPS LBP LPS
Gram− MD2 LTA
CD14 CD14
MAMPS Gram+ D cells
M cells
MyD88
TIRAP NOD1
Adaptor proteins for TLRs
TRAM NOD2
IRAK MAP Kinases
TRAF6
RIP
TRIF
CASPASE
γ γ RIP
Iκ - B kinase P
Activated
(IKK) α β α β
TNF-α (IKK-β)
Degradation of I-κ B IKK1
NO TBK1
activates NF- κ B
COX-2
SOCS P p
Iκ - B
IL-1 NF-κB
IL-6 immune cell IRF3
activation Migration of NF-κB
IL-8
IL-10
into nucleus Apoptosis
IL-12
Transcription of IRF3 P
Coactivator inflammatory cytokines
Fig. 7 Microbes modulate expression of receptors on the receptors (TLRs) are triggered by MAMPs and stimulate
cells of the gastrointestinal barrier activating downstream PRRs. Four adaptor proteins for TLRs are involved in
signaling: a schematic illustration of the recognition of propagation of signals and activation of MAP kinases
microbial associated molecular patterns (MAMPs), such that can result in transcription of pro-inflammatory cyto-
as lipopolysaccharides (LPS), by pattern recognition kines or apoptotic response through activation of NF-kB
receptors (PRRs) on epithelial cells and immune cell acti- (NF-kappa-B) (Fig. 2 page 14 from: Sharma et al. (2010),
vation or apoptotic response. Transmembrane toll-like copyright Springer)
Subepithelial cells include follicular dendritic The immune system of host defense is com-
cells that are located in the lymphoid follicles and posed of cellular and humoral components. T and
are important in non-phagocytic presentation of B lymphocytes are produced as early as 12 weeks
antigens to T cells as well as B cells. Peyer’s gestation, and are present with macrophages in the
patches are aggregates of lymphoid tissue that fetal intestine by 20 weeks gestation. Interspersed
are present by 19 weeks of gestation, but become between the intestinal epithelial enterocytes are
more prominent in the jejunum and ileum between blood-derived intraepithelial lymphocytes (IELs)
24 and 40 weeks. M cells occur in follicle- that are immune components of the host defense.
associated epithelium over areas of Peyer’s They are located in the basolateral side of the
patches (Miller et al. 2007) (Fig. 5). Mast cells epithelial layer where cells are exposed to various
bind immunoglobulin E and subsequently release food and microbial antigens. They are cytotoxic
histamine and serotonin that stimulate mucus pro- and capable of producing cytokines in order to
duction by adjacent goblet cells and increase protect the host from invasion of microorganisms
enterocyte permeability, chemotaxis of through the gut. Immature human enterocytes
granulocytes, contraction of smooth muscle react with excessive pro-inflammatory cytokine
cells, and lymphocyte function. production after inflammatory stimulation in
34 Physiology of the Gastrointestinal Tract in Newborns 527
premature infants exposed to initial colonizing preterm infants (Siahanidou et al. 2004). Since
bacteria, and this may lead to necrotizing entero- endogenous nucleotides are continuously pro-
colitis (NEC) (Nanthakumar et al. 2000). On the duced as the result of the cell recycling within
other hand, antigenic stimulation of the lymphoid the gut, the functional role of the contribution
tissues cannot be demonstrated before 46 weeks from exogenous nucleotide supply is still
of postmenstrual age, which poses a challenge for unclear.
preterm infants whose gut can absorb macromol- Long-chain polyunsaturated fatty acids
ecules directly by pinocytosis. Secretory IgA is (LC-PUFA), arachidonic acid (AA), and
present by 22 weeks of gestation, although in docosahexaenoic acid (DHA), which are metabo-
small amounts, because the newborn intestine lites of the essential n-3 and n-6 fatty acids, are
has few IgA-producing plasma cells. In addition known to modulate inflammation. Supplementa-
preterm infants are not able to form antibodies in tion of preterm infants’ food with LC-PUFA may
response to exogenous food proteins. reduce the risk of NEC (Caplan and Jilling 2001;
Enteral nutrients and food supplements may Lu et al. 2007) and also has beneficial effects on
also contribute to host defense. These include the developing visual system and cognitive devel-
amino acids (glutamine and arginine), nucleo- opment during the first year of life (Heird and
tides, long-chain fatty acids, probiotics, and Lapillonne 2005).
prebiotics. Although the cause of NEC is not entirely
Glutamine contributes to maintenance of small known, milk feeding and bacterial growth play a
intestinal inter-epithelial junctional integrity role. Probiotics are dietary supplements
(Potsic et al. 2002), intestinal epithelial cell containing potentially beneficial bacteria or
growth and proliferation (DeMarco et al. 1999), yeast, which have been used to prevent NEC
inflammatory responses, and active healing. (AlFaleh and Anabrees 2014a). Probiotic bacteria
Glutamine-deficient diet increased bacterial trans- have been shown to reinforce the different lines of
location in vitro by altering intestinal tight junc- gut defense, which are immune exclusion,
tions (Potsic et al. 2002; Li and Neu 2009), and immune elimination, and immune regulation.
glutamine supplementation decreased the inci- They also stimulate nonspecific host resistance
dence of sepsis in very-low-birth-weight infants to microbial pathogens, thereby aiding in patho-
(Neu et al. 1997). Glutamine and glutamic acid gen eradication. Documented effects include the
together with taurine are the only free amino acids alleviation of intestinal inflammation, normaliza-
that their concentrations are increased in human tion of gut mucosal dysfunction, and
milk during the first 3 months of lactation downregulation of hypersensitivity reactions.
(Agostoni et al. 2000). Thus, modification of gut microflora by probiotic
Arginine also plays an important role in therapy may be suitable for clinical conditions
immune function. Low plasma arginine levels in associated with gut barrier dysfunction and
preterm infants were associated with increased inflammatory response (Isolauri 2001). Conse-
risk for subsequent NEC (Becker et al. 2000), quently, probiotics are used in the treatment of
and its supplementation may prevent NEC (Shah acute diarrhea in children (Szajewska
and Shah 2007). et al. 2007). Probiotics modify the fecal flora,
Exogenous nucleotides may influence cell can reduce the overgrowth of pathogens in the
proliferation, differentiation and apoptosis in bowel of preterm infants, and thus contribute to
the crypt, and villus epithelium of the fetal and the reduction of the incidence of nosocomial
neonatal small intestine (Tanaka et al. 1996). infections in neonatal intensive care units (Dani
Nucleotides in infant formulas have been associ- et al. 2002). Bifidobacterium species are the most
ated with enhanced humoral antibody responses common bacteria in human milk-fed infants.
to immunizations (Pickering et al. 1998) and Infants consuming Bifidobacterium breve
with a favorable effect on the lipid profile of supplemented feedings had higher rates of fecal
528 A. Riskin et al.
bifidobacteria colonization with some clinical been suggested (Deshpande et al. 2011). It must
advantages including decreased gastric aspirates be emphasized that not all probiotics are effica-
and improved weight gain and feeding tolerance cious in preventing NEC and only probiotic
with no identified side effects (Kitajima strains that have been shown to be efficacious
et al. 1997). Significant reduction in the incidence should be used (Mihatsch et al. 2012). Further-
of NEC and NEC-associated fatalities was shown more, probiotics are usually marketed as food
by Hoyos et al. in preterm infants given daily supplements, and as such rigorous surveillance
doses of live L. acidophilus and B. infantis with of the products must be guaranteed before
no documented complications (Hoyos 1999). their use.
Dani et al. found that the incidence of NEC (Bell Another approach is to use prebiotic supple-
stage 2) was lower in preterm infants mentation. Prebiotics are defined as nondigestible
supplemented with Lactobacillus GG (LGG) substances that, when ingested, selectively pro-
(Dani et al. 2002). Lin et al. have shown that mote the growth and establishment of beneficial
supplementation of human milk (Lin et al. 2005) probiotic-like bacteria normally present in the gut
or formula feedings (Lin et al. 2008) with a mix- (Agostoni et al. 2004b). There are few studies on
ture of Lactobacillus acidophilus and the use of oligosaccharide prebiotic products in
Bifidobacterium infantis (Lin et al. 2005) or preterm infants that have been shown to increase
bifidum (Lin et al. 2008) significantly reduced the counts of fecal bifidobacteria, reduce stool pH,
the combined incidence of NEC or death in reduce stool viscosity, accelerate gastrointestinal
very-low-birth-weight (VLBW) infants, i.e., pre- transport, and improve mineral absorption (Moro
mature infants born weighing less than 1,500 g. et al. 2002; Lidestri et al. 2003; Knol et al. 2005;
There was a significant effect on NEC (Bell stage Mihatsch et al. 2006) with no negative impact on
2) itself as well. Bin-Nun et al. showed that a weight gain. More randomized trials in preterm
probiotic mixture (Bifidobacterium infantis, infants are needed to support their potential ben-
Streptococcus thermophilus, and Bifidobacterium eficial effects on feeding tolerance and on the
bifidum) had a significant protective effect on reduction of the incidence of NEC and hospital-
NEC of any Bell stage in VLBW infants, even acquired infections (Knol et al. 2005; Riskin
when Bell stage 2 NEC was only considered et al. 2010; Underwood et al. 2009, 2014). In a
(Bin-Nun et al. 2005). Recent meta-analyses con- meta-analysis including some of the above men-
clude that the use of probiotics significantly tioned studies, it was found that prebiotic
reduces the occurrence of NEC and death in supplemented formula for premature infants
VLBW premature infants (birth weight increased stool colony counts of bifidobacteria
1,500 g) born after less than 34 weeks gestation and lactobacilli without adversely affecting
(AlFaleh and Anabrees 2014a, b; Deshpande weight gain. However, the evidence was limited,
et al. 2010). There is insufficient data with regard and routine oligosaccharide supplementation
to the benefits and potential adverse effects in the could not have been recommended for NEC pre-
most at risk infants weighing less than 1,000 g at vention or improving gut health (Srinivasjois
birth (AlFaleh and Anabrees 2014a, b). The issue et al. 2009).
of safety (Land et al. 2005) in routine use of
probiotics in young premature infants with imma-
ture defense systems (Agostoni et al. 2004a) has
References
not yet been fully settled. Nevertheless, based on
all the studies done, it seems to be very low and Agostoni C, Carratu B, Boniglia C, Lammardo AM,
disproportionate when compared to the advan- Riva E, Sanzini E (2000) Free glutamine and glutamic
tages of their use in VLBW premature infants, acid increase in human milk through a three-month
lactation period. J Pediatr Gastroenterol Nutr 31
including the most premature ones weighing less
(5):508–512
than 1,000 g at birth. Practice guidelines for their Agostoni C, Axelsson I, Braegger C, Goulet O,
routine use in neonatal intensive care units have Koletzko B, Michaelsen KF et al (2004a) Probiotic
34 Physiology of the Gastrointestinal Tract in Newborns 529
bacteria in dietetic products for infants: a commentary Bin-Nun A, Bromiker R, Wilschanski M, Kaplan M,
by the ESPGHAN Committee on Nutrition. J Pediatr Rudensky B, Caplan M et al (2005) Oral probiotics
Gastroenterol Nutr 38(4):365–374 prevent necrotizing enterocolitis in very low birth
Agostoni C, Axelsson I, Goulet O, Koletzko B, Michaelsen weight neonates. J Pediatr 147(2):192–196
KF, Puntis JW et al (2004b) Prebiotic oligosaccharides Bohles H (1997) Antioxidative vitamins in prematurely
in dietetic products for infants: a commentary by the and maturely born infants. Int J Vitam Nutr Res 67
ESPGHAN Committee on Nutrition. J Pediatr (5):321–328
Gastroenterol Nutr 39(5):465–473 Bosscher D, Van Caillie-Bertrand M, Robberecht H, Van
AlFaleh K, Anabrees J (2014a) Probiotics for prevention of DK, Van CR, Deelstra H (2001) In vitro availability of
necrotizing enterocolitis in preterm infants. Evid Based calcium, iron, and zinc from first-age infant formulae and
Child Health: Cochrane Rev J 9(3):584–671 human milk. J Pediatr Gastroenterol Nutr 32(1):54–58
AlFaleh K, Anabrees J (2014b) Probiotics for prevention of Bracco U (1994) Effect of triglyceride structure on fat
necrotizing enterocolitis in preterm infants. Cochrane absorption. Am J Clin Nutr 60
Database Syst Rev 4:CD005496 (6 Suppl):1002S–1009S
Al-Tawil Y, Klee G, Berseth CL (2002) Extrinsic neural Caicedo RA, Schanler RJ, Li N, Neu J (2005) The devel-
regulation of antroduodenal motor activity in preterm oping intestinal ecosystem: implications for the neo-
infants. Dig Dis Sci 47(12):2657–2663 nate. Pediatr Res 58(4):625–628
Altschuler SM, Bao XM, Bieger D, Hopkins DA, Miselis Calder PC, Krauss-Etschmann S, de Jong EC, Dupont C,
RR (1989) Viscerotopic representation of the upper Frick JS, Frokiaer H et al (2006) Early nutrition and
alimentary tract in the rat: sensory ganglia and nuclei immunity – progress and perspectives. Br J Nutr 96
of the solitary and spinal trigeminal tracts. J Comp (4):774–790
Neurol 283(2):248–268 Caplan MS, Jilling T (2001) The role of polyunsaturated
Anderson RB, Newgreen DF, Young HM (2006) Neural fatty acid supplementation in intestinal inflammation
crest and the development of the enteric nervous sys- and neonatal necrotizing enterocolitis. Lipids 36
tem. Adv Exp Med Biol 589:181–196 (9):1053–1057
Baetge G, Pintar JE, Gershon MD (1990) Transiently cat- Chirico G, Marzollo R, Cortinovis S, Fonte C, Gasparoni A
echolaminergic (TC) cells in the bowel of the fetal rat: (2008) Antiinfective properties of human milk. J Nutr
precursors of noncatecholaminergic enteric neurons. 138(9):1801S–1806S
Dev Biol 141(2):353–380 Chowanadisai W, Lonnerdal B (2002) Alpha(1)-
Bar A, Riskin A, Iancu T, Manov I, Arad A, Shaoul R antitrypsin and antichymotrypsin in human milk: ori-
(2007) A newborn infant with protracted diarrhea and gin, concentrations, and stability. Am J Clin Nutr 76
metabolic acidosis. J Pediatr 150(2):198–201 (4):828–833
Beck F (2002) Homeobox genes in gut development. Gut Dani C, Biadaioli R, Bertini G, Martelli E, Rubaltelli FF
51(3):450–454 (2002) Probiotics feeding in prevention of urinary tract
Becker RM, Wu G, Galanko JA, Chen W, Maynor AR, infection, bacterial sepsis and necrotizing enterocolitis
Bose CL et al (2000) Reduced serum amino acid con- in preterm infants. A prospective double-blind study.
centrations in infants with necrotizing enterocolitis. J Biol Neonate 82(2):103–108
Pediatr 137(6):785–793 Davidson NO, Hausman AM, Ifkovits CA, Buse JB, Gould
Beck-Sague CM, Azimi P, Fonseca SN, Baltimore RS, GW, Burant CF et al (1992) Human intestinal glucose
Powell DA, Bland LA et al (1994) Bloodstream infec- transporter expression and localization of GLUT5. Am
tions in neonatal intensive care unit patients: results of a J Physiol 262(3 Pt 1):C795–C800
multicenter study. Pediatr Infect Dis J 13 Davis MJ, Hill MA (1999) Signaling mechanisms under-
(12):1110–1116 lying the vascular myogenic response. Physiol Rev 79
Berseth CL (1989) Gestational evolution of small intestine (2):387–423
motility in preterm and term infants. J Pediatr de Lorijn LF, Voskuijl WP, Omari TI, Kok JH, Taminiau
115:646–651 JA, Benninga MA (2005) Assessment of the rectoanal
Berseth CL (1992) Effect of early feeding on maturation of inhibitory reflex in preterm infants with delayed meco-
the preterm infant’s small intestine. J Pediatr 120 nium passage. J Pediatr Gastroenterol Nutr 40
(6):947–953 (4):434–437
Berseth CL (1996) Gastrointestinal motility in the neonate. de Santa BP, van den Brink GR, Roberts DJ (2003) Devel-
Clin Perinatol 23(2):179–190 opment and differentiation of the intestinal epithelium.
Berseth CL (2005) Developmental anatomy and physiol- Cell Mol Life Sci 60(7):1322–1332
ogy of the gastrointestinal tract. In: Taeusch HW, Bal- DeMarco V, Dyess K, Strauss D, West CM, Neu J (1999)
lard RA (eds) Avery’s diseases of the newborn, 8th edn. Inhibition of glutamine synthetase decreases prolifera-
W.B. Saunders Company, Philadelphia tion of cultured rat intestinal epithelial cells. J Nutr 129
Berthoud HR, Jedrzejewska A, Powley TL (1990) Simul- (1):57–62
taneous labeling of vagal innervation of the gut and Deshpande G, Rao S, Patole S, Bulsara M (2010) Updated
afferent projections from the visceral forebrain with dil meta-analysis of probiotics for preventing necrotizing
injected into the dorsal vagal complex in the rat. J enterocolitis in preterm neonates. Pediatrics 125
Comp Neurol 301(1):65–79 (5):921–930
530 A. Riskin et al.
Deshpande GC, Rao SC, Keil AD, Patole SK (2011) Guarner F, Malagelada JR (2003) Gut flora in health and
Evidence-based guidelines for use of probiotics in pre- disease. Lancet 361(9356):512–519
term neonates. BMC Med 9:92 Gupta A, Gulati P, Kim W, Fernandez S, Shaker R,
Di Mauro A, Neu J, Riezzo G, Raimondi F, Martinelli D, Jadcherla SR (2009) Effect of postnatal maturation on
Francavilla R et al (2013) Gastrointestinal function the mechanisms of esophageal propulsion in preterm
development and microbiota. Ital J Pediatr 39:15 human neonates: primary and secondary peristalsis.
Di LC, Flores AF, Hyman PE (1995) Age-related changes Am J Gastroenterol 104(2):411–419
in colon motility. J Pediatr 127(4):593–596 Halsted CH (2003) Absorption of water-soluble vitamins.
Faure C, Chalazonitis A, Rheaume C, Bouchard G, Curr Opin Gastroenterol 19(2):113–117
Sampathkumar SG, Yarema KJ et al (2007) Hamosh M (1987) Lipid metabolism in premature infants.
Gangliogenesis in the enteric nervous system: roles of Biol Neonate 52(Suppl 1):50–64
the polysialylation of the neural cell adhesion molecule Hamosh M (1990) Lingual and gastric lipases. Nutrition 6
and its regulation by bone morphogenetic protein-4. (6):421–428
Dev Dyn 236(1):44–59 Hamosh M (1995) Lipid metabolism in pediatric nutrition.
Fekete E, Benedeczky I, Timmermans JP, Resch BA, Pediatr Clin North Am 42(4):839–859
Scheuermann DW (1996) Sequential pattern of nerve- Harvey BJ, Alzamora R, Stubbs AK, Irnaten M,
muscle contacts in the small intestine of developing McEneaney V, Thomas W (2008) Rapid responses to
human fetus. An ultrastructural and immunohistochem- aldosterone in the kidney and colon. J Steroid Biochem
ical study. Histol Histopathol 11(4):845–850 Mol Biol 108(3–5):310–317
Furness JB, Costa M (1987) Arrangement of the enteric Havranek T, Thompson Z, Carver JD (2006) Factors that
plexuses. In: Furness JB, Costa M (eds) The enteric influence mesenteric artery blood flow velocity in new-
nervous system. Churchill Livingstone, New York born preterm infants. J Perinatol 26(8):493–497
Fusunyan RD, Nanthakumar NN, Baldeon ME, Walker Hecht G (1999) Innate mechanisms of epithelial host
WA (2001) Evidence for an innate immune response defense: spotlight on intestine. Am J Physiol 277(3 Pt
in the immature human intestine: toll-like receptors on 1):C351–C358
fetal enterocytes. Pediatr Res 49(4):589–593 Heird WC, Lapillonne A (2005) The role of essential fatty
Gardner CE Jr, Hart D (1934) Arch Surg 29:942 acids in development. Annu Rev Nutr 25:549–571
Garofalo RP, Goldman AS (1999) Expression of functional Henderson TR, Hamosh M, Armand M, Mehta NR,
immunomodulatory and anti-inflammatory factors in Hamosh P (2001) Gastric proteolysis in preterm infants
human milk. Clin Perinatol 26(2):361–377 fed mother’s milk or formula. Adv Exp Med Biol
Gaynes RP, Edwards JR, Jarvis WR, Culver DH, Tolson 501:403–408
JS, Martone WJ (1996) Nosocomial infections among Hernell O, Blackberg L (1994) Human milk bile salt-
neonates in high-risk nurseries in the United States. stimulated lipase: functional and molecular aspects. J
National Nosocomial Infections Surveillance System. Pediatr 125(5 Pt 2):S56–S61
Pediatrics 98(3 Pt 1):357–361 Hoecker C, Nelle M, Poeschl J, Beedgen B, Linderkamp O
Gershon MD, Chalazonitis A, Rothman TP (1993) From (2002) Caffeine impairs cerebral and intestinal blood
neural crest to bowel: development of the enteric ner- flow velocity in preterm infants. Pediatrics 109
vous system. J Neurobiol 24(2):199–214 (5):784–787
Gewolb IH, Schwalbe RS, Taciak VL, Harrison TS, Holle GE, Forth W (1990) Myoelectric activity of small
Panigrahi P (1999) Stool microflora in extremely low intestine after chemical ablation of myenteric neurons.
birthweight infants. Arch Dis Child Fetal Neonatal Ed Am J Physiol 258(4 Pt 1):G519–G526
80(3):F167–F173 Hooper LV, Midtvedt T, Gordon JI (2002) How host-
Gewolb IH, Vice FL, Schwietzer-Kenney EL, Taciak VL, microbial interactions shape the nutrient environment
Bosma JF (2001) Developmental patterns of rhythmic of the mammalian intestine. Annu Rev Nutr 22:283–307
suck and swallow in preterm infants. Dev Med Child Houghton LA, Vieth R (2006) The case against
Neurol 43(1):22–27 ergocalciferol (vitamin D2) as a vitamin supplement.
Gork AS, Ehrenkranz RA, Bracken MB (2008) Continu- Am J Clin Nutr 84(4):694–697
ous infusion versus intermittent bolus doses of indo- Hoyos AB (1999) Reduced incidence of necrotizing
methacin for patent ductus arteriosus closure in enterocolitis associated with enteral administration of
symptomatic preterm infants. Cochrane Database Syst Lactobacillus acidophilus and Bifidobacterium infantis
Rev 1:CD006071 to neonates in an intensive care unit. Int J Infect Dis 3
Greer FR (2000) Vitamin metabolism and requirements in (4):197–202
the micropremie. Clin Perinatol 27(1):95–118, vi Huizinga JD, Thuneberg L, Kluppel M, Malysz J,
Greer FR (2001) Do breastfed infants need supplemental Mikkelsen HB, Bernstein A (1995) W/kit gene required
vitamins? Pediatr Clin North Am 48(2):415–423 for interstitial cells of Cajal and for intestinal pace-
Grider JR, Murthy KS (2008) Autoinhibition of endothe- maker activity. Nature 373(6512):347–349
lial nitric oxide synthase (eNOS) in gut smooth muscle Huizinga JD, Ambrous K, Der-Silaphet T (1998)
by nitric oxide. Regul Pept 151(1–3):75–79 Co-operation between neural and myogenic
34 Physiology of the Gastrointestinal Tract in Newborns 531
mechanisms in the control of distension-induced peri- Koenig WJ, Amarnath RP, Hench V, Berseth CL (1995)
stalsis in the mouse small intestine. J Physiol 506 Manometrics for preterm and term infants: a new tool
(Pt 3):843–856 for old questions. Pediatrics 95(2):203–206
Iqbal J, Hussain M (2009) Intestinal lipid absorption. Am J Kolacek S, Puntis JW, Lloyd DR, Brown GA, Booth IW
Physiol Endocrinol Metab 296:E1183 (1990) Ontogeny of pancreatic exocrine function. Arch
Isolauri E (2001) Probiotics in human disease. Am J Clin Dis Child 65(2):178–181
Nutr 73(6):1142S–1146S Koletzko B, Demmelmair H, Socha P (1998) Nutritional
Ittmann PI, Amarnath R, Berseth CL (1992) Maturation of support of infants and children: supply and metabo-
antroduodenal motor activity in preterm and term lism of lipids. Baillieres Clin Gastroenterol 12(4):
infants. Dig Dis Sci 37(1):14–19 671–696
Kawai T, Fushiki T (2003) Importance of lipolysis in oral Koletzko S, Jesch I, Faus-Kebetaler T, Briner J, Meier-
cavity for orosensory detection of fat. Am J Physiol Ruge W, Muntefering H et al (1999) Rectal biopsy for
Regul Integr Comp Physiol 285(2):R447–R454 diagnosis of intestinal neuronal dysplasia in children: a
Keller KM, Wirth S, Baumann W, Sule D, Booth IW prospective multicentre study on interobserver varia-
(1990) Defective jejunal brush border membrane tion and clinical outcome. Gut 44(6):853–861
sodium/proton exchange in association with lethal Land MH, Rouster-Stevens K, Woods CR, Cannon ML,
familial protracted diarrhoea. Gut 31(10):1156–1158 Cnota J, Shetty AK (2005) Lactobacillus sepsis associ-
Kelly EJ, Lagopoulos M, Primrose JN (1993a) Immuno- ated with probiotic therapy. Pediatrics 115(1):178–181
cytochemical localisation of parietal cells and G cells Lau C, Alagugurusamy R, Schanler RJ, Smith EO,
in the developing human stomach. Gut 34 Shulman RJ (2000) Characterization of the develop-
(8):1057–1059 mental stages of sucking in preterm infants during
Kelly EJ, Newell SJ, Brownlee KG, Primrose JN, Dear PR bottle feeding. Acta Paediatr 89(7):846–852
(1993b) Gastric acid secretion in preterm infants. Early Lau C, Smith EO, Schanler RJ (2003) Coordination of
Hum Dev 35(3):215–220 suck-swallow and swallow respiration in preterm
Kelly EJ, Newell SJ, Brownlee KG, Farmery SM, infants. Acta Paediatr 92(6):721–727
Cullinane C, Reid WA et al (1997) Role of epidermal Lecoin L, Gabella G, Le DN (1996) Origin of the c-kit-
growth factor and transforming growth factor alpha in positive interstitial cells in the avian bowel. Develop-
the developing stomach. Arch Dis Child Fetal Neonatal ment 122(3):725–733
Ed 76(3):F158–F162 Li N, Neu J (2009) Glutamine deprivation alters intestinal
Kennedy K, Fewtrell MS, Morley R, Abbott R, Quinlan tight junctions via a PI3-K/Akt mediated pathway in
PT, Wells JC et al (1999) Double-blind, randomized Caco-2 cells. J Nutr 139(4):710–714
trial of a synthetic triacylglycerol in formula-fed term Lichnovsky V, Lojda Z (1992) Early prenatal development
infants: effects on stool biochemistry, stool character- of the brush border enzymes in the embryonal intestine.
istics, and bone mineralization. Am J Clin Nutr 70 Acta Univ Palacki Olomuc Fac Med 134:27–31
(5):920–927 Lidestri M, Agosti M, Marini A, Boehm G (2003) Oligo-
Kere J, Lohi H, Hoglund P (1999) Genetic disorders of saccharides might stimulate calcium absorption in
membrane transport III. Congenital chloride diarrhea. formula-fed preterm infants. Acta Paediatr Suppl 91
Am J Physiol 276(1 Pt 1):G7–G13 (441):91–92
Kessler JP (1993) Involvement of excitatory amino acids in Lin HC, Su BH, Chen AC, Lin TW, Tsai CH, Yeh TF
the activity of swallowing-related neurons of the et al (2005) Oral probiotics reduce the incidence and
ventro-lateral medulla. Brain Res 603(2):353–357 severity of necrotizing enterocolitis in very low birth
Kien CL, Heitlinger LA, Li BU, Murray RD (1989) Diges- weight infants. Pediatrics 115(1):1–4
tion, absorption, and fermentation of carbohydrates. Lin HC, Hsu CH, Chen HL, Chung MY, Hsu JF, Lien RI
Semin Perinatol 13(2):78–87 et al (2008) Oral probiotics prevent necrotizing entero-
Kirchgessner AL, Gershon MD (1989) Identification of colitis in very low birth weight preterm infants: a mul-
vagal efferent fibers and putative target neurons in the ticenter, randomized, controlled trial. Pediatrics 122
enteric nervous system of the rat. J Comp Neurol 285 (4):693–700
(1):38–53 Lindberg T, Skude G (1982) Amylase in human milk.
Kitajima H, Sumida Y, Tanaka R, Yuki N, Takayama H, Pediatrics 70(2):235–238
Fujimura M (1997) Early administration of Lohi H, Kujala M, Makela S, Lehtonen E, Kestila M,
Bifidobacterium breve to preterm infants: randomised Saarialho-Kere U et al (2002) Functional characteriza-
controlled trial. Arch Dis Child Fetal Neonatal Ed 76 tion of three novel tissue-specific anion exchangers
(2):F101–F107 SLC26A7, -A8, and -A9. J Biol Chem 277
Knol J, Boehm G, Lidestri M, Negretti F, Jelinek J, Agosti (16):14246–14254
M et al (2005) Increase of faecal bifidobacteria due to Lopez-Alonso M, Moya MJ, Cabo JA, Ribas J, del Carmen
dietary oligosaccharides induces a reduction of clini- MM, Silny J et al (2006) Twenty-four-hour esophageal
cally relevant pathogen germs in the faeces of formula- impedance-pH monitoring in healthy preterm neonates:
fed preterm infants. Acta Paediatr Suppl 94(449):31–33 rate and characteristics of acid, weakly acidic, and
532 A. Riskin et al.
weakly alkaline gastroesophageal reflux. Pediatrics 118 of sudden infant death syndrome and apparently life-
(2):e299–e308 threatening events. Biol Neonate 62(1):15–22
Louis NA, Lin PW (2009) The intestinal immune barrier. Murch SH, Winyard PJ, Koletzko S, Wehner B, Cheema
NeoReviews 10(4):e180–e190 HA, Risdon RA et al (1996) Congenital enterocyte
Louis NA, Hamilton KE, Canny G, Shekels LL, Ho SB, heparan sulphate deficiency with massive albumin
Colgan SP (2006) Selective induction of mucin-3 by loss, secretory diarrhoea, and malnutrition. Lancet
hypoxia in intestinal epithelia. J Cell Biochem 99 347(9011):1299–1301
(6):1616–1627 Murray RD, Boutton TW, Klein PD, Gilbert M, Paule CL,
Lu J, Jilling T, Li D, Caplan MS (2007) Polyunsaturated MacLean WC Jr (1990) Comparative absorption of
fatty acid supplementation alters proinflammatory gene [13C]glucose and [13C]lactose by premature infants.
expression and reduces the incidence of necrotizing Am J Clin Nutr 51(1):59–66
enterocolitis in a neonatal rat model. Pediatr Res 61 Nankervis CA, Nowicki PT (2000) Role of endothelin-1 in
(4):427–432 regulation of the postnatal intestinal circulation. Am J
Malo C (1990) Separation of two distinct Na+/D-glucose Physiol Gastrointest Liver Physiol 278(3):G367–G375
cotransport systems in the human fetal jejunum by Nanthakumar NN, Fusunyan RD, Sanderson I, Walker WA
means of their differential specificity for 3-O- (2000) Inflammation in the developing human intes-
methylglucose. Biochim Biophys Acta 1022(1):8–16 tine: a possible pathophysiologic contribution to nec-
Malo C, Berteloot A (1991) Analysis of kinetic data in rotizing enterocolitis. Proc Natl Acad Sci U S A 97
transport studies: new insights from kinetic studies of (11):6043–6048
Na(+)-D-glucose cotransport in human intestinal brush- Neish AS (2009) Microbes in gastrointestinal health and
border membrane vesicles using a fast sampling, rapid disease. Gastroenterology 136(1):65–80
filtration apparatus. J Membr Biol 122(2):127–141 Neu J, Caicedo R (2005) Probiotics: protecting the intesti-
Martinussen M, Brubakk AM, Vik T, Yao AC (1996) nal ecosystem? J Pediatr 147(2):143–146
Mesenteric blood flow velocity and its relation to tran- Neu J, Roig JC, Meetze WH, Veerman M, Carter C,
sitional circulatory adaptation in appropriate for gesta- Millsaps M et al (1997) Enteral glutamine supplemen-
tional age preterm infants. Pediatr Res 39(2):275–280 tation for very low birth weight infants decreases mor-
Medzhitov R (2007) Recognition of microorganisms and bidity. J Pediatr 131(5):691–699
activation of the immune response. Nature 449 Newell SJ, Sarkar PK, Durbin GM, Booth IW, McNeish
(7164):819–826 AS (1988) Maturation of the lower oesophageal sphinc-
Menard D, Dagenais P, Calvert R (1994) Morphological ter in the preterm baby. Gut 29(2):167–172
changes and cellular proliferation in mouse colon dur- Newgreen D, Young HM (2002a) Enteric nervous system:
ing fetal and postnatal development. Anat Rec 238 development and developmental disturbances – part
(3):349–359 1. Pediatr Dev Pathol 5(3):224–247
Mihatsch WA, Hoegel J, Pohlandt F (2006) Prebiotic oli- Newgreen D, Young HM (2002b) Enteric nervous system:
gosaccharides reduce stool viscosity and accelerate development and developmental disturbances – part
gastrointestinal transport in preterm infants. Acta 2. Pediatr Dev Pathol 5(4):329–349
Paediatr 95(7):843–848 Niot I, Poirier H, Tran TT, Besnard P (2009) Intestinal
Mihatsch WA, Braegger CP, Decsi T, Kolacek S, absorption of long-chain fatty acids: evidence and
Lanzinger H, Mayer B et al (2012) Critical systematic uncertainties. Prog Lipid Res 48(2):101–115
review of the level of evidence for routine use of Nowicki PT (1998) Postnatal changes in gut hemodynam-
probiotics for reduction of mortality and prevention of ics: a possible role for substance P. Am J Physiol 274
necrotizing enterocolitis and sepsis in preterm infants. (6 Pt 1):G1142–G1150
Clin Nutr 31:6–15 Nurko S (2005) What’s the value of diagnostic tools in
Miller H, Zhang J, Kuolee R, Patel GB, Chen W (2007) defecation disorders? J Pediatr Gastroenterol Nutr 41
Intestinal M cells: the fallible sentinels? World J (Suppl 1):S53–S55
Gastroenterol 13(10):1477–1486 Nusrat A, Turner JR, Madara JL (2000) Molecular physi-
Mimouni FB, Shamir R (2009) Vitamin D requirements in ology and pathophysiology of tight junctions.
the first year of life. Curr Opin Clin Nutr Metab Care 12 IV. Regulation of tight junctions by extracellular stim-
(3):287–292 uli: nutrients, cytokines, and immune cells. Am J
Montgomery RK, Mulberg AE, Grand RJ (1999) Devel- Physiol Gastrointest Liver Physiol 279(5):G851–G857
opment of the human gastrointestinal tract: twenty Omari TI, Benninga MA, Barnett CP, Haslam RR, David-
years of progress. Gastroenterology 116(3):702–731 son GP, Dent J (1999) Characterization of esophageal
Moro G, Minoli I, Mosca M, Fanaro S, Jelinek J, Stahl B body and lower esophageal sphincter motor function
et al (2002) Dosage-related bifidogenic effects of in the very premature neonate. J Pediatr 135(4):
galacto- and fructooligosaccharides in formula-fed 517–521
term infants. J Pediatr Gastroenterol Nutr 34 Park CW, Moon KC, Park JS, Jun JK, Romero R, Yoon
(3):291–295 BH (2009) The involvement of human amnion in
Mouterde O, Dacher JN, Basuyau JP, Mallet E (1992) histologic chorioamnionitis is an indicator that a fetal
Gastric secretion in infants. Application to the study and an intra-amniotic inflammatory response is more
34 Physiology of the Gastrointestinal Tract in Newborns 533
likely and severe: clinical implications. Placenta Shamir R, Johnson WJ, Zolfaghari R, Lee HS, Fisher EA
30(1):56–61 (1995) Role of bile salt-dependent cholesteryl ester
Phillips SF (1997) The growth of knowledge in human hydrolase in the uptake of micellar cholesterol by intes-
digestion and absorption. Gastroenterology 112 tinal cells. Biochemistry 34(19):6351–6358
(4):1404–1405 Sharma R, Tepas JJ 3rd (2010) Microecology, intestinal
Pickering LK, Granoff DM, Erickson JR, Masor ML, epithelial barrier and necrotizing enterocolitis. Pediatr
Cordle CT, Schaller JP et al (1998) Modulation of the Surg Int 26(1):11–21
immune system by human milk and infant formula Sharma et al (2010) Microecology, intestinal epithelial
containing nucleotides. Pediatrics 101(2):242–249 barrier and necrotizing enterocolitis. Pediatr Surg Int
Pinto D, Clevers H (2005) Wnt control of stem cells and 26:11–21. https://doi.org/10.1007/s00383-009-2536-2
differentiation in the intestinal epithelium. Exp Cell Sherman PM, Mitchell DJ, Cutz E (2004) Neonatal enter-
Res 306(2):357–363 opathies: defining the causes of protracted diarrhea of
Potsic B, Holliday N, Lewis P, Samuelson D, DeMarco V, infancy. J Pediatr Gastroenterol Nutr 38(1):16–26
Neu J (2002) Glutamine supplementation and depriva- Shulman RJ, Wong WW, Smith EO (2005) Influence of
tion: effect on artificially reared rat small intestinal changes in lactase activity and small-intestinal mucosal
morphology. Pediatr Res 52(3):430–436 growth on lactose digestion and absorption in preterm
Ramirez M, Amate L, Gil A (2001) Absorption and distri- infants. Am J Clin Nutr 81(2):472–479
bution of dietary fatty acids from different sources. Siahanidou T, Mandyla H, Papassotiriou I, Anagnostakis D
Early Hum Dev 65(Suppl):S95–S101 (2004) Serum lipids in preterm infants fed a formula
Ramirez A, Wong WW, Shulman RJ (2006) Factors regu- supplemented with nucleotides. J Pediatr Gastroenterol
lating gastric emptying in preterm infants. J Pediatr 149 Nutr 38(1):56–60
(4):475–479 Siegle ML, Buhner S, Schemann M, Schmid HR, Ehrlein
Rao SS, Welcher K (1996) Periodic rectal motor activity: HJ (1990) Propagation velocities and frequencies of
the intrinsic colonic gatekeeper? Am J Gastroenterol 91 contractions along canine small intestine. Am J Physiol
(5):890–897 258(5 Pt 1):G738–G744
Reber KM, Nankervis CA, Nowicki PT (2002) Newborn Simon-Assmann P, Turck N, Sidhoum-Jenny M,
intestinal circulation. Physiology and pathophysiology. Gradwohl G, Kedinger M (2007) In vitro models of
Clin Perinatol 29(1):23–39 intestinal epithelial cell differentiation. Cell Biol
Riskin A, Hochwald O, Bader D, Srugo I, Gabi N, Toxicol 23(4):241–256
Kugelman A et al (2010) The effects of lactulose sup- Simpson C, Schanler RJ, Lau C (2002) Early introduction
plementation to enteral feedings in premature infants: a of oral feeding in preterm infants. Pediatrics 110
pilot study. J Pediatr 156(2):209–214 (3):517–522
Salminen S, Isolauri E (2006) Intestinal colonization, Sparks SE (2006) Inherited disorders of glycosylation. Mol
microbiota, and probiotics. J Pediatr 149:S115–S120 Genet Metab 87(1):1–7
Salzman NH, Underwood MA, Bevins CL (2007) Paneth Srinivasjois R, Rao S, Patole S (2009) Prebiotic supple-
cells, defensins, and the commensal microbiota: a mentation of formula in preterm neonates: a systematic
hypothesis on intimate interplay at the intestinal review and meta-analysis of randomised controlled tri-
mucosa. Semin Immunol 19(2):70–83 als. Clin Nutr 28(3):237–242
Sarna SK, Otterson MF (1988) Gastrointestinal motility: Stahl A, Hirsch DJ, Gimeno RE, Punreddy S, Ge P, Watson
some basic concepts. Pharmacology 36(Suppl 1):7–14 N et al (1999) Identification of the major intestinal fatty
Sarna SK, Otterson MF (1989) Small intestinal physiology acid transport protein. Mol Cell 4(3):299–308
and pathophysiology. Gastroenterol Clin North Am 18 Stark ME, Bauer AJ, Sarr MG, Szurszewski JH (1993)
(2):375–404 Nitric oxide mediates inhibitory nerve input in human
Saur D, Vanderwinden JM, Seidler B, Schmid RM, De Laet and canine jejunum. Gastroenterology 104(2):398–409
MH, Allescher HD (2004) Single-nucleotide promoter Stevens BR, Preston RL (1998) Sodium-dependent amino
polymorphism alters transcription of neuronal nitric acid transport is preserved in lyophilized reconstituted
oxide synthase exon 1c in infantile hypertrophic pyloric apical membranes from intestinal epithelium. Anal
stenosis. Proc Natl Acad Sci U S A 101(6):1662–1667 Biochem 265(1):117–122
Schanler RJ (1995) Suitability of human milk for the Szajewska H, Skorka A, Ruszczynski M, Gieruszczak-
low-birthweight infant. Clin Perinatol 22(1):207–222 Bialek D (2007) Meta-analysis: lactobacillus GG for
Schanler RJ, Rifka M (1994) Calcium, phosphorus and treating acute diarrhoea in children. Aliment Pharmacol
magnesium needs for the low-birth-weight infant. Ther 25(8):871–881
Acta Paediatr Suppl 405:111–116 Tanaka M, Lee K, Martinez-Augustin O, He Y, Sanderson
Schultz SG (2007) From a pump handle to oral rehydration IR, Walker WA (1996) Exogenous nucleotides alter
therapy: a model of translational research. Adv Physiol the proliferation, differentiation and apoptosis of
Educ 31(4):288–293 human small intestinal epithelium. J Nutr 126
Shah P, Shah V (2007) Arginine supplementation for pre- (2):424–433
vention of necrotising enterocolitis in preterm infants. Thomson AB, Keelan M, Thiesen A, Clandinin MT,
Cochrane Database Syst Rev 3:CD004339 Ropeleski M, Wild GE (2001) Small bowel review:
534 A. Riskin et al.
normal physiology part 1. Dig Dis Sci 46(12): Villa M, Menard D, Semenza G, Mantei N (1992) The
2567–2587 expression of lactase enzymatic activity and mRNA in
Thureen P, Heird WC (2005) Protein and energy require- human fetal jejunum. Effect of organ culture and of
ments of the preterm/low birthweight (LBW) infant. treatment with hydrocortisone. FEBS Lett 301
Pediatr Res 57(5 Pt 2):95R–98R (2):202–206
Underwood MA, Salzman NH, Bennett SH, Barman M, Vorbach C, Capecchi MR, Penninger JM (2006) Evolution
Mills D, Marcobal A et al (2009) A randomized of the mammary gland from the innate immune system?
placebo-controlled comparison of two prebiotic/pro- Bioessays 28(6):606–616
biotic combinations in preterm infants: Impact on Walker WA (2002) Development of the intestinal mucosal
weight gain, intestinal microbiota, and fecal short barrier. J Pediatr Gastroenterol Nutr 34(Suppl 1):
chain fatty acids. J Pediatr Gastroenterol Nutr 48(2): S33–S39
216–225 Wang PA, Huang FY (1994) Time of the first defaecation
Underwood MA, Kalanetra KM, Bokulich NA, and urination in very low birth weight infants. Eur J
Mirmiran M, Barile D, Tancredi DJ et al (2014) Prebi- Pediatr 153(4):279–283
otic oligosaccharides in premature infants. J Pediatr Wenzl TG, Moroder C, Trachterna M, Thomson M, Silny J,
Gastroenterol Nutr 58(3):352–360 Heimann G et al (2002) Esophageal pH monitoring and
VanderWall KJ, Bealer JF, Adzick NS, Harrison MR (1995) impedance measurement: a comparison of two diag-
Cyclic GMP relaxes the internal anal sphincter in nostic tests for gastroesophageal reflux. J Pediatr
Hirschsprung’s disease. J Pediatr Surg 30(7):1013–1015 Gastroenterol Nutr 34(5):519–523
Vanderwinden JM, Liu H, De Laet MH, Vanderhaeghen JJ Wester T, O’Briain DS, Puri P (1999) Notable postnatal
(1996a) Study of the interstitial cells of Cajal in infan- alterations in the myenteric plexus of normal human
tile hypertrophic pyloric stenosis. Gastroenterology bowel. Gut 44(5):666–674
111(2):279–288 Wiley JW, Lu YX, Owyang C (1991) Evidence for a
Vanderwinden JM, Rumessen JJ, Liu H, Descamps D, De glutamatergic neural pathway in the myenteric plexus.
Laet MH, Vanderhaeghen JJ (1996b) Interstitial cells of Am J Physiol 261(4 Pt 1):G693–G700
Cajal in human colon and in Hirschsprung’s disease. Wong JM, de Souza R, Kendall CW, Emam A, Jenkins DJ
Gastroenterology 111(4):901–910 (2006) Colonic health: fermentation and short chain
Vanneste G, Van Nassauw NL, Kalfin R, Van Colen I, fatty acids. J Clin Gastroenterol 40(3):235–243
Elinck E, Van Crombruggen K et al (2008) Jejunal Zangen S, Di Lorenzo C, Zangen T, Mertz H,
cholinergic, nitrergic, and soluble guanylate cyclase Schwankovsky L, Hyman PE (2001) Rapid maturation
activity in postoperative ileus. Surgery 144(3): of gastric relaxation in newborn infants. Pediatr Res
410–426 50(5):629–632
Hormones and Gastrointestinal
Function of Newborns 35
Flavia Prodam, Simonetta Bellone, Roberta Ricotti,
Alice Monzani, Giulia Genoni, Enza Giglione, and Gianni Bona
Contents
35.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536
35.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536
35.3 Etiology, Pathogenesis, and Clinical Aspects: Gut Peptides . . . . . . . . . . . . . . 537
35.3.1 Peptides from Proglucagon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537
35.3.2 Glucose-Dependent Insulinotropic
Polypeptide (GIP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541
35.3.3 Peptide YY (PYY) 3–36 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 542
35.3.4 Peptides from Preproghrelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
35.3.5 Motilin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547
35.3.6 Cholecystokinin (CCK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 548
35.4 Therapy and Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549
Abstract delivery, in particular with the nutrient contact.
Development is a continuous process that does A growing knowledge about this complex
not stop after birth but progresses along a con- interplay among nutrients, gut peptides, and
tinuum. The intestinal absorptive process is the gut under development is an important
only partially mature before 26 weeks of ges- tool in the clinical care of preterm newborns.
tation, and gastroenteropancreatic peptides and The investigation of this system in fetal and
hormones are secreted in a basal rate and can neonatal life is still ongoing. This chapter will
be completely stimulated or inhibited after review the data about secretion of gut peptides
(GLP-1, GLP-2, oxyntomodulin, GIP, PYY,
ghrelin, obestatin, motilin, and cholecystoki-
nin) in the neonatal period with respect to
F. Prodam (*) · S. Bellone · R. Ricotti ·
A. Monzani · G. Genoni · E. Giglione · G. Bona full-term or preterm birth, weight status, and
Department of Health Sciences, Division of Pediatrics, feeding conditions. More detailed studies on
University of Piemonte Orientale, Novara, Italy this topic could offer the physiological basis
e-mail: fl[email protected];
for correct nutritional supports to preterm
[email protected];
[email protected]; [email protected]; infants as well as therapies for the necrotizing
[email protected]; [email protected]; enterocolitis.
[email protected]
# Springer International Publishing AG, part of Springer Nature 2018 535
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_184
536 F. Prodam et al.
35.1 Salient Points phenotypes such as the thrifty phenotype (de
Moura et al. 2008). Indeed, the nutritional support
• Many peptides produced from the gut are of gastrointestinal growth and function is an
involved in the development of gut functions important tool in the clinical care of newborn
as well as in the acute and chronic regulation of babies, in particular preterm neonates. In fact,
weight and energy balance. before birth, although amniotic fluid is not the
• Glucagon-like peptide 1 (GLP-1) and nutritional mainstay of fetus, it contributes up to
Glucagone-like peptide 2 (GLP-2) are secreted 15% of fetal nutrition requirements and plays a
from endocrine L cells of intestinal mucosa key role in its development and maturation
predominantly located at the ileum and colon (Mulvihill et al. 1985; Wagner 2002). Accord-
level. ingly, by 20 weeks of gestation, the anatomy of
• GLP-1 shows several activities including the fetal gut resembles that of a neonate. However, the
enhancement of insulin secretion, accumula- intestinal absorptive process is only partially
tion of fat, and suppression of glucagon secre- mature before 26 weeks of gestation and gastroen-
tion in the postprandial phase, thus increasing teropancreatic peptides are secreted in a basal rate
body weight. and can be completely stimulated or inhibited
• GLP-2 increases gut epithelial absorptive after delivery, in particular with the nutrient con-
capacity and mucosal growth with a peak of tact (Lebenthal and Lebenthal 1999; Burrin and
secrection from 30 to 40 weeks of gestational Stoll 2002). At the age of 2 years, the intestine
age, acting both on endocrine pathways and reaches its full range of functions (Corpeleijn et al.
enteric neurons. 2008). Gut hormones, peptides, and growth fac-
• Glucose-dependent insulinotrophic polypetide tors clearly have a role in gut growth after birth
has a precocious role on fat accrual and is and mediate directly and indirectly the trophic
linked to glucose metabolism. actions of the enteral nutrition in a still incom-
• Peptide YY may predict postnatal growth since pletely understood manner (Burrin and Stoll
it negatively correlates with gestational age 2002). On the other hand, hormones and growth
and anthropometric measures. factors which are present in breast milk seem to
• Ghrelin plays a role in the regulation of food co-exert trophic activities on gut development and
intake and energy expenditure but further stud- immune function in a complex interplay (de
ies are needed to clarify its exact role in Moura et al. 2008; Wagner 2002). Even less is
neonates. known about the development of these regulatory
• Motilin and cholecystokinin are responsible systems in the human neonate, and, as a conse-
respectively for gut and gallbladder motility quence, in premature infants there are still ongo-
and are potential therapeutic agents for the ing higher morbidity and mortality associated
treatment of colic dysfunction and the preven- with feeding problems (Corpeleijn et al. 2008).
tion of parenteral nutrition-associated Indeed, at present, clinical nutrition support to
cholestasis. preterm babies consists in enteral and parenteral
nutrition, but many complications are associated
with both of them (Corpeleijn et al. 2008; Amin et
35.2 Introduction al. 2008). Furthermore, if enteral feeding is impor-
tant to gut development, several acute or chronic
Development is a continuous process that does diseases could be due to formula fed with respect
not stop after birth but progresses along a contin- to human breast milk. In fact, formula milks
uum. Nutrition, environment, and stress act on contain higher amounts of proteins and lack
this development modulating the programming many endogenous hormones and growth factors
in an epigenetic manner. Prenatal and perinatal (Burrin and Stoll 2002; Corpeleijn et al. 2008;
nutrition can be imprinting factors and turn on Agostoni 2005). An improvement in the knowl-
different genes that provide organisms of different edge of factors linked to gastrointestinal function,
35 Hormones and Gastrointestinal Function of Newborns 537
and as a consequence of energy metabolism, full-length native GLP-1 is inactive (Holst 2007).
could improve strategies to better support In addition, almost all secreted GLP-1 from L
nutrition of preterm newborns as well as their cells is C-terminal amidated with an improved
follow-up. stability. Only 10–15% of the secreted GLP-1
The aim of this chapter is to review the knowl- reaches systemic circulation in the intact form.
edge about the secretion of gut peptides in neonatal This rapid initial whole-body clearance is due to
period with respect to weight status and feeding specific tissue metabolism in the liver and also to
conditions. It has to be underlined that many data the activity of dipeptidyl peptidase-4 (DPP-4)
are still anecdotical with respect to the knowledge which is expressed in both enterocytes and endo-
in childhood or adulthood and also contrasting thelial cells of the lamina propria capillaries
probably due to sample size, methods of measure- (Holst 2007).
ments, or stratification of subjects. GLP-1 shows several activities including the
enhancement of insulin and suppression of gluca-
gon secretion in the postprandial phase thus mod-
35.3 Etiology, Pathogenesis, and ulating the pancreatic glucose response (Neary et
Clinical Aspects: Gut Peptides al. 2004; Hellstrom et al. 2004). The amplification
of insulin secretion related to glucose levels has
In recent years, many peptides produced from the been named the incretin effect by hormones pro-
gut have been discovered that are strictly involved duced by the gut (Holst 2007).
in the development of gut functions as well as in GLP-1 levels have been shown to be modu-
the acute and chronic regulation of weight and lated by ingested micro- and macronutrients
energy balance. They are also modulated by nutri- through a direct activation of the secretion by L
ent ingestion and could influence pancreatic cells mainly via an interaction with nutrient-sens-
secretion and beta-cell proliferation and survival. ing receptors and with vagus nerve (Holst 2007).
The large accumulation of data about them A role for neural, endocrine mediators or both in
regards obesity and type 2 diabetes in adulthood. the rapid, nutrient-stimulated increase in plasma
However, the investigation of their role in neona- GLP-1 has been demonstrated (Spreckley and
tal period is ongoing and could offer interesting Murphy 2015). The meal size and composition
results for the treatment of preterm babies. seem to be key factors of GLP-1 secretion in
adulthood, correlating with gastric emptying. In
fact, smaller meals in particular those where
35.3.1 Peptides from Proglucagon nutrients are rapidly absorbed could not elicit
measurable GLP-1 secretion, whereas they
35.3.1.1 Glucagon-Like Peptide 1 were able to stimulate glucose-dependent
(GLP-1) insulinotropic polypeptide (GIP) in large
GLP-1 is a peptide of 30 amino acids expressed amounts. In contrast, larger meals containing
and secreted from endocrine L cells of intestinal more complex nutrients, namely, complex carbo-
mucosa predominantly located at the ileum and hydrates and monounsaturated lipids, were
colon level. GLP-1 derives from the same precur- followed by high and rapid GLP-1 secretion
sor of glucagon, the proglucagon, that in L cells is (Holst 2007; Spreckley and Murphy 2015; Pais
processed by the prohormone convertase 1/3 et al. 2016; Vilsboll et al. 2003).
(PC1/3). Proglucagon is also expressed in the GLP-1 plays a role in mediating appetite and
brain, in particular in arcuate and paraventricular feeding behavior. A reduction in hunger, coupled
nuclei. Three hormonal products, GLP-1, GLP-2, with the sensation of fullness, has been reported
and oxyntomodulin (OXM), derive simulta- after its administration (Naslund et al. 1999). Con-
neously from its processing in neurons. In the sistent with animal studies, in humans, GLP-1
gut, its truncated peptides (GLP-1 (7-36) amide induces a mild but significant dose-dependent
or GLP-1 (7-37)) are the active forms, while the inhibition of food intake in both lean and obese
538 F. Prodam et al.
subjects as well as in patients with type 2 diabetes gut or pancreatic production rate (Amin et al.
(Verdich et al. 2001). 2008; Konturek et al. 2004). GLP-1-stimulated
A role of GLP-1 in the development of gut insulin secretion may affect fat accumulation in
functions was hypothesized because of its incretin terms of catch-up fat in the early postnatal period,
action and, namely, on direct regulation by nutri- as evidenced by a higher increase in body weight
ents (Holst 2007). associated to higher GLP-1 levels in early preterm
In the context of developing of fetus and gut than in late preterm neonates (Shoji et al. 2016).
maturation from prenatal to postnatal life, studies High GLP-1 as well as high insulin and low insu-
on GLP-1 are limited. It has been demonstrated lin sensitivity in the early postnatal period in very
that it is involved in regulation of pancreatic beta- preterm infants may contribute to obesity in the
cell mass also in neonatal period (Holst 2007; future. This hypothesis seems to be also supported
Drucker 2002). Furthermore, it has been recently by the evidence that small for gestational age
shown that preterm and term neonates present (SGA) neonates had fasting GLP-1 levels similar
higher fasting GLP-1 levels than children and to AGA neonates when breastfed, meanwhile
adults, with premature babies presenting the higher GLP-1 levels when formula fed at 4 weeks
highest levels in both conditions, probably due of age (Díaz et al. 2015), by considering SGA
to an increase in production or a decrease in condition and the formula feeding, two of the
metabolism secondary to immaturity of DPP-4 main risk factors for later obesity and type 2 diabe-
and/or reduced glomerular filtration rate (Amin tes. Few preliminary studies conducted in adults
et al. 2008; Konturek et al. 2004; Padidela et al. born SGA with fasting and fed GLP-1 levels were
2009). More recently, also GLP-1 levels during similar to healthy controls (Konturek et al. 2004)
feeding have been shown to be higher in preterm without diurnal variations in the secretory profile
neonates than in older children or adults without (Brøns et al. 2016), although these studies did not
being linked to hypoglycemic episodes. The evaluate nutrition contribution in the first months of
majority of infants of this study were fed by naso- life, suggesting that more investigations are needed.
gastric tube, suggesting a direct stimulus on
enteric pathways without activation of cephalic 35.3.1.2 Glucagon-Like Peptide 2
vagal tone (Amin et al. 2008). Notably, the pre- (GLP-2)
mature neonatal gut is able to function as it typi- GLP-2 is a 33-amino acid peptide also produced
cally does suggesting an ontogenic key role of by the endocrine L cells by posttranslational pro-
GLP-1 (Amin et al. 2008). This role seems to be cessing of proglucagon and is secreted in response
crucial in the first months after birth in premature to food intake together with GLP-1 (Holst 2007).
newborns, with a peak 2–4 weeks after birth, more It is also produced in the brain (Drucker and Yusta
pronounced in those born before 30 weeks of 2014). It is rapidly cleaved in inactive GLP-2
gestational age, and with levels higher than the (3–33) by DPP-4 with a half-life of 7 min which
normal range in adults (Nagasaki and Ohta 2015; is longer than that of GLP-1 (Amin et al. 2008). It
Kawamata et al. 2014, 2015; Shoji et al. 2016). binds and activates an own receptor, the GLP-2
GLP-1 levels remain persistently high at least receptor (GLP-2R), which presents homology
until 38 weeks of life in both preterm and term with those of GLP-1, GIP, and glucagon and is
infants (Nagasaki and Ohta 2015; Kawamata et al. expressed predominantly in myofibroblasts and
2014). This enhanced GLP-1 could also regulate neurons in the intestinal tract and only in a subset
enteroendocrine systems by increasing beta-cell of epithelial cells, indicating an indirect mecha-
mass and regeneration. In fact, GLP-1 production nism of action (Burrin and Stoll 2002; Amin et al.
in preterm infants is related to the stimulation of 2008; Drucker and Yusta 2014). As GLP-1, it is
insulin secretion in early postnatal period, modulated by ingested macronutrients, namely,
although associated with lower insulin sensitivity carbohydrates and lipids (Xiao et al. 1999), short-
(Shoji et al. 2016). However, it is not known if chain fatty acids (Burrin and Stoll 2002), and fibers
increased GLP-1 levels derive also from a higher (Amato et al. 2016). In adulthood, after an oral
35 Hormones and Gastrointestinal Function of Newborns 539
feeding, GLP-2 secretion presents a biphasic for prebiotic-induced increases in intestinal bar-
increase with a first peak within 15 min and a rier function (Cani et al. 2009) and involves both
second one more prolonged after 1 h, suggesting IGF-1 and the intestinal-epithelial IGF-1 receptor
not only a direct stimulation by nutrients but also (IE-IGF-1R) (Dong et al. 2014).
several factors, in particular GIP and vagus nerve If GLP-2 secretion is regulated by carbohy-
(Burrin and Stoll 2002; Drucker and Yusta 2014). drates and lipids, a feedback loop is present. In
In contrast to GLP-1, the role of GLP-2 in the fact, GLP2 increases the uptake of sugars by
regulation of feeding and fasting balance is more augmenting the activity and the expression of
unclear. Intracerebroventricular administration of their transporters and by enhancing the expression
the peptide suppresses food intake in rodents in of several enzymes involved in digestion (Amato
similar fashion to GLP-1 (Tang-Christensen et al. et al. 2016). It also plays a role in lipid physiology
2000). In humans, no variations in feeding behav- by facilitating their intestinal absorption of lipids
ior as well as gastric emptying have been observed and by increasing and regulating chylomicron
after administration of GLP-2 (Schmidt et al. secretion from the gut predominantly via CD36
2003). On the other hand, knockout mice with (Amato et al. 2016; Xiao et al. 2015).
GLP-2R deletion selectively in hypothalamic The main role of GLP-1 is to be an incretin
arcuate nucleus neurons expressing pro- hormone, as discussed above. Conversely, an
opiomelanocortin (POMC) display hyperphagic action on glucose metabolism by GLP-2 was
behavior and late-onset obesity (Guan et al. 2012). largely ignored. GLP-2R knockout mice do not
Different from GLP-1, GLP-2 is mainly a tro- present an impairment in glucose tolerance or in
phic peptide of intestinal mucosa and seems to act glucagon secretion (Bahrami et al. 2010), and
on gastric motility with a slowing effect at least in treatments with a GLP-2R antagonist in animals
fasting conditions (Burrin and Stoll 2002; Amin et or agonist in humans failed to change glucose or
al. 2008). Its acute administration also inhibits insulin levels (Drucker and Yusta 2014;
gastric secretion (Burrin and Stoll 2002). GLP-2 Baldassano et al. 2015). On the contrary, GLP-2
is able to increase gut epithelial absorptive capac- iv administration seems to increase glucagon
ity and mucosal growth, acting both on endocrine secretion in healthy subjects (Amato et al. 2016).
pathways and enteric neurons (Amin et al. 2008; GLP-2 may act as a protective factor against the
Drucker and Yusta 2014; Martin et al. 2006). deregulation of the glucose metabolism in condi-
GLP-2 is involved in controlling the absorptive tions related to increased uptake of energy, such as
capacity of the proximal bowel. In fact, after gut obesity, at least in animal models (Amato et al.
resection, the residual bowel secretes higher 2016). GLP-2 acts to improve glucose metabo-
amounts of GLP-2 after feeding in both animals lism in a concentration-dependent manner in mice
and humans (Martin et al. 2006). Indeed, GLP-2 with high-fat diet-induced obesity (Baldassano et
regulates the adaptative intestinal regrowth after a al. 2016). Accordingly, in obese subjects without
period of fasting or in response to enteritis caused type 2 diabetes, GLP-2 concentrations are higher
by several agents (Drucker and Yusta 2014). The than controls (Valderas et al. 2014), suggesting a
malabsorpted dietary carbohydrates which stimu- protective feedback, although GLP-2 levels have
late production of short-chain fatty acids are the been shown associated with insulin resistance in a
hypothesized trigger mechanism of the increased pilot study (Geloneze et al. 2013). It has been
GLP-2 secretion (Burrin and Stoll 2002; Garcia- hypothesized that GLP-2 increased secretion
Diaz et al. 2007). GLP-2 has been shown to also could be the cause of insulin resistance as GLP-2
act on gut barrier functions reducing bowel per- increases absorption of nutrients, especially fatty
meability to macromolecules, decreasing bacteria acids, a key factor for insulin resistance or for its
translocation, and suppressing local expression of glucagonotrophic action in humans (Amato et al.
pro-inflammatory cytokines (Burrin and Stoll 2016). Because of so few data, more investiga-
2002; Drucker 2002; Drucker and Yusta 2014; tions are needed to elucidate the intriguing role of
Martin et al. 2006). GLP-2R signaling is required GLP-2 in metabolism.
540 F. Prodam et al.
According to its trophic activity, a role in response or ischemic components that may alter
development and maturation of gastrointestinal GLP-2 secretion in the remnant gut (Sigalet et al.
function has been investigated. Although the spe- 2004). Then, these results questioned if trying to
cific functions of GLP-2 in controlled gut devel- stimulate GLP-2 secretion in infant gut dysfunc-
opment are still largely unknown, it is active in the tion or in preterm newborns. Teduglutide, a long-
immature bowel, with a peak of secretion in the acting DPP-4-resistant analog of GLP-2, has
late weaning period (Burrin and Stoll 2002; recently been approved for the treatment of adult
Drucker and Yusta 2014). However, studies in short bowel syndrome and is in clinical trials for
mutant mice have demonstrated that it is not nec- Crohn’s disease in adults (http://www.ema.europa.
essary on bowel development during fetal life eu/ema/index.jsp?curl=pages/medicines/human/
(Hill et al. 1999), although its secretion mecha- orphans/2009/11/human_orphan_000210.jsp&
nism has been considered established at 24 weeks mid=WC0b01ac058001d12b&source=home
of gestation in humans (Yoshikawa et al. 2006). In MedSearch). GLP-2 supplementation could have
addition, its levels in utero would be expected a therapeutic role in neonatal conditions of gut
lower with respect to postnatal life because of dysfunction, and further studies which address
higher levels and activity of DPP-4 in the placenta to investigate the ontogeny of GLP-2 axis are
(Lambeir et al. 2003). mandatory. Although studies on the therapeutic
It has been clearly demonstrated that both application of GLP-2 in early life conducted on
fasting and fed GLP-2 levels are higher in neo- newborn pigs are encouraging (Baldassano and
nates when compared to older children or adults. Amato 2014), dose, time, and route of adminis-
As discussed for GLP-1, these findings could be tration are crucial and need to be investigated. As
due to either an increase in production and/or a an example, it has been shown that trophic
decrease in metabolism by DPP-4 immaturity or effects of enteral vs parenteral nutrition were
lower glomerular filtration (Amin et al. 2008; evident on gut growth, strongly linked to
Yoshikawa et al. 2006). Increasing GLP-2 levels increased GLP-2 secretion, and optimal when
in preterm babies may have an effect on the devel- given intermittently vs continuously in neonatal
oping gut acting as a stimulus. Of note, preterm pigs (Stoll et al. 2012). A recent pilot study on
neonates with feeding intolerance showed signif- seven infant patients with intestinal failure has
icantly lower levels of GLP-2 and increased dura- been published. Native human GLP-2 was well
tion to achieve full enteral feeding and tolerated in children, with a pharmacokinetic
hospitalization (Ozer et al. 2009). Notably, normal profile similar to that of adults (Sigalet et al.
infants with an age of 48 weeks have lower fed 2015). Studies on teduglutide are still missing.
GLP-2 levels with respect to the time of their Moreover, it is mandatory to verify acute and
delivery at 40 weeks. These data suggest that chronic side effects, in particular if GLP-2 by
gestational age may influence GLP-2 secretion stimulating mucosal proliferation which also
and that its peak of secretion could correspond encourages the growth of malignant cells in chil-
with the time of the most rapid growth of gut dren considering that they might need the treat-
which ranges from 30 to 40 weeks of gestational ment over a longer time and/or in a crucial
age (Amin et al. 2008). However, different from window of development.
previously discussed data in animals and adults,
infants with intestinal dysfunction or residual 35.3.1.3 Oxyntomodulin (OXM)
small bowel with intact colon do not appear able OXM is a 37-amino acid peptide derived the from
to produce GLP-2 in response to feeding stimula- posttranslational processing of tissue-specific pro-
tion (Sigalet et al. 2004). The reason of these glucagon molecule in intestinal cells, in particular
discordant findings remains unexplained. The in L cells in the distal portion of the small bowel
lack of GLP-2 secretion could be due to resection (Konturek et al. 2004; Cohen et al. 2003). OXM
of the L cell bearing ileum as well as an age- co-localizes with GLP-1, GLP-2, and PYY
related inability to produce an appropriate expression and secretion (Konturek et al. 2004;
35 Hormones and Gastrointestinal Function of Newborns 541
Cohen et al. 2003). Limited data are available about Although the role of OXM is intriguing, no
a possible feedback system among these peptides studies have been performed in neonatal time as
also in adults. OXM is also produced in the brain well as in childhood. This proglucagon-derived
(Cohen et al. 2003). Like GLP-1 and GLP-2, it is peptide which shares both effects of GLP-1 and
inactivated in large amounts by DPP-4 (Baldassano GLP-2 could be a good marker of nutritional
and Amato 2014). The only known receptors for status and gut development in infants (Ranganath
OXM are the same as for GLP-1 and glucagon 2008a).
(GCG-R); however, the existence of other
unknown receptor subtypes has been suggested
(Konturek et al. 2004; Gardiner et al. 2008; Dakin 35.3.2 Glucose-Dependent
et al. 2001; Pocai 2013; Irwin and Flatt 2015). Insulinotropic Polypeptide
Similar to GLP-1, OXM is released into the (GIP)
circulation after food ingestion in proportion to
the caloric intake (Chaudhri et al. 2008). How- GIP is a peptide of 42 amino acids which is
ever, it possesses a lower incretin effect when synthesized by K cells located mainly in the prox-
compared to GLP-1 itself (Konturek et al. 2004; imal small intestine (duodenum and jejunum)
Gardiner et al. 2008). This is because several data (Holst 2007). GIP is frequently found to be co-
demonstrated that activation of GCG-R contrib- localized with GLP-1 while rarely with PYY. As
utes to the insulinotropic effect of OXM and, as a with other incretin hormones, GIP is cleaved and
consequence, partially reduces its beneficial inactivated by DPP-4 with a half-life of approxi-
effects on glucose metabolism (Du et al. 2012). mately 5 min (Ranganath 2008a, b; Flatt 2007).
OXM also acts as an anorectic peptide (Konturek GIP receptors (GIP-R) are expressed in several
et al. 2004; Cohen et al. 2003; Gardiner et al. tissues, including the alpha and beta cells, stom-
2008). Its administration induces a prompt ach, adipose tissue, pituitary, heart, and brain
decrease in the sensation of hunger, food intake, (Ranganath 2008b; Flatt 2007).
and gastric emptying (Dakin et al. 2004). How- GIP secretion rises 15 min following nutrient
ever, the mechanisms of action for OXM are not ingestion of mainly glucose and fats (Pais et al.
been fully investigated at present. The reduction 2016; Wynne et al. 2006) and is also inhibited by
in energy intake after OXM administration is glucagon (Ranganath 2008b; Lu et al. 1993).
followed by weight reduction in both animals GIP can be considered as another incretin hor-
and humans (Wynne et al. 2006). This effect was mone (Holst 2007). However, it is clear that GIP
found to be not only due to the OXM anorectic alone cannot account for the full incretin effect
action but also to an increase in energy expendi- normally associated with a mixed meal, with the
ture (Gardiner et al. 2008). In vitro and in vivo main effect exerted by GLP-1 (Holst 2007; Jia et
rodent studies suggest OXM induces these cata- al. 1995). GIP, like GLP-1, is also able to promote
bolic effects that favor weight loss and subse- beta-cell neogenesis, proliferation, and differenti-
quently improved metabolic control through ation (Irwin and Flatt 2015; Ranganath 2008b).
both GLP-1 R and GCG-R agonisms (Pocai The administration of GIP improves glucose
2013). OXM levels also increase after gastric tolerance and insulin sensitivity in animals
bypass, in a similar fashion to GLP-1 (Mechanick (Naitoh et al. 2008; Althage et al. 2008). How-
et al. 2008). No studies have compared activities ever, it has been demonstrated that GIP receptor
of OXM with those of GLP-2. However, iv KO mice subjected to a high fat diet do not gain
administrations of OXM and glucagon increase weight and have a preserved insulin sensitivity
intestinal glucose uptake in rats. Because GLP-1 (Gault et al. 2005). The biological effects of GIP
does not stimulate glucose absorption, GLP-2 and appear to be markedly reduced in patients with
glucose-dependent insulinotropic peptide (GIP) type 2 diabetes when compared to normal indi-
and their receptors could be involved in this action viduals probably due to GIP-R downregulation or
(Pocai 2013). desensitization (Irwin and Flatt 2015; Skow et al.
542 F. Prodam et al.
2016), because its secretion is intact (Calanna et when babies were orally fed and started to also
al. 2013). On the other hand, the reduced increase after meals by the 24th day of life (Lucas
insulinotropic effect of GIP in type 2 diabetes et al. 1980). Fasting and post-meal GIP levels
seems an inducible and reversible pathophysio- have also been shown to be similar between
logical phenomenon when glucose levels normal- young subjects born SGA when compared with
ize. In contrast to the reduced insulinotropic AGA controls (King et al. 1989).
effect, the glucagonotropic effect of GIP seems The infants of diabetic mothers and the large
to be preserved in patients with diabetes (Irwin for gestational age (LGA) newborn babies have a
and Flatt 2015; Skow et al. 2016). more rapid insulin response to oral glucose with-
Overexpression of GIP has also been shown to out differences in GIP levels when compared to
be associated with reduced body weight in diet- AGA controls (Fallucca et al. 1985). Furthermore,
induced obese (DIO) mice (Kim et al. 2012). The amniotic fluid presents a higher GIP/insulin ratio
pronounced weight decrease after gastric bypass in diabetic pregnant women who delivered over-
seems to be dependent by surgical ablation of GIP weight infants with respect to nondiabetic preg-
secretion by the duodenum (Flatt 2008), nant women or those who delivered normal-
suggesting it has an obesogenic role more than weight babies (Heijboer et al. 2006). These data
an anti-obesity or incretin hormone role (Skow et suggest that the role of GIP on fat accrual is
al. 2016; Heptulla et al. 2000; Stock et al. 2005; precocious and linked to glucose metabolism.
Higgins et al. 2008).
Several studies on GIP were conducted in chil-
dren to investigate the integrity of its response 35.3.3 Peptide YY (PYY) 3–36
during the first phases of life.
The signals regulating the differentiation and Peptide YY (PYY) is a 36-amino acid polypeptide
the number of each endocrine cell type in embry- hormone, a member of the PP family. There are two
onic and adult intestinal tract is quite unknown. existing forms of PYY, differing by two amino
Notably most GLP-1 cells of the ileum of e-17 acids, PYY1–36 and PYY3–36, the most abundant
embryos co-express GIP and, therefore, are LK one in the bloodstream (Hellstrom et al. 2004;
cells that are more numerous than that in adult Konturek et al. 2004; Heijboer et al. 2006).
mouse ileum, suggesting a developmental role in PYY1–36 is released from distal intestinal L cells
glucose homeostasis (Grigoryan et al. 2012). In in response to luminal nutrient stimulation. In the
both term and preterm neonates, the entero-insular blood, PYY1–36 is rapidly converted to PYY3–36
axis has a functional role in response to glucose by the DPP-4, which cleaves the two N-terminal
with rising plasma GIP, which partially and pro- amino acids. PYY is able to bind to the receptor of
gressively contributes to an enhanced insulin the neuropeptide Y (NPY). Whereas PYY1–36 has
response to enterally infused glucose as well as similar affinities for the Y1 and Y2 receptor,
to oral feeding (Konturek et al. 2004). However, PYY3–36 is a high-affinity Y2 receptor ligand
as for GLP-1 and GLP-2, it has been shown that (Stadlbauer et al. 2015). Plasma PYY3–36 levels
parenteral and enteral nutrition when given con- increase after meal ingestion and remain elevated for
tinuously decreased the secretion of GIP at least in several hours (Gault et al. 2005; Stadlbauer et al.
neonatal pigs (Stoll et al. 2012). One preliminary 2015). Both isoforms, in addition to exerting secre-
study has shown that GIP levels are lower in both tory and motor activities throughout the gut, are
term and preterm neonates on cord blood at birth involved in the central regulation of food intake
with respect to adults. Furthermore, its blood- and energy balance (Stadlbauer et al. 2015). PYY
stream concentration increases 2 h after birth itself has been defined as an orexigenic peptide; in
(Knip et al. 1993) and is persistently high until particular PYY3–36 shows more potent anorectic
33 weeks of life with a following decrease (Naga- effects after either peripheral or central administra-
saki and Ohta 2015; Kawamata et al. 2014). How- tion acting on Y2 receptor at the hypothalamic level
ever, basal GIP levels progressively increased via the vagal-brainstem-hypothalamic pathway
35 Hormones and Gastrointestinal Function of Newborns 543
(Heijboer et al. 2006; Batterham et al. 2002). In Chen et al. 2012). PYY may predict postnatal
humans, the administration of PYY3–36 is followed growth; thus, the negative correlation between
by a 30% reduction of ingested nutrients and is PYY concentration and rate of weight gain in pre-
coupled with fullness sensation (Degen et al. 2005) term infants suggests that those who have higher
and nausea at higher doses (Holst 2007). Signaling PYY levels at birth will exhibit a lower rate of
at the Y2 receptor has been further implicated in weight gain later (Chen et al. 2012). PYY also
other behavioral and cognitive domains such as increases after enteral feeding with formula milk in
central information processing, salience learning, preterm babies also when affected by necrotizing
and working memory, throughout highly complex enterocolitis (Chen et al. 2012; Sharman-
interactions among homeostatic, hedonic, motiva- Koendjbiharie et al. 2002), without an effective
tional, and associative processes, being indeed role in the inflammatory response (Siahanidou et
involved in the pathways of rewarding (Stadlbauer al. 2015). An increase in postnatal age was associ-
et al. 2015). In mouse models, PYY is involved in ated with a concomitant increase in PYY (Chen et al.
regulating glucose homeostasis but differently from 2012), which remains persistently high until
other gut peptides, as it directly inhibits glucose- 10 weeks of life (Kawamata et al. 2014), and its
mediated insulin secretion (Van den Hoek et al. fasting concentration decreases in 9-month-old
2004). These effects are associated with an improve- infants (Adrian et al. 1986). Thus, it suggests that
ment of insulin action in glucose disposal indepen- the postnatal surge is a feature of early adaptation to
dently of those effects on food intake and weight the extrauterine life and could have effects not only
(Adams et al. 2006). Moreover, its production by on energy homeostasis but also on the gut, including
pancreatic islet cells, the presence on islets of NPY absorptive, trophic, and proliferative actions
receptors, and the demonstration that Y1 activation (Siahanidou et al. 2005, 2007; Adrian et al. 1986).
promotes proliferation of beta cells and protects Moreover, an early growth seems to have a role in
them from apoptosis suggest a role for this peptide programming appetite regulatory hormone secre-
in modulating beta-cell mass. Thus, a potential sig- tion, such as PYY, in later life, considering that
nificance of PYY in fetal pancreas formation is greater satiety responses after the meal are described
hypothesized (Persaud and Bewick 2014). PYY among subjects who grew slowly during early life
also directly promotes higher fat combustion in (Perala et al. 2013). Many data are needed to confirm
animals (Batterham et al. 2003). According to this these hypotheses.
data, fasting plasma PYY3–36 levels are lower in
obese rather than in lean subjects (Konturek et al.
2004), suggesting an involvement in the long-term 35.3.4 Peptides from Preproghrelin
control of weight. Therefore, weight loss in obese
children may restore a higher postprandial level of 35.3.4.1 Acylated (AG) and Unacylated
PYY in contrast with adults whose levels remain (UAG) Ghrelin
low (Wojcicki 2012). Ghrelin is a 28-amino acid peptide, recently iso-
There are increasing data describing the role of lated from the stomach, but also shown to be
PYY in neonates and infants (Misra et al. 2007, expressed in other tissues such as the pancreas,
2008). In newborn and infants, PYY3–36 levels adrenal gland, thyroid, breast, testes, placenta,
seem to account for almost half of the total circulat- pituitary and hypothalamus, myocardium, mus-
ing PYY (Siahanidou et al. 2005, 2007), whose cle, and colon (Müller et al. 2015). Ghrelin has
levels are higher in comparison with school-age been identified as an endogenous ligand of the
children and adults (Wojcicki 2012). It negatively orphan GH secretagogue (GHS) receptor type 1a
correlates with gestational age and anthropometric (Kojima and Kangawa 2005; Ghigo et al. 2001). It
measures and is higher either in cord blood or in the circulates in the blood in two forms, acylated
bloodstream of preterm than full-term infants, prob- (AG) and unacylated ghrelin (UAG) (Müller et
ably to compensate the negative body weight bal- al. 2015; Kojima and Kangawa 2005). The acyl
ance (Siahanidou et al. 2007; Berseth et al. 1992; group, which binds to ghrelin at the serine-3
544 F. Prodam et al.
residue, seems to be essential for the binding to Consistent with its effects on food intake and its
GHSR1a and the resulting neuroendocrine func- involvement in energy balance, circulating
tions, namely, GH secretion (Müller et al. 2015; ghrelin levels are negatively associated with
Kojima and Kangawa 2005). UAG, which is body mass index in humans (Wiedmer et al.
devoid of the acyl group, represents the most 2007; Paik et al. 2006; Leite-Moreira and Soares
abundant circulating form (Gauna et al. 2005; 2007). Several studies indicate that ghrelin hypo-
Wiedmer et al. 2007). UAG is biologically active, secretion in essential obesity is a functional
although it does not have direct neuroendocrine impairment in response to body weight alteration
actions (Müller et al. 2015; Kojima and Kangawa (Cummings et al. 2002). Roux-en-Y gastric
2005; Broglio et al. 2004) suggesting the exis- bypass has been shown to be associated with
tence of some GHS-R subtypes that are activated alterations in glucose kinetics and glucoregulatory
independently of its acylation (Müller et al. 2015; hormone secretion likely secondary to the ana-
Wiedmer et al. 2007; Gil-Campos et al. 2006). tomic rearrangement of the foregut, with
The mechanism of acylation of the preproghrelin increased PYY and GLP-1 concentrations and
or UAG is largely unknown. Recently, the decreased ghrelin levels (Barazzoni et al. 2007;
acyltransferase has been identified, which was Zwirska-Korczala et al. 2007). Furthermore, the
named GOAT, that octanoylates ghrelin through- majority of the data come from studies that have
out lipids, at least in part, directly recruited analyzed exclusively the total ghrelin levels.
from the pool of ingested dietary lipids (Müller Recent findings have also shown that UAG is
et al. 2015; Yang et al. 2008). GOAT and ghrelin decreased in obesity, while there are no concor-
share a similar tissue expression profiles and are dant results for AG also in children (Gualillo et al.
highly conserved across vertebrates (Müller et al. 2001; Cortelazzi et al. 2003; Chanoine et al. 2002;
2015). Bellone et al. 2004, 2012a; Soriano-Guillen et al.
Moreover, since its discovery, AG was identi- 2004). Ghrelin is also implicated in the regulation
fied first followed by UAG; ghrelin emerged as a of glucose homeostasis by modulating insulin
player in the regulation of food intake and energy secretion and action as described previously for
expenditure, with AG as the most potent periph- other gut peptides with incretin action (Yang et al.
eral orexigenic hormone known to date (Müller et 2008; Thompson et al. 2004). In particular, UAG
al. 2015; Wiedmer et al. 2007; Choi et al. 2003). and AG play opposite effects on pancreatic beta-
In animals and humans, AG, both after central and cell secretion and glucose metabolism (Müller et
peripheral administration, has been shown to al. 2015; Prodam et al. 2008). In fact, if AG may
induce appetite and food intake in a diverse fash- contribute to the worsening of insulin sensitivity,
ion to other described anorectic gut peptides suggesting a diabetogenic function, UAG could
(Wiedmer et al. 2007). Despite these clear exert its metabolic actions counterbalancing those
orexigenic effects of AG, the actual physiological of AG, at least in part at the pancreatic level
role of UAG in the regulation of appetite is still a (Gauna et al. 2005; Wiedmer et al. 2007). In
matter of debate (Choi et al. 2003), but it seems childhood, adolescence, and adulthood, it has
able to induce a negative energy balance by also been demonstrated that insulin modulates
decreasing food intake and delaying gastric emp- ghrelin levels through inhibition (Müller et al.
tying via the hypothalamus (Delhanty et al. 2012). 2015; Wiedmer et al. 2007; Baldelli et al. 2006).
It has also been clearly shown that both forms of Ghrelin secretion is also modulated by nutrients,
ghrelin also influence energy metabolism at the namely, carbohydrates, whereas the role of fats
peripheral level, most likely influencing fat oxi- and proteins is not completely understood due to
dation (Wortley et al. 2004, 2005). Reduced cel- discordant results (Müller et al. 2015; Wiedmer et
lular fat oxidation and promotion of adipogenesis al. 2007). In fact, if proteins result more effective
each contributes to an increase in fat mass induced in lowering ghrelin levels than lipids (Müller et al.
either by AG or UAG (Wiedmer et al. 2007; 2015), in other hand, both lipids and amino acids
Thompson et al. 2004; Zhang et al. 2004). seem to play a negligible role in the acute control
35 Hormones and Gastrointestinal Function of Newborns 545
of ghrelin secretion (Prodam et al. 2006). Never- trimester (Cortelazzi et al. 2003; Bellone et al.
theless it is noteworthy that administration of a 2006).
mixed meals in children does not inhibit total Higher ghrelin levels are detected in SGA new-
ghrelin levels unlike adults, suggesting a modula- borns than in AGA or LGA neonates (Stock et al.
tion by age and suggesting a functional profile 2005; Soriano-Guillen et al. 2004; Bunt et al.
oriented to anabolic processes of growth (Müller 2003) and in IUGR newborns (Chiesa et al.
et al. 2015; Wiedmer et al. 2007; Nakahara et al. 2008), suggesting a role in fetal adaptation to
2008; Prodam et al. 2014a). Particularly, its inhi- intrauterine malnutrition. Moreover, lower cord
bition seems to start from puberty at least in lean blood ghrelin is associated with slower weight
children, except for obese children and adoles- from birth to 3 and 12 months of age, at least in
cents. Conversely, total ghrelin levels decrease breastfed infants (James et al. 2004; Savino et al.
after OGTT at any age and weight (Prodam et al. 2005); this evidence, however, does not definitely
2014a). rule out a role of ghrelin in the control of
Furthermore, increasing evidence indicates somatotroph secretion but clearly suggests an
that the action of ghrelin affects a more complex involvement in both short- and long-term energy
pathway not completely known, including addi- balance (Bellone et al. 2006; Savino et al. 2005).
tional physiological functions such as learning Furthermore, preterm AGA newborns have higher
and memory, psychological stress, mood and anx- total ghrelin levels at birth (Chen et al. 2012;
iety, depression, sleep/wake rhythm, anticonvul- Cortelazzi et al. 2003; Bellone et al. 2006; Chiesa
sant effect, thymopoiesis, and aging (Müller et al. et al. 2008; Lanyi et al. 2008). Higher ghrelin
2015; Prodam et al. 2011). levels during the neonatal period could also influ-
Since pregnancy, ghrelin, both maternal and ence hormone levels later in life. In fact, increased
placental derived, seems to play an important ghrelin levels in preterm born children are
role in fetal and neonatal development by increas- sustained up to prepubertal ages (Savino et al.
ing maternal appetite and promoting nutrient sup- 2012a). It is still questioned if ghrelin concentra-
plies to the fetus resulting in its positive energy tion at birth in preterm neonates was independent
balance (Valsamakis et al. 2014). Therefore, or not by gender, body weight, and type of deliv-
ghrelin regulation and secretion in fetal and neo- ery (Bellone et al. 2006). However, it recently
natal period are not fully understood yet but inten- found a positive correlation between ghrelin
sively investigated in the last years. It has been levels and gestational age, birth weight, body
demonstrated that ghrelin has been detected in mass index, head circumference of babies at
human cord blood starting from 20 to 22 weeks birth, and anthropometric values on day 15
of life; it remains relatively constant throughout (Kahveci et al. 2015). Moreover, in preterm
the gestation and at birth and then increases infants, the positive correlations of ghrelin at
peaking during the first 2 years of life (Soriano- birth with time to reach recommended daily intake
Guillen et al. 2004; Whatmore et al. 2003; Bideci and with weight gain rate indicate that ghrelin
et al. 2008; Kasa-Vubu et al. 2007; Pomerants et may predict postnatal growth. Thus, it is
al. 2006; Savino et al. 2012a). Even though it may suggested that those babies with elevated neonatal
also originate from the maternal compartment or ghrelin concentrations will be delayed in reaching
may be secreted by the placenta, these ghrelin recommended daily intake (Chen et al. 2012). On
levels are directly produced by the fetus (Savino the other hand, what is clear is that ghrelin levels
et al. 2012a; Warchoł et al. 2014). In fact, increase from birth to fourth day of life and seem
immune-reactive ghrelin cells have been shown to negatively correlate with weight and anthropo-
in the fetal stomach, duodenum, pancreas, and metric parameters at that time in preterm and at
lung from the tenth week of gestation (Mitrovic birth in full-term newborns (Soriano-Guillen et al.
et al. 2014). Moreover, its concentration is similar 2004; Bellone et al. 2006).
between arterial and venous, and its expression is Notably, ghrelin secretion is refractory to feed-
almost absent in the placenta during the third ing in preterm AGA neonates in the first days of
546 F. Prodam et al.
life, suggesting that it could represent an anabolic Furthermore, it is also recently hypothesized a
drive in newborns (Bellone et al. 2006; James et possible role of ghrelin in the inflammatory
al. 2004). Accordingly, ghrelin positively corre- responses in adults (Prodam and Filigheddu 2014),
lates with the enteral nutrition intake in both with the evidence of higher circulating levels in
preterm and full-term babies on the second day neonates with infection (Siahanidou et al. 2015).
after birth (Hubler et al. 2006). However, it is Some preliminary studies have also analyzed
modulated by feeding, progressively increasing AG levels in newborns. It has been demonstrated
with prolonging fasting in full-term AGA infants that AG is present in both fetal and neonatal
from the first month of life (Savino et al. 2006a). circulation. AG and AG to total ghrelin ratio
Ghrelin secretion seems to be modulated by the seem to be higher in venous cord blood suggesting
type of enteral nutrition, suggesting a role of this that the placenta can produce AG with a small part
peptide in gut development and maturation. In of it transferred to the fetal circulation (Yokota et
fact, at 4 months of age, formula-fed infants have al. 2005). AG is also higher in preterm and SGA
higher ghrelin and IGF-I levels without newborns when compared to full-term and AGA
anthropometrical differences with respect to ones (Shimizu et al. 2007; Holst et al. 2007).
breastfed ones (Savino et al. 2005). At 6 months Interestingly, umbilical cord AG concentration is
of age, ghrelin levels are higher in infants with a lower than in maternal blood, and the acylation
mixed nutrition of solids and milk with respect to process seems to be affected by cortisol partly
those exclusively milk fed (Savino et al. 2005). It through a placental role (Lanyi et al. 2008). Fur-
has been demonstrated that ghrelinemia nega- ther studies are needed to clarify the exact role of
tively correlated with BMI at the first month in the different ghrelin forms in neonates. In fact,
breastfed full-term infants (Cesur et al. 2012) and newborns in physiological conditions, compared
weight gain at 12 months of age only in breastfed with children in later life, seem to have higher
but not in formula-fed infants (Savino et al. 2005, UAG and lower AG levels. Moreover, their AG
2006a). These data suggest that a precocious to UAG ratio results to be lower than in normal-
derangement in ghrelin regulation could be weight and obese children, thus suggesting a dif-
linked to the higher risk of elevated weight gain ferent metabolic function for the two forms at
in children who are breastfed for less than birth (Bellone et al. 2012b).
6 months (Kalies et al. 2005). Furthermore,
infant formula milks are devoid of many constit- 35.3.4.2 Obestatin
uents, ghrelin among others, and this fact could In 2005, Zhang and coworkers from a conserved
influence gut maturation and fat accrual. Accord- region of preproghrelin sequence identified a 23-
ingly, mature breast milk has higher ghrelin amino acid peptide which was named obestatin
levels than those of colostrum, with lower con- based on previously reported activities in animal
centrations in preterms (Han et al. 2014). Partic- models. Obestatin is amidated like GLP-1 for bio-
ularly, both total ghrelin and AG progressively activity. It was initially characterized as the active
increase in breast milk during lactation in the first ligand of the orphan receptor GPR39 (Bellone et al.
6 months, and their concentration in milk posi- 2006), but more recently, this result is discussed
tively correlated with those in plasma of the (Müller et al. 2015; Tang et al. 2008; Gourcerol et
breastfed infants (Savino et al. 2006a; Cesur et al. 2007). Obestatin, like ghrelin, is expressed in
al. 2012; Ilcol and Hizli 2007; Savino et al. several tissues which include among others the
2012b). Moreover, ghrelin levels in colostrum stomach, duodenum, pancreas, and brain (Zhang
and weight and anthropometric parameters at et al. 2005). Obestatin initially appeared to be a
least at birth seem to positively correlate (Han new regulator of appetite and body weight (Holst et
et al. 2014). Instead, there is a positive correla- al. 2007), inhibiting food intake, jejunum peristal-
tion between the level of fourth month breast sis, and weight gain, and thus is considered an
milk AG and early postnatal weight gain of antagonist of ghrelin (Zhang et al. 2014). Follow-
infants (Cesur et al. 2012). ing studies, however, failed to reproduce
35 Hormones and Gastrointestinal Function of Newborns 547
obestatin’s anorectic and anti-obesity effects and 2008; Itoh 1997). The mechanism by which
questioned its existence as just a ghrelin-associated motilin induces gut motility is still unclear. The
peptide (Qader et al. 2008). In contrast to other gut gut motilin-containing cells and enteric neurons
peptides, previous data regarding the modulation are separated only by a sheet of the basal lamina of
of insulin secretion are limited and controversial mucosal epithelium. However, the GPR38 has not
(Tang et al. 2008; Gourcerol et al. 2007). On the been demonstrated in the vagus nerve or nodose
other hand, preliminary studies in vivo recently ganglion although migrating motor complex
observed that obestatin is reduced in subjects with activity is atropine sensitive and abolished by
type 2 diabetes, type 1 diabetes at the onset, and vagotomy (Itoh 1997; Nishikubo et al. 2005).
obesity, while it is increased in anorexia (Müller et Otherwise, the GPR38 is expressed in the brain,
al. 2015; Harada et al. 2008; Prodam et al. 2014b). suggesting a role of motilin in feeding regulation
In line with the abundant studies on ghrelin, the (Savino et al. 2006a). It has to be underlined that
youngest gut peptide obestatin also started to be motilin and ghrelin precursors share almost 50%
investigated in pediatric subjects (Nakahara et al. similarity in their sequences, and, as a conse-
2008; Zou et al. 2009), but with limited data in quence, Tomasetto initially named it motilin-
neonates. Its association with birth weight is not related peptide (Tomasetto et al. 2000). More
well characterized with conflicting results, and its recently, motilin has been included in the ghrelin
role during neonatal period remains unclear. peptide family. The GPR38 and GHS-R1a are also
Obestatin levels seem to be high at fasting in part of the same family of G-protein-coupled
SGA neonates with respect to those in LGA, with- receptors with an overall sequence identity of
out differences in those preterm and term (Zhang et 53% (Poitras and Peeters 2008). Furthermore,
al. 2014). No differences in cord blood obestatin ghrelin and motilin are located in the same endo-
levels were observed between AGA and LGA crine cells and in the same secretory granules at
newborns in one published paper, probably due to duodenum and jejunum level (Wierup et al. 2007).
the sample size (Boutsikou et al. 2013). Moreover, Motilin role in gut development has been
obestatin has been detected in breast milk with a investigated in neonatal period. Motilin-secreting
positive correlation between lactating mothers and cells appear at 8–11 weeks of gestation in fetus
breastfed infants (Savino et al. 2012b). These data with a distribution similar to that in adulthood at
suggest that obestatin could play a role either in 12–15 weeks of gestation (Bryant et al. 1982). It
fetal or neonatal development and growth, also has been shown that motilin is present in duodenal
exerting effects on feeding behavior. However, epithelial cells of premature infants of <32 weeks
further studies are required to understand the rela- of gestation (Nishikubo et al. 2005). Its levels are
tionship between ghrelin, obestatin, and pre-/post- higher in preterm and SGA infants after receiving
natal development. enteral nutrition with respect to older children or
adults (Janik et al. 1982; Mahmoud et al. 1988;
Shulman and Kanarek 1993). It has been recently
35.3.5 Motilin demonstrated that motilin secretion in preterm
newborn could be modulated by prebiotics: a pre-
Motilin is a 22-amino acid peptide produced by biotic-enriched formula containing dietary oligo-
the endocrine cells of the duodenum and jejunum. saccharides (short-chain galacto-oligosaccharides/
It is able to bind and activate the receptor GPR38 long-chain fructo-oligosaccharides) resulted in sig-
through which it stimulates motility of digestive nificant surge of motilin with consequently reduced
organs (Poitras and Peeters 2008). In fact, it reg- gastric residue, compared with a common preterm
ulates gastrointestinal motility via migrating formula (Dasopoulou et al. 2015). Motilin is also
motor complex activity in its phase III of contrac- present in human milk, and its digestion in the
tion (Itoh 1997). This consists of cyclical stomach is retarded by milk itself, suggesting a
increases every 90–120 min during the biological role in the gut of newborns (De Clercq
interdigestive fasting periods (Poitras and Peeters et al. 1998). It has also been shown a positive
548 F. Prodam et al.
correlation between motilin concentration and age When administered intermittently before eating,
at 18 months of life which has not been explained CCK maintains its anorectic effect, but a compen-
yet (Savino et al. 2006a). Furthermore, colicky satory effect by increasing the daily number of
infants present higher motilin levels which could meals, with only a mild result on total food intake
have a role in this gut disorders (Lothe et al. 1987; and body weight, is observed (West et al. 1987).
Savino et al. 2006b). Motilin-receptor antagonists According to its anorectic activity as well as the
could be a potential therapeutic agent for colic stimulation of gallbladder contraction, CCK has
dysfunctions when they will become available for been investigated in neonatal life. It has been dem-
clinical exploration (Poitras and Peeters 2008). onstrated that it increases immediately after
breastfeeding, and this peak is followed by a decline
10 min later; a secondary rise occurs 30 and 60 min
35.3.6 Cholecystokinin (CCK) after it. The first increase of CCK levels may exert a
stimulatory effect on digestion, while the secondary
CCK was the first gut hormone described as inhib- increase could, namely, have an anorectic effect
itor of food intake in rodents (Gibbs et al. 1973). (Uvnas-Moberg et al. 1993). Higher CCK levels
CCK is widely expressed both at the central and correspond to a higher volume of ingested milk
peripheral levels, in particular in I cells in the during breastfeeding (Marchini and Linden 1992).
duodenum and jejunum mucosa (Moran 2000). The mechanisms of CCK effect on infant satiety
CCK is also detectable in the bloodstream in have been investigated in mice, and the anorectic
different forms, in particular CCK-8, CCK-33 effect of CCK seems to be mediated by the tempo-
and CCK-39 (Konturek et al. 2004). Two CCK rary expression of cholecystokinin-1 receptors on
receptor subtypes have been isolated: CCKA ependymal cells lining the third ventricle (Ozaki et
receptor which is expressed in the vagus nerve, al. 2013). CCK levels soon after birds and later on
enteric neurons, pancreas, and at central level and were also analyzed in mice-born IUGR by
CCKB expressed in the afferent vagus nerves, restricting the food intake of the mothers during
brain, and stomach (Moran 2000). pregnancy. Notably, gastrointestinal gene expres-
CCK possesses several activities on different sions and plasma levels of CCK were elevated in
tissues, among others the stimulatory effect on the male newborns, decreasing in adulthood,
pancreatic enzyme excretion and the induction of suggesting that, along with the altered gene expres-
gallbladder contraction (Neary et al. 2004). sions of other orexigenic and anorexigenic gut pep-
CCK has been demonstrated to be a satiety tides, an early increase followed by reduction of
signal, in particular in the short-term regulation CCK expression may provide a potential mecha-
of feeding behaviors (Konturek et al. 2004; Moran nism to explain hyperphagia and obesity seen in
2000; Woods 2004). It acts, synergistically with maternal undernutrition-induced IUGR offspring
leptin, on hypothalamic region (Konturek et al. (Nagata et al. 2011). CCK levels are negatively
2004; Gibbs et al. 1973). Its effect is reduced by correlated with age in full-term infants (Uvnas-
vagotomy (Konturek et al. 2004; Moran 2000; Moberg et al. 1993). Preterm infants present an
Woods 2004). increase of CCK concentration in cord blood 1 h
Peripheral CCK administration is followed by a later after the delivery without differences in AGA
rapid but short-term lasting effect on inhibition of and SGA babies (Tornhage et al. 1995, 1996). Nota-
food intake, with an activity peak at 30 min bly, plasma CCK concentration increases after naso-
(Shulman and Kanarek 1993). High doses of CCK gastric tube feeding only in preterm neonates who
determine nausea, vomiting, and taste aversion underwent kangaroo care. These results are still
(West et al. 1987). Notably, CCK mainly inhibits under investigation (Tornhage et al. 1998). Further-
fat ingestion (Covasa et al. 2001). The inhibitory more, CCK prophylaxis in high-risk neonates seems
effect of CCK on food intake undergoes a functional to help in preventing parenteral nutrition-associated
desensitization after high-dose administration as cholestasis (Teitelbaum et al. 1997). However, the
well as during continuous infusion (Moran 2000). role of CCK on gut maturation has never been
35 Hormones and Gastrointestinal Function of Newborns 549
explored yet. Finally, a role of CCK in visceral Amato A, Baldassano S, Mulè F (2016) GLP2: an
sensitivity could be hypothesized: it has been proven underestimated signal for improving glycaemic control
and insulin sensitivity. J Endocrinol 229:R57–R66
that an early-life antibiotic-induced disturbance of Amin H, Holst JJ, Hartmann B et al (2008) Functional ontog-
the gut microbiota induces visceral hypersensitivity eny of the proglucagon-derived peptide axis in the pre-
in male rats, mediated by parallel decrease in chole- mature human neonate. Pediatrics 121:e180–e186
cystokinin B receptor (O’Mahony et al. 2014). Bahrami J, Longuet C, Baggio LL et al (2010) The gluca-
gon-like peptide-2 receptor modulates islet adaptation
to metabolic stress in the ob/ob mouse. Gastroenterol-
ogy 139:857–868
35.4 Therapy and Treatments Baldassano S, Amato A (2014) GLP-2: what do we know?
What are we going to discover? Regul Pept 194-
195:6–10
Bioactive peptide, hormones, and factors present Baldassano S, Rappa F, Amato A et al (2015) GLP-2 as
in human milk and produced by the gut have been beneficial factor in the glucose homeostasis in mice fed
shown to stimulate gut development and functions a high fat diet. J Cell Physiol 230:3029–3036
and to be modulated by nutrients themselves. The Baldassano S, Amato A, Caldara GF, Mulè F (2016) Glu-
cagon-like peptide-2 treatment improves glucose
majority of findings come from studies on preterm dysmetabolism in mice fed a high fat diet. Endocrine
or SGA infants. However, the knowledge about 54(3):648–656
this topic is still largely incomplete with many Baldelli R, Bellone S, Castellino N et al (2006) Oral glu-
studies performed 20 years ago and abandoned cose load inhibits circulating ghrelin levels to the same
extent in normal and obese children. Clin Endocrinol
and many others linked to the new gut peptides 64:255–259
discovered in the last years. Various compounds Barazzoni R, Zanetti M, Ferreira C et al (2007) Relation-
derived by all these hormones can be hypothe- ships between desacylated and acylated ghrelin and
sized or are in trial for the treatment of preterm insulin sensitivity in the metabolic syndrome. J Clin
Endocrinol Metab 92:3935–3940
newborns and colic dysfunctions. However, both Batterham RL, Cowley MA, Small CJ et al (2002) Gut
the physiological and pharmaceutical researches hormone PYY(3-36) physiologically inhibits food
have to better explore this field. It has to look to intake. Nature 418:650–654
the future for more detailed studies to elaborate Batterham RL, Cohen MA, Ellis SM et al (2003) Inhibition
of food intake in obese subjects by peptide YY3-36. N
completely the functions of all these peptides and Engl J Med 349:941–948
the interaction of breastfed and formula milk and Bellone S, Rapa A, Vivenza D et al (2004) Circulating
solids with the gut. Nutrient sensing is a new ghrelin levels in the newborn are positively associated
crucial topic, and the influence of this complex with gestational age. Clin Endocrinol 60:613–617
Bellone S, Baldelli R, Radetti G et al (2006) Ghrelin
process in relation to hormones in the first steps of secretion in preterm neonates progressively increases
nutrition is a challenge. and is refractory to the inhibitory effect of food intake. J
Clin Endocrinol Metab 91:1929–1933
Bellone S, Prodam F, Savastio S et al (2012a) Acylated and
unacylated ghrelin levels in normal weight and obese
References children: influence of puberty and relationship with
insulin, leptin and adiponectin levels. J Endocrinol
Adams SH, Lei C, Jodka CM et al (2006) PYY[3-36] Investig 35(2):191–197
administration decreases the respiratory quotient and Bellone S, Prodam F, Savastio S et al (2012b) Acylated/
reduces adiposity in diet-induced obese mice. J Nutr unacylated ghrelin ratio in cord blood: correlation with
136:195–201 anthropometric and metabolic parameters and pediatric
Adrian TE, Smith HA, Calvert SA et al (1986) Elevated lifespan comparison. Eur J Endocrinol 166:115–120
plasma peptide YY in human neonates and infants. Berseth CL, Nordyke CK, Valdes MG et al (1992)
Pediatr Res 20:1225–1227 Responses of gastrointestinal peptides and motor activ-
Agostoni C (2005) Ghrelin, leptin and the neurometabolic ity to milk and water feedings in preterm and term
axis of breastfed and formula-fed infants. Acta Paediatr infants. Pediatr Res 31:587–590
94:523–525 Bideci A, Camurdan MO, Yesilkaya E et al (2008) Serum
Althage MC, Ford EL, Wang S et al (2008) Targeted ghrelin, leptin and resistin levels in adolescent girls
ablation of glucose-dependent insulinotropic polypep- with polycystic ovary syndrome. J Obstet Gynaecol
tide-producing cells in transgenic mice reduces obesity Res 34:578–584
and insulin resistance induced by a high fat diet. J Biol Boutsikou T, Briana DD, Boutsikou M et al (2013) Cord
Chem 283:18365–18376 blood chemerin and obestatin levels in large for
550 F. Prodam et al.
gestational age infants. J Matern Fetal Neonatal Med 26 enterally fed premature neonates. J Pediatr
(2):123–126 Gastroenterol Nutr 46:184–190
Broglio F, Gottero C, Prodam F et al (2004) Non-acylated Cortelazzi D, Cappiello V, Morpurgo PS et al (2003) Cir-
ghrelin counteracts the metabolic but not the neuroen- culating levels of ghrelin in human fetuses. Eur J Endo-
docrine response to acylated ghrelin in humans. J Clin crinol 149:111–116
Endocrinol Metab 89:3062–3065 Covasa M, Marcuson JK, Ritter RC (2001) Diminished
Brøns C, Saltbæk PN, Friedrichsen M et al (2016) Endo- satiation in rats exposed to elevated levels of endoge-
crine and metabolic diurnal rhythms in young adult nous or exogenous cholecystokinin. Am J Phys Regul
men born small vs appropriate for gestational age. Eur Integr Comp Phys 280:R331–R337
J Endocrinol 175:29–40 Cummings DE, Weigle DS, Frayo RS et al (2002) Plasma
Bryant MG, Buchan AM, Gregor M et al (1982) Develop- ghrelin levels after diet-induced weight loss or gastric
ment of intestinal regulatory peptides in the human bypass surgery. N Engl J Med 346:1623–1630
fetus. Gastroenterology 83:47–54 Dakin CL, Gunn I, Small CJ et al (2001) Oxyntomodulin
Bunt JC, Salbe AD, Tschop MH et al (2003) Cross-sec- inhibits food intake in the rat. Endocrinology
tional and prospective relationships of fasting plasma 142:4244–4250
ghrelin concentrations with anthropometric measures Dakin CL, Small CJ, Batterham RL et al (2004) Peripheral
in pima Indian children. J Clin Endocrinol Metab oxyntomodulin reduces food intake and body weight
88:3756–3761 gain in rats. Endocrinology 145:2687–2695
Burrin DG, Stoll B (2002) Key nutrients and growth fac- Dasopoulou M, Briana DD, Boutsikou T et al (2015)
tors for the neonatal gastrointestinal tract. Clin Peri- Motilin and gastrin secretion and lipid profile in pre-
natol 29:65–96 term neonates following prebiotics supplementation: a
Calanna S, Christensen M, Holst JJ et al (2013) Secretion double-blind randomized controlled study. JPEN J
of glucose-dependent insulinotropic polypeptide in Parenter Enteral Nutr 39(3):359–368
patients with type 2 diabetes: systematic review and De Clercq P, Springer S, Depoortere I, Peeters TL (1998)
meta-analysis of clinical studies. Diabetes Care Motilin in human milk: identification and stability dur-
36:3346–3352 ing digestion. Life Sci 63:1993–2000
Cani PD, Possemiers S, Van de Wiele T et al (2009) Changes de Moura EG, Lisboa PC, Passos MC (2008) Neonatal
in gut microbiota control inflammation in obese mice programming of neuroimmunomodulation–role of
through a mechanism involving GLP-2-driven improve- adipocytokines and neuropeptides. Neuroimmunomo-
ment of gut permeability. Gut 58:1091–1103 dulation 15:176–188
Cesur G, Ozguner F, Yilmaz N, Dundar B (2012) The Degen L, Oesch S, Casanova M et al (2005) Effect of
relationship between ghrelin and adiponectin levels in peptide YY3-36 on food intake in humans. Gastroen-
breast milk and infant serum and growth of infants terology 129:1430–1436
during early postnatal life. J Physiol Sci 62(3):185–190 Delhanty PJ, Neggers SJ, van der Lely AJ (2012) Mecha-
Chanoine JP, Yeung LP, Wong AC, Birmingham CL nisms in endocrinology: ghrelin: the differences
(2002) Immunoreactive ghrelin in human cord blood: between acyl- and des-acyl ghrelin. Eur J Endocrinol
relation to anthropometry, leptin, and growth hormone. 167:601–608
J Pediatr Gastroenterol Nutr 35:282–286 Díaz M, Bassols J, Sebastiani G et al (2015) Circulating
Chaudhri OB, Wynne K, Bloom SR (2008) Can gut hor- GLP-1 in infants born small-for-gestational-age:
mones control appetite and prevent obesity? Diabetes breast-feeding versus formula-feeding. Int J Obes
Care 31(Suppl 2):S284–S289 39:1501–1503
Chen X, Du X, Zhu J et al (2012) Correlations of circulat- Dong CX, Zhao W, Solomon C et al (2014) The intestinal
ing peptide YY and ghrelin with body weight, rate of epithelial insulin-like growth factor-1 receptor links
weight gain, and time required to achieve the glucagon-like peptide-2 action to gut barrier function.
recommended daily intake in preterm infants. Braz J Endocrinology 155:370–379
Med Biol Res 45:656–664 Drucker DJ (2002) Biological actions and therapeutic
Chiesa C, Osborn JF, Haass C et al (2008) Ghrelin, leptin, potential of the glucagon-like peptides. Gastroenterol-
IGF-1, IGFBP-3, and insulin concentrations at birth: is ogy 122:531–544
there a relationship with foetal growth and neonatal Drucker DJ, Yusta B (2014) Physiology and pharmacology
anthropometry? Clin Chem 54:550–558 of the enteroendocrine hormone glucagon-like peptide-
Choi K, Roh SG, Hong YH et al (2003) The role of ghrelin 2. Annu Rev Physiol 76:561–583
and growth hormone secretagogues receptor on rat Du X, Kosinski JR, Lao J et al (2012) Differential effects of
adipogenesis. Endocrinology 144:754–759 oxyntomodulin and GLP-1 on glucose metabolism.
Cohen MA, Ellis SM, le Roux CW et al (2003) Am J Physiol Endocrinol Metab 303:E265–E271
Oxyntomodulin suppresses appetite and reduces food Fallucca F, Kuhl C, Lauritsen KB et al (1985) Gastric
intake in humans. J Clin Endocrinol Metab inhibitory polypeptide (GIP) concentration in human
88:4696–4701 amniotic fluid. Horm Metab Res 17:251–255
Corpeleijn WE, van Vliet I, de Gast-Bakker DA et al Flatt PR (2007) Effective surgical treatment of obesity may
(2008) Effect of enteral IGF-1 supplementation on be mediated by ablation of the lipogenic gut hormone
feeding tolerance, growth, and gut permeability in gastric inhibitory polypeptide (GIP): evidence and
35 Hormones and Gastrointestinal Function of Newborns 551
clinical opportunity for development of new obesity- Hellstrom PM, Geliebter A, Naslund E et al (2004) Periph-
diabetes drugs? Diab Vasc Dis Res 4:151–153 eral and central signals in the control of eating in
Flatt PR (2008) Dorothy Hodgkin Lecture 2008. Gastric normal, obese and binge-eating human subjects. Br J
inhibitory polypeptide (GIP) revisited: a new thera- Nutr 92(Suppl 1):S47–S57
peutic target for obesity-diabetes? Diabet Med Heptulla RA, Tamborlane WV, Cavaghan M et al (2000)
25:759–764 Augmentation of alimentary insulin secretion despite
Garcia-Diaz D, Campion J, Milagro FI, Martinez JA similar gastric inhibitory peptide (GIP) responses in
(2007) Adiposity dependent apelin gene expression: juvenile obesity. Pediatr Res 47:628–633
relationships with oxidative and inflammation markers. Higgins PB, Fernandez JR, Garvey WT et al (2008) Entero-
Mol Cell Biochem 305:87–94 insular axis and postprandial insulin differences in
Gardiner JV, Jayasena CN, Bloom SR (2008) Gut hor- African American and European American children.
mones: a weight off your mind. J Neuroendocrinol Am J Clin Nutr 88:1277–1283
20:834–841 Hill ME, Asa SL, Drucker DJ (1999) Essential require-
Gault VA, Irwin N, Green BD et al (2005) Chemical ment for Pax6 in control of enteroendocrine pro-
ablation of gastric inhibitory polypeptide receptor glucagon gene transcription. Mol Endocrinol 13:
action by daily (Pro3)GIP administration improves glu- 1474–1486
cose tolerance and ameliorates insulin resistance and Holst JJ (2007) The physiology of glucagon-like peptide 1.
abnormalities of islet structure in obesity-related diabe- Physiol Rev 87:1409–1439
tes. Diabetes 54:2436–2446 Holst B, Egerod KL, Schild E et al (2007) GPR39 signaling
Gauna C, Delhanty PJ, Hofland LJ et al (2005) Ghrelin is stimulated by zinc ions but not by obestatin. Endo-
stimulates, whereas des-octanoyl ghrelin inhibits, glu- crinology 148:13–20
cose output by primary hepatocytes. J Clin Endocrinol http://www.ema.europa.eu/ema/index.jsp?curl=pages/
Metab 90:1055–1060 medicines/human/orphans/2009/11/human_orphan_
Geloneze B, Lima MM, Pareja JC et al (2013) Association 000210.jsp&mid=WC0b01ac058001d12b
of insulin resistance and GLP-2 secretion in obesity: a Hubler A, Rippel C, Kauf E et al (2006) Associations
pilot study. Arq Bras Endocrinol Metabol 57:632–635 between ghrelin levels in serum of preterm infants
Ghigo E, Arvat E, Giordano R et al (2001) Biologic activ- and enteral nutritional state during the first 6 months
ities of growth hormone secretagogues in humans. after birth. Clin Endocrinol 65:611–616
Endocrine 14:87–93 Ilcol YO, Hizli B (2007) Active and total ghrelin concen-
Gibbs J, Young RC, Smith GP (1973) Cholecystokinin trations increase in breast milk during lactation. Acta
decreases food intake in rats. J Comp Physiol Psychol Paediatr 96:1632–1639
84:488–495 Irwin N, Flatt PR (2015) New perspectives on exploitation
Gil-Campos M, Aguilera CM, Canete R, Gil A (2006) of incretin peptides for the treatment of diabetes and
Ghrelin: a hormone regulating food intake and energy related disorders. World J Diabetes 6:1285–1295
homeostasis. Br J Nutr 96:201–226 Itoh Z (1997) Motilin and clinical application. Peptides
Gourcerol G, St-Pierre DH, Tache Y (2007) Lack of 18:593–608
obestatin effects on food intake: should obestatin be James RJ, Drewett RF, Cheetham TD (2004) Low cord
renamed ghrelin-associated peptide (GAP)? Regul Pept ghrelin levels in term infants are associated with slow
141:1–7 weight gain over the first 3 months of life. J Clin
Grigoryan M, Kedees MH, Guz Y, Teitelman G (2012) Endocrinol Metab 89:3847–3850
Phenotype of entero-endocrine L cells becomes restricted Janik JS, Track NS, Filler RM (1982) Motilin, human
during development. Dev Dyn 241:1986–1992 pancreatic polypeptide, gastrin, and insulin
Gualillo O, Caminos J, Blanco M et al (2001) Ghrelin, a plasma concentrations in fasted children. J Pediatr
novel placental-derived hormone. Endocrinology 101:51–56
142:788–794 Jia X, Brown JC, Ma P et al (1995) Effects of glucose-
Guan X, Shi X, Li X, Chang B et al (2012) GLP-2 receptor dependent insulinotropic polypeptide and glucagon-
in POMC neurons suppresses feeding behavior and like peptide-I-(7-36) on insulin secretion. Am J Phys
gastric motility. Am J Physiol Endocrinol Metab 303: 268:E645–E651
E853–E864 Kahveci H, Laloglu F, Kilic O, Ciftel M, Kara M, Laloglu
Han L, Li M, Yu X et al (2014) Assay of adiponectin, E, Yildirim A, Orbak Z, Ertekin V, Cesur Y (2015)
leptin, true insulin and ghrelin levels in preterm Fasting and postprandial glucose, insulin, leptin, and
human milk, and its relationship with infants growth. ghrelin values in preterm babies and their mothers:
Zhonghua Er Ke Za Zhi 52(7):510–515 relationships among their levels, foetal growth, and
Harada T, Nakahara T, Yasuhara D et al (2008) Obestatin, neonatal anthropometry. J Matern Fetal Neonatal Med
acyl ghrelin, and des-acyl ghrelin responses to an oral 28(8):916–921
glucose tolerance test in the restricting type of anorexia Kalies H, Heinrich J, Borte N et al (2005) The effect of
nervosa. Biol Psychiatry 63:245–247 breastfeeding on weight gain in infants: results of a
Heijboer AC, Pijl H, Van den Hoek AM et al (2006) Gut- birth cohort study. Eur J Med Res 10:36–42
brain axis: regulation of glucose metabolism. J Kasa-Vubu JZ, Rosenthal A, Murdock EG, Welch KB
Neuroendocrinol 18:883–894 (2007) Impact of fatness, fitness, and ethnicity on the
552 F. Prodam et al.
relationship of nocturnal ghrelin to 24-hour luteinizing glucagon-like peptide-2 in the regulation of intestinal
hormone concentrations in adolescent girls. J Clin adaptation. World J Gastroenterol 12:4117–4129
Endocrinol Metab 92:3246–3252 Mechanick JI, Kushner RF, Sugerman HJ et al (2008)
Kawamata R, Suzuki Y, Yada Y et al (2014) Gut hormone American Association of Clinical Endocrinologists,
profiles in preterm and term infants during the first 2 months the obesity Society, and American Society for Meta-
of life. J Pediatr Endocrinol Metab 27(7–8):717–723 bolic & Bariatric Surgery Medical guidelines for clin-
Kawamata R, Suzuki Y, Yada Y et al (2015) Gut hormones ical practice for the perioperative nutritional,
of preterm infants with abdominal symptoms and hypo- metabolic, and nonsurgical support of the bariatric sur-
thyroxinemia. Pediatr Int 57:614–619 gery patient. Endocr Pract 14(Suppl 1):1–83
Kim SJ, Nian C, Karunakaran S et al (2012) GIP-over- Misra M, Miller KK, Cord J et al (2007) Relationships
expressing mice demonstrate reduced diet-induced between serum adipokines, insulin levels, and bone
obesity and steatosis, and improved glucose homeosta- density in girls with anorexia nervosa. J Clin Endo-
sis. PLoS One 7:e40156 crinol Metab 92:2046–2052
King KC, Oliven A, Kalhan SC (1989) Functional Misra M, Prabhakaran R, Miller KK et al (2008) Prognos-
enteroinsular axis in full-term newborn infants. Pediatr tic indicators of changes in bone density measures in
Res 25:490–495 adolescent girls with anorexia nervosa-II. J Clin Endo-
Knip M, Kaapa P, Koivisto M (1993) Hormonal enteroinsular crinol Metab 93:1292–1297
axis in newborn infants of insulin-treated diabetic Mitrovic O, Cokic V, Dikic D et al (2014) Ghrelin receptors
mothers. J Clin Endocrinol Metab 77:1340–1344 in human gastrointestinal tract during prenatal and
Kojima M, Kangawa K (2005) Ghrelin: structure and func- early postnatal development. Peptides 57:1–11
tion. Physiol Rev 85:495–522 Moran TH (2000) Cholecystokinin and satiety: current
Konturek SJ, Konturek JW, Pawlik T, Brzozowski T perspectives. Nutrition 16:858–865
(2004) Brain-gut axis and its role in the control of Müller TD, Nogueiras R, Andermann ML et al (2015)
food intake. J Physiol Pharmacol 55:137–154 Ghrelin. Mol Metab 4:437–460
Lambeir AM, Durinx C, Scharpe S, De Meester I (2003) Mulvihill SJ, Stone MM, Debas HT, Fonkalsrud EW
Dipeptidyl-peptidase IV from bench to bedside: an (1985) The role of amniotic fluid in foetal nutrition. J
update on structural properties, functions, and clinical Pediatr Surg 20:668–672
aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci Nagasaki H, Ohta T (2015) Extra-uterine growth and
40:209–294 adipocytokines in appropriate-for-gestational-age preterm
Lanyi E, Varnagy A, Kovacs KA et al (2008) Ghrelin and infants. Pediatr Int. https://doi.org/10.1111/ped.12896
acyl ghrelin in preterm infants and maternal blood: Nagata E, Nakagawa Y, Yamaguchi R et al (2011) Altered
relationship with endocrine and anthropometric mea- gene expressions of ghrelin, PYY, and CCK in the gas-
sures. Eur J Endocrinol 158:27–33 trointestinal tract of the hyperphagic intrauterine growth
Lebenthal A, Lebenthal E (1999) The ontogeny of the restriction rat offspring. Horm Metab Res 43(3):178–182
small intestinal epithelium. JPEN J Parenter Enteral Naitoh R, Miyawaki K, Harada N et al (2008) Inhibition of
Nutr 23:S3–S6 GIP signaling modulates adiponectin levels under high-
Leite-Moreira AF, Soares JB (2007) Physiological, patho- fat diet in mice. Biochem Biophys Res Commun
logical and potential therapeutic roles of ghrelin. Drug 376:21–25
Discov Today 12:276–288 Nakahara T, Harada T, Yasuhara D et al (2008) Plasma
Lothe L, Ivarsson SA, Lindberg T (1987) Motilin, vasoac- obestatin concentrations are negatively correlated with
tive intestinal peptide and gastrin in infantile colic. Acta body mass index, insulin resistance index, and plasma
Paediatr Scand 76:316–320 leptin concentrations in obesity and anorexia nervosa.
Lu M, Wheeler MB, Leng XH, Boyd AE III (1993) Stim- Biol Psychiatry 64:252–255
ulation of insulin secretion and insulin gene expression Naslund E, Barkeling B, King N et al (1999) Energy intake
by gastric inhibitory polypeptide. Trans Assoc Am and appetite are suppressed by glucagon-like peptide-1
Phys 106:42–53 (GLP-1) in obese men. Int J Obes Relat Metab Disord
Lucas A, Sarson DL, Bloom SR, Aynsley-Green A (1980) 23:304–311
Developmental aspects of gastric inhibitory polypep- Neary NM, Goldstone AP, Bloom SR (2004) Appetite
tide (GIP) and its possible role in the enteroinsular axis regulation: from the gut to the hypothalamus. Clin
in neonates. Acta Paediatr Scand 69:321–325 Endocrinol 60:153–160
Mahmoud EL, Benirschke K, Vaucher YE, Poitras P Nishikubo T, Yamakawa A, Kamitsuji H et al (2005) Iden-
(1988) Motilin levels in term neonates who have passed tification of the motilin cells in duodenal epithelium of
meconium prior to birth. J Pediatr Gastroenterol Nutr premature infants. Pediatr Int 47(3):248–251
7:95–99 O'Mahony SM, Felice VD, Nally K et al (2014) Distur-
Marchini G, Linden A (1992) Cholecystokinin, a satiety bance of the gut microbiota in early-life selectively
signal in newborn infants? J Dev Physiol 17:215–219 affects visceral pain in adulthood without impacting
Martin GR, Beck PL, Sigalet DL (2006) Gut hormones, cognitive or anxiety-related behaviors in male rats.
and short bowel syndrome: the enigmatic role of Neuroscience 277:885–901
35 Hormones and Gastrointestinal Function of Newborns 553
Ozaki T, Mohammad S, Morioka E et al (2013) Infant metabolic control in children with type 1 diabetes. J
satiety depends on transient expression of cholecysto- Clin Endocrinol Metab 99(4):E599–E607
kinin-1 receptors on ependymal cells lining the third Qader SS, Hakanson R, Rehfeld JF et al (2008) Proghrelin-
ventricle in mice. J Physiol 591(5):1295–1312 derived peptides influence the secretion of insulin, glu-
Ozer EA, Holst JJ, Duman N et al (2009) The relationship cagon, pancreatic polypeptide and somatostatin: a
between glucagon-like peptide 2 and feeding intoler- study on isolated islets from mouse and rat pancreas.
ance in preterm infants. J Trop Pediatr 55:276–277 Regul Pept 146:230–237
Padidela R, Patterson M, Sharief N et al (2009) Elevated Ranganath LR (2008a) The entero-insular axis: implications
basal and post-feed glucagon-like peptide 1 (GLP-1) for human metabolism. Clin Chem Lab Med 46:43–56
concentrations in the neonatal period. Eur J Endocrinol Ranganath LR (2008b) Incretins: pathophysiological and
160:53–58 therapeutic implications of glucose-dependent
Paik KH, Choe YH, Park WH et al (2006) Suppression of insulinotropic polypeptide and glucagon-like peptide-
acylated ghrelin during oral glucose tolerance test is 1. J Clin Pathol 61:401–409
correlated with whole-body insulin sensitivity in chil- Savino F, Fissore MF, Grassino EC et al (2005) Ghrelin,
dren with Prader-Willi syndrome. J Clin Endocrinol leptin and IGF-I levels in breast-fed and formula-fed
Metab 91:1876–1881 infants in the first years of life. Acta Paediatr 94:531–537
Pais R, Gribble FM, Reimann F (2016) Stimulation of Savino F, Grassino EC, Fissore MF et al (2006a) Ghrelin,
incretin secreting cells. Ther Adv Endocrinol Metab motilin, insulin concentration in healthy infants in the
7:24–42 first months of life: relation to fasting time and anthro-
Perala MM, Kajantie E, Valsta LM et al (2013) Early pometry. Clin Endocrinol 65:158–162
growth and postprandial appetite regulatory hormone Savino F, Grassino EC, Guidi C et al (2006b) Ghrelin and
responses. Br J Nutr 110:1591–1600 motilin concentration in colicky infants. Acta Paediatr
Persaud SJ, Bewick GA (2014) Peptide YY: more than just 95:738–741
an appetite regulator. Diabetologia 57:1762–1769 Savino F, Lupica MM, Liguori SA et al (2012a) Ghrelin
Pocai A (2013) Action and therapeutic potential of and feeding behaviour in preterm infants. Early Hum
oxyntomodulin. Mol Metab 3:241–251 Dev 88:S51–S55
Poitras P, Peeters TL (2008) Motilin. Curr Opin Endocrinol Savino F, Benetti S, Lupica MM et al (2012b) Ghrelin and
Diabetes Obes 15:54–57 obestatin in infants, lactating mothers and breast milk.
Pomerants T, Tillmann V, Jurimae J, Jurimae T (2006) Horm Res Paediatr 78(5–6):297–303
Relationship between ghrelin and anthropometrical, Schmidt PT, Naslund E, Gryback P et al (2003) Peripheral
body composition parameters and testosterone levels administration of GLP-2 to humans has no effect on
in boys at different stages of puberty. J Endocrinol gastric emptying or satiety. Regul Pept 116:21–25
Investig 29:962–967 Sharman-Koendjbiharie M, Hopman WP, Piena-Spoel M
Prodam F, Filigheddu N (2014) Ghrelin gene products in et al (2002) Gut hormones in preterm infants with
acute and chronic inflammation. Arch Immunol Ther necrotizing enterocolitis during starvation and
Exp (Warsz) 62(5):369–3684 reintroduction of enteral nutrition. J Pediatr
Prodam F, Me E, Riganti F et al (2006) The nutritional Gastroenterol Nutr 35:674–679
control of ghrelin secretion in humans: the effects Shimizu T, Kitamura T, Yoshikawa N et al (2007) Plasma
of enteral vs. parenteral nutrition. Eur J Nutr levels of active ghrelin until 8 weeks after birth in
45:399–405 preterm infants: relationship with anthropometric and
Prodam F, Bellone S, Corneli G et al (2008) Ghrelin: a biochemical measures. Arch Dis Child Fetal Neonatal
molecular target for weight regulation, glucose and Ed 92:F291–F292
lipid metabolism. Recent Patents Endocrine Metab Shoji H, Watanabe A, Ikeda N et al (2016) Influence of
Immune Drug Discov 2(3):1–1 gestational age on serum incretin levels in preterm
Prodam F, Bellone S, Ricotti R et al (2011) Ghrelin regu- infants. J Dev Orig Health Dis 25:1–4
lation in epilepsy. Underlying mechanisms of epilepsy. Shulman DI, Kanarek K (1993) Gastrin, motilin, insulin,
InTech, Prof. Fatima Shad Kaneez (ed). and insulin-like growth factor-I concentrations in very-
ISBN:978–953–307-765-9, pp 151–180. Available low-birth-weight infants receiving enteral or parenteral
from: http://www.intechopen.com/books/underlying- nutrition. JPEN J Parenter Enteral Nutr 17:130–133
mechanisms-ofepilepsy/ghrelin-regulation-in-epilepsy Siahanidou T, Mandyla H, Vounatsou M et al (2005) Cir-
Prodam F, Monzani A, Ricotti R et al (2014a) Systematic culating peptide YY concentrations are higher in pre-
review of ghrelin response to food intake in pediatric term than full-term infants and correlate negatively
age, from neonates to adolescents. J Clin Endocrinol with body weight and positively with serum ghrelin
Metab 99(5):1556–1568 concentrations. Clin Chem 51:2131–2137
Prodam F, Cadario F, Bellone S et al (2014b) Obestatin Siahanidou T, Mandyla H, Militsi H et al (2007) Peptide
levels are associated with C-peptide and antiinsulin YY (3-36) represents a high percentage of total PYY
antibodies at the onset, whereas unacylated and acyl- immunoreactivity in preterm and full-term infants
ated ghrelin levels are not predictive of long-term and correlates independently with markers of adiposity
554 F. Prodam et al.
and serum ghrelin concentrations. Pediatr Res Tornhage CJ, Serenius F, Uvnas-Moberg K, Lindberg T
62:200–203 (1996) Plasma somatostatin and cholecystokinin levels
Siahanidou T, Margeli A, Tsirogianni C et al (2015) Ele- in preterm infants during the first day of life. Biol
vated circulating ghrelin, but not peptide YY(3-36) Neonate 70:311–321
levels, in term neonates with infection. Clin Chem Tornhage CJ, Serenius F, Uvnas-Moberg K, Lindberg T
Lab Med 53(11):1815–1824 (1998) Plasma somatostatin and cholecystokinin levels
Sigalet DL, Martin G, Meddings J et al (2004) GLP-2 in preterm infants during kangaroo care with and with-
levels in infants with intestinal dysfunction. Pediatr out nasogastric tube-feeding. J Pediatr Endocrinol
Res 56:371–376 Metab 11:645–651
Sigalet DL, Brindle M, Boctor D et al (2015) A safety and Uvnas-Moberg K, Marchini G, Winberg J (1993) Plasma
dosing study of glucagon-like peptide 2 in children cholecystokinin concentrations after breast feeding in
with intestinal failure. JPEN J Parenter Enteral Nutr. healthy 4 day old infants. Arch Dis Child 68:46–48
56(3):371–376 Valderas JP, Padilla O, Solari S et al (2014) Feeding and
Skow MA, Bergmann NC, Knop FK (2016) Diabetes and bone turnover in gastric bypass. J Clin Endocrinol
obesity treatment based on dual incretin receptor acti- Metab 99:491–497
vation – “twincretins”. Diabetes Obes Metab 18 Valsamakis G, Papatheodorou DC, Naouma A et al (2014)
(9):847–854. https://doi.org/10.1111/dom.12685 Neonatal birthwaist is positively predicted by second
Soriano-Guillen L, Barrios V, Chowen JA et al (2004) trimester maternal active ghrelin, a pro-appetite hor-
Ghrelin levels from foetal life through early adulthood: mone, and negatively associated with third trimester
relationship with endocrine and metabolic and anthro- maternal leptin, a pro-satiety hormone. Early Hum
pometric measures. J Pediatr 144:30–35 Dev 90:487–492
Spreckley E, Murphy KG (2015) The L-Cell in nutritional Van den Hoek AM, Heijboer AC, Corssmit EP et al
sensing and the regulation of appetite. Front Nutr 2:23 (2004) PYY3-36 reinforces insulin action on glucose
Stadlbauer U, Woods SC, Langhans W, Meyer U (2015) disposal in mice fed a high-fat diet. Diabetes
PYY3–36: beyond food intake. Front Neuroendocrinol 53:1949–1952
38:1–11 Verdich C, Flint A, Gutzwiller JP et al (2001) A meta-
Stock S, Leichner P, Wong AC et al (2005) Ghrelin, peptide analysis of the effect of glucagon-like peptide-1 (7-36)
YY, glucose-dependent insulinotropic polypeptide, and amide on ad libitum energy intake in humans. J Clin
hunger responses to a mixed meal in anorexic, obese, Endocrinol Metab 86:4382–4389
and control female adolescents. J Clin Endocrinol Vilsboll T, Krarup T, Sonne J et al (2003) Incretin secre-
Metab 90:2161–2168 tion in relation to meal size and body weight in
Stoll B, Puiman PJ, Cui L et al (2012) Continuous paren- healthy subjects and people with type 1 and type 2
teral and enteral nutrition induces metabolic dysfunc- diabetes mellitus. J Clin Endocrinol Metab
tion in neonatal pigs. JPEN J Parenter Enteral Nutr 88:2706–2713
36:538–550 Wagner CL (2002) Amniotic fluid and human milk: a
Tang SQ, Jiang QY, Zhang YL et al (2008) Obestatin: its continuum of effect? J Pediatr Gastroenterol Nutr
physicochemical characteristics and physiological 34:513–514
functions. Peptides 29:639–645 Warchoł M, Krauss H, Wojciechowska M et al (2014) The
Tang-Christensen M, Larsen PJ, Thulesen J et al (2000) role of ghrelin, leptin and insulin in foetal development.
The proglucagon-derived peptide, glucagon-like pep- Ann Agri Env Med 21(2):349–352
tide-2, is a neurotransmitter involved in the regulation West DB, Greenwood MR, Marshall KA, Woods SC (1987)
of food intake. Nat Med 6:802–807 Lithium chloride, cholecystokinin and meal patterns:
Teitelbaum DH, Han-Markey T, Drongowski RA et al evidence that cholecystokinin suppresses meal size in
(1997) Use of cholecystokinin to prevent the develop- rats without causing malaise. Appetite 8:221–227
ment of parenteral nutrition-associated cholestasis. Whatmore AJ, Hall CM, Jones J et al (2003) Ghrelin
JPEN J Parenter Enteral Nutr 21:100–103 concentrations in healthy children and adolescents.
Thompson NM, Gill DA, Davies R et al (2004) Ghrelin and Clin Endocrinol 59:649–654
des-octanoyl ghrelin promote adipogenesis directly in Wiedmer P, Nogueiras R, Broglio F et al (2007) Ghrelin,
vivo by a mechanism independent of the type 1a obesity and diabetes. Nat Clin Pract Endocrinol Metab
growth hormone secretagogue receptor. Endocrinology 3:705–712
145:234–242 Wierup N, Bjorkqvist M, Westrom B et al (2007) Ghrelin
Tomasetto C, Karam SM, Ribieras S et al (2000) Identifi- and motilin are cosecreted from a prominent endocrine
cation and characterization of a novel gastric peptide cell population in the small intestine. J Clin Endocrinol
hormone: the motilin-related peptide. Gastroenterology Metab 92:3573–3581
119:395–405 Wojcicki JM (2012) Peptide YY in children: a review.
Tornhage CJ, Serenius F, Uvnas-Moberg K, Lindberg T J Pediatr Endocrinol Metab 25(3–4):227–232
(1995) Plasma somatostatin and cholecystokinin levels Woods SC (2004) Gastrointestinal satiety signals I. An over-
in preterm infants and their mothers at birth. Pediatr Res view of gastrointestinal signals that influence food intake.
37:771–776 Am J Physiol Gastrointest Liver Physiol 286:G7–13
35 Hormones and Gastrointestinal Function of Newborns 555
Wortley KE, Anderson KD, Garcia K et al (2004) Genetic Yokota I, Kitamura S, Hosoda H et al (2005) Concentration
deletion of ghrelin does not decrease food intake but of the n-octanoylated active form of ghrelin in foetal
influences metabolic fuel preference. Proc Natl Acad and neonatal circulation. Endocr J 52:271–276
Sci U S A 101:8227–8232 Yoshikawa H, Miyata I, Eto Y (2006) Serum glucagon-like
Wortley KE, del Rincon JP, Murray JD et al (2005) peptide-2 levels in neonates: comparison between
Absence of ghrelin protects against early-onset obesity. extremely low-birthweight infants and normal-term
J Clin Invest 115:3573–3578 infants. Pediatr Int 48:464–469
Wynne K, Park AJ, Small CJ et al (2006) Oxyntomodulin Zhang W, Zhao L, Lin TR et al (2004) Inhibition of
increases energy expenditure in addition to decreasing adipogenesis by ghrelin. Mol Biol Cell 15:2484–2491
energy intake in overweight and obese humans: a Zhang JV, Ren PG, Avsian-Kretchmer O et al (2005)
randomised controlled trial. Int J Obes(Lond) 30: Obestatin, a peptide encoded by the ghrelin gene, opposes
1729–1736 ghrelin’s effects on food intake. Science 310:996–999
Xiao Q, Boushey RP, Drucker DJ, Brubaker PL (1999) Zhang S, Zhai G, Zhang J et al (2014) Ghrelin and
Secretion of the intestinotropic hormone glucagon-like obestatin plasma levels and ghrelin/obestatin pre-
peptide 2 is differentially regulated by nutrients in propeptide gene polymorphisms in small for gesta-
humans. Gastroenterology 117:99–105 tional age infants. J Int Med Res 42(6):1232–1242
Xiao C, Dash S, Morgantini C et al (2015) Gut peptides are Zou CC, Liang L, Wang CL, Fu JF, Zhao ZY (2009) The
novel regulators of intestinal lipoprotein secretion: change in ghrelin and obestatin levels in obese children
experimental and pharmacological manipulation of after weight reduction. Acta Paediatr 98:159–165
lipoprotein metabolism. Diabetes 64:2310–2318 Zwirska-Korczala K, Adamczyk-Sowa M, Sowa P et al
Yang J, Brown MS, Liang G et al (2008) Identification (2007) Role of leptin, ghrelin, angiotensin II and
of the acyltransferase that octanoylates ghrelin, an orexins in 3 T3 L1 preadipocyte cells proliferation
appetite-stimulating peptide hormone. Cell 132: and oxidative metabolism. J Physiol Pharmacol 58
387–396 (Suppl 1):53–64
Human Milk and Formulas for
Neonatal Nutrition 36
Riccardo Davanzo, Jenny Bua, and Laura Travan
Contents
36.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 558
36.2 The Uniqueness of Human milk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 558
36.3 Recommendations on Infant Feeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561
36.4 From the Physiology of Lactation to Breastfeeding Management . . . . . 561
36.4.1 Lactogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561
36.4.2 From Calibration to Maintenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562
36.5 Hospital Practices and the Baby-Friendly
Hospital Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562
36.6 Skin-to-Skin Contact and the Prevention of
Neonatal Collapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564
36.7 The First Days of Life and Neonatal Weight Loss . . . . . . . . . . . . . . . . . . . . . . 565
36.8 Low Breast Milk Supply . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566
36.9 Controversies Surrounding Breastfeeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568
36.9.1 Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568
36.9.2 Environmental Contamination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569
36.9.3 New Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569
36.9.4 Medications and Mothers’ Milk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569
36.9.5 Radiological Contrast Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570
36.9.6 Contraception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570
36.10 Human Milk Sharing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570
R. Davanzo (*)
Department of Mother and Child Health, Madonna delle
Grazie Hospital, Matera, Italy
e-mail: [email protected]
J. Bua · L. Travan
Division of Neonatology, Institute for Maternal and Child
Health IRCCS ‘Burlo Garofolo’, Trieste, Italy
e-mail: [email protected]; [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 557
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_185
558 R. Davanzo et al.
36.11 Nutrition with Human Milk in the Neonatal
Intensive Care Unit (NICU) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570
36.11.1 The NICU Population and Breastfeeding Epidemiology . . . . . . . . . . . . . . . . . . . 570
36.11.2 Nutrition on NICU Admission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571
36.11.3 Oropharyngeal Colostrum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572
36.11.4 Minimal Enteral Feeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572
36.11.5 Advancement of Enteral Feeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572
36.11.6 Benefits of Human Milk for the Preterm Infant . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572
36.11.7 Fat in Preterm Human Milk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572
36.11.8 Protein in Preterm Breast Milk and Fortification . . . . . . . . . . . . . . . . . . . . . . . . . . . 573
36.11.9 Expression and Storage of Breast Milk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574
36.11.10 Human Milk Bank . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574
36.11.11 Kangaroo Mother Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574
36.11.12 Feeding Competence of the Preterm Newborn
and the Transition from Tube to Breast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575
36.11.13 Semi-demand Feeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
36.12 Infant Formula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578
36.12.1 General Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578
36.12.2 Nutritional Characteristics of Starting Formula . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579
36.12.3 Special Formulas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582
Abstract • There are very few true contraindications to
Human milk is a unique highly individualized breastfeeding such as HIV infection or few drugs.
nutritional liquid, with multiple biological • Breastfeeding should be supported with efficient
effects. Extensive research has demonstrated and clearly stated hospital-based strategies.
health benefits for both the nursed infant and • Breast milk is the optimal form of nutrition in
her/his mother. Moreover, breastfeeding carries the preterm babies.
social, economic, and environmental benefits. • Besides the other benefits, kangaroo mother
Consequently, International Health Agencies care (KMC) has been demonstrated to be a
and Pediatric Scientific Societies recommend galactagogue.
early initiation of breastfeeding, exclusive • When breastfeeding is not achievable or desir-
breastfeeding for around 6 months, and continu- able, cow milk formula should be started.
ing breastfeeding after the start of weaning. • While preterm formulas are recommended for
Breastfeeding should be promoted among the VLBW preterm babies, evidence on post-
population of healthy term infants as well as discharge formulas is still controversial.
among the NICU population. Effective promo-
tion of breastfeeding requires adequate knowl-
edge of the physiology of lactation, of the factors
facilitating and constraining the beginning and 36.2 The Uniqueness of Human milk
the continuation of breastfeeding, and of the true
contraindications to breastfeed. Human milk is a species- and individual-specific
nutritional and biological liquid. Mature human
milk contains 4 g/dL fat, 0.9 g/dL protein, 7 g/dL
36.1 Salient Points carbohydrate calculated as lactose, and 0.2 g/dL
mineral constituents expressed as ash. Its energy
• Breastfeeding is proven to be beneficial for the content is around 67 kcal/dl. As 87% of human
nursed infant and the mother. milk is water, the exclusively breastfed infant does
• Pediatricians should be trained to support not need extra water. Despite individual variation
breastfeeding. in maternal nutrition, the macronutrient content in
36 Human Milk and Formulas for Neonatal Nutrition 559
human milk, as a whole, appears to be sufficient to Protein content is markedly higher in colostrum
ensure adequate infant nutrition. than in mature milk and higher in preterm than in
About 50% of the energy in mature human milk term milk. Human milk contains two types of pro-
is derived from fat, which is present as globules; it is teins: casein (beta and kappa) (about 40%) and
essential for growth and development, particularly whey proteins (about 60%) which protect against
of the brain and the retina. The fat content (around infection. The principal whey proteins of human
4 g/dL in both human and bovine milk) increases by milk are alpha-lactalbumin, lactoferrin, immuno-
nearly 10% during the second semester of lactation, globulins (particularly IgA), lysozyme, and serum
during afternoon and evening as compared to night albumin. In the whey fraction, enzymes (particu-
and morning, and during the course of each larly, bile salt-stimulated lipase, amylase, and pro-
breastfeed. In fact, the last milk of a feed (hind tease) are present in sufficient quantities to aid
milk) contains three times the fat concentration in infants in digestion and absorption. About 25% of
the initial milk of a feed (foremilk). Triglycerides the total nitrogen content of human milk is com-
constitute more than 98% of human milk lipids, posed of nonprotein compounds, including urea,
while the remaining 2% are composed of cholesterol uric acid, creatine, creatinine, a large variety of
and phospholipids. Each triglyceride contains three free amino acids (predominantly glutamic acid,
fatty acids derived from endogenous synthesis in the glutamine, alanine, and taurine), and nucleotides.
lactocytes of the mammary glands or from maternal Moreover, nucleotides and their related metabolic
plasma. Most triglycerides are structured in long- products (nucleosides) play an essential role in cell
chain fatty acids plus several medium-chain fatty replication, particularly in rapidly growing infants.
acids. Human milk fat has a high content of palmitic Nucleotides have a beneficial effect on gut micro-
and oleic acids. The former is heavily concentrated flora: they reduce the number of episodes of diar-
in the 2-position of triglycerides and the latter in the rhea, enhance immune function, increase natural
1- and 3-positions, which facilitate gut absorption. killer cell activity, and stimulate antibody response
Human milk also contains 10–15 mg/dL cho- to immunization with Haemophilus influenzae vac-
lesterol. Though its cholesterol content is much cine, diphtheria toxoid, and oral polio vaccine.
higher than in infant formula, cholesterol intake Nucleotides can be synthesized de novo or recycled
during early infancy seems beneficial. In fact, through salvage pathways; however, the capacity
adults who were breastfed in infancy have lower for nucleotide synthesis in the neonate is low. It is
cholesterol levels than those who were bottle-fed, estimated that an infant consuming human milk as
supporting the theory that activation of homeostatic a primary nutrition source will ingest 1.4–2.1 mg of
mechanisms in early infancy downregulates nucleotide nitrogen per day.
cholesterogenesis. Carbohydrate content is lower in colostrum
Long-chain polyunsaturated fatty acids (5.8 g/dL) than in mature milk. The principal
(LC- PUFAs) make up 15% (0.6 g/dL) of the fat sugar of human milk is lactose, a disaccharide
content in human milk. Arachidonic (ARA) and that promotes the gut growth of bifidobacteria and
docosahexaenoic (DHA) acids are the most abun- that, as compared to glucose, has a more stabilizing
dant LC-PUFAs in the brain, where they consti- effect on plasma glycemia. Other significant carbo-
tute important components of neuronal hydrates are human milk oligosaccharides
membranes and play a role in neural development. (HMOs, approximately 1 g/dL). The more than
Moreover, DHA is also a component of photore- 100 HMOs so far identified are not digested by
ceptors and is implicated in visual acuity. DHA is the infant gut and so make up part of the intestinal
one of the most variable fatty acids in human milk, flora. They help to prevent infectious diseases by
its concentration being directly influenced by the acting as decoy receptors at receptor sites on the
amount of DHA in the mother’s diet. The lowest intestinal, urinary, and respiratory mucosa where
values are found in milk from vegan mothers and they block the attachment of disease-causing path-
generally with little or no preformed sources of ogens. HMOs may also alter immune cell
DHA (i.e., fatty fish). responses, which may benefit the infant.
560 R. Davanzo et al.
Table 1 Bioactive substances in human milk (Modified Table 1 (continued)
from Ballard and Morrow 2013)
Component Function
Component Function Oligosaccharides Stimulate beneficial gut
Cells (prebiotics) microbiome
Macrophages Protect against infection Block attachment of
Stem cells Potential regeneration pathogens to mucosa
Immunoglobulins Inhibit pathogens; activate Anti-inflammatory action
phagocytosis and Mucins Block infection by viruses
complement and bacteria
Cytokines (IL, IFN- Modulate inflammatory
gamma, TGF-beta, TNF- responses (pro- and anti-
alpha) and cytokine inflammatory)
inhibitors Human milk also provides a source of various
Chemokines different types of micronutrients, including min-
G-CSF Granulocyte colony- erals, vitamins, and hormones.
stimulating factor, a Iron content appears to be adequate (0.3–0.5 mg/
trophic intestinal factor
L) even in the milk produced by iron-deficient or
MIF Macrophage migratory
anemic mothers, although breastfeeding may
inhibitory factor
Growth factors
worsen maternal iron deficiency. The iron bioavail-
EGF Stimulate epithelial cell ability in human milk is higher than in infant for-
proliferation mulas (nearly 30% vs. <20%).
HB-EGF (heparin Protect against hypoxia Similar to intracellular fluids, the potassium level
binding-EGF) and ischemia in human milk is much higher than sodium (57 mEq/
VEGF Vascular endothelial L vs. 7 mEq/L). In contrast, the sodium level in cow
growth factor promoting
angiogenesis
milk (22 mEq/L) is threefold that in human milk,
NGF Stimulate neuron growth
accounting for the well-known higher risk of hyper-
angiogenesis natremic dehydration in newborns with diarrhea.
IGF Stimulate growth and The calcium and phosphorus content of human
maturation milk is 35 mg/dL and 57 mg/dL, respectively. The
Erythropoietin Stimulate growth; increase Ca/P ratio (2:1) facilitates the high bioavailability
formation of red blood
of calcium from human milk.
cells and hemoglobin
Hormones
Regardless of maternal diet, vitamin K is low in
Calcitonin Development of enteric human milk; therefore, intramuscular injection at
hormones birth and/or repeated oral administration of vita-
Somatostatin Regulate gastric epithelial min K is recommended to prevent both early and
growth late vitamin K deficiency bleeding (VKDB). The
Adiponectin Reduce weight only infants who are not fully protected against
Ghrelin Regulate energy late VKDB by repeated oral doses of vitamin K
conversion and appetite
are those with yet unrecognized malabsorption/
Leptin Made by adipose cells that
helps to regulate energy cholestasis (McNinch et al. 2007).
balance by inhibiting hunger The mean level of vitamin D in human milk in
Antimicrobial factors healthy lactating women, unsupplemented or
Lactadherin Antiviral supplemented, ranges from 10 to 80 IU/L. The
Lactoferrin Binding and gut transport prevalence of serum 25(OH)D <25–37.5 nmol/L
of iron ions in exclusively breastfed infants is high, particu-
Broad-spectrum larly in those born to mothers with low exposure
antimicrobial and
immunomodulatory milk to sunshine, hence warranting postnatal vitamin D
glycoprotein supplementation in breastfed infants (400 IU/day)
Promote bifidus flora to prevent osteopenia and/or overt rickets. Actu-
(continued) ally, the cutoff values of serum 25(OH)D levels
36 Human Milk and Formulas for Neonatal Nutrition 561
<25–37.5 nmol/L (<10–12 μg/L) reported in increased risk of postpartum hemorrhage, breast,
most studies are very conservative, because the and ovarian cancer (Luan et al. 2013) and will lack
current recommended cutoff value for vitamin D the same empowerment related to their successful
deficiency in children is defined as serum 25(OH) nursing role within their family and society.
D <50 nmol/L (<20 μg/L).
Human milk also contains many hundreds of
bioactive substances (Table 1) (Ballard and Mor- 36.3 Recommendations on Infant
row 2013) with multiple nutritional, biological, Feeding
and immunological roles in protecting against
infection and inflammation and to promote In view of the demonstrated benefits of
immune maturation, organ development, and breastfeeding, international health agencies (World
healthy microbial colonization. Health Organization [WHO] (http://www.who.int/
The passage from nutrition with mother’s milk mediacentre/factsheets/fs342/en/) and the United
to formula feeding has long been recognized as Nations Children’s Fund [UNICEF]), governmental
having short- and long-term implications for both entities (Centers for Disease Control and Prevention
the nursed infant and the mother. Formula- 2013), and professional pediatric societies (Johnston
fed individuals are more prone to a wide et al. 2012; Davanzo et al. 2015a) strongly make the
range of diseases (infectious, immunomediated, followingfeeding recommendations: (1) exclusive
noncommunicable, cancer) (Table 2) (Department breastfeeding from the very beginning, (2) until
of Health and Human Services 2011) leading to about 6 months of age, (3) continuing during
increased cost for ambulatory and hospital care of weaning, and (4) possibly keeping some occasional
formula-fed infants (Cattaneo et al. 2006) and to breastfeeding beyond 1–2 years of life.
slightly impaired cognitive development (von
Stumm and Plomin 2015) and poorer social
achievement (Sacker et al. 2013). On their part,
women formula feeding their babies are at 36.4 From the Physiology of
Lactation to Breastfeeding
Table 2 Benefits of breastfeeding and nutrition with Management
human milk, expressed as excess risk in different health
outcomes for both the infant and the mother (Modified 36.4.1 Lactogenesis
from US Department of Health and Human Services 2011)
Outcome Excess risk (%) Colostrum, the first breast milk, is already produced
Acute ear infection (otitis media) 100 during late pregnancy under the influence of pro-
Eczema (atopic dermatitis) 47 lactin (PRL) and human placental lactogen (HPL)
Diarrhea and vomiting 178 (stage I of lactation or lactogenesis I). It is normally
(gastrointestinal infection)
available for the breastfeeding newborn from child-
Hospitalization for lower respiratory 257
tract disease in the first year birth until the milk comes in (stage II of lactation or
Asthma, with family history 67 lactogenesis II), usually around 40–48 h postpar-
Asthma, no family history 35 tum. The decrease in maternal serum progesterone
Childhood obesity 32 levels after delivery of the placenta triggers the shift
Type 2 diabetes mellitus 64 in production from limited amounts of colostrum
Acute lymphocytic leukemia 23 (the daily intake by newborn infants is usually
Acute myelogenous leukemia 18 10–100 mL/day) to the sharply increased amounts
Sudden infant death syndrome 56 of mature human milk over the following days and
Among preterm infants weeks. Although lactogenesis II is an automatic
Necrotizing enterocolitis 138 phenomenon, it can be anticipated nearly 12 h in
Among mothers pluriparous women or by the active and frequent
Breast cancer 4
sucking of a newborn properly latched on to the
Ovarian cancer 27
breast. Lactogenesis II may be postponed beyond
562 R. Davanzo et al.
72 h after childbirth due to maternal conditions The supply of breast milk progressively
(obesity, diabetes, prolonged bed rest, acute illness increases during the first weeks postpartum (cali-
at childbirth), mode of delivery (cesarean versus bration phase) and reaches an average production
vaginal), and obstetric procedures (vacuum or for- of around 700 mL/day at 6–8 weeks postpartum.
ceps extraction for assisted vaginal delivery, induc- The secretion of PRL from the anterior pituitary
tion of labor) (De Bortoli and Amir 2016). gland in response to sucking is not per se the only
determinant of milk production. By this time, PRL
secretion is merely a prerequisite for the production
36.4.2 From Calibration to of breast milk, while efficient milk removal from
Maintenance the breast is more relevant. If breast milk is not
removed, the alveolar level of a peptide hormone
The supply of breast milk subsequent to known asfeedback inhibitor of lactation (FIL)
lactogenesis II follows the demand of the newborn increases, hindering the ability of PRL to act at the
at the breast. This cycle from stimulation to secre- alveolar level, thus limiting or impeding further
tion is called the prolactin (PRL) reflex or the milk breast milk production. This is the basis for inde-
secretion reflex. The more the baby sucks at the pendent autocrine regulation of lactation in each
breast, the larger the volume of milk produced. A mammary gland, which explains the differences in
proper, efficient suck at the breast determines PRL the rate of milk production between the two breasts.
release and breast milk production by lactocytes
in the subsequent hours. In other words, sucking
at the breast is not only the way the newborn 36.5 Hospital Practices and the
obtains breast milk immediately but is also an Baby-Friendly Hospital Model
investment for the following feeds.
Oxytocin (OXT), a hormone produced by the A series of practices have been shown to promote
posterior pituitary gland, is responsible for contrac- breastfeeding in hospital settings (Table 3)
tion of the myoepithelium around the mammary (Holmes et al. 2013). As most of these practices
acini and ejection of the milk. Because OXT is are interdependent, the WHO and the UNICEF
produced in response to stimulation of the nipple have developed a global program for the promo-
by sucking, as well as by the thought, sight, or tion, protection, and support of breastfeeding in
sound of the baby, it may activate breast milk maternity hospitals: the Baby-friendly Hospital
ejection even before the baby gets to the breast. Initiative (BFHI) (Cleminson et al. 2015). The
Furthermore, because OXT release is affected by BFHI program was launched to credit maternity
the mother’s emotions, a relaxed and confident hospitals that have implemented evidence-based
attitude helps elicit this milk ejection reflex. On practices that better enable mothers to breastfeed.
the other hand, psychological distress, pain (due Becoming baby-friendly compels facilities to
to stitches, hemorrhoids, nipple fissures, etc.), and examine and modify their long-standing policies
lack of confidence hinder milk flow. This under- and procedures. It requires training, education,
lines the importance of having a supportive envi- and skill building of health professionals.
ronment and empathetic health professionals to A maternity facility can be designated “baby-
reassure the mother and help her gain confidence friendly” when it is compliant with the Interna-
so that she can successfully breastfeed. The milk tional Code of Marketing of Breast-milk Substi-
intake by the nursing newborn during a single tutes (Table 4) and when it has implemented the
breastfeed depends not only on the ability of the Ten Steps to support successful breastfeeding
baby to suck efficiently but also on the contribution (Table 5) (Joint WHO/UNICEF statement 1989).
of the letdown reflex in the mother. During a single Each of the ten steps has its own evidence base.
breastfeed, one or more ejections of milk mediated Current scientific evidence demonstrates that the
by OXT may occur. Two subsequent ejections are baby-friendly hospital practices lead to higher
separated by an interval of 2–3 min due to the breastfeeding rates at hospital discharge and lon-
refractory period of the myoepithelial cells. ger duration of breastfeeding. Moreover, a
Table 3 Hospital-based practices and breastfeeding (Holmes et al. 2013; Davanzo et al. 2015a)
36
Information to expectant mothers. During pregnancy, expectant mothers should be informed about the unique characteristics of breast milk and its benefits for the child and the mother, the correct
breastfeeding positions, and the concept of breastfeeding on demand.
Rooming-in. Rooming-in implies that the newborn and the mother should be allowed to remain together in the same room 24 h a day. Separate care for the mother and the infant should to be limited to
specific cases and after having informed the mother on the importance of rooming-in.
Breastfeeding on demand. Mothers should be encouraged to breastfeed on demand, without restricting the number and duration of feeds, and to recognize early signs of hunger in newborns other than
crying (i.e., open eyes, sucking movements, sucking hands). Breastfeeding on demand helps improve lactation. Health professionals should support mothers during the first days after delivery as some
newborns may be especially demanding.
Proper positioning on the breast. How the baby latches on the breast and how he/she sucks should be observed and evaluated using an appropriate scoring system (e.g., LATCH score). Many common
problems (e.g., cracked nipples, breast engorgement, infant frustration while breastfeeding, slow growth) can be avoided and in some cases completely solved by improving and correcting the baby’s
position on the breast.
Formula supplementation. Before giving milk formula to a breastfed newborn, the health conditions of baby and mother should be carefully evaluated; mothers should be adequately informed about
whether formula supplementation is absolutely necessary, as it may interfere with breastfeeding.
Pacifiers. The use of pacifiers, soothers, and dummies should be limited as much as possible since it may create nipple confusion or nipple preference, especially if begun before breastfeeding has been
fully established. In breastfed babies, pacifiers may be used, given their protective role in the prevention of sudden infant death syndrome (SIDS), but only after the third to fourth week of life
Cup versus bottle. Bottles are often used to feed babies with expressed breast milk or formulas. However, sucking on a bottle teat is different from sucking at the breast and may contribute to nipple
confusion. The use of small cups may reduce this risk.
Expressed breast milk. Whenever maternal (e.g., intolerable pain during breastfeeding, breast engorgement, return to work) or newborn problems are present (e.g., difficulty to latch on because of
prematurity, congenital malformations, or other conditions), mothers should be advised and taught to express their milk.
Human Milk and Formulas for Neonatal Nutrition
Breastfeeding and early jaundice. Early physiological jaundice appears between 2 and 7 days of life and resolves within a few days. Jaundice can make a baby sleepy so that he or she sucks less. Early
initiation of breastfeeding and frequent breastfeeding reduce the severity of early jaundice. If phototherapy is initiated, breastfeeding on demand should be encouraged, and expressed breast milk may be
given to the baby at the end of the breastfeed. Glucose solution does not help; indeed, it may even worsen jaundice and make a baby suckle less at the breast. Routine formula supplementation in babies
undergoing phototherapy should be avoided, and formula should be offered only when breast milk production is insufficient. In newborns with bilirubin values close to exchange transfusion, expressed
breast milk may be recommended.
Breastfeeding and late jaundice. Late jaundice occurs in about 1 in 200 newborns. It starts or persists after the first week of life and usually peaks during the second or third week. It is most often due to
substances in the mother’s milk that interfere with the ability of the infant’s liver to metabolize bilirubin (so-called breast milk jaundice). Breast milk jaundice does not cause any serious problems, whether
treated or not, and it is usually not a reason to stop nursing. Nevertheless, infants still jaundiced at 2–3 weeks of age, particularly if pale stools and/or dark urine are passed or there is suspicion of enlarged
liver or spleen, should be assessed and tested (total and direct bilirubin) to rule out cholestasis.
Breastfeeding and newborns at risk of hypoglycemia. Newborns at risk of hypoglycemia (e.g., small for gestational age or born to a mother with diabetes) should undergo glycemic monitoring according to
local hospital protocols. If glycemia is normal, preventive formula feeding should be avoided in order not to interfere with exclusive breastfeeding.
Newborns at risk of infection. Newborns at risk of infection (e.g., born to mothers with premature rupture of membranes [PROM], fever, or a positive group B strep [GBS] vaginal/rectal swab) should
undergo clinical monitoring without separating them from their mothers; this allows rooming-in and does not interfere with breastfeeding. However, routine clinical monitoring may not be sufficient in
babies born to mothers with chorioamnionitis, who may need to receive antibiotics; in such cases, newborns will be admitted to a different ward from their mothers.
Discharge home. When discharging babies home, formula prescription should be given only when necessary. In exclusively breastfed babies who are not yet growing, a follow-up visit with weight check
should be scheduled within 24–72 h after discharge.
Support for breastfeeding mothers. Mothers should be informed about the professional help with breastfeeding available in hospitals or healthcare centers. Many mothers stop breastfeeding before they
want to because of all sorts of problems, many of which are preventable with good care and support. To help mothers reach their breastfeeding goals, extra support (face to face or by telephone) can be
obtained from professionals and/or trained or untrained lay people. Reassurance, information, praise, and practical help are all part of the support that should be tailored to the particular cultural and
socioeconomic setting. Health professionals should recognize the effectiveness in supporting breastfeeding provided by peer counselors and lactation consultants and should be ready to cooperate
fruitfully with them.
563
564 R. Davanzo et al.
Table 4 WHO international code of marketing of breast- valuable in facilities that are not candidates for a
milk substitutes full designation of baby-friendly hospital.
Breast milk substitute companies may not: In 2010, the Joint Commission International
Promote their products in hospitals, shops, or to the (JCI) included “exclusive breast milk feeding” in
general public the Perinatal Care Core Measure set as a standard-
Give free samples to mothers or free/subsidized supplies
ized performance measurement for the assessment
to hospitals
Give gifts to health workers or mothers
of care in maternity hospitals, thus underscoring
Promote their products to health workers: any their responsibility as agents to facilitate the suc-
information provided by companies must contain only cessful start of breastfeeding and recognizing the
scientific and factual matters evidence connecting promotion of breastfeeding as
Promote foods or drinks for babies a process of care to improved outcome (https://
Give misleading information manual.jointcommission.org/releases/TJC2015A1/
Have direct contact with mothers PerinatalCare.html).
Infant formula package should:
Show labels in a language understood by the mother
Include a clear health warning
36.6 Skin-to-Skin Contact and the
Not use baby pictures idealizing formula feeding
Prevention of Neonatal
Collapse
Table 5 The revised Ten Steps to successful
breastfeeding (WHO/UNICEF 2018) Prolonged skin-to-skin (STS) contact between the
mother and her healthy newborn soon after birth
1. a) Comply fully with the International Code of
Marketing of Breast-milk Substitutes and relevant World (particularly in the first 2 h postpartum) and con-
Health Assembly resolutions; b) Have a written tinuing in the first days of life is recommended for
breastfeeding policy that is routinely communicated to a variety of reasons: to improve mother–infant
staff and parents; c) Establish ongoing monitoring and bonding, facilitate breastfeeding, aid in coloniza-
data-management systems.
tion of the skin and the gastrointestinal tract of the
2. Ensure that staff have sufficient knowledge,
competence and skills to support breastfeeding newborn infant with mother’s nonpathogenic
3. Discuss the importance and management of microorganisms, and facilitate metabolic, cardio-
breastfeeding with pregnant women and their families. respiratory, and thermal adaptation to extrauterine
4. Facilitate immediate and uninterrupted skin-to-skin life. STS is recommended by step 4 of the Ten
contact and support mothers to initiate breastfeeding as Steps of UNICEF-BFHI.
soon as possible after birth.
In view of the reported association between
5. Support mothers to initiate and maintain breastfeeding
and manage common difficulties. STS contact and increased risk of sudden unex-
6. Do not provide breastfed newborns any food or fluids pected postnatal collapse (SUPC) (Herlenius and
other than breast milk, unless medically indicated. Kuhn 2013) of apparently healthy term infants,
7. Enable mothers and their infants to remain together and STS contact in the delivery room has come under
to practice rooming-in 24 hours a day. criticism for health safety reasons. In many such
8. Support mothers to recognize and respond to their cases, the mother is primiparous, very tired, not
infants’ cues for feeding.
observed by health professionals when initiating
9. Counsel mothers on the use and risks of feeding
bottles, teats and pacifiers. STS contact and breastfeeding, and sometimes
10. Coordinate discharge so that parents and their infants distracted by smartphone use.
have timely access to ongoing support and care. Surveillance protocols that promote safe
mother–infant bonding and early beginning of
breastfeeding have recently been proposed while
dose–effect relationship has been documented for correcting the risk factors for SUPC. The surveil-
the number of steps implemented in a maternity lance protocol developed at the Maternal and
hospital and the success of breastfeeding among Child Health Institute of Trieste (Italy) is espe-
the served population of women. Eventually, even cially focused on the first 2 h of life (Davanzo
partial amelioration of hospital practices is et al. 2015b). Interventions include antenatal and
36 Human Milk and Formulas for Neonatal Nutrition 565
Table 6 Protocol checklist to prevent SUPC in the deliv- Table 7 Clinical approach to neonatal weight loss
ery room. Checks by midwife and/or pediatrician are done (Davanzo et al. 2013a)
at 10, 30, 60, 90, and 120 min of life
Percentage of weight loss compared to birth weight
Infant positioned with visible and unobstructed mouth <8% 8–10% 10%
and nose Routine care for Newborn Newborn
Pink color (skin and mucous membranes) the clinical clinical
Normal breathing (no retractions nor grunting nor flaring mother–baby assessment assessment
of the nares) couple Assess and Assess and
Normal respiratory rate 30–60 breaths/min improve improve
Normal SpO2 >90% (only if deemed necessary) breastfeeding breastfeeding
Subaxillary temperature at 60 and/or 120 min after birth Consider Consider
(normal range 36.5–37.5 C) expressed breast expressed breast
Mother never left alone with her infant milk milk and/or
formula
Verify mother’s Verify mother’s
early postnatal oral and written information to capability to capability to
parents and periodic assessment (position, color, respond to the respond to the
breathing) of the infant (at 10, 30, 60, 90, and baby’s demand baby’s demand
Recheck weight Recheck weight
120 min of life) by midwifes and/or pediatrician
12 h later 12 h later
in the delivery room (Table 6), ensuring that
Measure serum
mothers are not left alone with their baby in the sodium level
first hours after birth, particularly during STS
contact and first breastfeeding attempts. Since
there is no evidence concerning which interven- the breast milk comes in. In the first days postpar-
tions may be effective to prevent SUPC, our pro- tum during hospital stay, taking the daily weight
tocol simply represents a potential best practice. of the newborn and recording it on a weight graph
STS may be not possible in newborns requiring are an established method to assess breast milk
resuscitation or when the mother is not well. The intake by the newborn and breastfeeding success.
first baby bath can be postponed (up to 6 h of life Weighing a healthy term newborn before and after
according to the WHO) in order not to interfere feeds in order to estimate the amount of breast
with STS and breastfeeding. milk ingested yields inconsistent and only partial
information about the success of breastfeeding,
and moreover, it can be stressful for new mothers.
36.7 The First Days of Life and Postnatal weight loss has a nadir at 48–72 h
Neonatal Weight Loss postpartum (Bertini et al. 2015) and results not
only from feeding practices and milk intake during
Concern over sufficient milk supply is one of the the first days postpartum but also from the physio-
main reasons why mothers wean their infants logical fall in extracellular fluid after birth and the
from the breast, particularly during the first days elimination of parenteral fluids in excess given to
after birth when physiological weight loss occurs. the mother intrapartum. The average normal weight
On their part, health professionals may sometimes loss in the exclusively breastfed newborn is around
prescribe unnecessary formula supplementation 6–7% of birth weight, possibly less (5%) in for-
to prevent hypernatremic dehydration and infant mula-fed newborns. The upper limit of a safe weight
malnutrition or simply to deal with a fussy/crying loss is around 10%. Although some healthy new-
baby or an unconfident mother. borns will tolerate a weight loss of up to 12%, the
Mothers should be given correct information 10% upper safety limit virtually excludes the possi-
on the feeding behavior of the healthy newborn in ble coexistence of dehydration and hypernatremia.
the first days of life. Most babies need frequent When interpreting early neonatal weight
feeds, between 2 and 3 h apart or even more often loss, and before prescribing the use of expressed
and 8–15 feeds every 24 h, particularly in the breast milk and/or formula, we should
period between 24 and 72 h after childbirth, until routinely consider three other factors (Table 7)
566 R. Davanzo et al.
(Davanzo et al. 2013a): (1) the infant’s general is measured in newborn infants with a weight loss
condition, including hydration status; (2) the 10% and in those with a weight loss between
mother’s general condition in relation to her capa- 8 and 10% and either clinical signs of dehydration
bility to meet the newborn’s feeding demand; and or “unconvincing” appearance. Such infants are
(3) the assessment of a breastfeed. given at least some expressed breast milk and/or
Delayed onset of lactation, defined as >72 h after formula, and weight is measured after 12 h.
delivery, is a recognized risk factor for excessive Healthy newborns can be discharged from hos-
weight loss and should be considered when deciding pital at postnatal age 36 h. Newborns with a
whether to prescribe formula supplementation. neonatal weight loss >10% are not considered
Accurate feeding assessment of infant position ready for discharge. A postdischarge weight
and latch on to the breast is essential because it check can be scheduled 24–72 h after discharge
allows to determine the neurobehavioral matura- depending on (1) percentage of in-hospital weight
tion of the neonate, anticipates proper breast loss, (2) need for jaundice assessment, and (3)
milk intake, and provides information on maternal uncertainty about breastfeeding.
competence in breastfeeding, all of which need
to be considered before hospital discharge after
childbirth. Close attention to these factors by 36.8 Low Breast Milk Supply
healthcare professionals assisting the new mother
in these early days and weeks may prevent or Sooner or later, most mothers feel that they do not
resolve many common breastfeeding problems have enough milk because the baby cries continu-
(breast engorgement, nipple fissures, mastitis, ously and does not seem to be satisfied with feeds
poor growth) that arise in the first months after or because the baby wants to feed very often or the
childbirth. breasts are soft, or attempts to express breast milk
The LATCH charting system (Jensen et al. are unsuccessful. These are not reliable signs of low
1994) is a simple, effective tool health profes- breast milk production. If a mother is worried about
sionals can use to assess breastfeeding in maternity her milk supply, we must try to understand whether
wards, to record data and communicate information the problem of low milk supply (hypogalactia) is
on breastfeeding to colleagues and to identify true or simply perceived as such. Two reliable signs
mother–infant pairs requiring extra help and fol- that a baby is not getting enough milk are poor
low-up (Tornese et al. 2012). The LATCH system weight gain and low urine output.
assigns a numerical score (0, 1, or 2) to five key Weight gain. Each baby follows his/her own
breastfeeding components designated by the letters pattern of weight gain; accurate assessment relies
of the acrostic L.A.T.C.H.: “L” denotes how well on recording weight changes on a graph during
the infant latches on to the breast, “A” the amount the first 14 days of life. Birth weight recovery is
of audible swallowing noted, “T” the mother’s generally expected within the first 2 weeks of life,
nipple type/condition, “C” the mother’s level of although most healthy babies will regain weight
comfort, and “H” the amount of help the mother by the end of the first week of life. If breastfeeding
needs to hold her infant to the breast. The total score problems (difficulty latching on, breast engorge-
ranges from 0 to 10, where a higher score indicates ment, crackled nipples, etc.) persist beyond the
a better breastfeeding technique. A LATCH score first 2 weeks of life, the upper time limit for birth
>7 or higher at subsequent assessments predicts weight recovery may be extended up to 21 days of
breastfeeding at discharge (Table 8). life, and if the baby is otherwise healthy, the
In newborns with a neonatal weight loss of breastfeeding techniques and patterns and
8–10%, special support during breastfeeds is mother–baby interaction are adequate.
given to both mother and baby. Aneonatal weight If the infant does not gain weight properly,
loss of >8% in postterm newborns and >10% in efforts to improve latch on to the breast and the
term newborns is an indicator of possible hyper- use of expressed breast milk should be advised
natremic dehydration. Serum sodium concentration before suggesting formula supplementation.
36 Human Milk and Formulas for Neonatal Nutrition 567
Table 8 The LATCH score (Jensen et al. 1994)
0 1 2
L Too sleepy or reluctant Repeated attempts Grasps breast
Latch No latch obtained Must hold nipple in mouth Tongue down and forward
Must stimulate to suck Lips flanged
Rhythmic suckling
A None A few with stimulation Spontaneous, intermittent
Audible (<24 h old)
swallowing Spontaneous, frequent
(>24 h old)
T Inverted Flat Everted (after stimulation)
Type of nipple
C Engorged Filling, small blisters, or bruises Soft tender intact nipples
Comfort Cracked, bleeding, large Mother complains of pinching (no damage)
(breast/nipple) blisters, or bruises Mild/moderate discomfort
Severe discomfort
H Full assist (staff holds infant Minimal assist (i.e., elevate head of No assist from staff
at breast) bed, place pillows)
Hold Teach one side, mother does the Mother able to position/
(positioning) other hold infant
Help Staff help, mother takes over feeding
From the recovery of the birth weight Low urine output. After the breast milk comes
onward, exclusively breastfed infants are in (>72 h postpartum), an exclusively breastfed
expected to gain at least 150–200 g per week baby who is passing urine (especially dark yel-
during the first 3 months of life. A proper refer- low) <5 times per day is not getting enough
ence chart is essential for accurate assessment of fluid. In infants with low milk intake, but other-
infant growth. Old, outdated weight charts are wise healthy, the breastfeeding technique or pat-
an inadequate reference as they were based pre- tern should be evaluated to see whether it can be
dominantly on formula-fed infants. The growth improved before prescribing an infant formula.
pattern of healthy breastfed infants deviates sig- In fact, when an infant takes only part of the milk
nificantly from bottle-fed infants and is charac- from the breast, milk production increases when
terized by more rapid growth occurring in the the baby takes more or if the breast milk is
first 3 months of life followed by slower growth expressed and given to the baby by bottle or an
over subsequent months. This major difference alternative means (cup or syringe). If the
in growth rate can be due to the different nutri- breastfeeding technique or pattern is adequate,
ent composition of breast milk and formula, the other causes of low breast milk production
presence of growth factors in breast milk, and a should be considered (Table 9).
better control of food intake by the breastfed Factors affecting the rate of milk production
infant. include the frequency and completeness of milk
The WHO charts (de Onis 2006) (http://www. removal and also the mass of tissue actively synthe-
who.int/childgrowth/standards/en/) report the sizing milk. The mammary gland tissue may be
growth patterns of children who were predomi- reduced in such conditions as congenital hypoplastic
nantly breastfed for at least 4 months and still breast anomalies, acquired breast hypoplasia follow-
breastfeeding at 12 months, with complementary ing postinfectious scar or radiotherapy, reduction
foods introduced by 6 months of age. The current mammoplasty, or partial mastectomy and more
WHO standards establish growth of the breastfed often after preterm delivery which misses the mam-
infant as the norm for growth for the whole popu- mary gland development of late pregnancy. Low
lation of infants, both breastfed and bottle-fed. milk production may also occur after prolonged
568 R. Davanzo et al.
Table 9 Causes of low breast milk intake (Modified from UNICEF/WHO)
Maternal psychological
Breastfeeding factors factors Maternal physical factors Infant-related factors
Common Uncommon
Delayed start Lack of confidence Contraceptive pill, diuretics Illness
Feeding at fixed times Depression Pregnancy Prematurity
Infrequent feeds Worry, stress Severe malnutrition Low birth weight
No night feeds Dislike of breastfeeding Alcohol use Some specific congenital
malformations
Short feeds Rejection of baby Smoking
Poor attachment Retained piece of placenta
Bottles, pacifiers Pituitary failure (rare)
Other food or fruit Poor breast development
(water, teas) (very rare)
reduced drainage (e.g., secondary to mastitis) that 36.9.1.1 Hepatitis B Virus (HBV)
leads to apoptosis of lactocytes and results in There is wide consensus that HBV-positive
decreased breast gland functioning. The role of mothers can safely breastfeed their newborn
maternal diet in low milk production has been over- infants provided that the infant receives active
emphasized. The overall maternal nutrition status and passive prophylaxis (Chen et al. 2013).
(except in severe malnutrition) has little influence
on milk quantity and quality. In addition, neither 36.9.1.2 Hepatitis C Virus (HCV)
increased nor restricted fluid intake affects the vol- The percentage of HCV-infected mothers that dem-
ume of milk produced; however, maternal fever and onstrate milk positivity to HCV varies widely
dehydration (e.g., due to diarrhea or a flu-like syn- across studies (from 10% to 100%). Viral load is
drome) may limit the fluid available for optimal usually very low, and HCV is inactivated by gastric
breast milk production. acidity. Moreover, transplacental antibodies are
In brief, because new mothers are often active against HCV, and lactoferrin may also play
concerned about their breast milk production, true a role in inactivating the virus. Vertical mother-to-
hypogalactia should be assessed and confirmed child transmission occurs in about 3–7% of
according to reliable criteria. Nevertheless, some mothers testing positive to HCV-RNA by PCR
mothers may not be completely reassured by health techniques. Because it has not been documented
professionals that hypogalactia is not true and will whether breastfeeding increases the risk of infec-
decide to begin formula supplementation. Ulti- tion, breastfeeding by an HCV-positive mother is
mately, the choice of an informed mother should allowed (Tosone et al. 2014). No specific prophy-
be accepted and supported by health professionals. laxis is currently recommended, although there is
some concern from the Centers for Disease Control
and Prevention (CDC) (http://www.cdc.gov/
36.9 Controversies Surrounding breastfeeding/disease/hepatitis.htm) about possible
Breastfeeding virus transmission by cracked nipples. Some
authors have suggested temporary suspension of
36.9.1 Infection breastfeeding and expression of breast milk until
bleeding fissures have healed.
Isolation of infectious agents (particularly
viruses) from breast milk is important; in most 36.9.1.3 Cytomegalovirus (CMV)
cases, however, breast milk has not been shown Between 50% and 85% of women are CMV posi-
to be a vector of transmission. tive, and CMV can be isolated in 14–69% of their
36 Human Milk and Formulas for Neonatal Nutrition 569
expressed breast milk. While postnatal CMV infec- although the causative role of GBS-positive
tion is not a matter of concern in healthy term mother’s milk as a vector of mother-to-infant
infants, postnatal CMV transmission via human transmission has not been definitively proven.
milk may produce a late-onset sepsis-like syn- Nevertheless, maternal compliance with profes-
drome in very low birth weight (BW <1,500 g) sional advice to continue breastfeeding is low.
preterm infants and possibly also minor longterm
neurodevelopmental abnormalities at 4 and 14
years of age (Goelz et al. 2013; Brecht et al. 36.9.2 Environmental Contamination
2015), although these long-term consequences
have not been confirmed by recent literature The transfer of persistent organic pollutants
(Gunkel et al. 2018). (POPs) from mother to infant via breastfeeding
Freezing expressed breast milk has been is characterized by their lipophilic nature. POPs
shown to reduce CMV positivity from 40% to are known to accumulate in the food chain and can
10–15% (Hayashi et al. 2011), but it also lowers be detected in human milk. Nevertheless,
the benefits of expressed fresh mother’s milk for breastfeeding seems to counteract adverse devel-
high-risk preterm newborns. opmental effects after prenatal exposure to POPs,
Holder pasteurization (heating at 62.5 C for and breast milk remains superior to infant formula
30 min) or high-temperature short pasteurization from the perspective of overall child health, after
(72 C for 5–10 s) eliminates CMV from the milk “weighing the risks against the benefits of
(Harmsen et al. 1995), but it also reduces the breastfeeding” (Mead 2008).
bioactive factors in human milk and possibly
affects protection against necrotizing enterocolitis 36.9.3 New Pregnancy
(NEC). Finally, in order to prevent NEC
(Chowning et al. 2015; Kurath and Resch 2010), In the past, mothers were advised to stop
it is preferable to use fresh mother’s own milk also breastfeeding when they became pregnant because
in very low birth weight infants (VLBWIs) and/or it was claimed that breastfeeding during pregnancy
preterms <32 weeks of gestational age, including posed a higher risk for the embryo/fetus and the
those born to CMV-positive mothers. breastfed newborn infant. Based on current knowl-
edge, breastfeeding can be continued during the first
36.9.1.4 Group B Streptococcus (GBS) two trimesters of pregnancy and possibly extended
The incidence of the breast carriage rate of GBS into the third trimester. Caution may be warranted in
in lactating mothers is 3.5%. There is inconclu- women at risk of premature delivery, although no
sive documentation on the use of breast milk of evidence exists that breastfeeding can trigger labor-
GBS-positive mothers after late-onset GBS inducing uterine contractions (Cetin et al. 2014).
infections (sepsis and meningitis). Although
clinical protocols have been proposed (Davanzo
et al. 2013b), the best strategy has yet to be 36.9.4 Medications and Mothers’ Milk
developed (Filleron et al. 2014). The
recommended pasteurization of maternal milk Few drugs (mainly cytostatic and some psychotro-
does not change the overall incidence of late- pic or cardiovascular drugs) produce significant
onset GBS infections in preterm infants. Some adverse effects on the breastfed infant. The risk
authors have suggested temporary discontinua- for a nursed infant exposed to a hazardous drug is
tion of breastfeeding until eradication of infec- higher when he/she is exclusively breastfed or
tion (rifampicin for 7 days for mother and infant, metabolism is still immature (preterm or younger
especially in preterms) (Gagneur et al. 2009; than 2 months). This risk significantly decreases
Soukka et al. 2010). In recurrent GBS infections after 2 months of life or complementary feeding is
and coexistent GBS-positive mother’s milk, given, that is, mixed feeding or when weaning
maintaining breastfeeding remains controversial, foods are introduced. Lists of medications declared
570 R. Davanzo et al.
safe or hazardous during lactation are inherently the human immunodeficiency virus (HIV). Infor-
limited by the fact that they are not comprehensive mal milk sharing agreements are arranged via pri-
and often are not updated. These limitations not- vate donor networks as well as via the Internet.
withstanding, such lists serve to simply orient pro- Online sites that connect people interested in buy-
fessional advice. In general, the assessment of ing and selling human milk are growing in popu-
potential effects a medication may have on lacta- larity, although recent research (Reyes-Foster et al.
tion should be based on a precise methodology 2015) has shown that most mother-to-mother milk
(Davanzo et al. 2016) and taken from authoritative exchanges happen in person as gifts and that selling
sources, such as LactMed (http://toxnet.nlm.nih. and shipping breast milk are actually rare.
gov/newtoxnet/lactmed.htm). Concern has been raised after the demonstrated
microbial contamination of human milk pur-
chased in the USA via the Internet (Keim et al.
36.9.5 Radiological Contrast Agents
2013). Another risk is purchasing milk through
the Internet that is not 100% human in origin. In
The majority of radiological contrast agents pose no
fact, 10% of analyzed samples ordered from pop-
additional health risk for the nursing infant of any
ular websites were “topped off” with cow’s milk.
postconceptional age (Cova et al. 2014). As a pre-
All samples contained human DNA, but 11 out of
caution, only gadolinium-based agents considered at
102 also contained bovine DNA (Keim et al.
high risk of nephrogenic systemic fibrosis
2015). In conclusion, health professionals should
(gadopentetate dimeglumine, gadodiamide,
be aware of the increasing trend of human breast
gadoversetamide) should be avoided in breastfeeding
milk sharing and the potential risks due to adul-
mothers. There is no need to temporarily discontinue
teration and microbial contamination.
breastfeeding or to express and discard breast milk
following the administration of contrast agents
declared compatible with breastfeeding.
36.11 Nutrition with Human Milk in
the Neonatal Intensive Care
36.9.6 Contraception Unit (NICU)
Breastfeeding is compatible with a wide range of 36.11.1 The NICU Population and
safe and effective contraceptive methods for fam- Breastfeeding Epidemiology
ily planning (World Health Organization 2015).
Copper intrauterine devices (IUDs) may be a first Human milk is the optimal form of nutrition for
choice from the end of the first month of life high-risk newborn infants admitted to the NICU,
onward. Progestin-only contraceptives (POC) including the entire category of preterm infants
and implants are a first choice during the whole (<37 weeks of gestational age [GA]), low birth
lactation period. Combined oral contraceptives weight infants (<2,500 g at birth), asphyxiated
(COCs) are recommended only after 6 months term newborns, newborns with congenital
postpartum. Although less effective, female con- malformations, or otherwise compromised
doms, male condoms, and the lactational amenor- infants. Notwithstanding the variety of this case
rhea method are other appropriate contraceptive mix, the literature on the impact of early nutrition
options for breastfeeding women. has mainly focused on very low birth weight
infants (VLBWIs) and preterm infants
<32 weeks GA, as these two groups represent a
36.10 Human Milk Sharing well-characterized subpopulation of NICU
patients with very special nutritional needs. Obvi-
Human milk sharing, defined as cross nursing or ously, this is not to say that the type of nutrition is
exchange of expressed milk, is a potential source of irrelevant for preterm infants with higher birth
microbial transmission, including transmission of weight (BW 1,500–2,499 g) or gestational age
36 Human Milk and Formulas for Neonatal Nutrition 571
(32–36 weeks), but simply that differences in Although interventions promoting nutrition
short- and long-term outcome are less clinically with human milk in the NICU population have
remarkable and perceptible. proven effective (Renfrew et al. 2010), they are
Breastfeeding (at the breast, expressed) is gener- often inconsistently applied. Such interventions
ally low for infants discharged from NICUs, regard- will involve (1) providing open access to the
less of their birth weight or gestational age. However, NICU for parents, (2) improving knowledge of
breastfeeding prevalence varies according to the spe- the science of lactation and the breastfeeding com-
cific setting. In accordance with international data petence of the high-risk infant, (3) fostering peer
from the Vermont Oxford Network Database, in support in hospital settings, (4) offering kangaroo
2013 only 11.3% of VLBWIs were breastfed at mother care, and (5) having a clear plan in place
NICU discharge. A multicenter Italian study for breast milk expression.
reported that, as compared with other birth weight
categories of infants fed exclusively with human
milk at NICU discharge, the breastfeeding rates are 36.11.2 Nutrition on NICU Admission
markedly lower for the two intermediate birth weight
categories (25% for BW 1,500–2,000 g and 22% for Three subpopulations of newborn infants can be
BW 2,000–2,499 g vs. 31% for BW <1,500 g and identified based on birth weight and gestational
33% for BW 2,500 g) (Davanzo et al. 2013c). age, each of which requires a specific nutritional
Although intermediate birth weight newborn approach:
infants are expected to show better motor compe-
tence in the transition from parenteral nutrition to 1. Term newborn infants, small for gestational
enteral tube feeding and finally to breastfeeding, age infants (SGA), infants 35–36 weeks GA,
the breastfeeding rate for this subpopulation is and, in general, neonates with a BW >2 kg can
surprisingly lower. One explanation for the low be expected to be able to take milk by mouth. If
rates of exclusive breastfeeding seen for the BW not breastfed, infants can be given donor milk
1,500–2,499 g category is that NICU feeding pro- or a starting formula using a cup or a bottle.
tocols do not adequately recognize the oromotor Tube feeding is reserved for infants unable to
competence of these infants and do not encourage feed autonomously. Intake should be
the use of human milk. Another factor hindering 40–80 mL/kg/day. Glucose monitoring can be
the promotion of breastfeeding in the NICU is that scheduled in the first 12 h of life, as indicated
infants in this birth weight group have a shorter by current hypoglycemia protocols.
length of hospital stay than those in the lower birth 2. Preterm infants born at 33–34 weeks GA or
weight category. Recent UK data on GA catego- newborn infants with BW 1.5–2 kg can be
ries show that late preterm infants (34–36.6 weeks given mother’s or donor milk or a nutrient-
GA) are less breastfed than either moderately enriched formula via tube, initially as continu-
preterm infants (32–33.6 weeks) or term infants, ous enteral feeding of milk, then as bolus feed-
confirming that the intermediate GA category is ing. Intake should be 80 mL/kg/day. Mother’s
the most disadvantaged (Boyle et al. 2015). own milk will be fortified in infants showing
Many other factors can interfere with the use poor growth or abnormal nutritional indexes.
of human milk and breastfeeding in a NICU, Fortification of human milk and nutrient-
including mother/baby separation, fragility and enriched formula will be continued until
limited neurological competence of preterm and NICU discharge. Glucose monitoring can be
sick infants, anxiety and stress following the scheduled in the first 12 h of life, as indicated
birth of a high-risk baby, maternal difficulty in by current hypoglycemia protocols.
milk production, and, last but not least, sub- 3. VLBWIs need parenteral nutrition. Minimal
optimal knowledge about lactation and potential enteral feeding is started possibly within
opposition toward breastfeeding among NICU 48–72 h, while expecting the mother’s colos-
staff. trum. Appropriate lab tests are selected and
572 R. Davanzo et al.
scheduled according to the infant’s general or growth-restricted infants. Advancement of
health conditions. enteral nutrition entails careful assessment for
signs of gut intolerance: elevated gastric residual
and abdominal distention.
36.11.3 Oropharyngeal Colostrum The reference growth rate for the preterm
infant is the same as for the fetus at the
Small quantities of maternal colostrum (0.2 mL, corresponding gestational age: 20 g/kg/day for
8–12 times/day) can be administered into the VLBWIs and 15 g/kg/day for infants with a birth
inner buccal mucosa of severe preterm infants weight 1,500–2,200 g (Ziegler 2011). This can be
(Rodriguez et al. 2010; Lee et al. 2015). This assumed at least after the first 2 weeks of life, a
method is feasible, safe, and effective in increas- phase of possible instability and birth weight
ing the blood levels of immunoactive factors and recovery. Achieving normal growth is an essential
may reduce the risk of neonatal infections (Lee nutritional goal for the preterm infant and is
et al. 2015). closely related to neurodevelopmental outcome
(Weisglas-Kuperus et al. 2009). Nevertheless,
extrauterine growth retardation is frequently due
36.11.4 Minimal Enteral Feeding to the poor health conditions of the high-risk
infant and possibly also because of suboptimal
Minimal enteral feeding (MEF) or trophic feeding nutrition during the NICU stay.
(Lucas et al. 1986) involves the administration of
small amounts of milk (possibly the mother’s
colostrum) 5–25 mL/kg/day via tube to the 36.11.6 Benefits of Human Milk for the
VLBWI. MEF is started as soon as possible within Preterm Infant
the first 72 h and is maintained for 7–10 days
depending on the risk category and health condi- Breast milk (preferably fresh; frozen only as a
tions of the preterm infant. Unless otherwise moti- second choice) ranks first in the biological and
vated, delaying MEF carries no advantages and nutritional hierarchy for the high-risk newborn
can reduce gut feeding tolerance with later attain- (Davanzo and Pastore 2011) and should definitely
ment of full enteral feeding, increase the risk of be preferred over pasteurized donated bank milk
neonatal infections (also because of longer dura- and preterm formula (Section on Breastfeeding
tion of parenteral nutrition), and lengthen hospital 2012). Nutrition of preterm infants with breast
stay (Flidel-Rimon et al. 2004). Colostrum-based milk confers a variety of short- and long-term
MEF is an optimal way to prevent NEC. health benefits: better feeding tolerance, faster
achievement of full enteral regimen, less risk of
serious neonatal infections (e.g., sepsis, meningi-
36.11.5 Advancement of Enteral tis) (de Silva et al. 2004) and NEC (Meinzen-Derr
Feeding et al. 2009; Maayan-Metzger et al. 2012), lower
risk of retinopathy of premature (ROP) (Zhou
Advancing enteral feed volumes at daily increments et al. 2015), and better visual acuity,
of 30–40 mL/kg (rather than 15–24 mL/kg) does neurobehavioral, and cognitive development
not increase the risk of NEC or death in VLBW (Rozé et al. 2012).
infants (Morgan et al. 2015). On the contrary,
advancing the volume of enteral feeds by smaller
steps delays the establishment of full enteral 36.11.7 Fat in Preterm Human Milk
feeds by several days and increases the risk of
invasive infection. Nevertheless, great caution Preterm milk has a higher mean fat content
is warranted when applying these findings to (4.7 g/dL) (Moltó-Puigmartí et al. 2011) and
extremely preterm, extremely low birth weight, energy content (around 77–79 kcal/dL) than
36 Human Milk and Formulas for Neonatal Nutrition 573
Table 10 Comparison of the content of selected nutrients between preterm and breast milk (Modified from Moltó-
Puigmartí et al. 2011)
Gestational age (weeks)
<28 extremely 28–31 severely 32–33 moderately
Nutrient preterm preterm preterm Term
Protein (g/dL) 2.3 0.5 2.1 0.3 1.9 0.3 1.6 0.4
Carbohydrates (g/dL) 7.6 0.6 7.5 0.6 7.5 0.5 6.2 0.9
Fat (g/dL) 4.4 0.9 4.4 0.8 4.8 1.0 4.1 0.7
Energy (kcal/dL) 77.8 8.4 77.6 5.9 76.7 6.5 67.7 3.9
Sodium (mmol/L) 10.6 1.9 10.6 2.2 10.4 1.9 11.2 2.1
Calcium (mmol/L) 6.2 1.4 6.5 1.0 7.4 1.1 5.4 0.8
term milk. The fat concentration in human milk 32–33 weeks GA (Bauer and Gerss 2011)
varies considerably between foremilk (32 g/dL (Table 10). This variability is teleologically
15 SD; range 11–86) and hind milk (83 g/dL 25 fascinating; however, because the protein con-
SD; range 36–149). As hind milk is remarkably centration in preterm milk declines over the
energy dense (87 kcal /100 mL 18 SD), it may first few weeks postpartum unpredictably, it
be preferentially used for the nutrition of preterm no longer meets the nutritional needs of most
newborn infants with poor growth, even before preterm infants. Therefore, preterm milk for
giving medium-chain triglycerides (MCT) (Meier VLWBIs needs to be fortified with a commer-
et al. 2013). cially available product containing protein, cal-
The fat intake by the high-risk newborn infant cium, and phosphorus. The common practice is
varies with the mode of breast milk administra- to add a fixed amount of fortifier to human milk,
tion. Continuous enteral feeding (CEF) of milk assuming that the milk has an average protein
by nasogastric tube varies up to 25% in fat con- content.
tent, with recovery of much of the fat content in At the recommended dosage, common prod-
tubing, as nutrient losses can result from adher- ucts provide 1 g/dL extra protein. Fortification of
ence to the delivery system. Practical solutions human milk is usually started when the enteral
include (1) placing the syringe containing the feeding volume reaches 100 mL/kg per day
milk vertically (exit upward), so that the floating (Klingenberg et al. 2012).
fat is administered; (2) using a shorter set since Milk fortification is expected to improve short-
the fat adheres to the tube’s inner surface; and (3) term growth, increase bone mineralization and
using a bolus or infusion for 30 min instead of prevent rickets, increase nitrogen retention, and
continuous feeds. improve neuromotor development (Arslanoglu
et al. 2010). Currently, human breast milk-derived
fortifiers are also available; although expensive,
36.11.8 Protein in Preterm Breast Milk they seem to further reduce the risk of NEC
and Fortification (Assad et al. 2015; Sullivan et al. 2010).
The two proposed methods for individualized
Nutritional protein requirements increase with fortification are targeted fortification and adjust-
decreasing gestational age (GA): 1.5–2 g/kg/day able fortification (Arslanoglu et al. 2010).
at >36 weeks GA, 2.3 g/kg/day at 30–36 weeks Targeted fortification is based on the periodic
GA, and 3.6–4 g/kg/day at 24–30 weeks GA (Hay analysis of human milk with a specific instru-
2008). In parallel, preterm milk has a higher pro- ment (milk analyzer). The amount of added for-
tein content than term milk, proportional to the tifier is based on the protein intake with the milk.
degree of prematurity: 2.3 g/dL at <28 weeks GA, Milk analysis may be useful for deciding when to
2.1 g/dL at 28–31 weeks GA, and 1.9 g/dL at start breast milk fortification for VLBWI or how
574 R. Davanzo et al.
Table 11 Nutritional assessment of the high-risk new- Breast pump accessories and milk containers
born infant and the need for human milk fortification should be washed and disinfected with physical
Abnormality (saturated steam) or chemical agents. Milk
Parameter cutoff values expressed in hospital or at home should be col-
Auxological Weight <20 g/day lected in a sterile container. After each milk col-
indexes Length <0.5 cm/week lection, the container should be placed in the
Cranial <0.5 cm/week
coldest part of the refrigerator and kept at 4 C
circumference
Laboratory BUN <5 mg/dL
up to 72–96 h (Slutzah et al. 2010). If not used
tests Blood <4.5 mg/dL immediately, expressed breast milk should be fro-
phosphorus zen ( 20 C) and can be stored for up to 3 (for
Alkaline >450 U/L feeding high-risk infants) or 6 months (for healthy
phosphatase term newborns). Frozen milk can be thawed
slowly in the refrigerator for up to 24 h or quickly
in a water bath (maximum 37 C). After thawing,
to adjust protein fortification, particularly when the milk should be used within 24 h, if kept
the infant does not show adequate growth. refrigerated. Fresh milk should not be refrozen.
Adjustable fortification seems to be more practi-
cal and is calibrated to infant metabolic response,
as measured by blood urea nitrogen (BUN) and,
36.11.10 Human Milk Bank
in general, by other nutritional indexes
(Table 11).
Human milk bank (HMB), or breast milk bank,
While the need for milk fortification during hos-
is a service which collects, screens, processes,
pital stay is unanimously recognized, its use after
and dispenses by prescription human milk
hospital discharge is controversial due to its possible
donated by nursing mothers, who are not biolog-
interference with feeding directly from the breast
ically related to the recipient infant. The milk
(Zachariassen et al. 2011; Young et al. 2013).
provided by milk banking is predominantly a
pool of donated expressed term breast milks,
but some milk banks may also provide preterm
36.11.9 Expression and Storage of
breast milk.
Breast Milk
Holder pasteurization (62.5 C for 30 min) of
banked human milk is the method of choice to
The hospitalized high-risk newborn infant may be
eliminate potential microbiological contaminants.
unable to suck at the breast and so may be separated
Although indispensable, pasteurization alters the
from its mother, possibly for extended periods of
nutritional (5% loss of fat and 4% of protein) and
time. Mothers should start expressing their breast
the biological quality (loss of IgA, lactoferrin,
milk manually or with a milk pump as soon as
lysozyme, IgA, lymphocytes, etc.) (Vieira et al.
possible (i.e., within the first 48 h postpartum).
2011), reducing its protective capacity against
Milk should be expressed at least six times a day.
NEC. Because HMB is a kind of “mature” milk,
Breast milk expression alongside the incubator
it needs to be fortified if given to VLBWIs.
or cot or while looking at the baby’s photograph
has been shown to have a positive psychological
effect and to increase breast milk production.
Breast pumps for simultaneous expression of 36.11.11 Kangaroo Mother Care
both breasts maximize stimulation and save
time. During the first days postpartum, the Kangaroo mother care (KMC) is the practice of
recommended duration of expression is about skin-to-skin contact between the preterm low birth
10–15 min per breast, which can later be pro- weight infant and his/her mother (or father). Dur-
longed until the final drops are expressed. ing KMC, the infant, clad in a diaper, is held in an
36 Human Milk and Formulas for Neonatal Nutrition 575
upright prone position against the bare chest of the KMC implemented as limited sessions with
mother and covered with clothing and/or a blanket mother–infant skin-to-skin contact in kangaroo
and a cap. KMC is effective and beneficial for position for 1–2 h is termed Intermittent Kangaroo
thermal control, breastfeeding, maternal–infant Mother Care (I-KMC) (Davanzo et al. 2013d).
relationship, and the health of preterm low birth Each KMC session should last at least 1 h in
weight and full-term infants. There is mounting order to facilitate the infant’s state of adaptation.
evidence for the benefits of KMC in high-income KMC creates an opportunity for the feeding com-
settings (Table 12) (Davanzo et al. 2013d), and petence of the preterm infant to emerge and spon-
enhanced KMC practice has been strongly taneously promotes breastfeeding.
recommended also in high-tech settings (Nyqvist The decision to practice KMC does not depend
et al. 2010; Boundy et al. 2016). per se on either the degree of neurodevelopment or
The original KMC method, ideally with 24 h/ postgestational age but rather is based on infant
day of mother–infant skin-to-skin care, termed stability and maternal information and readiness.
continuous KMC, was intended as an alternative Parents should be examined for skin infections and
to conventional care in incubators in low-income may need skin cleansing before contact with the
settings. In many NICUs in affluent settings, infant. A recliner chaise lounge is provided to
mothers for comfort, as well as a peaceful, diffusely
lit environment. During I-KMC, correct infant’s
Table 12 Benefits of KMC in high-tech care settings
(Modified from Davanzo et al. 2013d) position should be assessed and vital parameters
monitored (including temperature). Most nursing
Benefits for infant
Prevents hypothermia by warmth transfer from mother to
procedures can be performed during I-KMC,
child including oral/nasal or endotracheal suctioning,
Improves and/or maintains stability even in very preterm feeding tube insertion, parental nutrition adminis-
infants. Heart and respiratory rates show lower variation tration, and i.v. injections. There is no upper time
in oxygen saturation and fewer episodes of apnea and limit for the duration of an I-KMC session, and
bradycardia
there is no evidence that slow is preferable to
Reduces stress, decreasing cortisol release during KMC
rapid and/or casual progression from short to longer
Positive effects on infant sleep patterns as a result of
improved brain maturation and longer sessions, provided the mother enjoys the
Improves neurobehavioral and psychomotor experience and the baby remains stable. Parents can
development sleep or read during sessions.
Decreases pain response in preterm infants during painful
procedures
Benefits for parents
36.11.12 Feeding Competence of the
Improves parent–infant interaction
Preterm Newborn and the
Increases psychological well-being and improves
psychological adaptation and recovery after preterm
Transition from Tube to
delivery Breast
Promotes recovery from postpartum depression
Salivary cortisol decreases in mothers of infants born at Attainment of full oral feeds, via either bottle or
25–33 weeks GA and who practice KMC breast, is considered one of the goals for preterm
Benefits for breastfeeding infants to meet prior to discharge. In many set-
Facilitates access to breast and increases human milk tings, “full oral feeding” is unfairly interpreted as
production
full bottle feeding, not recognizing the fact that the
Increases breastfeeding rate, proportion of exclusive
breastfeeding at NICU discharge, and longer experience of feeding directly at the breast during
breastfeeding duration hospital stay is key to attaining successful
Other possible benefits breastfeeding at and after hospital discharge. Bot-
Facilitates earlier hospital discharge tle feeding is often considered an obvious and
Could be implemented for back transport of high-risk necessary intermediate step along the pathway
preterm infants between hospitals from tube feeding to breastfeeding, based on the
576 R. Davanzo et al.
assumption that it is less energetically expensive possible despite their immature sucking pattern,
than breastfeeding. On the contrary, bottle feeding which is characterized by slow sucking, short
is less physiological for preterm infants, and it sucking bursts with long pauses, and oxygen
may disregard emerging neurodevelopmental desaturation events during feeding. In order to
competences and eventually divert from obtain a satisfactory result with the breastfeed,
breastfeeding. In NICUs, unjustified delays in the mother–infant couple should be offered ade-
and restrictions on breastfeeding often occur due quate information and support, and breast milk
to persistent nonevidence-based opinions about should be expressed prior to the breastfeed, thus
the feeding capacity of preterm infants. facilitating latch on with the technique known as
Although swallowing is first detected at 11 “sucking at the emptied breast.” Eventually, pre-
weeks gestation, coordinated suck–swallow is term infants can be frequently fed small milk
commonly, but dogmatically, believed not to be volumes in combination with another adequate
present until 32–24 weeks and even then consid- complementary feeding method such as tube feed-
ered to be immature. Swallowing and respiration ing. Preterm infants should be given very small
must be coordinated since the two processes share volume, frequent (12 better than 8 per day) feeds
the same channel, that is, the pharynx. In preterm for a more physiological feeding pattern. This
infants, the difficulty in coordinating swallowing “preterm pattern” should be adopted in routine
and respiration during the transition from tube to clinical practice whenever possible and sustain-
oral feeding may create a significant barrier to the able. Preterm infants show a gradual transition, at
establishment of full breastfeeding. In addition, varying postconceptual ages, to a mature sucking
weak sucking at the breast can complicate breast pattern, as observed also in healthy term infants.
milk production. In other words, for preterm infants, successful
In clinical practice, the decision to commence breastfeeding should be defined only as the ability
direct breastfeeds is based on various categories of to consume a sufficient daily milk volume, inde-
long-standing guiding principles. These catego- pendent of the sucking pattern, to support
ries mostly refer to gestational age (GA), non- sustained growth. Reasonable expectations about
nutritive sucking of the pacifier, capability to the normal breastfeed of a preterm infant can help
feed at the bottle, and a repertoire of readiness to promote the breastfeeding process and avoid
cues from an infant that has been observed to be hasty decisions by health professionals, as well as
alert and active and makes sucking motions with frustration in mothers.
his/her mouth. Although checklists assessing the The studies by Pineda (2011) and Nyqvist
readiness cues of preterm infants are commonly (2008) have demonstrated that the feeding com-
used in NICUs in the management of feeding, we petences of preterm newborns can emerge much
must admit that there is no evidence that they can earlier than expected, although the mean post-
reliably predict the successful introduction of oral conceptional age (PCA) for a full breastfeed
(breast or bottle) feeding. Moreover, as it concerns remains fixed at around 33 weeks and the mean
the GA category, we must observe that consistent PCA for full breastfeeding at around 36 weeks
with individual variability, infant breastfeeding (Table 13).
competence can emerge across a wide spectrum Table 14 presents the relative gestational ages
of gestational ages rather than at any specific time. for the emergence and development of feeding
Exclusive breastfeeding in preterm infants is competence. The gestational ages reported in the
Table 13 Variability of the emergence of oromotor competence in the preterm infant (Pineda 2011; Nyqvist 2008)
Feeding competence First attempt to the breast First breastfeed Full breastfeeding
PCAa (weeks; range) 31; 29.6–33.6 33; 30–37 36; 33–39
Study (author and year) Pineda (2011) Nyqvist (2008)
a
PCA denotes postconceptional age
36 Human Milk and Formulas for Neonatal Nutrition 577
Table 14 Steps from tube feeding to breastfeeding (The minimal age at onset of each competence is given in the shaded
box) (Modified from Davanzo et al. 2014)
GA (weeks) 24–25 26 27 28 29 30 31 32 33 34 35
Oropharyngeal colostrum
Minimal enteral feeding
Kangaroo mother care +/
Nonnutritive sucking
Initial attempts at the breast +/
Syringe feeding of expressed breast +/ +/ +/
milk
First feed at the breast
Cup feeding
Bottle feeding +/
Semi-demand feeding
Full breastfeeding +/ +/
table do not indicate the recommended time to on exclusive enteral nutrition with at least one
offer a feeding practice but rather are intended as successful breastfeeding in the previous 24 h
the minimal age for the emergence of a specific and an adequate weight gain in the previous
competence, given the health conditions of the days (Davanzo et al. 2014). Mothers who are
preterm infant and optimal facilitation by existing candidates for semi-demand feeding should
NICU organizational policies and protocols. Pro- have a basic breast milk production, be
viding mothers the opportunity of having unlim- informed about the nutritional plan for their
ited time with their babies and to engage in preterm infants, and be motivated to breastfeed
prolonged kangaroo mother care without their infants and to provide their extended pres-
unjustified restrictions is a relevant prerequisite ence in the NICU granted during the semi-
for breastfeeding experience and success. There- demand feeding period (minimum 6 h). During
fore, the table does not represent a standardized each semi-demand session, mothers should test-
approach to testing infant skills in the weigh the infant and record the breast milk
breastfeeding process; instead, it depicts the flex- intake at each feed. Although the precision of
ible sequence of highly individualized develop- this method has been criticized, test weighing is
ment of feeding capacities in preterm infants. considered more accurate and reliable than clin-
ical indicators in feeding preterm infants. Dur-
ing the session, the infant may be fed ad
36.11.13 Semi-demand Feeding libitum. The use of pacifiers and dextrose solu-
tion is discouraged during the session as long as
Feeding preterm infants in response to their the mother is present. At the end of the session,
hunger and satiation cues, rather than at sched- the total amount of milk taken should be deter-
uled intervals and with a predefined amount of mined to assess whether supplementation is
milk, is referred to as semi-demand feeding. necessary. If the infant does not ingest the
Semi-demand feeding for preterm infants dur- total prescribed milk volume orally over the
ing the transition from scheduled to full demand 6-h session, supplementation should be given
feeding in response to their hunger and satiation by gavage and divided in nightly feeds.
cues has been proposed to promote the estab- A predischarge 48-h period of intensive
lishment of self-regulated oral feeding, without rooming-in in the NICU for the preterm infant
affecting growth, risk of hypoglycemia, and and her/his mother may be a useful practice to
length of hospital stay. The protocol can be establish breastfeeding and to better define the
applied for 33–36 weeks PCA preterm infants, feeding plan at discharge.
578 R. Davanzo et al.
Once the infant has fed the total milk volume Table 15 Modified from WHO document of acceptable
required in a 24-h period, without any gavage, it is medical reasons for use of breast milk substitutes (WHO,
UNICEF 2009)
considered to have attained “full oral feeding.” At
this point, the infant may be permitted to feed ad Infant conditions
libitum in the last few days before hospital Infants who should not receive breast milk or any other
milk except special formula
discharge.
Classic galactosemia: special galactose-free formula
Maple syrup urine disease: special formula free of
leucine, isoleucine, and valine
36.12 Infant Formula Phenylketonuria: a special phenylalanine-free formula
(some breastfeeding under careful monitoring is possible)
36.12.1 General Principles Infants for whom breast milk remains the best feeding
option but who may need other food in addition to breast
milk for a limited period
Even though the best health choice for both new- Very low birth weight (<1,500 g)
born and mother is exclusive breastfeeding, this Infants born <32 weeks of gestation
may not always be achievable. Formula feeding Newborn infants at risk of hypoglycemia because of
should be considered particularly when (1) there impaired metabolic adaptation or increased glucose
demand (preterms, small for gestational age, intrapartum
are medical contraindications against
hypoxic/ischemic stress, newborns born to diabetic
breastfeeding, (2) true low breast milk production mothers) if their blood sugar fails to respond to optimal
is present (see related section), and (3) the fully breastfeeding or breast milk feeding
informed mother has decided that bottle feeding is Maternal conditions
the better alternative. Medical contraindication to Maternal conditions that may justify permanent
breastfeeding may be defined as “acceptable med- avoidance of breastfeeding
ical reasons for the use of breast-milk substitutes.” HIV infection: if replacement feeding is acceptable,
feasible, affordable, sustainable, and safe
Several health conditions (WHO, UNICEF 2009)
Maternal conditions that may justify temporary
(Table 15) related to the health of the infant or the avoidance of breastfeeding
mother may justify avoidance of breastfeeding, Severe illness that prevents a mother from caring for her
temporarily or permanently. Whenever stopping infant, e.g., sepsis
breastfeeding is considered, the benefits of Herpes simplex virus type 1 (HSV-1): direct contact
breastfeeding should be weighed against the between lesions on the mother’s breasts and the infant’s
mouth should be avoided until all active lesions have
risks posed by the specific conditions listed in resolved
the table. Maternal medications judged to be hazardous while
When prescribing formulas, health profes- breastfeeding
sionals should educate parents on adequate (safe Maternal conditions during which breastfeeding can
still continue, although health problems may be of
and correct) bottle preparation, particularly when
concern
powdered milk is used (FAO, WHO 2007). Sum-
Breast abscess: breastfeeding should continue on the
marizing, parents should check the “best before” unaffected breast; feeding from the affected breast can
date and the condition of the container, wash their resume once treatment has started
hands before preparing the formula, dilute the Hepatitis B: infants should be given im hepatitis B
powdered formula with water (heated to at least vaccine within the first 48 h or as soon as possible
thereafter and im Hepatitis B immune globulins (HBIG)
70 C to the volume according to the manufac-
Hepatitis C
turer’s or the doctor’s instructions), offer the bottle Mastitis: if breastfeeding is very painful, milk should be
after the formula has cooled to a temperature removed by expression to prevent progression of the
appropriate for consumption, safely store condition
unopened formula containers in a cool dry envi- Tuberculosis: mother and baby should be managed
according to national tuberculosis guidelines substance
ronment, and keep diluted formula in a refrigera-
abuse
tor at 4 C until use.
36 Human Milk and Formulas for Neonatal Nutrition 579
Since powdered infant formulas are usually not the food industry have led to the development of
supplied sterile, they may be contaminated by bac- new formulas more similar to human milk.
teria. Cronobacter species, previously known as Advances in molecular biology may open the
Enterobacter sakazakii, is one of the most harmful way for the large-scale production of recombinant
and is considered a potential causative agent of human milk proteins, including bioactive sub-
sepsis and meningitis in newborns and preterm stances and functional nutrients. Nevertheless,
infants during the first weeks of life. There is wide the need, safety, and efficacy of introducing
consensus that a powdered formula should be used these substances into infant formulas will need
immediately after being diluted or, if not, stored at to be carefully assessed before they can be used
<5 C until use. Current knowledge suggests the in infant nutrition.
use of hot water (70 C) to dilute powdered infant Currently available data are still inadequate to
formula in order to prevent Cronobacter contami- reach a consensus on the mandatory supplemen-
nation and growth (Silano et al. 2016). The use of tation of infant formula with components that
liquid formula (sterilized after bottling) may be a have been identified in human milk, are recog-
more convenient option, especially for preterm nized to have a relevant biological and immuno-
infants and in the first month of life. logical effect, and are already included in many
Contamination of infant formula. There have marketed products. This is the case for DHA/
been recent reports of contamination of infant ARA (Sun et al. 2015), nucleotides (European
formula, including the epidemic of melamine con- Food Safety Authority (EFSA) 2014), probiotics
tamination of baby formula in China associated and prebiotics (European Food Safety Authority
with the development of urinary tract stones. Such (EFSA) 2014; Braegger et al. 2011), and taurine
episodes are not expected to occur when rigorous (European Food Safety Authority (EFSA) 2014),
standards are followed and comprehensive testing which do not per se provide the same health
regimens are implemented. benefits to the formula-fed infant as human milk
to the breastfed infant.
Given these uncertainties, the European Food
36.12.2 Nutritional Characteristics of Safety Authority (EFSA) Panel on Dietetic Prod-
Starting Formula ucts, Nutrition, and Allergies (DNA) has issued a
document on the essential composition of infant
When breastfeeding is not possible, the first alter- formulas (Table 16) (European Food Safety
native is a cow milk-based formula adapted to Authority (EFSA) 2014).
human infant needs. Formulas are used for infant Energy. The EFSA suggests an energy density
nutrition for several months. Starting formulas, of a formula between 60 and 70 kcal/100. The
for example, are indicated until 6 months of age, mean formula intake in the first month of age is
but their composition remains unchanged. In around 150 mL/kg/day. The estimated energy
striking contrast, the nutrient composition of requirement for physiological weight gain in
breast milk changes continuously during lactation healthy infants is 115 kcal/kg/day in the first
and most dramatically during the early days. month of life, then 100 kcal/kg/day at 3 months
Except for follow-up formulas, which are of age (Butte et al. 2000).
marketed in Europe for the nutrition of infants Lipids. Lipids represent 40–50% of the daily
6–12 months of age, there have been no system- energy intake for a formula-fed infant. The
atic attempts to graduate the change in the com- recommended intake is 4.4–6.0 g/100 kcal. The
position of infant formula as occurs naturally in endogenous synthesis of LC- PUFAs (chain length
breast milk. >18 carbons) may be insufficient, leading to low
Nutritional research on the novel components DHA content in plasma, red blood cell membranes,
of human milk and new technologies applied by and cerebral cortex cells (Lauritzen et al. 2001).
580 R. Davanzo et al.
Table 16 Compositional requirements of infant starting sources can be cows’ milk proteins (also in hydro-
formulas for energy and selected nutrients according to the lyzed form) and soy protein isolates. There is some
EFSA panel on NDA
evidence that bovine lactoferrin is highly homolo-
Compositional gous to human lactoferrin; however, few formulas
Component in formula requirement
marketed in Italy contain this immunomodulating
Energy (kcal/100 ml) 60–70
protein.
Total fat (g/100 kcal) 4.4–6
Carbohydrates. These nutrients are the second
Linoleic acid (LA) (mg/100 kcal) 500–1,200
Alpha-linolenic acid (ALA) (mg/ 50–100
source of energy intake after lipids. The minimum
100 kcal) recommended amount is 9.0 g/100 kcal and the
Docosahexaenoic acid (DHA) 20–50 maximum 14 g/100 kcal. Lactose (at least 4.5 g/
(mg/100 kcal) 100 kcal) is the preferable carbohydrate in formu-
Protein (g/100 kcal) 1.8–2.5 las, whereas sucrose and fructose should not be
Total carbohydrates (g/100 kcal) 9–14 added as they may increase the risk of fructose
Lactose (g/100 kcal) >4.5 intolerance and saccharase deficiency in infants.
Oligosaccharides (g/100 ml) 0.8 Due to the marked increase in osmolality, the addi-
Calcium (mg/100 kcal) 50
tion of glucose to infant formula is also discour-
Phosphorus (mg/100 kcal) 25–30
aged, but it is permitted for infant formulas
Magnesium (mg/100 kcal) 5
containing hydrolyzed protein to counteract the
Sodium (mg/100 kcal) 25
bitter taste. Maltose and maltodextins are two
Chloride (mg/100 kcal) 60
Potassium (mg/100 kcal) 80
other suitable carbohydrates for infant formula.
Iron (mg/100 kcal) 0.3 Starches may be added up to 30% of total carbo-
Vitamin A (μg retinol equivalents 70 hydrates (2 g/100 mL). Human milk oligosaccha-
or RE/100 kcal) rides (HMOs) constitute the third largest
Vitamin D (μg/100 kcal) 2 component after lactose and lipids in human milk
Vitamin E (mg alpha-tocopherol 0.6 and have several effects. The EFSA recommends
(100 kcal) 0.8 g/100 kcal. A combination of 90% galacto-
Vitamin K (μg/100 kcal) 1 oligosaccharides (GOS) and 10% fructo-oligosac-
Inositol (mg/100 kcal) 4 charides (FOS) is suggested to increase
Carnitine (mg/100 kcal) 1.2
bifidobacteria and lactobacilli and to reduce stool
pH and consistency (Ziegler et al. 2007). However,
the clinical significance of this finding is still
Recognizing the important role LC-PUFAs play unclear (Braegger et al. 2011).
in the development and maturation of the neo-
natal nervous system, the European Society for
Paediatric Gastroenterology, Hepatology, and 36.12.3 Special Formulas
Nutrition (ESPGHAN) (unlike the EFSA) rec-
ommends their addition to infant formula (Euro- Cow’s milk formula is suitable for most full-term
pean Food Safety Authority (EFSA) 2014). newborns. Moreover, special formulas are avail-
Proteins. Healthy infants need no more than 12% able for infants with special nutritional needs
of energy from proteins. Some studies have shown a and/or specific diseases. In this section, we will
positive association between early protein intake focus on some selected formulas to be used
and later obesity: a higher body mass index during the first 6 months of life: soy formula,
([BMI] weight in kg divided by height in m 2) hydrolyzed formula, elemental formula, and
was observed in the high-protein as compared to nutrient-enriched formula (preterm formula and
the low-protein group (Michaelsen et al. 2012; Gun- postdischarge formula). The composition of and
ther et al. 2007). The EFSA recommends a mini- indications for special formulas are presented in
mum protein content of 1.8 g/100 kcal and a Table 17 (Amesz et al. 2010; Morgan et al.
maximum no higher than 2.5 g/100 kcal. Protein 2012).
36 Human Milk and Formulas for Neonatal Nutrition 581
Table 17 Composition in energy and selected nutrients and indications for the use of special formulas (Amesz et al.
2010; Morgan et al. 2012)
Type of special formula
Term
(starting
formula) Preterm Post-discharge Hydrolyzed Hypercaloric
Indications Healthy Preterm (<1,500 g) Possibly for infants Food allergy, Neurologic
term and continued until discharged with lower malabsorption conditions,
late 3,500 g or 40 weeks than normal weight for disorders fluid
preterm postconceptual age postconceptional age restriction
newborns
Energy (kcal/ 67–68 80–90 72–74 67 100
100 mL)
Proteins (g/ 1.4–1.5 2.2–2.4 1.8–1.9 1.8 2.6
100 mL)
Lipids (g/ 3.6 4.3 4.0 3.4 5.4
100 mL)
Carbohydrates 7.3 8.6 7.6 7.2 10.3
(g/100 mL)
Calcium (mg/ 35–54 100–140 70–80 65.6 100
100 mL)
Phosphorus 30 75 50 47.1 50
(mg/100 mL)
Special formulas for managing inborn errors given to preterm infants. Finally, the possible
of metabolism and formula for severe infant interaction of soy-based formula with thyroxine
cholestasis are outside the scope of the present replacement therapy should be considered in chil-
review. dren with thyroid disorders.
Soy formula. Soy formulas contain a protein Hydrolyzed formula. This is a cow’s milk for-
(soy) and carbohydrates (either glucose or mula that has been processed to break down the
sucrose) different from milk-based formulas. proteins into smaller particles. There is limited
According to the American Academy of Pediat- evidence that as compared with cow’s milk for-
rics (Bhatia et al. 2008), the only real indications mula, the use of hydrolyzed formula reduces
for soy formula use are for infants with congenital infant risk of allergy. Moreover, its use for sup-
galactosemia, for use by families who are strict plementary feeds in maternity hospitals during the
vegans, or for infants who are truly lactose intol- first days of life has not been demonstrated effec-
erant. The safety of soy infant formula has been a tive in preventing allergy. Conversely, infants
topic of continuing debate because it contains with proven cow’s milk allergy who are not
isoflavones, naturally occurring compounds breastfed should be given hydrolyzed infant
found primarily in beans and other legumes. formula.
These isoflavones are referred to as Amino acid-based formula (elemental for-
phytoestrogens because they are found in plants mula). This formula contains component nutrients
(phyto) and because of their ability to act like the including individual amino acids, making it easily
hormone estrogen in the body. Nevertheless, no digestable. Amino acid-based formulas are most
deleterious hormonal effects have been detected commonly indicated in infants with multiple food
in growing infants fed soy formula. Although intolerances and malabsorption disorders, includ-
normal growth has been reported in term new- ing the short bowel syndrome.
borns, less weight gain and osteopenia have been Goat milk formula. Although popular for the
documented among preterm infants fed soy for- treatment of allergy, it is not recommended for
mula. Consequently, soy formula should not be preventing or treating allergic disease.
582 R. Davanzo et al.
Nutrient-enriched formulas. Preterm formu- evidence and recommendations. J Perinat Med 38(4):
las and postdischarge formula (PDF) were 347–351. https://doi.org/10.1515/JPM.2010.064
Assad M, Elliott MJ, Abraham JH (2015) Decreased cost
developed to meet the higher requirements of and improved feeding tolerance in VLBW infants fed
energy, protein calcium, phosphorus, and mag- an exclusive human milk diet. J Perinatol 36(3):
nesium in preterm infants. Their nutritional 216–220. https://doi.org/10.1038/jp.2015.168
composition is an intermediate between term Ballard O, Morrow AL (2013) Human milk composition:
nutrients and bioactive factors. Pediatr Clin North
formula and preterm formula. Preterm infants, Am 60(1):49–74. https://doi.org/10.1016/j.pcl.2012.
particularly the most immature, are often 10.002
growth-restricted at hospital discharge. Feeding Bauer J, Gerss J (2011) Longitudinal analysis of macronu-
infants after hospital discharge with nutrient- trients and minerals in human milk produced by
mothers of preterm infants. Clin Nutr 30:215–220
enriched formula rather than standard term for- Bertini G, Breschi R, Dani C (2015) Physiological weight
mula is expected to facilitate “catch-up” growth loss chart helps to identify high-risk infants who need
and improve development. Nevertheless, feed- breastfeeding support. Acta Paediatr 104(10):
ing preterm infants with PDF rather than term 1024–1027
Bhatia J, Greer F, American Academy of Pediatrics Com-
formula does not carry clear short- or long-term mittee on Nutrition (2008) Use of soy protein-based
benefit (Young et al. 2012) probably because ad formulas in infant feeding. Pediatrics 12(5):
libitum fed infants reduce their intake relative 1062–1068. https://doi.org/10.1542/peds.2008-0564
to the calorie density of the milk. Current evi- Boundy EO, Dastjerdi R, Spiegelman D, Fawzi WW,
Missmer SA, Lieberman E, Kajeepeta S, Wall S,
dence does not support prescribing “post- Chan GJ (2016) Kangaroo mother care and neonatal
discharge formula” for preterm infants outcomes: a meta-analysis. Pediatrics 137(1):1–16.
following hospital discharge, whereas feeding https://doi.org/10.1542/peds.2015-2238, Epub 2015
preterm infants with “preterm formula” follow- Dec 23. Review
Boyle EM, Johnson S, Manktelow B, Seaton SE, Draper
ing hospital discharge may increase growth ES, Smith LK, Dorling J, Marlow N, Petrou S, Field DJ
rates and is recommended for the most prema- (2015) Neonatal outcomes and delivery of care for
ture newborn infants (BW <1,500 g) at least infants born late preterm or moderately preterm: a
until 40 weeks postconceptual age. prospective population-based study. Arch Dis Child
Fetal Neonatal Ed 100(6):F479–F485. https://doi.org/
Hypercaloric formula. This type of formula 10.1136/archdischild-2014-307347
provides over 1 kcal/mL and should be given Braegger C, Chmielewska A, Decsi T, Kolacek S,
only to infants requiring both higher energy intake Mihatsch W, Moreno L, Pieścik M, Puntis J, Shamir
and fluid restriction. Hypercaloric formula can be R, Szajewska H, Turck D, van Goudoever J,
ESPGHAN Committee on Nutrition (2011) Supple-
given to infants with severe perinatal brain dam- mentation of infant formula with probiotics and/or pre-
age that have higher energy and protein require- biotics: a systematic review and comment by the
ments (120% recommended average intake) in ESPGHAN committee on nutrition. J Pediatr
their first postnatal year in order to promote Gastroenterol Nutr 52(2):238–250. https://doi.org/
10.1097/MPG.0b013e3181fb9e80
brain and corticospinal tract growth (Dabydeen Brecht KF, Goelz R, Bevot A, Krägeloh-Mann I, Wilke M,
et al. 2008). Lidzba K (2015) Postnatal human cytomegalovirus
infection in preterm infants has long-term neuropsy-
chological sequelae. J Pediatr 166(4):834–839. https://
doi.org/10.1016/j.jpeds2014.11.002
References Butte NF, Wong WW, Hopkinson JM, Heinz CJ, Mehta
NR, Smith EO (2000) Energy requirements derived from
Amesz EM, Schaafsma A, Cranendonk A, Lafeber HN total energy expenditure and energy deposition during
(2010) Optimal growth and lower fat mass in preterm the first 2 y of life. Am J Clin Nutr 72(6):1558–1569
infants fed a protein-enriched postdischarge formula. J Cattaneo A, Ronfani L, Burmaz T, Quintero-Romero S,
Pediatr Gastroenterol Nutr 50(2):200–207. https://doi. Macaluso A, Di Mario S (2006) Infant feeding and cost
org/10.1097/MPG.0b013e3181a8150d of health care: a cohort study. Acta Paediatr 95(5):
Arslanoglu S, Ziegler EE, Moro GE, World Association of 540–546
Perinatal Medicine Working Group On Nutrition Centers for Disease Control and Prevention (2013) Strate-
(2010) Donor human milk in preterm infant feeding: gies to prevent obesity and other chronic diseases: the
36 Human Milk and Formulas for Neonatal Nutrition 583
CDC guide to strategies to support breastfeeding Davanzo R, Brovedani P, Travan L, Kennedy J, Crocetta A,
mothers and babies. U.S. Department of Health and Sanesi C, Strajn T, De Cunto A (2013d) Intermittent
Human Services, Atlanta, http://www.cdc.gov/ kangaroo mother care: a NICU protocol. J Hum Lact
breastfeeding/pdf/BF-Guide-508.PDF 29(3):332–338
Cetin I, Assandro P, Massari M, Sagone A, Gennaretti R, Davanzo R, Strajn T, Kennedy J, Crocetta A, De Cunto A
Donzelli G, Knowles A, Monasta L, Davanzo R, Work- (2014) From tube to breast: the bridging role of semi-
ing Group On Breastfeeding, Italian Society Of Perinatal demand breastfeeding. J Hum Lact 30(4):405–409.
Medicine And Task Force On Breastfeeding, Ministry https://doi.org/10.1177/0890334414548697
Of Health, Italy (2014) Breastfeeding during pregnancy: Davanzo R, Romagnoli C, Corsello G (2015a) Position
position paper of the Italian Society of Perinatal Medi- statement on breastfeeding from the Italian Pediatric
cine and the Task Force on Breastfeeding, Ministry of Societies. Ital J Pediatr 41:80. https://doi.org/10.1186/
Health, Italy. J Hum Lact 30:20–22 s13052-015-0191-x
Chen X, Chen J, Wen J, Xu C, Zhang S, Zhou YH, Hu Y Davanzo R, De Cunto A, Paviotti G, Travan L, Inglese S,
(2013) Breastfeeding is not a risk factor for mother- Brovedani P, Crocetta A, Calligaris C, Corubolo E,
to-child transmission of hepatitis B virus. PLoS Dussich V, Verardi G, Causin E, Kennedy J, Marrazzo
One 8(1), e55303. https://doi.org/10.1371/journal. F, Strajn T, Sanesi C, Demarini S (2015b) Making the
pone.0055303 first days of life safer: preventing sudden unexpected
Chowning R, Radmacher P, Lewis S, Serke L, Pettit N, postnatal collapse while promoting breastfeeding. J
Adamkin DH (2015) A retrospective analysis of the Hum Lact 31(1):47–52
effect of human milk on prevention of necrotizing Davanzo R, Bua J, De Cunto A, Farina ML, De Ponti F,
enterocolitis and postnatal growth. J Perinatol 36(3): Clavenna A, Mandrella S, Sagone A, Clementi M (2016)
221–224. https://doi.org/10.1038/jp.2015.179 Advising mothers on the use of medications during
Cleminson J, Oddie S, Renfrew MJ, McGuire W (2015) breastfeeding: a need for a positive attitude. J Hum Lact
Being baby friendly: evidence-based breastfeeding 32(1):15–19. https://doi.org/10.1177/0890334415595513
support. Arch Dis Child Fetal Neonatal Ed 100: De Bortoli J, Amir LH (2016) Is onset of lactation delayed
F173–F178 in women with diabetes in pregnancy? A systematic
Cova MA, Stacul F, Quaranta R, Guastalla P, Salvatori G, review. Diabet Med 33(1):17–24
Banderali G, Fonda C, David V, Gregori M, Zuppa AA, de Onis M, Garcia C, Onyango AW, et al (2006) WHO
Davanzo R (2014) Radiological contrast media in the Child Growth Standards based on length/height, weight
breastfeeding woman: a position paper of the Italian and age. Acta Paediatr Suppl 450:76
Society of Radiology (SIRM), the Italian Society of de Silva A, Jones PW, Spencer SA (2004) Does human
Paediatrics (SIP), the Italian Society of Neonatology milk reduce infection rates in preterm infants? A sys-
(SIN) and the Task Force on Breastfeeding, Ministry of tematic review. Arch Dis Child Fetal Neonatal Ed 89(6):
Health, Italy. Eur Radiol 24(8):2012–2022 F509–F513
Dabydeen L, Thomas JE, Aston TJ, Hartley H, Sinha SK, Department of Health and Human Services (2011) The
Eyre JA (2008) High-energy and -protein diet increases surgeon general’s call to action to support
brain and corticospinal tract growth in term and preterm breastfeeding. Washington, DC. http://www.ncbi.nlm.
infants after perinatal brain injury. Pediatrics 121: nih.gov/books/NBK52687/
148–156 European Food Safety Authority (EFSA) (2014) EFSA
Davanzo R, Pastore S (2011) Promoting mother’s milk Panel on Dietetic Products, Nutrition and Allergies
use in very low birth weight infants: when nutritional (NDA). Scientific Opinion on the essential composition
hierarchy deals with the professional value system. J of infant and follow on formulae. EFSA J 12(7):3760
Hum Lact 27(4):329–330. https://doi.org/10.1177/ Filleron A, Lombard F, Jacquot A, Jumas-Bilak E, Rodière
0890334411422705 M, Cambonie G, Marchandin H (2014) Group B strep-
Davanzo R, Cannioto Z, Ronfani L, Monasta L, Demarini S tococci in milk and late neonatal infections: an analysis
(2013a) Breastfeeding and neonatal weight loss in healthy of cases in the literature. Arch Dis Child Fetal Neonatal
term infants. J Hum Lact 29(1):45–53 Ed 99:F41–F47. https://doi.org/10.1136/archdischild-
Davanzo R, De Cunto A, Travan L, Bacolla G, Creti R, 2013-304362
Demarini S (2013b) To feed or not to feed? Case Flidel-Rimon O, Friedman S, Lev E, Juster-Reicher A,
presentation and best practice guidance for human Amitay M, Shinwell ES (2004) Early enteral feeding
milk feeding and group B streptococcus in developed and nosocomial sepsis in very low birthweight infants.
countries. J Hum Lact 29:452–457. https://doi.org/ Arch Dis Child Fetal Neonatal Ed 89(4):F289–F292
10.1177/0890334413480427 Gagneur A, Héry-Arnaud G, Croly-Labourdette S,
Davanzo R, Monasta L, Ronfani L, Brovedani P, Demarini Gremmo-Feger G, Vallet S, Sizun J, Quentin R,
S, Breastfeeding in Neonatal Intensive Care Unit Study Tandé D (2009) Infected breast milk associated with
Group (2013c) Breastfeeding at NICU discharge: a late-onset and recurrent group B streptococcal infection
multicenter Italian study. J Hum Lact 29(3):374–380. in neonatal twins: a genetic analysis. Eur J Pediatr
https://doi.org/10.1177/0890334412451055 168:1155–1158
584 R. Davanzo et al.
Goelz R, Meisner C, Bevot A, Hamprecht K, Kraegeloh- Cow’s milk contamination of human milk purchased
Mann I, Poets CF (2013) Long-term cognitive and via the internet. Pediatrics 135:e1157–e1162. https://
neurological outcome of preterm infants with postna- doi.org/10.1542/peds.2014-3554
tally acquired CMV infection through breast milk. Arch Klingenberg C, Embleton ND, Jacobs SE, O’Connell LA,
Dis Child Fetal Neonatal Ed 98:F430–F433. https:// Kuschel CA (2012) Enteral feeding practices in very
doi.org/10.1136/archdischild-2012-303384 preterm infants: an international survey. Arch Dis Child
Gunkel J, de Vries LS, Jongmans M, Koopman-Esseboom Fetal Neonatal Ed 97(1):F56–F61. https://doi.org/
C, van Haastert IC, Eijsermans MCJ et al (2018) Out- 10.1136/adc.2010.204123
come of preterm infants with postnatal cytomegalovi- Kurath S, Resch B (2010) Cytomegalovirus and transmis-
rus infection. Pediatrics 141(2). pii: e20170635. https:// sion via breast milk: how to support breast milk to
doi.org/10.1542/peds.2017-0635 premature infants and prevent severe infection? Pediatr
Gunther AL, Remer T, Kroke A, Buyken AE (2007) Early Infect Dis J 29:680–681
protein intake and later obesity risk: which protein Lauritzen L, Hansen HS, Jørgensen MH, Michaelsen KF
sources at which time points throughout infancy and (2001) The essentiality of long chain n-3 fatty acids in
childhood are important for body mass index and body relation to development and function of the brain and
fat percentage at 7 y of age? Am J Clin Nutr retina. Prog Lipid Res 40:1–94
86:1765–1772 Lee J, Kim HS, Jung YH, Choi KY, Shin SH, Kim EK,
Harmsen MC, Swart PJ, de Béthune MP, Pauwels R, De Choi JH (2015) Oropharyngeal colostrum administra-
Clercq E, The TH, Meijer DK (1995) Antiviral effects tion in extremely premature infants: an RCT. Pediatrics
of plasma and milk proteins: lactoferrin shows potent 135(2):e357–e366. https://doi.org/10.1542/peds.2014-
activity against both human immunodeficiency virus 2004
and human cytomegalovirus replication in vitro. J Luan NN, Wu QJ, Gong TT, Vogtmann E, Wang YL, Lin B
Infect Dis 172:380–388 (2013) Breastfeeding and ovarian cancer risk: a meta-
Hay WW Jr (2008) Strategies for feeding the preterm analysis of epidemiologic studies. Am J Clin Nutr 98(4):
infant. Neonatology 94(4):245–254. https://doi.org/ 1020–1031. https://doi.org/10.3945/ajcn.113.062794
10.1159/000151643 Lucas A, Bloom SR, Aynsley-Green A (1986) Gut hor-
Hayashi S, Kimura H, Oshiro M, Kato Y, Yasuda A, Suzuki mones and ‘minimal enteral feeding’. Acta Paediatr
C, Watanabe Y, Morishima T, Hayakawa M (2011) Scand 75(5):719–723
Transmission of cytomegalovirus via breast milk in Maayan-Metzger A, Avivi S, Schushan-Eisen I, Kuint J
extremely premature infants. J Perinatol 31(6): (2012) Human milk versus formula feeding
440–445. https://doi.org/10.1038/jp.2010.150 among preterm infants: short-term outcomes. Am J
Herlenius E, Kuhn P (2013) Sudden unexpected postnatal Perinatol 29(2):121–126. https://doi.org/10.1055/s-
collapse of newborn infants: a review of cases, defini- 0031-1295652
tions, risks, and preventive measures. Transl Stroke Res McNinch A, Busfield A, Tripp J (2007) Vitamin K defi-
4:236–247 ciency bleeding in Great Britain and Ireland: British Pae-
Holmes AV, McLeod AY, Bunik M (2013) ABM clinical diatric Surveillance Unit Surveys, 1993-94 and 2001-02.
protocol #5: peripartum breastfeeding management for Arch Dis Child 92(9):759–766, Epub 2007 May 30
the healthy mother and infant at term, revision 2013. Mead MN (2008) Contaminants in human milk: weighing
Breastfeed Med 8(6):469–473. https://doi.org/10.1089/ the risks against the benefits of breastfeeding. Environ
bfm.2013.9979 Health Perspect 116:A427–A434
Jensen D, Wallace S, Kelsay P (1994) LATCH: a Meier PP, Patel AL, Bigger HR, Rossman B, Engstrom JL
breastfeeding charting system and documentation (2013) Supporting breastfeeding in the neonatal
tool. J Obstet Gynecol Neonatal Nurs 23(1):27–32 intensive care unit: Rush Mother’s Milk Club as a
Johnston M, Landers S, Noble L, Szucs K, Viehmann L case study of evidence-based care. Pediatr Clin North
(2012) Breastfeeding and the use of human milk. Sec- Am 60(1):209–226. https://doi.org/10.1016/j.pcl.2012.
tion on Breastfeeding. Pediatrics 129(3):e827–e841. 10.007
https://doi.org/10.1542/peds.2011-3552. Epub 2012 Meinzen-Derr J, Poindexter B, Wrage L, Morrow AL, Stoll
Feb 27 B, Donovan EF (2009) Role of human milk in
Joint WHO/UNICEF statement (1989) Protecting, promot- extremely low birth weight infants’ risk of necrotizing
ing, and supporting breastfeeding: the special role of enterocolitis or death. J Perinatol 29(1):57–62. https://
maternity services. WHO, Geneva, http://www.who.int/ doi.org/10.1038/jp.2008.117
nutrition/publications/infantfeeding/9241561300/en/ Michaelsen KF, Larnkjær A, Mølgaard C (2012) Amount
Keim SA, Hogan JS, McNamara KA, Gudimetla V, Dillon and quality of dietary proteins during the first two years
CE, Kwiek JJ, Geraghty SR (2013) Microbial contam- of life in relation to NCD risk in adulthood. Nutr Metab
ination of human milk purchased via the Internet. Pedi- Cardiovasc Dis 22:781–786
atrics 132(5):e1227–e1235. https://doi.org/10.1542/ Moltó-Puigmartí C, Castellote AI, Carbonell-Estrany X,
peds.2013-1687 López-Sabater MC (2011) Differences in fat content
Keim SA, Kulkarni MM, McNamara K, Geraghty SR, and fatty acid proportions among colostrum, transitional,
Billock RM, Ronau R, Hogan JS, Kwiek JJ (2015) and mature milk from women delivering very preterm,
36 Human Milk and Formulas for Neonatal Nutrition 585
preterm, and term infants. Clin Nutr 30(1):116–123. Slutzah M, Codipilly CN, Potak D, Clark RM, Schanler RJ
https://doi.org/10.1016/j.clnu.2010.07.013 (2010) Refrigerator storage of expressed human milk in
Morgan JA, Young L, McCormick FM, McGuire W (2012) the neonatal intensive care unit. J Pediatr 156(1):26–28
Promoting growth for preterm infants following Soukka H, Rantakokko-Jalava K, Vähäkuopus S,
hospital discharge. Arch Dis Child Fetal Neonatal Ed Ruuskanen O (2010) Three distinct episodes of GBS
97(4):F295–F298. https://doi.org/10.1136/adc.2009. septicemia in a healthy newborn during the first month
170910 of life. Eur J Pediatr 169(10):1275–1277
Morgan J, Young L, McGuire W (2015) Slow advance- Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawöger R,
ment of enteral feed volumes to prevent necrotising Kiechl-Kohlendorfer U, Chan GM, Blanco CL,
enterocolitis in very low birth weight infants. Cochrane Abrams S, Cotten CM, Laroia N, Ehrenkranz RA,
Database Syst Rev 10:CD001241. https://doi.org/ Dudell G, Cristofalo EA, Meier P, Lee ML, Rechtman
10.1002/14651858.CD001241.pub6, Review DJ, Lucas A (2010) An exclusively human milk-based
Nyqvist KH (2008) Early attainment of breastfeeding com- diet is associated with a lower rate of necrotizing
petence in very preterm infants. Acta Paediatr 97 enterocolitis than a diet of human milk and bovine
(6):776–781 milk-based products. J Pediatr 156(4):562–567.
Nyqvist K, Expert Group of the International Network on https://doi.org/10.1016/j.jpeds.2009.10.040, Epub
International Network on Kangaroo Mother Care, 2009 Dec 29
Anderson G, Bergman N, Cattaneo A, Charpak N, Sun H, Como PG, Downey LC, Murphy D, Ariagno RL,
Davanzo R, Ewald U, Ludington-Hoe S, Mendoza S, Rodriguez W (2015) Infant formula and neurocognitive
Pallás-Allonso C, Peláez J, Sizun J, Widström AM outcomes: impact of study end-point selection. J Peri-
(2010) State of the art and recommendations Kangaroo natol 35(10):867–874. https://doi.org/10.1038/jp.2015.
mother care: application in a high-tech environment. 87, Epub 2015 Aug 6
Acta Paediatr 99(6):812–819. https://doi.org/10.1111/ Tornese G, Ronfani L, Pavan C, Demarini S, Monasta L,
j.1651-2227.2010.01794.x Davanzo R (2012) Does the LATCH score assessed in
Pineda R (2011) Direct breast-feeding in the neonatal the first 24 hours after delivery predict non-exclusive
intensive care unit: is it important? J Perinatol 31 breastfeeding at hospital discharge? Breastfeed Med 7
(8):540–545. https://doi.org/10.1038/jp.2010.205 (6):423–430
Renfrew MJ, Dyson L, McCormick F, Misso K, Stenhouse Tosone G, Maraolo AE, Mascolo S, Palmiero G, Tambaro
E, King SE, Williams AF (2010) Breastfeeding promo- O, Orlando R (2014) Vertical hepatitis C virus trans-
tion for infants in neonatal units: a systematic review. mission: main questions and answers. World J Hepatol
Child Care Health Dev 36(2):165–178. https://doi.org/ 6(8):538–548. https://doi.org/10.4254/wjh.v6.i8.538
10.1111/j.1365-2214.2009.01018.x Vieira AA, Soares FV, Pimenta HP, Abranches AD,
Reyes-Foster BM, Carter SK, Hinojosa MS (2015) Milk Moreira ME (2011) Analysis of the influence of pas-
sharing in practice: a descriptive analysis of peer teurization, freezing/thawing, and offer processes on
breastmilk sharing. Breastfeed Med 10(5):263–269. human milk’s macronutrient concentrations. Early
https://doi.org/10.1089/bfm.2015.0009 Hum Dev 87(8):577–580. https://doi.org/10.1016/j.
Rodriguez NA, Meier PP, Groer MW, Zeller JM, Engstrom earlhumdev.2011.04.016, Epub 2011 May 17
JL, Fogg L (2010) A pilot study to determine the safety von Stumm S, Plomin R (2015) Breastfeeding and IQ
and feasibility of oropharyngeal administration of own growth from toddlerhood through adolescence. PLoS
mother’s colostrum to extremely low-birth-weight One 10(9):e0138676
infants. Adv Neonatal Care 10(4):206–212 Weisglas-Kuperus N, Hille ET, Duivenvoorden HJ,
Rozé JC, Darmaun D, Boquien CY, Flamant C, Picaud JC, Finken MJ, Wit JM, van Buuren S, van Goudoever
Savagner C, Claris O, Lapillonne A, Mitanchez D, JB, Verloove-Vanhorick SP, Dutch POPS-19 Collabo-
Branger B, Simeoni U, Kaminski M, Ancel PY rative Study Group (2009) Intelligence of very pre-
(2012) The apparent breastfeeding paradox in very term or very low birthweight infants in young
preterm infants: relationship between breast feeding, adulthood. Arch Dis Child Fetal Neonatal Ed 94(3):
early weight gain and neurodevelopment based on F196–F200. https://doi.org/10.1136/adc.2007.135095,
results from two cohorts, EPIPAGE and LIFT. BMJ Epub 2008 Sep 19
Open 2(2):e000834. https://doi.org/10.1136/bmjopen- FAO, WHO (2007) Safe preparation, storage and handling
2012-000834, Print 2012 of powdered milk formula. Guidelines, Geneva
Sacker A, Kelly Y, Iacovou M, Cable N, Bartley M (2013) WHO, UNICEF (2009) Acceptable medical reasons for
Breast feeding and intergenerational social mobility: what use of breast-milk substitutes. WHO, Geneva
are the mechanisms? Arch Dis Child 98(9):666–671 WHO, UNICEF (2018) Implementation guidance: pro-
Section on Breastfeeding (2012) Breastfeeding and the use tecting, promoting and supporting breastfeeding in
of human milk. Pediatrics 115(2):496–506 facilities providing maternity and newborn services –
Silano M, Paganin P, Davanzo R (2016) Time for the 70 C the revised Baby-friendly Hospital Initiative. WHO,
water precautionary option in the home dilution of Geneva
powdered infant formula. Ital J Pediatr 42:17. https:// World Health Organization. Department of reproductive
doi.org/10.1186/s13052-016-0228-9 health and research. Medical eligibility criteria
586 R. Davanzo et al.
wheel for contraceptive use. http://www.who.int/ 127(4):e995–e1003. https://doi.org/10.1542/peds.2010-
reproductivehealth/publications/family_planning/MEC- 0723, Epub 2011 Mar 14
5/en/. Published August 2015. Accessed 20 Dec 2015 Zhou J, Shukla VV, John D, Chen C (2015) Human milk
Young L, Morgan J, McCormick FM, McGuire W (2012) feeding as a protective factor for retinopathy of prematu-
Nutrient-enriched formula versus standard term for- rity: a meta-analysis. Pediatrics 136(6):e1576–e1586.
mula for preterm infants following hospital discharge. https://doi.org/10.1542/peds.2015-2372, Epub 2015 Nov
Cochrane Database Syst Rev 3:CD004696. https://doi. 16. Review
org/10.1002/14651858.CD004696.pub4, Review Ziegler EE (2011) Meeting the nutritional needs of the
Young L, Embleton ND, McCormick FM, McGuire W low-birth-weight infant. Ann Nutr Metab 58(Suppl
(2013) Multinutrient fortification of human breast 1):8–18. https://doi.org/10.1159/000323381, Epub
milk for preterm infants following hospital discharge. 2011 Jun 21
Cochrane Database Syst Rev 2:CD004866. https://doi. Ziegler E, Vanderhoof JA, Petschow B, Mitmesser SH,
org/10.1002/14651858.CD004866.pub4 Stolz SI, Harris CL, Berseth CL (2007) Term infants
Zachariassen G, Faerk J, Grytter C, Esberg BH, Hjelmborg fed formula supplemented with selected blends of pre-
J, Mortensen S, Thybo Christesen H, Halken S (2011) biotics grow normally and have soft stools similar to
Nutrient enrichment of mother’s milk and growth of those reported for breast-fed infants. J Pediatr
very preterm infants after hospital discharge. Pediatrics Gastroenterol Nutr 44:359–364
Nutritional Recommendations for the
Very-Low-Birth-Weight Newborn 37
Ekhard E. Ziegler
Contents
37.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588
37.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588
37.3 Protein Requirements Determined by the Factorial Approach . . . . . . . . . . . 589
37.4 Protein Requirements Determined by the Empirical Approach . . . . . . . . . . 590
37.5 Recommended Protein Intakes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590
37.6 Requirements for Energy and Other Nutrients . . . . . . . . . . . . . . . . . . . . . . . . . . . . 591
37.7 Catch-Up Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 591
37.8 Nutrient Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592
37.8.1 Parenteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592
37.8.2 Early Enteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
37.8.3 Late Enteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 594
Abstract utero and, more importantly, suffer impairment
To ensure uninterrupted growth and develop- of their neurocognitive development. The main
ment of the prematurely born infant, all nutri- obstacles to delivery of nutrients historically
ents must be provided in the necessary amounts have been concerns regarding presumed risks
at all times. Delivery of nutrients meets with a attendant to the administration of nutrients.
variety of obstacles in very low birth weight Recent years have seen a gradual dissipation
(VLBW) infants, which is why VLBW infants of these concerns as scientific evidence of the
frequently receive less than the required safety of providing nutrients has accumulated.
amounts of nutrients. As a consequence they This reassessment of the risks of nutrient admin-
often fail to grow like they would have in istration has nearly been completed in the area
of parenteral nutrition but is an ongoing process
in the area of enteral nutrition. The more realis-
tic assessment of risks, together with a desire to
E. E. Ziegler (*)
Department of Pediatrics, University of Iowa, Iowa City, prevent postnatal growth failure and thereby
IA, USA minimize the risk of impaired neurocognitive
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 587
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_186
588 E. E. Ziegler
impairment, has led to more aggressive regi- but is an ongoing process in the area of enteral
mens of nutrient administration. nutrition. The more realistic assessment of risks,
together with a desire to prevent postnatal growth
failure and thereby minimize the risk of impaired
37.1 Salient Points neurocognitive development has led to more
aggressive regimens of nutrient administration.
• Premature birth entails an interruption of the There is principal agreement that postnatal
nutrient flow to the fetus/premature baby, growth of the premature infant should emulate that
which must be kept to a minimum if not of the fetus in utero. Such “normal” growth would
avoided altogether. be proof of the absence of substantive nutrient defi-
• Nutrient needs of the VLBW baby for growth ciency and would provide assurance of unimpaired
like the fetus are exceedingly high. neurocognitive development. The American Acad-
• Failure to meet the high protein needs leads to emy of Pediatrics (Committee on Nutrition and
growth failure, which carries the risk of American Academy of Pediatrics 1985) recom-
impaired cognitive development. mends that “postnatal growth that approximates
• Immaturity of the gastrointestinal tract neces- the in utero growth of a normal fetus of the same
sitates initial delivery of nutrients via the par- postconception age” should be the basis for estimat-
enteral route. ing nutrient requirements. It is recognized that birth
• Gut priming is needed until the gut is function- engenders a permanent contraction of body water
ally mature enough to accept feedings. spaces, amounting to about 10–15% of extracellular
• Human milk is the preferred feeding because of fluid space. However, there are no known reasons
its trophic effect on the gut and its protective why other body components should not be accumu-
effect against sepsis and NEC. lating in the premature infant as they would have in
• But human milk is nutritionally deficient and the fetus. The fetal model is therefore appropriate for
must be supplemented with substantial the estimation of nutrient intakes needed for normal
amounts of all nutrients. growth and development.
Nutrient needs of the premature infant have
been determined principally by two methods, the
37.2 Introduction factorial method and the empirical method.
Although both methods are ultimately based on
To ensure uninterrupted growth and development the fetal model, they use very different
of the prematurely born infant, all nutrients must be approaches. In the factorial approach, fetal accre-
provided in the necessary amounts at all times. tion of body components is used as the starting
Delivery of nutrients meets with a variety of obsta- point. After correction for inevitable losses, inef-
cles in very low birth weight (VLBW) infants, ficiency of conversion of nutrients into body com-
which is why VLBW infants frequently receive ponents (in the case of protein), and absorptive
less than the required amounts of nutrients. As a inefficiency, the required intake for a nutrient is
consequence they fail to grow like they would have obtained. An important advantage of this
in utero and, more importantly, suffer impairment approach is that it yields requirements for all
of their neurocognitive development. The main nutrients for which fetal accumulation is known,
obstacles to delivery of nutrients historically have which includes, besides protein and energy, all
been concerns regarding presumed risks attendant major minerals and most trace minerals. The fac-
to the administration of nutrients. Recent years torial approach can also provide needs specifically
have seen a gradual dissipation of these concerns for parenteral administration of nutrients. In the
as scientific evidence of the safety of providing empirical approach, the intake of a nutrient is
nutrients has accumulated. This reassessment of experimentally manipulated and a response, such
the risks of nutrient administration has nearly as weight gain or, in the case of protein, nitrogen
been completed in the area of parenteral nutrition balance, is observed. This approach has been
37 Nutritional Recommendations for the Very-Low-Birth-Weight Newborn 589
applied to protein end energy and yields energy permit derivation of fetal accretion rates of the var-
and/or protein intakes that produce weight gain or ious body components (Sparks 1984; Forbes 1987,
protein accretion comparable to the fetus. 1989).
Utilizing a different approach, Ziegler
et al. (1976) used select data for the construction
37.3 Protein Requirements of a “reference fetus” and derived fetal accretion
Determined by the Factorial rates. Accretion rates by the different approaches
Approach are similar and the fetal accretion rates in Table 1
represent a composite of the different approaches
The factorial approach derives nutrient require- (Sparks 1984; Forbes 1987, 1989; Ziegler
ments as the sum of two (in the case of parenteral et al. 1976) in combination with contemporary
requirements) or three components (in the case of fetal growth data (Kramer et al. 2001). Fetal accre-
enteral requirements). The largest component, and tion rates shown in Table 1 are corrected for pre-
the component that changes most with body size, sumed inefficiency (90%) of the conversion of
is nutrient accretion. The other components are dietary protein to body protein. Energy accretion
inevitable losses and, in the case of enteral values include the energy cost of growth, estimated
requirements, efficiency of nutrient absorption. by Micheli et al. (1992) at 10 kcal/kg/day.
Nutrient accretion is derived from body compo- Inevitable losses of protein (nitrogen) through
sition of the fetus. Going back to the nineteenth desquamation of skin were assumed to be 27 mg/
century, the chemical composition of a sizable num- kg/day (Snyderman et al. 1969) and urinary losses
ber of term and preterm infants, who were stillborn in the form of urea to be 133 mg/kg/day (Saini
or died soon after birth, has been reported by a et al. 1989; Rivera et al. 1993). Energy losses in
number of investigators. Sparks (1984) and Forbes the form of resting energy expenditure were
(1987, 1989) have provided comprehensive summa- assumed to be 45 kcal/kg/day in infants <900 g
ries of the chemical data derived from whole body and 50 kcal/kg/day in larger infants, and other
chemical analyses of over 160 infants. The data expenditures, e.g., for occasional cold exposure
Table 1 Estimated nutrient intakes needed to achieve fetal weight gain
Body weight (g) 500–700 700–900 900–1,200 1,200–1,500 1,500–1,800 1,800–2,200
Fetal weight gain (g/day) 13 16 20 24 26 29
(g/kg/day) 21 20 19 18 16 14
Protein (g/kg/day)
Loss 1.0 1.0 1.0 1.0 1.0 1.0
Growth (accretion) 2.5 2.5 2.5 2.4 2.2 2.0
Required intake
Parenteral 3.5 3.5 3.5 3.4 3.2 3.0
Enteral 4.0 4.0 4.0 3.9 3.6 3.4
Energy (kcal/kg/day)
Loss 60 60 65 70 70 70
Resting expenditure 45 45 50 50 50 50
Other expenditure 15 15 15 20 20 20
Growth (accretion) 29 32 36 38 39 41
Required intake
Parenteral 89 92 101 108 109 111
Enteral 105 108 119 127 128 131
Protein/energy (g/100 kcal)
Parenteral 3.9 3.8 3.5 3.1 2.9 2.7
Enteral 3.8 3.7 3.4 3.1 2.8 2.6
590 E. E. Ziegler
and physical activity, were assumed to be 15 kcal/ Table 2 Protein requirements by the factorial method
kg/day in infants <1,200 g and 20 kcal/kg/day in (Ziegler) and by empirical methods
larger infants (DeMarie et al. 1999; Olhager and Weight <1,200 g Weight >1,200
Forsum 2003). The requirements for parenterally g/kg/day g/100 kcal g/kg/day g/100 kcal
Ziegler 4.0 3.7 3.6 2.8
administered protein and energy (Table 1) are (Table 1)
calculated as the sum of accretion plus inevitable Kashyap and – – 3.0 2.5
losses. Enteral requirements are derived from par- Heird
(Kashyap
enteral requirements by application of corrections et al. 1986;
for percentage absorption, assumed to be 88% for 1988; 1990)
protein and 85% for energy. Rigo (2005) 3.8–4.2 3.3 3.4–3.6 2.8
Absolute fetal weight gain (g/day) increases
with increasing body size, but fractional fetal
weight gain (g/kg/day) decreases markedly with
increasing body size. In spite of this, the rate of and therefore represented catch-up growth. Kashyap
protein accretion remains constant up to a weight et al. (1986, 1988, 1990) performed a series of
of 1,200 g. This is so because the protein content growth and metabolic balance studies with feedings
of fat-free body mass increases with increasing (human milk, formulas) that varied in protein and
body size/age, offsetting the effect of the decrease energy content. They used the data to derive equa-
in fractional growth rate. Energy accretion, on the tions predicting protein and energy intakes neces-
other hand, increases with increasing body weight sary to duplicate fetal weight gain. The authors
due to a marked increase in fetal body fat content. estimated that protein intake necessary for infants
As the accumulation of body fat is not an absolute with birth weight greater than 1,200 g to duplicate
necessity, lesser energy intakes do not limit fetal weight gain was about 3.0 g/kg/day (Table 2).
growth of lean body mass as long as they are Using a variety of end points, including
greater than 100 kcal/kg/day (Micheli et al. 1992). growth, body composition, and nitrogen balance,
Rigo (2005) estimated the protein requirements
(“advisable recommendation”) of infants born at
37.4 Protein Requirements 26–30 weeks gestation (corresponding to weight of
Determined by the Empirical about 800–1,500 g) at 3.8–4.2 g/kg/day (3.3 g/
Approach 100 kcal) and those of infants born at
30–36 weeks gestation (corresponding to weight of
The empirical approach utilizes feedings (formulas 1,500–2,700 g) at 3.4–3.6 g/kg/day (2.8 g/100 kcal).
or human milk) that provide precisely known Table 2 provides a summary of the different
intakes of energy and protein, with growth and/or estimates of requirements for infants weighing
nitrogen balance as outcomes. Because of the fragil- less than 1,200 g and those weighing more than
ity of extremely immature infants, the necessary 1,200 g. It is apparent that there is reasonably
studies have been performed for the most part with close agreement among the different estimates in
infants weighing >1,200 g. As requirements are spite of differences in methods and end
strongly influenced by body size, estimates by the points used.
empirical approach are generally applicable only to
infants weighing >1,200 g. Data published before
1986 (Ziegler 1986) showed that weight gain 37.5 Recommended Protein Intakes
(g/day) increased with increasing protein intake all
the way to the highest intake studied (3.6 g/kg/day). Current recommendations (van Goudoever
Weight gain did not seem to be influenced by energy et al. 2014) are to provide initially (i.e., from
intake. The high protein intake of 3.6 g/kg/day was birth) 2.0–2.5 g/kg/day and to gradually increase
shown to produce a weight gain of about 30 g/day, to 3.5 g/kg/day. At full enteral nutrition, infants
which was more than the weight gain of the fetus need 3.5–4.5 g/kg/day of protein.
37 Nutritional Recommendations for the Very-Low-Birth-Weight Newborn 591
37.6 Requirements for Energy cardiovascular and metabolic risks later in life
and Other Nutrients (Singhal et al. 2003), the overriding concern is
with neurocognitive development. Therefore, in
Estimates of energy requirements are available by order to minimize the adverse effects of growth
the factorial method (Table 1). However, esti- restriction, efforts should be made to allow infants
mates by the empirical method are considered to make up any growth deficit as soon as possible.
more relevant with regard to energy. Empirical Accelerated growth following a period of growth
estimates (Micheli et al. 1992) indicate that restriction is referred to as catch-up growth.
energy needs are 90–100 kcal/kg/day. Energy Most infants are capable of catch-up growth,
taken in excess of this amount is used for storage and catch-up growth will occur if the requisite
in adipose tissue. amounts of nutrients are provided. Nutrient
Requirements for major minerals and electro- needs for catch-up growth are above and beyond
lytes derived by the factorial method are summa- the needs for growth like the fetus. Since most
rized in Table 3. Because there is considerable premature infants will have incurred some growth
uncertainty regarding the minimal urinary losses deficit during the immediate postnatal period, it is
of electrolytes and phosphorus, and because there advisable to provide all VLBW infants with suf-
is large variation of the efficiency of intestinal ficient nutrients for making up the growth deficit.
absorption of calcium, the required intakes Attempts to estimate nutrient needs of growth-
shown in Table 2 are somewhat uncertain. Since restricted infants and needs for catch-up growth
accumulation of less than the fetal amounts of have been made (Ziegler 2005).
bone mineral (Ca, P) seems to be compatible Table 5 presents nutrient requirements of hypo-
with reasonable bone health, there is even uncer- thetical growth-restricted infants. The first column
tainty with regard to the minimum amount of Ca gives nutrient requirements of a normally grown
and P that must be accrued. Nevertheless, fetal 26-week gestation infant weighing 900 g. The next
accretion rates are considered the norm and devi- column shows requirement of a growth-restricted
ations from them need to be justified. Table 4 infant of similar weight and growing at the same
summarizes the mineral and vitamin intakes for rate as the normally grown infant. Because the lean
fully enterally fed premature infants as body mass of this infant has a more mature compo-
recommended in 2014 by Koletzko et al. (2014). sition (lower water content), the infant’s metabolic
rate is higher and accordingly its energy requirement
is higher than that of the normally grown infant. The
37.7 Catch-Up Growth hypothetical infant in the far right column is also
growth restricted but is assumed to undergo catch-
Growth restriction, whether occurring before birth up growth. As shown, this increases the require-
(intrauterine) or postnatally, is associated with ments for energy and, especially for protein, by a
impaired neurocognitive development. Although considerable margin. If the infant is to undergo
postnatal growth restriction may lead to lower catch-up growth, these high needs have to be met.
Table 3 Requirements for major minerals and electrolytes determined by the factorial method (all values per kg/day)
500–1,000 g 1,000–1,500 g 1,500–2,000 g
Accretion Required intake Accretion Required intake Accretion Required intake
Ca (mg) 102 184 99 178 96 173
P (mg) 66 126 65 124 63 120
Mg (mg) 2.8 6.9 2.7 6.7 2.5 6.4
Na (meq) 1.54 3.3 1.37 3.0 1.06 2.6
K (meq) 0.78 2.4 0.72 2.3 0.63 2.2
Cl (meq) 2.26 2.8 0.99 2.7 0.74 2.5
592 E. E. Ziegler
Table 4 Recommended nutrient intakes of fully enterally 37.8 Nutrient Delivery
fed preterm infants (Koletzko et al. 2014)
Amounts per 100 kcal Ideally, the flow of nutrients should continue
Minerals without interruption and at the same level as
Na (mg) 63–105 the fetus transitions to become an infant.
K (mg) 71–177 Although the goal of an uninterrupted flow of
Cl (mg) 95–161 nutrients is difficult to attain, it should be the
Ca (mg) 109–182 goal that the caretaker strives to achieve. After
P (mg) 55–127 all, it is not known what degree of shortfall
Mg (mg) 7.3–13.6
from the goal, if any, is safe in terms of
Fe (mg) 1.8–2.7
neurocognitive outcome.
Zn (mg) 1.3–2.3
Nutrients are initially delivered to VLBW
Cu (μg) 90–210
infants parenterally. While nutrients are provided
Mn (μg) 0.9–13.6
F (μg) 1.4–55
parenterally, trophic feedings are initiated with the
I (μg) 9–50 objective of fostering maturation of the immature
Se (μg) 4.5–9 intestinal tract. When maturation has advanced to
Cr (ng) 27–2,045 the point where full feedings can be administered,
Mo (μg) 0.27–4.5 parenteral nutrition can be terminated. This marks
Vitamins the beginning of the late feeding period, during
A (μg RE) 365–1,000 which enteral feedings are the exclusive source of
D (IU) 100–350 nutrients. Growth similar to the fetus, or faster than
E (mg α-TE) 2–10 the fetus, is by consensus optimal. Yet, growth
K (μg) 4–25 frequently proceeds at a slower rate (postnatal
Thiamin (μg) 127–273 growth failure). The reason for growth failure is
Riboflavin (μg) 181–364 inadequate protein intake, which is caused by the
Niacin (mg) 0.9–5 low protein content of most feedings. Inadequate
B6 (μg) 45–273 protein intake is thus ultimately responsible
B12 (μg) 0.09–0.73
for the poor neurocognitive development with
Folic acid (μg) 32–91
which growth failure is associated (Ehrenkranz
Pantothenic acid (μg) 300
et al. 2006). Therefore, the achievement of ade-
Biotin (μg) 1.5–15
quate protein intake is mandatory if neurocognitive
C (mg) 18–50
impairment is to be minimized.
Table 5 Nutrient requirements of growth-restricted 37.8.1 Parenteral Nutrition
VLBW infants without and with catch-up growth
Gestational age 26 weeks 30 week 30 week Delivery of nutrients via the parenteral route
Weight (g) 900 900 900 should commence immediately at birth. Nutri-
Weight status NG GR GR
ents may initially be limited to amino acids,
Catch-up growth No No Yes
energy in the form of glucose, and certain min-
Weight gain 20 20 34
(g/day) erals, such as calcium, phosphorus, and magne-
Required intake sium. Full parenteral nutrition, including
Protein (g/kg/day) 4.0 4.0 4.9 intravenous lipids, should be instituted within
Energy (kcal/kg/ 119 126 141 24 h of birth. Parenteral nutrition starting within
day) 2 h of birth has been shown to be effective and
Protein/energy 3.4 3.2 3.5 safe (te Braake et al. 2005). Delivery of amino
(g/100 kcal) acids in the needed amounts (Table 1) presents
NG normally grown, GR growth restricted no difficulty, whereas delivery of energy can
37 Nutritional Recommendations for the Very-Low-Birth-Weight Newborn 593
usually not be achieved for some days without optimal bowel maturation. Vigilance for signs of
incurring hyperglycemia, even if lipids are pro- necrotizing enterocolitis must be maintained at all
vided. The best strategy is to start glucose at a times. However, gastric residuals are not an early
rate of 4.2 mg/kg/min and to increase delivery sign of necrotizing enterocolitis, and their monitor-
stepwise as long as euglycemia is maintained. ing is not of proven value in the prevention of
Lipid emulsions based on soy oil provide needed necrotizing enterocolitis. Delays in reaching full
energy and deliver modest amounts of the essen- feedings should be minimized as early achieve-
tial long-chain polyunsaturated fatty acids, ment of full feedings offers relative protection
docosahexaenoic acid, and arachidonic acid. Pre- against late-onset sepsis (Ronnestad et al. 2005).
mature reduction and/or discontinuation of par-
enteral nutrition before enteral nutrition has
reached full levels leads to inadequate protein 37.8.3 Late Enteral Nutrition
and energy intakes and slows growth (Miller
et al. 2014). Parenteral nutrition should therefore It is widely appreciated that human milk does not
be continued until enteral feedings provide all provide the nutrients required by premature
the nutrients that are needed. infants (Tables 1 and 3). The nutrient intake
from human milk must therefore be increased by
the addition of nutrient supplements (fortifiers).
37.8.2 Early Enteral Nutrition Infants fed unsupplemented human milk show
slow growth, which carries the risk of impaired
While adequate amounts of nutrients are being neurocognitive development. In addition, prema-
delivered via the parenteral route, enteral feedings ture infants can develop deficiency states of spe-
should be started soon after birth. The sole objec- cific nutrients, such as osteopenia (Ca, P) or zinc
tive of early (trophic) feeding is to stimulate the deficiency. Commercially available human milk
immature intestinal tract to undergo maturation. A fortifiers provide protein, energy, and the neces-
marker of the intestinal tract’s immaturity is the sary minerals and vitamins. The amounts of min-
frequent gastric residuals, which can therefore be erals and vitamins are designed to meet or exceed,
used to follow the intestinal tract’s maturation. together with the nutrients intrinsically present in
The best trophic feeding is human milk because human milk, the concentrations specified in
of its superior ability to mature the gut while Table 4. Fortifiers provide energy in the form of
keeping the risk of necrotizing enterocolitis to a carbohydrates and lipids. The protein provided by
minimum. Because it usually takes some days for powder fortifiers (1.0–1.1 g/100 mL) is insuffi-
the mother’s milk to become available, donor milk cient to meet the needs for protein at all times. The
may be used to initiate gut priming in a timely newer liquid fortifiers provide between 1.6 and
manner, i.e., on the first day of life. 1.8 g of protein/100 ml milk and thereby ensure
Gastric residuals should be monitored and their adequate protein intakes most of the time. Ade-
size taken into account in advancing feedings. It is quate protein intakes can be achieved if, in addi-
probably prudent to keep the volume of trophic tion to a powder fortifier, protein is added in
feedings low (<10 mL/kg/day) until gastric resid- able form or in the form of additional fortifier.
uals are substantially diminished. When they are, Additional protein can also be added as part of
cautious advancement of feeds can begin. Contrary a targeted fortification regimen (Polberger
to earlier perceptions, neither the age at which et al. 1999) or in an adjustable fortification regi-
trophic feedings are started nor the rate of advance- men (Arslanoglu et al. 2006). There is no consen-
ment of feedings has an impact on the risk of sus regarding which of these methods is preferred.
necrotizing enterocolitis (Chauhan et al. 2008). There is, however, no question that the amount of
Regardless of how feedings are advanced, it is protein provided by commercial powder fortifiers
important not to withhold feedings for more than is inadequate and that additional protein must be
a few hours because persistent feeding is crucial for provided in some form.
594 E. E. Ziegler
References Olhager E, Forsum E (2003) Total energy expenditure,
body composition and weight gain in moderately
Arslanoglu S, Moro GE, Ziegler EE (2006) Adjustable preterm and full-term infants at term post-
fortification of human milk fed to preterm infants: conceptional age. Acta Paediatr 92:1327–1334,
does it make a difference? J Perinatol 26:614–621, PubMed CrossRef
PubMed CrossRef Polberger S, Räihä NCR, Juvonen P et al (1999) Individ-
Chauhan M, Henderson G, McGuire W (2008) Enteral ualized protein fortification of human milk for preterm
feeding for very low birth weight infants: reducing the infants: comparison of ultrafiltrated human milk protein
risk of necrotising enterocolitis. Arch Dis Child Fetal and a bovine whey fortifier. JPGN 29:332–338,
Neonatal Ed 93:F162–F166, CrossRef PubMed
Committee on Nutrition, American Academy of Pediatrics Rigo J (2005) Protein, amino acid and other nitrogen
(1985) Nutritional needs of low-birth-weight infants. compounds. In: Tsang RC, Uauy R, Koletzko B,
Pediatrics 75:976–986 Zlotkin S (eds) Nutrition of the preterm infant, 2nd
DeMarie MP, Hoffenberg A, Biggerstaff SLB et al (1999) edn. Digital Educational Publishing, Cincinnati
Determinants of energy expenditure in ventilated pre- Rivera JA, Bell EF, Bier DM (1993) Effect of intravenous
term infants. J Perinat Med 27:465–472 amino acids on protein metabolism of preterm infants
Ehrenkranz RA, Dusick AM, Vohr BR et al (2006) Growth during the first three days of life. Pediatr Res
in the neonatal intensive care unit influences 33:106–111, PubMed CrossRef
neurodevelopmental and growth outcomes of Ronnestad A, Abrahamson TG, Medbo S et al (2005) Sep-
extremely low birth weight infants. Pediatrics ticemia in the first week of life in a Norwegian national
117:1253–1261, PubMed CrossRef cohort of extremely premature infants. Pediatrics 115:
Forbes GB (1987) Human body composition. Springer- e262–e268, PubMed CrossRef
Verlag, New York, pp 101–124, CrossRef Saini J, Macmahon P, Morgan JB et al (1989) Early paren-
Forbes G (1989) Nutritional adequacy of human breast teral feeding of amino acids. Arch Dis Child
milk for prematurely born infants. In: Lebenthal E 64:1362–1366, PubMed CrossRef
(ed) Textbook of gastroenterology and nutrition in Singhal A, Fewtrell M, Cole TJ, Lucas A (2003) Low
infancy. Raven Press, New York, pp 27–34 nutrient intake and early growth for later insulin resis-
Kashyap S, Forsyth M, Zucker C et al (1986) Effects of tance in adolescents born preterm. Lancet
varying protein and energy intakes on growth and met- 361:1089–1097, PubMed CrossRef
abolic response in low birth weight infants. J Pediatr Snyderman SE, Boyer A, Kogut MD et al (1969) The
108:955–963, PubMed CrossRef protein requirement of the premature infant. I. The
Kashyap S, Schulze KF, Forsyth M et al (1988) Growth, effect of protein intake on the retention of nitrogen.
nutrient retention, and metabolic response of low birth J Pediatr 74:872–880, PubMed CrossRef
weight infants fed varying intakes of protein and Sparks JW (1984) Human intrauterine growth and nutrient
energy. J Pediatr 113:713–721, PubMed CrossRef accretion. Semin Perinatol 8:74–93, PubMed
Kashyap S, Schulze KF, Forsyth M et al (1990) Growth, te Braake FWJ, van den Akker CHP, Wattimena DJL
nutrient retention, and metabolic response of low-birth- et al (2005) Amino acid administration to premature
weight infants fed supplemented and unsupplemented infants directly after birth. J Pediatr 147:457–461,
preterm human milk. Am J Clin Nutr 52:254–262 CrossRef
Koletzko B, Poindexter B, Uauy R (eds) (2014) Nutritional van Goudoever JB, Vlaardingerbroek H, van den Akker C,
care of preterm infants. Karger, Basel de Groof F, van der Schoor SRD (2014) Amino acids
Kramer MS, Platt RW, Wen SW et al (2001) A new and and proteins. In: Koletzko B, Poindexter B, Uauy R
improved population-based Canadian reference for birth (eds) Nutritional care of preterm infants. Karger, Basel,
weight for gestational age. Pediatrics 108:1–7, CrossRef pp 49–63
Micheli JL, Schutz Y, Jequier E (1992) Protein metabolism Ziegler EE (1986) Protein requirements of preterm
of the newborn. In: Polin RA, Fox WW (eds) Fetal and infants. In: Fomon SJ, Heird WC (eds) Energy and
neonatal physiology. Saunders, Philadelphia, pp protein needs during in-fancy. Academic, New York,
462–472 pp 69–85
Miller M, Vaidya R, Rastogi D, Bhutada A, Rastogi S Ziegler EE (2005) Nutrition of SGA/IUGR newborn
(2014) From parenteral to enteral nutrition: a infants. Minerva Pediatr 57(Suppl 1):16–18
nutrition-based approach for evaluation of postnatal Ziegler EE, O’Donnell AM, Nelson SE et al (1976) Body
growth failure in preterm infants. J Parenter Enteral composition of the reference fetus. Growth
Nutr 38:489–497 40:329–341, PubMed
Enteral Feeding of the Very-Low-Birth-
Weight Infant 38
Johannes B. (Hans) van Goudoever
Contents
38.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
38.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
38.3 Feeding Mode . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597
38.3.1 Minimal Enteral Feeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597
38.3.2 Bolus or (Semi)Continuous Feeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598
38.3.3 Oral Feeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598
38.3.4 Intragastric Feeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598
38.3.5 Transpyloric Feeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598
38.4 Type of Enteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
38.4.1 Preterm Human Milk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
38.4.2 Expressed Mother’s Milk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
38.4.3 Human Milk Banks and Donor Milk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 600
38.4.4 Fortifier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 600
38.4.5 Preterm Formula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
38.5 Approach to Improve Enteral Feeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
Abstract maturation process of digestion and absorp-
Enteral nutrition is the natural way of feeding tion, enhance tolerance to larger volumes of
infants. There have been concerns that preterm enteral nutrition, and avoid the complications
infants have limited digestive capacity; how- of parenteral nutrition. Adequate oral feeding
ever, there is evidence that digestive enzymes is possible from 32 weeks onwards, when an
are present in fetal life. Minimal enteral nutri- infant is capable of an adequate suck-swallow
tion should be started as soon as possible reflex. As oral feeding is not possible in
because enteral feeding itself may induce the VLBW infants, most frequently gastric tubes
are used. The most important reason for with-
holding enteral feedings is the fear that enteral
J. B. (Hans) van Goudoever (*) nutrition will enhance the development of nec-
Department of Pediatrics, Emma Children’s Hospital – rotizing enterocolitis (NEC); however, there is
AMC and VU University Medical Center, Amsterdam, The
Netherlands
no evidence that withholding enteral nutrition
e-mail: [email protected] prevents NEC. Own mother’s human milk is
# Springer International Publishing AG, part of Springer Nature 2018 595
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_187
596 J. B. (Hans) van Goudoever
the natural choice for infant feed, even for The fetus starts to swallow considerable
preterm infants. However, the concentrations amount of amniotic fluid in the last trimester. By
of nutrients decline rapidly following birth and term, the fetus swallows about 700 mL/day,
do not meet the requirements after approxi- corresponding with 170–230 mL/kg/day (Harding
mately 2–4 weeks. Fortification is thus neces- et al. 1984). It is estimated that up to 10–15% of
sary; protein fortification has been shown to the nitrogenous requirement of the fetus can be
increase in-hospital weight gain and head cir- met by swallowing amniotic fluid (Pitkin and
cumference. More clinical trials are needed to Reynolds 1975).
improve the quality of the nutrient supply. There have been concerns that preterm infants
have limited capacity to process carbohydrates,
fats, and proteins. Peptidases, brush border
38.1 Salient Points enzymes, and hydrolases are present in fetal life,
with an increase in enzyme activity with the gluco-
• Preterm infants have limited digestive capac- corticoid surge just before birth (Mooij et al. 2014;
ity; however, digestive enzymes are present in Sangild and Elnif 1996). Pancreas enzymes such as
fetal life. trypsin, lipase, and amylase are secreted into the
• Preterm infants fed with hydrolyzed formula duodenum by 31 weeks. From approximately
reach full enteral feedings approximately 2 26 weeks of gestation, lingual and gastric lipases
days earlier than when fed nonhydrolyzed are present, which might help in digestion and
formula. absorption of lipids. Bile acids are already secreted
• Parenteral nutrition might induce complica- by 22 weeks, although the synthesis is much lower
tions for infants. in preterm compared to term infants. Adding bile
• Enteral nutrition downregulates the intestinal salt-stimulated lipase (BSSL) to infant formula did
inflammatory response and promotes postnatal not exert an effect on weight gain rates in preterm
maturation of intestinal motor activity. infants, indicating that apparently enough lipase
• Delaying enteral feeding does not decrease the activity is present in infants born before 32 weeks
incidence of NEC, but increases the time to of gestation (Casper et al. 2016).
reach full enteral feeding. The effect of extreme premature birth
• There is an association of the use of human (<26 weeks) and antenatal steroids on digestion
milk-based fortifier with a lower NEC inci- and absorption is not precisely known, but may
dence compared to cow milk-based fortifier enhance these processes. Lactase activity is also
and preterm formula. lower in preterm infants, but preterm infants dis-
play normal growth when they are fed lactose-
containing milk. Preterm infants fed formula pre-
38.2 Introduction treated with lactase showed a modest increase in
initial weight gain, an effect that disappeared at
Enteral nutrition is the natural way of feeding the end of the study (Erasmus et al. 2002). Pro-
infants. The fetus receives enteral nutrition via teins are taken up rather efficiently in preterm
the amniotic fluid. The amniotic fluid is largely infants, a process that might be facilitated by
composed of fetal urine, but lung fluids, nasopha- pinocytosis and also, because of the increased
ryngeal secretions, and intra- and trans- intestinal permeability (Corpeleijn et al. 2008),
membranous fluids contribute as well. Amniotic intact proteins such as lactoferrin can be absorbed
fluid contains protein and carbohydrates, but also (Hutchens et al. 1991).
bacteria important for neonatal colonization Preterm infants fed hydrolyzed formula reach
(Walker 2017). The amino acid concentrations of full enteral feedings approximately 2 days earlier
amniotic fluid resemble the fetal plasma amino than when fed nonhydrolyzed formula, with similar
acid concentrations. protein metabolism indices (Mihatsch et al. 2002;
38 Enteral Feeding of the Very-Low-Birth-Weight Infant 597
Rigo et al. 1995). Enteral nutrition itself may induce effects of minimal enteral feeding in VLBW
the maturation process of digestion and absorption infants (Morgan et al. 2013). Delaying enteral
and enhance tolerance to larger volumes of enteral feeding does not decrease the incidence of NEC,
nutrition (Berseth 1992; Meetze et al. 1992). Alto- but increases the time to reach full enteral feed-
gether it follows that enteral nutrition should be ing (Morgan et al. 2014). Many different defini-
installed as soon as possible also to avoid the com- tions of minimal enteral feeding/trophic feeding
plications of parenteral nutrient administration. This exist, but in general these are considered rela-
chapter will focus on feeding mode and type of tively small enteral volumes of human milk or
enteral nutrition. formula (<25 mL/kg/day). They can be started
as early as day one of life, even in extremely
low-birth-weight infants. In neonatal piglets,
38.3 Feeding Mode mucosal growth is not observed before 30% of
the total amount of nutrition is administered
38.3.1 Minimal Enteral Feeding enterally, so minimal enteral feeding is not
intended to serve as a nutritional source (Burrin
The most important reason for withholding et al. 2000). Gut hormone levels are stimulated
enteral feedings is the fear that enteral nutrition by minimal enteral nutrition, possibly
will enhance the development of necrotizing explaining the improved motility (Lucas et al.
enterocolitis (NEC). This serious gastrointesti- 1986). Also less need for phototherapy and
nal problem affects approximately 5% of very- reduced rates of osteopenia and cholestasis has
low-birth-weight (VLBW) infants, but the inci- been reported, probably all related to a reduced
dence may vary widely among centers. Mortal- time on parenteral nutrition (Berseth 1992;
ity rates are high, ranging from 20% to 40%. The Meetze et al. 1992; Schanler et al. 1999). Lack
multifactorial etiology includes gut hypoxia, of any enteral nutrition is associated with an
impaired intestinal host defense mechanisms, increase in neonatal late onset infections (Sohn
and alterations in microbial intestinal content et al. 2001). This might be due to bacterial trans-
(in amount, diversity and timing of coloniza- location from the intestine. In addition, the intes-
tion). Enteral nutrition is considered a risk factor tinal immune/inflammatory response is affected
as well, since in preterm infants NEC develops by the route of feeding, with an altered balance
in the second or third week of life, after the of cytokines, lower IL-4 and IL-10 levels in the
introduction of enteral feedings (Neu and nonenterally fed state, and subsequent lower
Walker 2011). However, prevention of NEC by IgA production (Fukatsu et al. 2001a, b). Enteral
withholding enteral nutrition has not been nutrition has been demonstrated to down-
shown. On the contrary, withholding enteral regulate the intestinal inflammatory response
nutrition to neonatal animals reduces intestinal (van Goudoever et al. 2001). However, clinical
cell proliferation, gut mass, and enzyme activity trials have not demonstrated a beneficial effect
(Burrin et al. 2003, 2000). On the other hand, of minimal enteral feeding on invasive
introducing large amounts of enteral feeding is a infections.
way of establishing NEC in premature piglets, Although large clinical trials on minimal enteral
despite the fact that in utero large amount of nutrition in VLBW infants are lacking, many stud-
amniotic fluids are ingested (Shen et al. 2015). ies including animal studies show beneficial effects
Large amounts of enteral feedings are frequently of minimal enteral feeding in growth and feeding
not tolerated by the VLBW infants. Poor motil- tolerance and provide indications of improved
ity, pathogenic microorganisms, and inflamma- defense mechanisms against bacterial infections
tory processes are related to the differences and inflammatory processes. This favors initiation
observed in postnatal life compared to prenatal of minimal enteral feeding shortly following birth
life. At least nine trials have examined the as no adverse effects are reported.
598 J. B. (Hans) van Goudoever
38.3.2 Bolus or (Semi)Continuous and swallowing function from 32 weeks. Enteral
Feeding nutrition promotes postnatal maturation of intes-
tinal motor activity. It follows that adequate oral
Bolus feeding results in a significant increase in feeding is possible from 32 weeks onwards. Even
blood flow to the portal-drained viscera (i.e., wireless monitoring systems are present nowa-
stomach, spleen, intestine, and pancreas). There days to evaluate the feeding behavior of infants
is a surge in gastrointestinal hormones, which is quantitatively and objectively and analyze the
however not higher in bolus fed infants than when characteristics of these actions under oral feeding
neonates are fed continuously (van Goudoever et (Chen et al. 2017). Oral feeding protocols (includ-
al. 2001). Clinical trials show that even very small ing nonnutritive suckling) can be started however
preterm infants tolerate bolus feeding well. even before 30 weeks of gestation, with a positive
Smaller infants seem to benefit more from contin- influence on time to reach full oral feeding
uous feeding (Dsilna et al. 2005) and a small trial (Kamitsuka et al. 2017; Foster et al. 2016). The
showed that preterm infants underwent more preterm infant of less than 32 weeks may be put on
behavioral stress when fed intermittently (Dsilna the breast, but the likelihood that the infant will
et al. 2008). However, a large randomized con- ingest a significant volume of milk is very small.
trolled trial with 250 VLBW infants show that However, it may offer the mother a considerable
even infants less than 1000 g tolerate bolus feed- psychological benefit and should therefore be
ing well (Rovekamp-Abels et al. 2015). However, strongly encouraged. Cup-feeding might serve as
some older trials have demonstrated less tolerance alternative, although the results are mixed (Flint et
to intermittent bolus feeds than continuous milk al. 2016).
infusion. Bolus feeding may result in apnea, dete-
riorating respiratory mechanics with decreased
tidal volumes, and transient hypoxia (Blondheim 38.3.4 Intragastric Feeding
et al. 1993; Heldt 1988). These complications
might aggravate in the presence of blocking mate- As oral feeding is not possible in VLBW infants,
rials of the nostrils such as nasogastric tubes, or most frequently gastric tubes are used. Either
CPAP devices. In conclusion, there is still not nasogastric or orogastric tubes can be installed,
enough evidence to recommend either bolus or both checked in the right position by checking the
(semi)continuous feeding as the preferred aspirate for acidity with litmus paper or by injec-
method. tion a small amount of air while listening with a
stethoscope placed over the stomach. The naso-
gastric tube has the advantage of easier fixation
38.3.3 Oral Feeding but has the disadvantage of (partially) blocking
one nostril. With the use of some CPAP devices, a
Oral feeding is possible when an infant is capable nasogastric tube is not possible. With the use of
of an adequate suck-swallow reflex. In the term tubes and syringes, one should be aware of a
infant, the full, complex, integrated mechanism of potential loss of nutrients such as lipids and cal-
swallowing, with the movement of the bolus of cium that may not reach the infant (Greer and
milk into the stomach, protection of the airway, McCormick 1988).
inhibition of respiration, and appropriate relaxa-
tion of the esophageal sphincter and gastric fun-
dus is achieved within 2 days of birth (Lebenthal 38.3.5 Transpyloric Feeding
and Leung 1988). The swallow function is present
from 16 weeks of gestational age, and gastroin- Although transpyloric feeding is frequently used
testinal motor activity, in small bursts, from in pediatric intensive care (de Lucas et al. 2000), it
24 weeks onwards. Organized motility is present should not be used in neonatal intensive care. The
from around 30 weeks of gestation and nutritive available data do not provide evidence of any
38 Enteral Feeding of the Very-Low-Birth-Weight Infant 599
beneficial effect of transpyloric feeding for pre- milk might reduce intestinal permeability as well
term infants. Some evidence of harm exists, (Shulman et al. 1998). Long-term benefits of
including a higher risk of gastrointestinal distur- human milk as compared to formula include
bance and mortality, but these findings should be lower blood pressure, lower LDL to HDL ratio,
interpreted and applied cautiously because of and possibly a reduced risk of obesity and higher
methodological weaknesses in the included trials. IQ, although the validity of these results have
No proven benefits in tolerance, growth, or in been questioned (Vohr et al. 2006; Lechner and
aspiration rates have been reported consistently Vohr 2017; Singhal et al. 2001; Lucas et al. 1992;
(Watson and McGuire 2013). Isaacs et al. 2010).
38.4 Type of Enteral Nutrition 38.4.1 Preterm Human Milk
The aim of the nutritional support of the low- The milk from mothers, who have delivered pre-
birth-weight infant is to mimic intrauterine maturely, so-called preterm human milk, varies
growth rate and obtain a long-term functional significantly from milk from mothers who deliv-
development similar to the term infant. The nutri- ered at term. Concentrations of proteins, lipids
ent requirements for the VLBW infant are (and thus energy), hormones, vitamins, calcium,
described elsewhere (see ▶ Chap. 37, “Nutri- sodium, and trace elements are higher. However,
tional Recommendations for the Very-Low- the concentrations of these nutrients decline rap-
Birth-Weight Newborn”), but in general nutri- idly following birth and do not meet the require-
tional support should be designed to compensate ments after approximately 2–4 weeks (Ballard
for metabolic and gastrointestinal immaturity, and Morrow 2013). In addition, clinical problems
immunological compromise, and other problems such as patent ductus arteriosus and
associated with prematurity. Own mother’s bronchopulmonary dysplasia often restrict fluid
human milk is the preferred choice, even for intake demand fluid restrictions with the conse-
preterm infants although it does not provide the quent need for nutrient dense feedings. The ade-
required nutrients. Fortification is thus necessary, quacy of nutrient intake is further compromised
as unfortified human milk leads to in hospital by the variability in composition. For example,
suboptimal growth (Brown et al. 2016). Human the within-feed change in lipid content is well
milk is superior to cow’s milk-based formulas known and can be two to threefolds different
because of the species specificity. This results in between fore- and hind milk.
the availability of, for instance, functional pro-
teins and oligosaccharides important for the host
defense, which might explain the reduced rates of 38.4.2 Expressed Mother’s Milk
NEC observed in human milk fed infants
(Corpeleijn et al. 2012). Bioavailability of cal- As most low-birth-weight infants are not able to
cium and phosphorus is higher in human milk, drink from the breast directly, most mothers
but preterm infants still frequently need supple- choose to express their milk and deliver the milk
mentation, although evidence lacks (Harding et to the unit themselves. As human milk is not
al. 2017). Bacterial flora in infants fed preterm homogenized, the fat content may separate from
formula differs markedly from those who have the remaining milk. Fresh milk is favorable, since
been fed human milk (Cong et al. 2016), although freezing and thawing reduces the function of some
the recent improvements in preterm formula facil- beneficial components in human milk. Light
itate the growth of Bifidobacterium and Lactoba- exposure of breast milk reduces the riboflavin
cillus species as well (Boehm et al. 2002). Human and vitamin A content substantially within a few
milk is better tolerated than formula, with a faster hours. Human milk, even when fortified, can be
gastric emptying (Ewer et al. 1994), while human stored at refrigerator temperature for 72 h.
600 J. B. (Hans) van Goudoever
38.4.3 Human Milk Banks and Donor nitrogen and energy content of milk very easy, to
Milk be informed about some quality aspects of the
donor milk.
An alternative to own mother’s milk is the use of
milk from a milk bank (Corpeleijn et al. 2010;
Nutrition ECo et al. 2013). Setting up a milk bank 38.4.4 Fortifier
may be costly and after setting up the average cost
per liter is around €30/l (Meier et al. 2017). Many Exclusively unfortified human milk fed preterm
units around the world have such a milk bank, infants show lower serum albumin, total protein,
where mothers donate their milk to be used, most and transthyretin concentrations as a result of an
often without payment. inadequate protein intake. Growth rates are lower
Although some argue that banked milk does than fetal growth rates (Kashyap et al. 1990). In
not need to be pasteurized, almost all banks do, addition, calcium and phosphorus content are too
due to fear of pathogens. Human milk can trans- low to meet the preterm infants requirements,
mit infection. Donors should be screened for hep- resulting in decreases in serum phosphorus and
atitis B, hepatitis C, and HIV, with counseling increases in alkaline phosphatase (Pettifor et al.
offered when needed. Pasteurization destroys 1989) in the short term and linear growth reduc-
HIV (Eglin and Wilkinson 1987). HIV is the tion in the long term (Fewtrell et al. 2000). Hypo-
most well-recognized viral pathogen, but trans- natremia may result in a later stage, especially
mission of cytomegalovirus is not uncommon, when diuretics are used. The protein-related defi-
and raw breast milk can cause serious and even cits that might occur using unfortified milk can be
fatal illness in preterm babies (Hamprecht et al. corrected with supplementation. Protein fortifica-
2001). Pasteurization, freezing, and thawing tion has been shown to increase in-hospital weight
lower antimicrobial factors and denature milk gain (Brown et al. 2016) and increase head cir-
lipase (Evans et al. 1978). It may reduce vitamin cumference. Both human milk protein sources as
content as well. Therefore, benefits are not as clear well as bovine protein supplementation has been
as with nonpasteurized, own mother’s milk. On used, with similar results (Polberger et al. 1999).
the other hand, most of the lysozyme, IgG, and Recent study show an association of the use of
almost all IgA remain intact. Pasteurization does human milk-based fortifier with a lower NEC
not affect gastric emptying (de Oliveira et al. incidence than cow milk-based fortifier and pre-
2017). term formula although severe methodological
The benefit of donor milk may be related to the issues remain (Cristofalo et al. 2013; Sullivan et
avoidance of exposing the preterm gut to cow’s al. 2010).
milk proteins, but that hypothesis was rejected The vitamin K concentration of human milk is
based on a large multicenter trial providing either very low and for the newborn breastfed infant, a
donor milk or preterm formula as add on to own deficiency state has been described. Vitamin K is
mothers milk during the first 10 days of life produced by Bacteroides and E. coli, bacteria that
(Corpeleijn et al. 2016). No effect was observed are usually not common in breastfed infants.
on the cumulative incidence of mortality, NEC, and However, if prophylactic vitamin K is given at
sepsis. Exposing infants for a longer period than birth, no signs of deficiency have been described
10 days resulted in a significant reduction of NEC for 3 months (Greer et al. 1998), although the
in a similarly large trial (O’Connor et al. 2016), but addition of vitamin K in fortifiers is logical and
no effect was observed on the primary outcome: current practice.
neurocognitive development at 2 years of age. As human milk composition changes in time,
Donors have usually delivered at term or have even fortified milk might not meet the require-
been lactating for some time, both of which result ments of the rapidly growing preterm infant. Fre-
in lower nutritional content. Nowadays, commer- quent monitoring of the administered amount of
cial instruments are available that can screen the nutrients remains necessary. Milk analyzers
38 Enteral Feeding of the Very-Low-Birth-Weight Infant 601
should therefore be available on all units as stan- Paediatric Gastroenterology, Hepatology and
dard of care. The policy of waiting to change the Nutrition (ESPGHAN) together with a group of
composition of the nutrient intake until growth is experts have indicated major changes in require-
faltering should be considered as suboptimal ther- ments, which are discussed elsewhere (see
apy, which can seriously affect long-term out- ▶ Chap. 37, “Nutritional Recommendations for
come. Human milk fortifiers have been criticized the Very-Low-Birth-Weight Newborn”). Readers
for possible side effects, such as a loss of intrinsic are referred to these published recommendations
host defense. As described above, there is an for a detailed description.
indication that infants fed a human milk-based
fortifier with human milk might be less prone to
develop NEC, although the largest trial to date 38.5 Approach to Improve Enteral
does not support that hypothesis (O’Connor et Feeding
al. 2016). Another fear of the use of fortifiers is a
reduced tolerance. A recent meta-analysis has As yet, current enteral feeding strategies fail to
revealed no differences between infants fed forti- meet the requirements of VLBW infants. Many
fied or unfortified human milk (Brown et al. more clinical trials are needed to improve the
2016). Also no differences were observed quality of the nutrient supply. An alternative
between infants fed preterm formula or fortified approach would be to determine the quantity and
human milk. quality of intrauterine nutrition by measuring fetal
intake and fetal metabolism. Obviously, there are
many differences between life in or outside the
38.4.5 Preterm Formula uterus. Mimicking the uterus seems still far away,
although recently a lamb model was developed
Although the goal of providing nutrients to the (Partridge et al. 2017). Compared to the fetus,
preterm infant is to achieve a functional outcome preterm infants are depending on their own
similar to that of the breastfed term infants, it is metabolism, use their lungs, and are subject to
obvious that the composition of preterm formula is more gravity forces. In addition, they are fre-
different from term formula, since the requirements quently ill, which might demand specific nutrients
are much higher. Until now, the factorial approach to support defense mechanisms. Medication usage
has been used, with only moderate success. With may alter metabolism. Their intestines start to be
the factorial approach, estimations of requirements colonized, and bacteria have their own nutrient
are made based upon intrauterine accretion rates, requirements. However, intrauterine nutrition
while accounting for endogenous losses, incom- and metabolism might provide very valuable
plete digestion, and absorption. Intrauterine accre- insight in to what the fetus is capable of with
tion rates are obtained from carcass analyses of regard to metabolic activity, although the mother
fetuses, with sometimes limited information of plays a role in the conversion to and excretion of
the nutritional status of the mother or possible metabolic end products. Glucose is the major oxi-
diseases and on intrauterine growth curves. Subse- dative substrate in utero. The ovine fetus utilizes
quent modifications of such formulas were made glucose at a rate of approximately 4–7 mg/kg/min,
following clinical studies. As stated above, this but has the capability to metabolize double (Hay
approach has yielded only limited success. Weight et al. 1983). Lactate is also important as energy
gain rates are lacking behind intrauterine rates, source, especially when other sources of energy
especially in the extremely low-birth-weight are lacking (Harding and Johnston 1995). When
infants (Hulst et al. 2004). Mainly retrospective born at term, the human baby has a large portion
studies have shown detrimental effects of weight of fat. Fat deposition increases exponentially with
gain rates that are suboptimal (Ehrenkranz et al. gestational age. Near term, the fat accretion is 7 g/
2006; Latal-Hajnal et al. 2003). Recent developed day. In the fetal sheep, large quantities of amino
guidelines from the European Society for acids are taken up by both the placenta and the
602 J. B. (Hans) van Goudoever
fetus (Lemons et al. 1976). About half of the Cong X, Xu W, Janton S, Henderson WA, Matson A,
retained amount is used as fuel source and the McGrath JM et al (2016) Gut microbiome developmen-
tal patterns in early life of preterm infants: impacts of
ammonia produced in this process is converted feeding and gender. PLoS One 11(4):e0152751
into urea by the fetal liver. The human fetus Corpeleijn WE, van Vliet I, de Gast-Bakker DA, van der
shows a very active amino acid transport as well Schoor SR, Alles MS, Hoijer M et al (2008) Effect of
(Van den Akker et al. 2009). Comparison of albu- enteral IGF-1 supplementation on feeding tolerance,
growth, and gut permeability in enterally fed prema-
min synthesis rates, using stable isotope tech- ture neonates. J Pediatr Gastroenterol Nutr 46(2):
niques, revealed that very immature fetuses 184–190
produce large quantities of albumin, rates that Corpeleijn WE, Vermeulen MJ, van Vliet I, Kruger C, van
are not reached following birth with the present Goudoever JB (2010) Human milk banking-facts and
issues to resolve. Forum Nutr 2(7):762–769
nutritional strategies (Van den Akker et al. 2008; Corpeleijn WE, Kouwenhoven SM, Paap MC, van Vliet I,
Vlaardingerbroek et al. 2016). This information Scheerder I, Muizer Y et al (2012) Intake of own
provides guidelines as to which extent anabolism mother’s milk during the first days of life is associated
can occur and to which extent postnatal nutrition with decreased morbidity and mortality in very low
birth weight infants during the first 60 days of life.
should be provided (van den Akker and van Neonatology 102(4):276–281
Goudoever 2016). Corpeleijn WE, de Waard M, Christmann V, van
Goudoever JB, Jansen-van der Weide MC, Kooi EM
et al (2016) Effect of donor milk on severe infections
and mortality in very low-birth-weight infants: the early
References nutrition study randomized clinical trial. JAMA Pediatr
170(7):654–661
Ballard O, Morrow AL (2013) Human milk composition: Cristofalo EA, Schanler RJ, Blanco CL, Sullivan S,
nutrients and bioactive factors. Pediatr Clin N Am 60 Trawoeger R, Kiechl-Kohlendorfer U et al (2013) Ran-
(1):49–74 domized trial of exclusive human milk versus preterm
Berseth CL (1992) Effect of early feeding on maturation of formula diets in extremely premature infants. J Pediatr
the preterm infant’s small intestine. J Pediatr 120 163(6):1592–5.e1
(6):947–953 de Lucas C, Moreno M, Lopez-Herce J, Ruiz F, Perez-
Blondheim O, Abbasi S, Fox WW, Bhutani VK (1993) Palencia M, Carrillo A (2000) Transpyloric enteral
Effect of enteral gavage feeding rate on pulmonary nutrition reduces the complication rate and cost in the
functions of very low birth weight infants. J Pediatr critically ill child. J Pediatr Gastroenterol Nutr 30(2):
122(5 Pt 1):751–755 175–180
Boehm G, Lidestri M, Casetta P, Jelinek J, Negretti F, Stahl de Oliveira SC, Bellanger A, Menard O, Pladys P, Le
B et al (2002) Supplementation of a bovine milk for- Gouar Y, Dirson E et al (2017) Impact of human milk
mula with an oligosaccharide mixture increases counts pasteurization on gastric digestion in preterm infants: a
of faecal bifidobacteria in preterm infants. Arch Dis randomized controlled trial. Am J Clin Nutr 105(2):
Child Fetal Neonatal Ed 86(3):F178–F181 379–390
Brown JV, Embleton ND, Harding JE, McGuire W (2016) Dsilna A, Christensson K, Alfredsson L, Lagercrantz H,
Multi-nutrient fortification of human milk for preterm Blennow M (2005) Continuous feeding promotes gas-
infants. Cochrane Database Syst Rev 5:CD000343 trointestinal tolerance and growth in very low birth
Burrin DG, Stoll B, Jiang R, Chang X, Hartmann B, Holst weight infants. J Pediatr 147(1):43–49
JJ et al (2000) Minimal enteral nutrient requirements Dsilna A, Christensson K, Gustafsson AS, Lagercrantz H,
for intestinal growth in neonatal piglets: how much is Alfredsson L (2008) Behavioral stress is affected by the
enough? Am J Clin Nutr 71(6):1603–1610 mode of tube feeding in very low birth weight infants.
Burrin DG, Stoll B, Chang X, Van Goudoever JB, Fujii H, Clin J Pain 24(5):447–455
Hutson SM et al (2003) Parenteral nutrition results in Eglin RP, Wilkinson AR (1987) HIV infection and
impaired lactose digestion and hexose absorption when pasteurisation of breast milk. Lancet 1(8541):1093
enteral feeding is initiated in infant pigs. Am J Clin Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage
Nutr 78(3):461–470 LA, Poole WK (2006) Growth in the neonatal intensive
Casper C, Hascoet JM, Ertl T, Gadzinowski JS, Carnielli V, care unit influences neurodevelopmental and growth
Rigo J et al (2016) Recombinant bile salt-stimulated outcomes of extremely low birth weight infants. Pedi-
lipase in preterm infant feeding: a randomized phase 3 atrics 117(4):1253–1261
study. PLoS One 11(5):e0156071 Erasmus HD, Ludwig-Auser HM, Paterson PG, Sun D,
Chen CT, Wang LY, Wang YL, Lin BS (2017) Quantitative Sankaran K (2002) Enhanced weight gain in preterm
real-time assessment for feeding skill of preterm infants receiving lactase-treated feeds: a randomized,
infants. J Med Syst 41(6):95 double-blind, controlled trial. J Pediatr 141(4):532–537
38 Enteral Feeding of the Very-Low-Birth-Weight Infant 603
Evans TJ, Ryley HC, Neale LM, Dodge JA, Lewarne VM Hutchens TW, Henry JF, Yip TT, Hachey DL, Schanler RJ,
(1978) Effect of storage and heat on antimicrobial pro- Motil KJ et al (1991) Origin of intact lactoferrin and its
teins in human milk. Arch Dis Child 53(3):239–241 DNA-binding fragments found in the urine of human
Ewer AK, Durbin GM, Morgan ME, Booth IW (1994) milk-fed preterm infants. Evaluation by stable isotopic
Gastric emptying in preterm infants. Arch Dis Child enrichment. Pediatr Res 29(3):243–250
Fetal Neonatal Ed 71(1):F24–F27 Isaacs EB, Fischl BR, Quinn BT, Chong WK, Gadian DG,
Fewtrell MS, Cole TJ, Bishop NJ, Lucas A (2000) Neona- Lucas A (2010) Impact of breast milk on intelligence
tal factors predicting childhood height in preterm quotient, brain size, and white matter development.
infants: evidence for a persisting effect of early meta- Pediatr Res 67(4):357–362
bolic bone disease? J Pediatr 137(5):668–673 Kamitsuka MD, Nervik PA, Nielsen SL, Clark RH (2017)
Flint A, New K, Davies MW (2016) Cup feeding versus Incidence of nasogastric and gastrostomy tube at dis-
other forms of supplemental enteral feeding for new- charge is reduced after implementing an oral feeding
born infants unable to fully breastfeed. Cochrane Data- protocol in premature (<30 weeks) infants. Am J Peri-
base Syst Rev 8:CD005092 natol 34(6):606–613
Foster JP, Psaila K, Patterson T (2016) Non-nutritive suck- Kashyap S, Schulze KF, Forsyth M, Dell RB,
ing for increasing physiologic stability and nutrition in Ramakrishnan R, Heird WC (1990) Growth, nutrient
preterm infants. Cochrane Database Syst Rev 10: retention, and metabolic response of low-birth-weight
CD001071 infants fed supplemented and unsupplemented preterm
Fukatsu K, Zarzaur BL, Johnson CD, Lundberg AH, human milk. Am J Clin Nutr 52(2):254–262
Hanna MK, Wilcox HG et al (2001a) Lack of enteral Latal-Hajnal B, von Siebenthal K, Kovari H, Bucher HU,
feeding increases expression of E-selectin after LPS Largo RH (2003) Postnatal growth in VLBW infants:
challenge. J Surg Res 97(1):41–48 significant association with neurodevelopmental out-
Fukatsu K, Kudsk KA, Zarzaur BL, Wu Y, Hanna MK, come. J Pediatr 143(2):163–170
DeWitt RC (2001b) TPN decreases IL-4 and IL-10 Lebenthal E, Leung YK (1988) Feeding the premature and
mRNA expression in lipopolysaccharide stimulated compromised infant: gastrointestinal considerations.
intestinal lamina propria cells but glutamine supplemen- Pediatr Clin N Am 35(2):215–238
tation preserves the expression. Shock 15(4):318–322 Lechner BE, Vohr BR (2017) Neurodevelopmental out-
Greer FR, McCormick A (1988) Improved bone mineral- comes of preterm infants fed human milk: a systematic
ization and growth in premature infants fed fortified review. Clin Perinatol 44(1):69–83
own mother’s milk. J Pediatr 112(6):961–969 Lemons JA, Adcock EW, 3rd, Jones MD, Jr., Naughton
Greer FR, Marshall SP, Severson RR, Smith DA, Shearer MA, Meschia G, Battaglia FC. Umbilical uptake of
MJ, Pace DG et al (1998) A new mixed micellar prep- amino acids in the unstressed fetal lamb. J Clin Invest
aration for oral vitamin K prophylaxis: randomised 1976;58(6):1428-1434
controlled comparison with an intramuscular formula- Lucas A, Bloom SR, Aynsley-Green A (1986) Gut hor-
tion in breast fed infants. Arch Dis Child 79 mones and ‘minimal enteral feeding’. Acta Paediatr
(4):300–305 Scand 75(5):719–723
Hamprecht K, Maschmann J, Vochem M, Dietz K, Speer Lucas A, Morley R, Cole TJ, Lister G, Leeson-Payne C
CP, Jahn G (2001) Epidemiology of transmission of (1992) Breast milk and subsequent intelligence quo-
cytomegalovirus from mother to preterm infant by tient in children born preterm. Lancet 339
breastfeeding. Lancet 357(9255):513–518 (8788):261–264
Harding JE, Johnston BM (1995) Nutrition and fetal Meetze WH, Valentine C, McGuigan JE, Conlon M, Sacks
growth. Reprod Fertil Dev 7(3):539–547 N, Neu J (1992) Gastrointestinal priming prior to full
Harding R, Bocking AD, Sigger JN, Wickham PJ (1984) enteral nutrition in very low birth weight infants. J
Composition and volume of fluid swallowed by fetal Pediatr Gastroenterol Nutr 15(2):163–170
sheep. Q J Exp Physiol 69(3):487–495 Meier P, Patel A, Esquerra-Zwiers A (2017) Donor human
Harding JE, Wilson J, Brown J (2017) Calcium and phos- milk update: evidence, mechanisms, and priorities for
phorus supplementation of human milk for preterm research and practice. J Pediatr 180:15–21
infants. Cochrane Database Syst Rev 2:CD003310 Mihatsch WA, Franz AR, Hogel J, Pohlandt F (2002) Hydro-
Hay WW, Jr., Myers SA, Sparks JW, Wilkening RB, lyzed protein accelerates feeding advancement in very
Meschia G, Battaglia FC. Glucose and lactate oxidation low birth weight infants. Pediatrics 110(6):1199–1203
rates in the fetal lamb. Proc Soc Exp Biol Med Mooij MG, Schwarz UI, de Koning BA, Leeder JS,
1983;173(4):553-563 Gaedigk R, Samsom JN et al (2014) Ontogeny of
Heldt GP (1988) The effect of gavage feeding on the human hepatic and intestinal transporter gene expres-
mechanics of the lung, chest wall, and diaphragm of sion during childhood: age matters. Drug Metab Dispos
preterm infants. Pediatr Res 24(1):55–58 42(8):1268–1274
Hulst J, Joosten K, Zimmermann L, Hop W, van Buuren S, Morgan J, Bombell S, McGuire W (2013) Early trophic
Buller H et al (2004) Malnutrition in critically ill chil- feeding versus enteral fasting for very preterm or very
dren: from admission to 6 months after discharge. Clin low birth weight infants. Cochrane Database Syst Rev
Nutr 23(2):223–232 3:CD000504
604 J. B. (Hans) van Goudoever
Morgan J, Young L, McGuire W (2014) Delayed introduc- resistance relative to infant formula in preterm pigs.
tion of progressive enteral feeds to prevent necrotising Am J Physiol Gastrointest Liver Physiol. https://doi.
enterocolitis in very low birth weight infants. Cochrane org/10.1152/ajpgi.00163.2015
Database Syst Rev 12:CD001970 Shulman RJ, Schanler RJ, Lau C, Heitkemper M, Ou CN,
Neu J, Walker WA (2011) Necrotizing enterocolitis. N Smith EO (1998) Early feeding, antenatal glucocorti-
Engl J Med 364(3):255–264 coids, and human milk decrease intestinal permeability
Nutrition ECo, Arslanoglu S, Corpeleijn W, Moro G, in preterm infants. Pediatr Res 44(4):519–523
Braegger C, Campoy C et al (2013) Donor human Singhal A, Cole TJ, Lucas A (2001) Early nutrition in
milk for preterm infants: current evidence and research preterm infants and later blood pressure: two cohorts
directions. J Pediatr Gastroenterol Nutr 57(4):535–542 after randomised trials. Lancet 357(9254):413–419
O’Connor DL, Gibbins S, Kiss A, Bando N, Brennan- Sohn AH, Garrett DO, Sinkowitz-Cochran RL, Grohskopf
Donnan J, Ng E et al (2016) Effect of supplemental LA, Levine GL, Stover BH et al (2001) Prevalence of
donor human milk compared with preterm formula on nosocomial infections in neonatal intensive care unit
neurodevelopment of very low-birth-weight infants at patients: results from the first national point-prevalence
18 months: a randomized clinical trial. JAMA 316 survey. J Pediatr 139(6):821–827
(18):1897–1905 Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawoger R,
Partridge EA, Davey MG, Hornick MA, McGovern PE, Kiechl-Kohlendorfer U et al (2010) An exclusively
Mejaddam AY, Vrecenak JD et al (2017) An extra- human milk-based diet is associated with a lower rate
uterine system to physiologically support the extreme of necrotizing enterocolitis than a diet of human milk and
premature lamb. Nat Commun 8:15112 bovine milk-based products. J Pediatr 156(4):562–7.e1
Pettifor JM, Rajah R, Venter A, Moodley GP, Opperman L, van den Akker CH, van Goudoever JB (2016) Defining
Cavaleros M et al (1989) Bone mineralization and protein requirements of preterm infants by using meta-
mineral homeostasis in very low-birth-weight infants bolic studies in fetuses and preterm infants. Nestle Nutr
fed either human milk or fortified human milk. J Pediatr Inst Workshop Ser 86:139–149
Gastroenterol Nutr 8(2):217–224 Van den Akker CH, Schierbeek H, Rietveld T, Vermes A,
Pitkin RM, Reynolds WA (1975) Fetal ingestion and Duvekot JJ, Steegers EA et al (2008) Human fetal
metabolism of amniotic fluid protein. Am J Obstet albumin synthesis rates during different periods of ges-
Gynecol 123(4):356–363 tation. Am J Clin Nutr 88(4):997–1003
Polberger S, Raiha NC, Juvonen P, Moro GE, Minoli I, Van den Akker CH, Schierbeek H, Dorst KY,
Warm A (1999) Individualized protein fortification of Schoonderwaldt EM, Vermes A, Duvekot JJ et al
human milk for preterm infants: comparison of ultra- (2009) Human fetal amino acid metabolism at term
filtrated human milk protein and a bovine whey forti- gestation. Am J Clin Nutr 89(1):153–160
fier. J Pediatr Gastroenterol Nutr 29(3):332–338 van Goudoever JB, Stoll B, Hartmann B, Holst JJ, Reeds
Rigo J, Salle BL, Picaud JC, Putet G, Senterre J (1995) PJ, Burrin DG (2001) Secretion of trophic gut peptides
Nutritional evaluation of protein hydrolysate formulas. is not different in bolus- and continuously fed piglets. J
Eur J Clin Nutr 49(Suppl 1):S26–S38 Nutr 131(3):729–732
Rovekamp-Abels LW, Hogewind-Schoonenboom JE, de Vlaardingerbroek H, Schierbeek H, Rook D, Vermeulen
Wijs-Meijler DP, Maduro MD, Jansen-van der Weide MJ, Dorst K, Vermes A et al (2016) Albumin synthesis
MC, van Goudoever JB et al (2015) Intermittent bolus in very low birth weight infants is enhanced by early
or semicontinuous feeding for preterm infants? J parenteral lipid and high-dose amino acid administra-
Pediatr Gastroenterol Nutr 61(6):659–664 tion. Clin Nutr 35(2):344–350
Sangild PT, Elnif J (1996) Intestinal hydrolytic activity in Vohr BR, Poindexter BB, Dusick AM, McKinley LT,
young mink (Mustela Vison) develops slowly postna- Wright LL, Langer JC et al (2006) Beneficial effects of
tally and exhibits late sensitivity to glucocorticoids. J breast milk in the neonatal intensive care unit on the
Nutr 126(9):2061–2068 developmental outcome of extremely low birth weight
Schanler RJ, Shulman RJ, Lau C (1999) Feeding strategies infants at 18 months of age. Pediatrics 118(1):e115–e123
for premature infants: beneficial outcomes of feeding Walker WA (2017) Bacterial colonization of the newborn
fortified human milk versus preterm formula. Pediatrics gut, immune development, and prevention of disease.
103(6 Pt 1):1150–1157 Nestle Nutr Inst Workshop Ser 88:23–33
Shen RL, Thymann T, Ostergaard MV, Stoy AC, Krych L, Watson J, McGuire W (2013) Transpyloric versus gastric
Nielsen DS et al (2015) Early gradual feeding with tube feeding for preterm infants. Cochrane Database
bovine colostrum improves gut function and NEC Syst Rev 2:CD003487
Parenteral Nutrition
39
Jacques Rigo and Thibault Senterre
Contents
39.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606
39.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606
39.3 Nutritional Support in VLBW Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
39.3.1 Parenteral Nutrition During the Transitional Period . . . . . . . . . . . . . . . . . . . . . . . . . . 607
39.3.2 Parenteral Nutrition During the Stable Growing Period . . . . . . . . . . . . . . . . . . . . . . 610
39.4 Practical Aspects of Parenteral Nutrition in VLBW Infants . . . . . . . . . . . . . 612
39.4.1 Basic Components Available for Parenteral Nutrition in Preterm Infant . . . . . 612
39.4.2 Tailored or Standard Parenteral Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614
39.4.3 Nutrient Intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616
Abstract positive nitrogen retention and growth. Par-
Modern perinatal medicine has resulted in a enteral nutrition may be required or prolonged
dramatic decrease of mortality in premature during the stable “growing” period due to
infants, especially in very low birth weight feeding intolerance, gastrointestinal disor-
(VLBW, <1500 g) infants. Nutrition has ders, or surgery. Parenteral nutrition can be
become one of the most debated issues in the prescribed using tailored or standard solution;
care of low-birth-weight infants. Nutrition of the former is formulated specifically to meet
VLBW infants may be divided into two sub- the daily nutritional requirements of the indi-
sequent periods: the immediate adaptive or vidual patient, whereas the latter is designed
“transitional” period after birth and a stable to provide a formulation that meets most of
“growing” period up to discharge from the the nutritional needs of the stable biochemical
NICU. VLBW infants need parenteral nutri- and metabolic parameters. Very recently, it
tion from the first days of life to promote early was suggested that the use of unique standard
parenteral solution may contribute to a signif-
icant improvement of nutritional support for
both extremely and very preterm infants.
J. Rigo (*) · T. Senterre
Department of Neonatology, University of Liège, CHR de
la Citadelle, Liège, Belgium
# Springer International Publishing AG, part of Springer Nature 2018 605
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_188
606 J. Rigo and T. Senterre
39.1 Salient Points Incidence of intrauterine growth restriction
(IUGR) is relatively high in VLBW infants and
• Nutrition of VLBW infants may be divided postnatal growth restriction (PNGR) is frequently
into a “transitional” period (after birth) and a observed during the early weeks of life resulting
stable “growing” period (up to discharge from in a major growth deficit at the time of discharge.
the NICU). According to population, clinical disorders and
• The aim of nutritional support during the tran- nutritional support, growth restriction affected
sitional period is: to reduce protein catabolism, 60–100% of VLBW and extremely low birth
to provide amino acid, water, and electrolytes; weight (ELBW) infants (Ehrenkranz et al. 1999).
to promote nitrogen retention; and to limit PNGR is mainly the result of the cumulative
postnatal metabolic stress. nutritional deficit occurring during the transitional
• The aim of the nutritional support during the period from birth to the time of full enteral feeding
stable growing period is to induce the growth (Embleton et al. 2001; Rigo et al. 2002) but addi-
of body mass; to abolish the nutritional deficit tional effects during the stable growing period
during the first weeks of life; and to reach have also been suggested (Curtis and Rigo
normal anthropometric parameters. 2004). Therefore, several studies evaluated the
effect of more optimal (aggressive) nutrition dur-
ing the early weeks of life (Wilson et al. 1997;
39.2 Introduction Thureen et al. 2003; Ziegler et al. 2002; Simmer
2007) and various international scientific commit-
Modern perinatal medicine has resulted in dra- tees reconsidered current nutritional recommen-
matic decrease of mortality in premature infants, dations in preterm infants focusing on ELBW and
especially very low birth weight (VLBW, VLBW infants (Table 1) (Tsang et al. 2005;
<1500 g) infants. With the major advances in Agostoni et al. 2010).
life-support measures, nutrition has become one Due to gastrointestinal tract immaturity,
the most debated issues in the care of low-birth- cardio-respiratory adaptation, clinical status and
weight infants. In this regard, several reports have high nutritional requirements, VLBW infants
shown the major effect of quantitative and quali- require parenteral nutrition from the first days of
tative nutrition during the first period of life on life to promote early positive nitrogen retention
early and late outcome. and growth. In addition, parenteral nutrition could
Table 1 Recent recommendations of daily parenteral intakes for ELBW and VLBW infants
Tsang et al. (2005) ESPEN-ESPGHAN (Koletzko et al. 2005)
Day 0 Transition Growing Day 0 Transition Growing
FluIDs mL/kg/day 90–120 90–140 120–180 80–90 100–150 140–180
Energy kcal/kg/day 40–50 75–85 90–115 50–60 60–100 100–120
Protein g/kg/day 2 3.5 3.5–4 1.5–2.5 2.0–3.5 3.5–4
Carbohydrate g/kg/day 7 8–15 13–17 7–10 9–15 12–18
Fat g/kg/day 1 1–3 3–4 0–1 1–3 2–4
Sodium mmol/kg/day 0–1 2–5 3–7 0–3 2–3 2–7
Potassium mmol/kg/day 0 0–2 2–3 0–2 1–2 2–5
Chloride mmol/kg/day 0–1 2–5 3–7 0–3 2–3 2–5
Calcium mmol/kg/day 0.5–1.5 1.5 1.3–4 NP 1–2 1.3–3.0
Phosphorus mmol/kg/day 0–1 1.5–2 1.5–2 NP 1–2 1.0–2.5
Magnesium mmol/kg/day 0 0–0.3 0.2–0.3 NP NP 0.2–0.4
Zinc μmol/kg/day 0–2 2,5 6 NP 3 4
NP not provIDed
39 Parenteral Nutrition 607
be required or prolonged during the stable “grow- 2. To provide amino acids (AA) at a level suffi-
ing” period due to feeding intolerance, gastrointes- cient to induce a positive nitrogen retention;
tinal disorders or surgery. Provision of parenteral 3. To provide water and electrolytes to control
nutrition (PN), total or suppletive, can be ordered hydration status and postnatal physiological
using individualized prescription, homemade stan- fluid adaptation;
dardized parenteral solution or ready to use indus- 4. To progressively increase AA, energy and min-
trialized prepared multichamber bags. eral intake to promote nitrogen retention and
In this chapter we discuss the most important early growth and to limit a possible cumulative
features regarding parenteral nutrition that have nutritional deficit;
been recently reviewed (Rigo and Curtis 2004; 5. To limit postnatal metabolic stress in this high-
Koletzko et al. 2005; Ben 2008; Fusch et al. risk population.
2009) (Table 1), outlining more recent practical
aspects and guidelines particularly for ELBW and Recent data suggest that provision of a more
VLBW infants. “aggressive” nutritional support from the first day
of life reduces postnatal growth deficit and
improves neurodevelopmental outcomes in
39.3 Nutritional Support in VLBW VLBW infants (Senterre and Rigo 2011a; Martin
Infants et al. 2009).
Nutrition of VLBW infants may be divided into 39.3.1.1 Fluids and Electrolytes
two subsequent periods, firstly the immediate A number of adaptive processes occurring at birth
adaptive or “transitional” period after birth, and affect nutritional support. During the early weeks
a stable “growing” period up to discharge from the of life, water, electrolyte and mineral homeostasis,
NICU. Depending on birth weight (BW) and ges- and glucose control are more challenging. Placen-
tational age (GA) the transitional period may be tal clearance and placental supply of fluids, elec-
prolonged, particularly in the more vulnerable trolytes, minerals and nutrients are discontinued.
infants with major clinical disorders. The more Thermoregulation and insensible water losses
premature a neonate, the more challenging are influence water metabolism, especially in
the influences of immaturity and the accompany- VLBW infants. Subsequent adaptation and com-
ing morbidity on nutritional supply. Most of these pensatory regulative processes need time to
infants receive parenterally delivered nutrients as stabilize.
their major source of nutrition for the first days, Fluid and electrolyte administration during the
and sometimes weeks, of life. transitional period should allow contraction of
Nutrition during the “stable-growing” period extracellular fluid space without compromising
on PN is exceptional, used only when preterm intravascular fluid volume and cardiovascular
infants are recovering from surgery and/or severe function, maintain normal plasma electrolyte con-
gastrointestinal problems, to prevent or limit the centrations, without impairing urinary output
use of the gastrointestinal tract. (<0.5–1.0 mL/kg/h) for more than 12 h.
Water balance may be very unstable, especially
in ELBW infants, urinary output may be high
39.3.1 Parenteral Nutrition During (6–10 mL/kg/h) and insensible fluid losses can
the Transitional Period be huge, especially under a radiant warmer
and/or with phototherapy.
The aim of the nutritional support in VLBW A negative net balance for sodium is allowed
infants during the transitional period is: and intakes should be less than 2 mmol/kg ini-
tially. Restricted sodium intake in VLBW infants
1. To reduce protein catabolism providing an energy has a positive influence on oxygen supply and risk
intake at least at the level of energy expenditure; of later bronchopulmonary dysplasia. However,
608 J. Rigo and T. Senterre
high sodium urinary excretion (10 mmol/kg) may 39.3.1.3 Energy
occur, especially in case of high fluid perfusion Energy intake is required for both protein metab-
over 170–200 mL/kg/d compromising sodium olism and deposition. Theoretically, an energy
balance. intake approximating the resting energy expendi-
This transitional phase may last for a variable ture (i.e., 40–60 kcal/kg/day) allows the minimi-
period of several hours or days and result in zation of protein catabolism to about 1.5 g of
initial weight loss. The end of the transitional protein/kg/d in ELBW infants. If amino acid
period is usually characterized by a urine volume intake is adequate and energy intake is in excess
<2.0 mL/kg/h, urine osmolarity>serum osmo- of resting energy expenditure, weight gain is
larity, fractional Na excretion diminishing from achieved. However, because of individual differ-
>3% to <1% and specific gravity above 1012. In ences in energy expenditure, the resting energy
preterm infants, these changes complete after requirement varies considerably in this popula-
3–5 days and water and electrolytes intake will tion. New recommendations (Koletzko et al.
be progressively increased to replete the body 2005; Fusch et al. 2009) suggest providing
losses. 40 kcal/kg/d on the first day of life, to increase
During the transitional period, VLBW infants up to 75–85 kcal/kg/d during the transitional
should be weighted twice daily and in/out bal- period and to reach close to 100 kcal/kg/d at the
ance, plasma sodium concentration and urinary end of the first week of life.
excretion should be monitored attentively during
first days of life. Fluid intake on PN should be 39.3.1.4 Carbohydrates
50–100 mL/kg/d in VLBW infants according to Glucose homeostasis is still immature during the
clinical and environmental conditions and sodium early days of life in VLBW infants who are sub-
and potassium intake limited to less than 2 mmol/ ject to hyper or hypoglycemia. Glucose is the
kg/d (Koletzko et al. 2005; Fusch et al. 2009). main carbohydrate in fetal life and approximately
7 g/kg/d (4 mg/kg/min) of glucose crosses the
39.3.1.2 Amino Acids placenta in the last trimester of pregnancy. Glu-
To reduce the temporary interruption of the trans- cose production around 8 mg/kg/min (11.5 g/kg/
fer of nutrients, to limit the high protein catabo- d) in preterm infants is maximal in the postnatal
lism up to 1.5 g/kg/d and to induce a positive period and decreases gradually with age. Gluco-
nitrogen balance from the first day of life a high- neogenesis may be responsible for a part of glu-
protein supply (>2 g amino acids/kg per day) has cose production. During high rates of glucose
recently been suggested in the so-called “aggres- infusion, endogenous production is not
sive” nutrition (Thureen et al. 2003; Ziegler et al. completely suppressed in VLBW infants. By con-
2002; Simmer 2007). trast, maximum glucose oxidation is relatively
Although, long-term benefits were not clearly limited, 7–8.5 mg/kg/min (10–12 g/kg/d), but
demonstrated, it has been suggested that high could be less in critically ill VLBW infants. The
protein intake during the first week of life induces imbalance between glucose infusion rate and
positive nitrogen balance, increases insulin secre- endogenous production on one hand and the max-
tion, improves glucose tolerance, promotes early imum oxidation rate explain the increasing inci-
weight gain and improves neurodevelopmental dence of hyperglycemia in VLBW infants. In
outcome at 18 months (Stephens et al. 2009). addition, due to their immaturity and their under-
Thus, new recommendations (Koletzko et al. lying diseases, VLBW infants are relatively resis-
2005; Fusch et al. 2009) suggest providing 2–3 g tant to insulin during the first week of life.
of AA on the first day of life using a parenteral During the transitional phase, fluctuations in
solution with a high AA:energy ratio and to pro- blood sugar levels are frequently observed
gressively increase the AA intake up to 4 g/kg/d at resulting from an insufficient glucose and energy
the end of the first week of life. intake associated with low substrate reserves
39 Parenteral Nutrition 609
(hypoglycemia) or from a relative excess of glu- been recognized. Intravenous lipid emulsions con-
cose and energy intake associated with some tain small amounts of these fatty acids as part of the
degree of insulin resistance (hyperglycemia). egg phospholipid used as a stabilizer. However,
Although the definition and the long-term conse- clearance of lipid emulsion could be impaired in
quences of neonatal hypo- and hyperglycemia ELBW infants particularly those with IUGR
remain controversial, plasma glucose concentra- requiring the monitoring of triglyceridemia.
tion should be monitored to remain in a normal Actually, new recommendations (Koletzko
range for VLBW infants on parenteral nutrition et al. 2005; Fusch et al. 2009) suggest providing
between 50 mg/dL (2.75 mmol/L) and 150 mg/dL 1 g/kg/d on the first day increasing stepwise fash-
(8.3 mmol/L). Hyperglycemia can be decreased ion to 3.0 g/kg/d at the end of the first week of age.
by reducing insensible water loss, glucose infu-
sion rate and by providing exogenous insulin sup- 39.3.1.6 Minerals: Ca, P and Mg
ply. Insulin administration may help to control Calcium and phosphorus transfer and retention is
plasma glucose concentration, to achieve high during the last trimester of gestation. Com-
increased energy intake and to promote nitrogen bined with a relative immaturity of hormonal con-
retention and growth, although there is need for trol (Vit D, PTH), VLBW infants particularly are
more data on its safety and long-term conse- at risk of early neonatal hypocalcemia and hypo-
quences as a growth-promoting agent. More phosphoremia (see ▶ Chap. 41, “Calcium and
recently, it has been proposed that high AA intake Phosphorus Homeostasis: Pathophysiology”).
from the first day (2–3 g/kg/d) improves glucose Calcium supply needs to be provided from the
tolerance in ELBW infants by stimulating growth, first day of life in combination with an adequate
by enhancing insulin and insulin-like growth fac- calcium phosphorus ratio to limit the risk of hypo-
tors secretion (Thureen et al. 2003). This approach calcemia and/or hypophosphoremia. Phosphorus
requires further randomized control trials. plays a critical role in energy metabolism, and
In practice, 6 g glucose/kg per day are gener- deficiency of phosphorus results in clinical disease,
ally well tolerated (4–5 mg/kg/min) even on the including muscle weakness. Early phosphorus
first day of life in VLBW infants. If this intake is deficiency is also potentiated by IUGR. Reference
tolerated, it may be increased progressively to values for plasma phosphorus concentration differ
12–16 g/kg per day at the end of the first week in adults (>1.0 mmol/L, 3 mg/dL) and in preterm
of life. If it is not tolerated, progression of glucose infants (>1.6 mmol/L, 5 mg/dL). Unfortunately,
intake will be reduced and insulin perfusion will most neonatologists are unaware that the laboratory
be considered according to clinical and nutritional reports plasma phosphorus concentration of
status with an initial dose of 0.05 IU/kg/h. VLBW infants with regard to adult references and
tolerates hypophosphatemia with the risk of hyper-
39.3.1.5 Lipids calciuria and osteopenia. Optimal calcium to phos-
Intravenous lipid emulsions are important constit- phorus ratio differs in parenteral and oral nutrition
uents of total PN as they provide in an isotonic due to the bypass of the gastrointestinal tract; phos-
solution, high energy density and essential fatty phorus retention is related to bone mineralization
acids to VLBW infants. Intravenous lipids play with a weight-to-weight calcium:phosphorus ratio
two separate roles in the PN of VLBW infants. of 2.15:1 but also to nitrogen retention with a
The first role is as a high-density energy substrate weight-to-weight nitrogen:phosphorus ratio of
to be readily utilized by VLBW infants. The other 15:1. Therefore optimal Ca to P ratio in parenteral
role is as a source of essential fatty acids as well as nutrition ranges between 1.5 and 1.3.
long-chain PUFAs. Essential fatty acid deficiency Magnesium is rarely adjusted even in the tran-
is avoided by infusions of 0.5–1.0 g lipid per kg per sitional period unless the infant has persistent
day. The importance of long-chain PUFAs for the hypocalcemia secondary to hypomagnesemia, or
development of the brain and the retina has also has abnormally high magnesium levels due to
610 J. Rigo and T. Senterre
maternal levels. Serum magnesium levels should most stable growing infants. In parenteral solu-
be checked in any small infant whose mother was tion, sodium is frequently provided with phospho-
treated for hypertension or preeclampsia. rus in the form of sodium glycerophosphate and
Actually, new recommendations (Koletzko limitation of sodium content also limits the phos-
et al. 2005; Fusch et al. 2009) suggest providing phorus content. Chloride supply requires particu-
around 25–40 mg (0.6–1 mmol) of Ca/kg/d, lar attention in parenteral nutrition. Chloride
18–31 mg (0.6–1 mmol) of P/kg/d and requirement is generally considered similar to
2.5–4.0 mg (0.1–0.2 mmol)/kg/d of magnesium sodium requirement. Chloride content in paren-
on the first day and to progressively increase the teral solution is related to several potential com-
intake according to energy and AA supplies up to ponents, AA solution, sodium chloride, potassium
65–100 mg (1.6–2.5 mmol) of Ca/kg/d, 50–78 mg chloride or calcium chloride and is difficult to
(1.6–2.5 mmol) of Phosphorus and 7–10 mg control. However, chloride intake plays a role in
(0.3–0.4 mmol/kg/d) of magnesium. the acid-base homeostasis and imbalance between
Na+ + K+ and Cl promotes metabolic acidosis or
alkalosis (Kalhoff et al. 1997). Therefore, moni-
39.3.2 Parenteral Nutrition During toring of plasma and urinary electrolyte concen-
the Stable Growing Period trations and appropriate correction remains
recommended, during parenteral nutrition.
The aim of the nutritional support in VLBW
infants during the stable growing period is: 39.3.2.2 Amino Acids
Nitrogen requirement in parenteral nutrition is
1. To induce growth rate and protein accretion in close to 95% of the enteral requirement, but corre-
the range of the fetal weight gain considering sponds in terms of g AA/kg/g to the figure in g
the lean body mass gain as reference; protein/kg/d recommended in enteral nutrition, due
2. To abolish the development of a cumulative to a relatively lower nitrogen content. Protein
nutritional deficit during the first weeks of life; requirement has been recently reviewed according
3. To reach, at the time of discharge and/or of to fetal nitrogen accretion, lean body mass gain and
theoretical term, an anthropometric parameter the need to compensate early cumulative protein
in the range of reference values for term infants. deficits during the transitional period. 3.5–4.5 g of
AA /kg/d is recommended during the stable grow-
39.3.2.1 Fluids and Electrolytes ing period in ELBW and VLBW infants (Tsang
Intravenous fluid is the carrying vehicle for par- et al. 2005; Agostoni et al. 2010; Rigo 2005).
enteral nutrition. A fluid intake about
140–160 mL/kg/d in both VLBW and VLBW 39.3.2.3 Energy
preterm infants allows for covering the water In contrast to what is generally suggested, the
requirement for replacing water loss and provid- energy requirement in PN approximates to that
ing enough extra water to build new tissues during of enteral nutrition. In fact, the gross energy con-
the stable growing period. Fat mass is relatively tent, measured by bomb calorimetry, of 1 g of
free of water content. By contrast, lean body mass amino acid is lower than that of 1 g of protein.
content is about 80%. Thus a weight gain of 20 g/ Similarly, gross energy content of glucose is less
kg/d containing 40% of fat results in a net storage than that of more complex carbohydrates. In con-
of 13 g of water and 1–1.5 mmol of Na+/kg/d. trast, while in parenteral nutrition the metaboliz-
Sodium and potassium requirements are in the able energy of amino acid and fat solutions are
range of 3–7 mmol/kg/d for Na+ and 2–5 mmol/ identical to the gross energy, the metabolizable
kg/d for K+ in VLBW infants respectively. A energy of dietary protein and fat in oral nutrition
mean intake of 3 mmol/kg/day of sodium and represents about 90% and 80% respectively
2 mmol/kg/day of potassium seem to be appropri- (Curtis et al. 1986). Consequently, the recommen-
ate to maintain normal plasma concentration for dation for energy intake during the stable-growing
39 Parenteral Nutrition 611
period in VLBW infants on parenteral nutrition is prudent to avoid high lipid supplies in infants
relatively similar to that in oral nutrition and cor- with sepsis, impaired oxygenation, or severe
responds to 110–130 kcal/kg per day in VLBW hyperbilirubinemia and lipid emulsion infusion
infants. should be continued at least at 0.5–1.0 g/kg/day,
which is sufficient to prevent essential fatty acid
39.3.2.4 Carbohydrates deficiency.
Glucose contributes to most of the osmolality of Lipid supply may result in enhanced lipid per-
PN solution (510 mOsm/L for a 10% solution) by oxidation and the formation of free radicals. An
contrast to lipid solutions. An excessive glucose increased lipid utilization by reducing the carbo-
intake increases CO2 production and may be hydrate/lipid ratio results in a reduction of lipid
responsible for hyperglycemia, cause lipogenesis, peroxidation and free radical formation. PN
steatosis and may contribute to liver dysfunction. should be supplemented with multi-vitamin prep-
The maximum glucose intake should not exceed arations including both vitamin C and vitamin E
the glucose oxidation rate in parenteral nutrition (alpha-tocopherol), which have anti-oxidative
of 13–18 g/kg/d and more than 60–75% of the effects. Excessive exposure of the bottle to light
non-protein energy during the stable growing should be avoided.
period. Carnitine is necessary for the transportation of
long-chain fatty acids via the mitochondrial mem-
39.3.2.5 Lipids brane and its oxidative metabolism. Because car-
Intravenous lipid emulsions are important constit- nitine synthesis and storage are not sufficiently
uents of total parenteral nutrition as they provide developed at birth, particularly in preterm infants,
most of the energy intake and essential fatty acids and because no commercial intravenous solution
(EFA). The CO2 production is lowered compared has carnitine, parenterally fed infants present low
to PN with a high proportion of carbohydrates and plasma and tissue carnitine levels that decline with
the nitrogen metabolism can be improved by postnatal age (Borum 2009). Although a meta
adding lipid emulsions to PN. Lipid oxidation analysis (based on 14 randomised, controlled
depends on the overall energy intake and con- studies) showed there to be no effect of carnitine
sumption, intake of carbohydrates and triglycer- supplementation on the metabolism of lipids, lipo-
ides and the carbohydrate/lipid ratio. Lipid genesis or weight gain (Cairns and Stalker 2000),
oxidation decreases as the carbohydrate intake a carnitine supplementation of 15 μmol/100 kcal
increases and is replaced by lipid storage. could be advisible for infants on total parenteral
Maximum fat oxidation occur when lipid nutrition for more than 4 weeks.
emulsions provide 40% of the non-protein energy
in newborns so it is recommended that lipid intake 39.3.2.6 Minerals: Ca, P and Mg
should provide 25–40% of non-protein energy Calcium and phosphorus cannot be provided
with a maximum of 3–4 g/kg/day (Koletzko through the same parenteral solution at concentra-
et al. 2005). An increase in the concentration of tions needed to support in utero accretion, because
plasma triglycerides is to be expected if the infu- of solubility. With a fluid intake range of
sion speed of the lipid emulsion exceeds the speed 120–150 mL/kg/day, it is advisable to supply
of triglyceride hydrolysis that depends on lipopro- 65–100 mg (1.6–2.5 mmol) of Ca /kg/d,
tein lipase activity. In all cases, the triglyceride 50–78 mg (1.6–2.5 mmol) of iP and 7–10 mg
infusion dose should be adjusted to maintain a (0.3–0.4 mmol/kg/d) of Mg, corresponding to a
serum triglyceride concentration not exceeding Ca/P ratio of 1.3:1 by weight and 1:1 by molar
200–250 mg/dL, especially in ELBW or severely ratio in the TPN solution. It must be underlined
ill infants who may have limited lipid tolerance. that this quantity of calcium provided by paren-
Concerns had been raised on the potentially teral route is about 55–80% of that deposited by
adverse effects of lipid infusion on hemodynam- the fetus during the last trimester of gestation
ics, infections or hyperbilirubinemia. It appears (120 mg/kg/day) but similar or higher than that
612 J. Rigo and T. Senterre
obtained in enteral nutrition with the available used in pediatric care, nitrogen utilization does
preterm formula (see ▶ Chap. 41, “Calcium and not change significantly (Fig. 1) (Rigo and Curtis
Phosphorus Homeostasis: Pathophysiology”). 2004; Rigo 2005) (Table 2).
Therefore, optimal amino acid patterns for par-
39.3.2.7 Trace Elements and Vitamins enteral amino acid solutions in preterm infants
Vitamin mixtures for parenteral use have been still need to be determined and new solutions
available since the early time of parenteral nutrition should be developed to potentially improve sulfur
and the amounts provided were (and are) deter- and aromatic AA imbalances and to provide addi-
mined to a large extent by the preparations avail- tional glutamine. However, up to now, the use of
able. Today, additives of all trace minerals for cystein-HCl, acetyl-cystein, acetyl-tyrosine
which a deficiency has been demonstrated are (Goudoever et al. 1994) and the supplementation
available. However, little definitive information is with glutamine (Tubman et al. 2008) have not
available concerning the parenteral requirements of demonstrated beneficial effects. The recent data
either trace minerals or vitamins in VLBW infants. evaluating the effect of bypassing the intestine on
Research concerning the parenteral requirements individual AA requirements has not been trans-
of these nutrients by infants, of course, is hindered lated to designing and evaluating new AA
by the difficulties both of measuring plasma con- solutions.
centrations of the nutrients using small volumes of
plasma and of interpreting the physiological signif- 39.4.1.2 Lipid Emulsions
icance of plasma concentrations. Intravenous lipid emulsions consist of different
oils (soybean, safflower, coconut, olive and fish
oils), egg yolk phospholipids and glycerol
39.4 Practical Aspects of Parenteral [reviewed in 12, 14, 26, 27] (see Table 3). Intra-
Nutrition in VLBW Infants venous lipid emulsions provide high caloric, iso-
tonic solutions and can also be given through
39.4.1 Basic Components Available peripheral lines Traditionally, lipid infusions are
for Parenteral Nutrition prepared from soybean oil triglycerides emulsi-
in Preterm Infant fied with egg yolk phospholipids. Typical soybean
oil contains about 45–55% linoleic acid (18:2n-6)
39.4.1.1 AA Solutions and 6–9% linolenic acid (18:3n-3), but very little
Considerable improvement of parenteral amino saturated or monounsaturated fat. Although clini-
acid solutions have occurred from the late 1960s cally safe, experimental reports indicated that soy-
when the source of intravenous protein was casein bean oil based lipid emulsion could exert a
hydrolysate. More specific pediatric amino acid negative influence on immunological functions.
solutions have been designed in the early 1990s Those findings were related to its absolute and
with high essential/non-essential AA ratios and relative excess of ω-6 polyunsaturated fatty acids
conditionally essential amino acid content for (PUFA) and the low amount of ω-3 PUFA and
use in preterm infants. At least three different also to its high PUFA content with an increased
“gold standards” have been proposed for prema- peroxidation risk. The new lipid emulsion was
ture infants: (1) the amino acid concentrations basically designed in order to obtain balanced
from the umbilical cord obtained following fetal levels in polyunsaturated (ω-6 and ω-3), monoun-
cord puncture or after birth, (2) the amino acid saturated, and saturated fatty acids. They are dif-
concentrations of rapidly growing preterm infants ferentiated by their fatty acid content, as well as
receiving their mother’s milk or human milk fatty acid source of their origin, including soy,
supplemented with human milk proteins, (3) the safflower, coconut, olive, and fish oil. Newer
amino acid concentrations of healthy breast-fed emulsions comprise physical mixtures of either a
term infants. Nevertheless, despite the diverse 20:80 mixture of soy ω-6 PUFA and ω-9 medium-
composition of parenteral amino acid solutions chain monounsaturates (MUFA) from olive oil or
39 Parenteral Nutrition 613
Fig. 1 Relationship
between nitrogen retention
and nitrogen intake in
parenterally fed preterm
infants computing of
various studies (the
different symbols represent
individual studies)
Table 2 Main composition of commercial parenteral amino acID solutions for preterm infants
Total AA EAA Cyst(e)ine Tyrosine Taurine Osmolality
Product % (g/L) (%) (g/L) (g/L) (g/L) (mosm/L) pH
Aminopäd 10 100 42 0.5a 1.1c 0.3 790 6.1
Aminoplasmal 10 100 42 b
0.4 – 864 5.7–6.3
Primene 10 100 48 1.9 0.5 0.6 780 5.5
Aminoven infant 10 100 51 0.5 4.2c 0.4 885 5.5–6.0
Vaminolact 6.5 65 44 1.0 0.5 0.3 510 5.2
b
TrophAmin 10 100 49 0.2 0.3 875 5.5
EAA Essential amino acID (n = 8)
a
As acetyl-cystein
b
Separately as cystein HCl
c
As acetyl-tyrosine
Table 3 Oil content (%) in commercially manufactured intravenous lipid emulsions
Product Soy (LCT) Coconut (MCT) Olive (MUFA) Fish (ω3)
IntralipID 100 0 0 0
Lipofundin MCT/LCT 50 50 0 0
StructolipID 64 36 0 0
ClinOleic 20 0 80 0
LipoPlus 40 50 0 10
SMOFlipID 30 30 25 15
Omegaven 0 0 0 100
LCT long-chain triglycerides, MCT medium-chain triglycerides, MUFA mono unsaturated fatty acid
a 1:1 ratio of LCT with coconut oil-derived from blood in moderately catabolic patients. The
medium chain triglycerides (MCT). Structured newer lipid combinations with a smaller propor-
MCT/LCT emulsions formulated from a random tion of soy oil, have a much lower content of
combination of triglycerides synthesized on the linoleic acid and linolenic acid, the potentially
same glycerol carbon chain are cleared faster pro-inflammatory ω-6 PUFA, and less myristic,
614 J. Rigo and T. Senterre
palmitic, and stearic acids. These long-chain SFAs Phosphorus may be provided in inorganic
are believed to have increased cardiovascular risk (sodium or potassium phosphate) or organic
and can also have acute effects on cell growth and form (glucose 1 phosphate, fructose 1–6 diphos-
apoptosis. In MCT/LCT emulsions, MCT may be phate, sodium glycerophosphate). Potassium
preferentially metabolized under certain clinical phosphate is frequently preferred to sodium phos-
conditions and structured MCT may have a phate and used as the unique source of potassium
reduced tendency to accumulate in the reticulo- in the parenteral solution. Potassium phosphate is
endothelial system. The olive oil-derived ω-9 easy to use but its high potassium content (1 mmol
MUFA appears less immunosuppressive and P3 /1 mmol K for the monobasic form, 1 mmol
may inhibit release of pro-inflammatory cyto- P3 /2 mmol K for the dibasic form or 1 mmol P3 /
kines. They are also less susceptible to peroxida- 1.7 mmol K for the mixed form) limit its utiliza-
tion and well tolerated in critically ill neonates. tion in parenteral nutrition for VLBW infants.
Fish oil emulsions are predominantly ω-3 long- Organic phosphorus in the form of disodium glu-
chain PUFA. Alone, they lack EFA and are for- cose 1 phosphate (Phocytan) is widely used in
mulated as a supplement to be administered with parenteral solution for VLBW infants. However,
other nutritionally complete lipid products, or are as for the use of sodium glycerophosphate,
manufactured as physical mixtures (10% fish: 2 mmol Na+/1 mmol P3 , or fructose 1–6 diphos-
40% soy: 50% MCT or 30% soy:30% MCT:25% phate (Esafosfina) the sodium content, 3 mmol
olive oil:15% fish). Fish oil-derived ω-3 PUFAs Na+/2 mmol P3 , limits its utilization in VLBW
appear to alleviate symptoms of cholestasis, espe- infants particularly during the first weeks of life.
cially in neonates. Modern lipid products, based Magnesium is generally provided as magne-
on olive, coconut, and/or fish oils, have demon- sium sulfate in parenteral solution. Magnesium
strable formulation and clinical benefits over tra- chloride has also been associated with the risk of
ditional soybean and safflower IVLE and, when inducing anionic-cationic imbalance in the paren-
combined in the new multi-chamber bags, can teral solution.
also offer improvements in stability and safety
(Hardy and Puzovic 2009; Diamond et al. 2009; 39.4.1.4 Vitamins and Trace Elements
Waitzberg et al. 2006). With the daily use of hydro- and lipo-soluble
vitamins combined with trace elements clinical
39.4.1.3 Mineral Sources and biochemical evidence of deficiency were no
In parenteral nutrition, calcium may be provided longer reported.
in the form of calcium gluconate, calcium chloride
or calcium glycerophosphate. Due to aluminium
contamination calcium gluconate was progres- 39.4.2 Tailored or Standard Parenteral
sively abandoned by industry to meet the new Solutions
FDA rule of 25 μg/L of aluminium in parenteral
solution but remains frequently used in home- Parenteral solutions can be prescribed using either
made hospital pharmacy preparations. Calcium of two formats: tailored or standard (Poole and
chloride is easy to use but its high chloride content Kerner 1992; Lapillonne et al. 2009). Tailored
(2 mmol Cl /1 mmol Ca++) limits its utilization solutions are formulated specifically to meet the
in parenteral nutrition for VLBW infants (Poole daily nutritional requirements of the individual
et al. 2008; Bohrer et al. 2010). Calcium gly- patient, whereas standard solutions are designed
cerophosphate with a 1:1 molar ratio is an ade- to provide a formulation that meets most of the
quate source of calcium and phosphorus, but is not nutritional needs of the stable biochemical and
registered for use in parenteral nutrition and needs metabolic parameters. Both of these methods
to be prescribed from powdered anhydrous have advantages and disadvantages associated
CaGlyP. with their use.
39 Parenteral Nutrition 615
Tailored solutions are based on the principle disadvantage of standard solutions is their lack
that no single parenteral regimen can be ideal for of patient specificity and the need of minimal
all patients, for a wide variety of pathological adjustment particularly during the first days
processes, all age groups, or for the same patient of life.
during a single disease. The main advantage of Very recently, it was suggested that the use of
tailored solutions is flexibility. Each solution is unique standard parenteral solution contribute to a
formulated for an individual patient and can be significant improvement of nutritional support in
modified when the patient’s nutritional needs and both extremely and very preterm infants (Senterre
metabolic, electrolyte or clinical status changes. and Rigo 2011b). In addition, ready to use indus-
The disadvantage of these solutions is linked to trially manufactured multi-chamber bags (MCB)
the time involved in calculation and label prepa- containing the three sterilized macro-nutrient
ration, which today is nevertheless diminished solutions (amino acids, glucose, and lipids), in
with the use of specific computer programs. separate chambers of a single closed plastic sys-
These solutions should be prepared with strict tem were evaluated in multicentric study and pro-
aseptic techniques, possibly in the pharmacy, not vides similar benefits (Rigo et al. 2011). Their
in the ward, and stored in a refrigerator at 4 C. guaranteed sterility and longer shelf life are
The solutions thus prepared are stable for 96 h and major technological advances that minimize the
should be allowed to reach room temperature risks of inadvertent contamination during
slowly and not warmed before infusion. compounding and storage.
Standard solutions contain fixed amounts of
each component per unit volume. In some hospi-
tals there are a few types of fixed solutions to 39.4.3 Nutrient Intake
better cover the nutritional requirements of pre-
mature infants. The advantages of these solutions Table 4 shows the composition of a ready to use
are that they include all the essential nutrients in parenteral solution for VLBW infants used in our
fixed amounts, which eliminates the chances of NICU and the daily nutrient intake (kg/d) given
inadvertent omission or overload. The by total parenteral nutrition according to the new
Table 4 Parenteral nutrition solution and daily nutrient intake (kg/d) of very low birth weight infants (<1500 g) in total
parenteral nutrition according the “aggressive approach”
Day of life Composition D1 D2 D3 D4 D5 D6 >D6
/kg/d /kg/d /kg/d /kg/d /kg/d /kg/d /kg/d
Parenteral solution (mL) 100 50 70 100 120 140 150 150
Glucose (g) 12.5 6.3 8.8 12.5 15.0 17.5 18.8 18.8
Amino acid (g) 2.7 1.4 1.9 2.7 3.2 3.8 4.1 4.1
Calcium (mg) 72 36 50 72 86 100 108 108
Phosphorus (mg) 55 27 38 55 66 77 82 82
Magnesium (mg) 8 4.0 5.6 8.0 9.6 11.2 12.0 12.0
Natrium (mmol) 1.6 0.8 1.1 1.6 1.9 2.2 2.4 2.4
Kalium (mmol) 1.5 0.8 1.1 1.5 1.8 2.1 2.3 2.3
Chloride (mmol) 2.0 1.0 1.4 2.0 2.4 2.8 3.0 3.0
AA supplement (g)a 1.0 1.0 0.5 – – – –
Lipid emulsion 20% (g)a 1.0 1.5 2.0 2.5 3.0 3.0 3.0
Total fluid (mL) 65 83 110 132 155 165 165
Total energy (kcal)b 57 42 69 76 91 108 113 113
Total AA g 2.4 2.9 3.2 3.2 3.8 4.1 4.1
a
ProvIDed separately in Y route
b
Energy (kcal) = AA 3.75 + Glu 3.75 + lip 9.3
616 J. Rigo and T. Senterre
practice of “aggressive nutrition” for VLBW gradually increased to 3–3.5 g/kg/d. The lipid
infants. In any case nutrient intakes are always infusion should be adjusted to maintain a
indicative and may be modified according to serum lipid <250 mg/dL. Using a similar
each patient, his/her clinical picture, biochemical approach allows to reduce the cumulative
data and tolerance to nutrient intake. Thus, this nutritional deficit and limit or abolish postnatal
standard solution could be diluted with free water growth restriction in VLBW infants (Senterre
according to fluid requirement and sodium intake and Rigo 2011a; Lapillonne et al. 2009).
could be adapted after a few days of life.
These nutrient intakes are a mere indication
and have to be modified according to the clinical References
picture and biochemical data of the single patient.
The following suggestions could be useful in the Agostoni C, Buonocore G, Carnielli VP et al (2010)
management of a parenterally fed VLBW infant. Enteral nutrient supply for preterm infants: commen-
tary from the European Society of Paediatric Gastroen-
terology, Hepatology and Nutrition Committee on
• In the first days of life fluid intake should be Nutrition. J Pediatr Gastroenterol Nutr 50:85–91
increased if daily weight loss is >5%, total Ben XM (2008) Nutritional management of newborn
weight loss>12–15%, serum Na >150 mmol/ infants: practical guidelines. World J Gastroenterol
28:6133–6139
L, urinary osmolality >350 mOsm/L and if the Bohrer D, Oliveira SM, Garcia SC et al (2010) Aluminum
infant is under phototherapy or managed in a loading in preterm neonates revisited. J Pediatr
radiant incubator. On the contrary fluid intakes Gastroenterol Nutr 51:237–241
should be reduced if daily weight loss <2% or Borum PR (2009) Carnitine in parenteral nutrition. Gastro-
enterology 137(Suppl 5):S129–S134
there is a weight gain and serum Na Cairns PA, Stalker DJ (2000) Carnitine supplementation of
<130 mmol/L. parenterally fed neonates. Cochrane Database Syst Rev
• Glucose should be routinely administered after (4):CD000950
birth and progressively increased with the De Curtis M, Rigo J (2004) Extrauterine growth restriction
in very-low-birthweight infants. Acta Paediatr
objective to increase energy intake. When a 93:1563–1568
glucose infusion rate of 6 mg/kg/min or less De Curtis M, Senterre J, Rigo J (1986) Estimated and
leads to hyperglycemia, the use of insulin is measured energy content of infant formulas. J Pediatr
advised. Insulin should be discontinued as Gastroenterol Nutr 5:746–749
Diamond IR, Pencharz PB, Wales PW (2009) What is the
soon as glucose tolerance is established and current role for parenteral lipid emulsions containing
the energy supply necessary for growth can omega-3 fatty acids in infants with short bowel syn-
be delivered without hyperglycemia. If insulin drome? Minerva Pediatr 61:263–272
is used, strict blood glucose monitoring is man- Donovan R, Puppala B, Angst D, Coyle BW (2006) Out-
comes of early nutrition support in extremely low-
datory to avoid hypoglycemia. birth-weight infants. Nutr Clin Pract 21:395–400
• The starting dose of AA in the first day of life Ehrenkranz RA, Younes N, Lemons JA et al (1999) Lon-
should be higher than what is currently gitudinal growth of hospitalized very low birth weight
advised. Intake should never be less than infants. Pediatrics 104:280–289
Embleton NE, Pang N, Cooke RJ (2001) Postnatal malnu-
1.5 g/kg/d and the starting dose should prefer- trition and growth retardation: an inevitable conse-
ably be 2.0–3 g/kg/d. When energy intakes quence of current recommendations in preterm
reach about 70 kcal/kg/d and there is no enteral infants? Pediatrics 107:270–273
protein intake, the dose should be increased Fusch C, Bauer K, Böhles HJ et al (2009) Neonatology/
paediatrics. Guidelines on parenteral nutrition,
progressively to 3.5–4.4 g/kg/d. Chapter 13. Ger Med Sci 7: Doc15
• Although many neonatal intensive care units Hardy G, Puzovic M (2009) Formulation, stability and
start lipid infusion only after the first days, it administration of parenteral nutrition with new lipid
seems logical to start parenteral lipid within the emulsions. Nutr Clin Pract 24:616
Kalhoff H, Diekmann L, Hettrich B et al (1997) Modified
first day in order to avoid a prolonged interrup- cow’s milk formula with reduced renal acid load pre-
tion of essential fatty acids and LC-PUFA. The venting incipient late metabolic acidosis in premature
starting dose of 0.5–1 g/kg/d should be infants. J Pediatr Gastroenterol Nutr 25:46–50
39 Parenteral Nutrition 617
Koletzko B, Goulet O, Hunt J et al (2005) Guidelines on Senterre T, Rigo J (2011a) Optimizing early nutritional
Paediatric Parenteral Nutrition of the European Soci- support based on recent recommendations in VLBW
ety Pediatric Gastroenterology, Hepatology and Nutri- infants allows abolishing postnatal growth restriction.
tion (ESPGHAN) and the European Society for J Pediatr Gastroenterol Nutr [Epub ahead of print]
Clinical Nutrition and Metabolism (ESPEN), Senterre T, Rigo J (2011b) Reduction of postnatal cumula-
Supported by the European Society of Paediatric tive nutritional deficit and improvement of growth in
Research (ESPR). J Pediatr Gastroenterol Nutr 41 extremely preterm infants. Acta Paediatr [Epub ahead
(Suppl 2):S1–S87 of print]
Lapillonne A, Fellous L, Mokthari M, Kermorvant- Simmer K (2007) Aggressive nutrition for preterm infants.
Duchemin E (2009) Parenteral nutrition objectives for Benefits and risks. Early Hum Dev 83:631–634
very low birth weight infants: results of a national Stephens BE, Walden RV, Gargus RA et al (2009) First-
survey. J Pediatr Gastroenterol Nutr 48:618–626 week protein and energy intakes are associated with
Martin CR, Brown YF, Ehrenkranz RA et al (2009) Nutri- 18-month developmental outcomes in extremely low
tional practices and growth velocity in the first month birth weight infants. Pediatrics 123:1337–1343
of life in extremely premature infants. Pediatrics Thureen PJ, Melara D, Fennessey V et al (2003) Effect of
124:649–657 low versus high intravenous amino acid intake on very
Poole RL, Kerner JA (1992) Practical steps in prescribing low birth wight infants in the early neonatal period.
intravenous feeding. In: Yu VYH, MacMahon RA (eds) Pediatr Res 53:24–32
Intravenous feeding of the neonate. Edward Arnold, Tsang RC, Uauy R, Koletzko B, Zlotkin SH (eds) (2005)
London, pp 259–264 Nutrition of the preterm infant: scientific basis and
Poole RL, Hintz SR, Mackenzie NI, Kerner JA Jr (2008) practice, 2nd edn. Digital educational Publishing, Cin-
Aluminum exposure from pediatric parenteral nutri- cinnati, pp 415–418
tion: meeting the new FDA regulation. JPEN Tubman TR, Thompson SW, McGuire W (2008) Gluta-
32:242–246 mine supplementation to prevent morbidity and mor-
Rigo J (2005) Protein, amino acid and other nitrogen tality in preterm infants. Cochrane Database Syst Rev
compounds. In: Tsang RC, Uauy R, Koletzko B, (23):CD001457
Zlotkin SH (eds) Nutrition of the preterm infant: scien- Van Goudoever JB, Sulkers EJ, Timmermans M et al
tific basis and practice, 2nd edn. Digital educational (1994) Amino acid solutions for premature infants dur-
Publishing, Cincinnati, pp 45–80 ing the first week of life: The role of N-acetyl-L-cysteine
Rigo J, De Curtis M (2004) Parenteral nutrition in prema- and N-acetyl-L-tyrosine. JPEN 18:404–408
ture infants. In: Guandalini S (ed) Texbook of pediatric Waitzberg DL, Torrinhas RS, Jacintho TM (2006) New
gastroenterology and nutrition. Taylor and Francis, parenteral lipid emulsions for clinical use. JPEN
London/New York, pp 619–638 30:351–367
Rigo J, De Curtis M, Pieltain C (2002) Nutritional assess- Wilson DC, Cairns P, Halliday HL et al (1997)
ment and body composition of preterm infants. Semin Randomised controlled trial of an aggressive nutri-
Neonatol 6:383–391 tional regimen in sick very low birthweight infants.
Rigo J, Marlowe ML, Bonnot D (2011) Practical handling, Arch Dis Child 77:4F–11F
ease of use, safety, and efficacy of a new pediatric triple- Ziegler EE, Thureen PJ, Carlson SJ (2002) Aggressive
chamber bag for parenteral nutrition in preterm infants. J nutrition of the very low birthweight infant. Clin Peri-
Pediatr Gastroenterol Nutr [Epub ahead of print] natol 29:225–244
Postdischarge Nutrition in Preterm
Infants 40
Richard J. Cooke
Contents
40.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620
40.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620
40.3 Postnatal Malnutrition and Growth Failure in
Preterm VLBWI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620
40.4 Importance of Postnatal Malnutrition and
Growth Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
40.5 Catch-Up Growth, Insulin Resistance, and
Visceral Obesity in Preterm Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
40.6 Post-discharge Nutritional Support in Preterm Infant . . . . . . . . . . . . . . . . . . . . 627
40.6.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627
40.6.2 Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629
40.6.3 Breastfeeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631
40.7 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633
Abstract with poorer neurodevelopmental outcome.
Most preterm, particularly very-low-birth- Before hospital discharge, preterm infants fed
weight, infants (VLBWI) are undernourished human milk do not grow as well as infants fed
and undergrown at hospital discharge. Growth nutrient-enriched formulas; also after dis-
is “preprogrammed” to occur at a certain time charge, it seems prudent to use milk fortifica-
or “critical” epoch which if missed may not be tion for all breastfed infants. The nutritional
recoverable. Studies indicate that poor growth content of fortifiers differs: the level of fortifi-
between birth-hospital discharge is associated cation should be adjusted to ensure that
growth, in terms of weight and length gain, is
“tracking” in the right direction. Evidence sug-
gests that a reduced body size is paralleled by a
R. J. Cooke (*)
Department of Pediatrics, University of Tennessee Health reduction in fat-free mass but a relative
Science Center, Memphis, TN, USA increase in fat mass, so particular attention
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 619
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_189
620 R. J. Cooke
should be paid to dietary protein and energy • Continuing and close communication
intakes in these infants. Close communication between designated personnel in the neonatal
between designated personnel in the neonatal intensive care unit and the infant’s family as
intensive care unit and the infant’s family is well as the primary care providers is essential
essential during this critical “epoch” of growth during this critical “epoch” of growth and
and development. development.
40.1 Salient Points 40.2 Introduction
• Current recommendations are that the rate of The fundamental principle underlying nutritional
weight gain parallels that of a fetus of the same support is that intake meets needs, thereby ensur-
gestational age once birth weight has been ing the best outcome, in the case of the preterm
regained. infant, optimal growth, and development. Achiev-
• Post-natal growth failure is not preventable ing this goal is problematic and most, if not all,
given current recommendations and the way \very-low-birth-weight infants (VLBWI) are
infants are fed. undernourished and undergrown when first
• Close attention should be paid to the nutri- discharged home. This has important implications
tional support and growth of these infants for nutritional care of these high-risk infants after
after hospital discharge. A reduced body hospital discharge.
size that is paralleled by a reduction in fat- In this chapter the following issues will be
free mass but a relative increase in fat mass addressed:
suggests that particular attention should be
paid to dietary protein and energy intakes in • Postnatal malnutrition and growth failure
these infants. (PGF) between birth and hospital discharge in
• The extent to which “catch-up” occurs depends preterm infants
on many factors, including timing of the insult. • Catch-up growth, insulin resistance, and vis-
Growth and development are thought to be ceral obesity in preterm infants
programmed within specific time frames or • Nutritional care of VLBWI after hospital
critical epochs, which if missed may not be discharge
recoverable.
• Since all VLBWI accrue a significant nutrient
deficit between birth and hospital discharge 40.3 Postnatal Malnutrition
and mature human milk is designed for the and Growth Failure in Preterm
needs of “normal” infants, it seems prudent to VLBWI
use milk fortification for all breastfed infants
after discharge. Several studies have examined postnatal growth
• The nutritional content of fortifiers differs. Fur- in preterm infants during initial hospital stay and
ther studies are needed to examine if one is noted that most preterm, if not all very-low-birth-
better than another. In the meantime, the level weight infants (VLBWI), are growth retarded at
of fortification should be adjusted to ensure hospital discharge (Wilson et al. 1997; Carlson
that growth, in terms of weight and length and Ziegler 1998; Embleton et al. 2001; Clark
gain, is “tracking” in the right direction. et al. 2003; Olsen et al. 2002; Ehrenkranz
• Irrespective of what feed is used, growth et al. 1999; Cooke et al. 2004). In studies where
should be closely monitored and intake nutritional intake was measured, recommended
adjusted with the goal that birth centile, at dietary intakes (RDIs) took time to establish, and
least for weight, is reestablished between dis- infants accrued a significant nutrient deficit that
charge and 1–2 mca. was directly related to the growth deficit (Wilson
40 Postdischarge Nutrition in Preterm Infants 621
et al. 1997; Carlson and Ziegler 1998; Embleton SGA infant who regains birth weight at 2 weeks
et al. 2001; Clark et al. 2003; Olsen et al. 2002). and then gains at the recommended rate of 17 g/
In studies where intake was not measured, poor kg/day will weigh 1,727 g at 37 weeks, 800 g less
growth was related to non-nutritional factors such than the 690 AGA infant at the same gestational
as “illness” (Ehrenkranz et al. 1999; Cooke age and ~1,300 g less than the fetus at the same
et al. 2004). In the recent study of Griffin gestational age (Fig. 2). Recommendations related
et al. (2016), necrotizing enterocolitis was noted to suboptimal weight will systematically underes-
to have a significant negative on growth (Griffin timate needs and growth potential in these high-
et al. 2016). This is not surprising because inter- risk infants.
current “illness” not only reduces intake but also At the same time, current recommendations
may alter nutrient assimilation and increase assume that nutritional requirements are con-
requirements (Mehta et al. 2013). However, sistent throughout gestation for all preterm
other factors underpin the development of growth VLBWI (AAPCON 1998; Klein 2002). How-
failure in these infants. ever, Ziegler et al. have noted that protein and
Current recommendations are that the rate of energy requirements change with advancing
weight gain parallels that of the fetus of the same gestation (Ziegler et al. 2002; Table 1). In
gestational age once birth weight has been effect, a formula containing a protein-energy
regained (AAPCON 1998; Klein 2002). Yet, a ratio of 3.0 g/100 kcal, as is currently fed to
24-week appropriately grown (AGA) infant preterm infants, does not meet the protein needs
weighing ~690 g at birth who regains birth weight of the infants weighing 1,500 g at birth, i.e.,
by 2 weeks of age and grows at the recommended the VLBWI.
rate, i.e., 17 g/kg/day, will weigh 2,527 g, ~531 g Recommended dietary intakes are based on
less than the fetus, and be growth retarded at needs for maintenance and normal growth
37 weeks (Fig. 1). If the same infant takes (AAPCON 1998; Klein 2002), and no allowance
3 weeks to regain birth weight and grows at the is made for recovery or “catch-up” growth (Heird
same rate, then she/he will weigh 2,285 g, 773 g 2001). In the study of Embleton et al., the accrued
less than the fetus at 37 weeks. protein deficit at hospital discharge varied from
Up to 40% of infants born prematurely are 15 to 25 g/kg (Embleton et al. 2001). An addi-
undergrown or small for gestational age (SGA) tional protein intake of 0.5–1.0 g/kg/day would
at birth (Larsen et al. 1990). A 24-week 550 g have been required to recoup this deficit before
Fig. 1 Growth curve for a Postnatal Growth In A 24 w 690 AGA Infant*
24-week AGA preterm 3500
infant who regains birth Fetus 3058 g
weight by 7, 14, and 21 days 3000
and then grows at a rate of 1 w – 2792 g
17 g/kg/day 2500 2 w – 2527 g
Weight (g)
3 w – 2285 g
2000
1500
1000
500
0
23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38
Gestational Age w
• Regaining birth weight at 1,2 and 3 w and growing at 17 g/kg/d
622 R. J. Cooke
Fig. 2 Growth curve for a Postnatal Growth in 24 w AGA and SGA Infant*
24-week AGA and SGA 3000
preterm infants who regain
birth weight by 14 and then AGA – 2527 g
2500
grow at a rate of 17 g/kg/day
SGA – 1727 g
2000
Weight (g)
1500
1000
500
0
23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38
Gestational Age w
• Regaining birth weight at 2 w and growing at 17 g/kg/d
Table 1 Protein and energy needs in preterm infants
Weight g 500–700 700–900 900–1,200 1,200–1,500
Protein g/kg/day 4.0 4.0 4.0 3.9
Energy kcal/kg/day 105 108 119 127
P:E g/100 kcal 3.8 3.7 3.4 3.1
hospital discharge, further compounding the Table 2 Body size and composition of study infants com-
problem. pared to the reference infant at the same weight and same
gestation (Cooke and Griffin 2009)
To further examine this issue, body size and
body composition were measured in preterm Reference Reference
Study at at
infants (n = 149) at hospital discharge (Cooke
infantsa 35 weeksa 37 weeksa
and Griffin 2009). Weight, length, and head cir-
Body 2,369 305 2,450 2,940
cumference were measured using standard meth- weight g
odology (Cooke et al. 1998). Body composition Fat-free 2,062 277a 2,252a 2,667a
was measured using dual-emission x-ray absorp- mass g
tiometry (Cooke et al. 1999). Fat-free 87 3.4 91.9 90.7
The post-menstrual age at discharge was mass %
37 1.2 weeks. However, Z-score for head cir- Fat mass 307 130b 198b 273b
g
cumference ( 0.1 0.6) was significantly
Fat mass 13 3.4b 8.1b 9.3b
greater than that for weight ( 1.4 0.6) which %
in turn was greater than for crown-heel length a
Study infants < reference at 35 week or 37 weeks
( 1.9 0.6; p < 0.0001) (Cooke and Griffin ( p < 0.0001)
2009). Body composition results are compared
b
Study infants > reference at 35 week or 37 weeks
to the reference infant at the same weight and ( p < 0.001)
same gestation in Table 2.
Global fat-free mass was less in study infants
than the reference infant at the same weight 13 > 8%) or gestation (307 > 273 g; 13 > 9%;
(2,062 < 2,252 g; p < 0.0001) or gestation p < 0.0001) (Cooke and Griffin 2009).
(2,062 < 2,667 g; p < 0.0001). Global fat mass A reduced body size that is paralleled by
was greater in study infants than the reference reduced linear growth and a reduced fat-free
infant at the same weight (307 > 198 g, mass indicate that dietary protein needs were
40 Postdischarge Nutrition in Preterm Infants 623
not met in these infants before hospital dis- term infant will double birth weight by 4–5 m,
charge, as has been previously suggested triple birth weight by 12 m, and approximately
(Ziegler et al. 2002). A reduced fat-free mass quadruple it by 24 m.
coupled with an increased global and central fat Growth is also thought to be “preprogrammed”
mass echoes concerns about visceral obesity to occur at a certain time or “critical” epoch which
and the development of insulin resistance in if missed may not be recoverable (Dobbing 1981).
these high-risk infants (Uthaya et al. 2005; Thus, even short periods of nutritional deprivation
Yeung 2006). may not only affect somatic but also brain growth
Although many factors contribute to the devel- and development (Dobbing 1981), the area of the
opment of PGF and the degree of which will vary, brain that is “programmed” to grow fastest being
depending upon the level of maturity/size of the the most affected (Bedi 1987).
infant (Embleton et al. 2001), it is clear that: In term infants, malnutrition during infancy is
associated with permanent alterations in brain
1. It is not preventable given current recommen- growth and function. Brain size is reduced (Galler
dations and the way infants are fed; i.e., target et al. 1996; Stoch et al. 1982; Dobbing 1987;
growth rates related to a suboptimal body Winick and Rosso 1969a, b), the brain cortex is
ensure that most, if not all, infants will be thinner (Dobbing and Sands 1971), neuronal
moderately/severely growth retarded at hospi- numbers are decreased (Dobbing et al. 1971),
tal discharge. myelination is reduced (Krigman and Hogan
2. Close attention must be paid to nutritional 1976), and dendritic morphology is altered
support and growth of these infants after (Benitez-Bribiesca et al. 1999; Cordero
hospital discharge. A reduced body size et al. 1993), all of which can be related to poorer
that is paralleled by a reduction in fat-free neurodevelopmental outcome (Pryor et al. 1995;
mass but a relative increase in fat mass indi- Ounsted et al. 1988; Gross et al. 1983; Hack and
cates that particular attention be paid to die- Breslau 1986; Hack et al. 1991; Kitchen
tary protein and energy intakes in these et al. 1992a; Cooke and Foulder-Hughes 2003;
infants. Stathis et al. 1999; Peterson et al. 2006).
These concerns are greater in preterm infants.
Growth rates are greater. A preterm infant is
40.4 Importance of Postnatal “programmed” to quadruple brain weight
Malnutrition and Growth between 24 and 40 weeks gestation or 16 weeks
Failure (Alexander et al. 1996), almost six times faster
than the term infant. Preterm infants are also more
The importance of malnutrition cannot be vulnerable to the effects of perinatal ischemia and
underestimated. Nutrients play a critical role on inflammation, therefore the development of
the promotion of normal health and prevention of periventricular intraventricular hemorrhage and
disease (Shils et al. 2006). It is not surprising, periventricular leukomalacia (Volpe 2008).
therefore, that it can be directly related to alter- Compared to term, preterm infants are also
ations in organ structure and function which, in more likely to be fetally and/or postnatally mal-
turn, are paralleled by an increased morbidity and nourished. Up to 40% of preterm infants are
mortality in adults and children (Shils et al. 2006). growth retarded or small for gestational age
However, the effects of malnutrition are greater (SGA) at birth (Greisen 1992). At the same time,
during infancy than later in life. There are several up to 100% of preterm VLBWI undergo signifi-
reasons for this. cant postnatal growth failure and are SGA at hos-
Requirements are a function of growth rate; the pital discharge (Ehrenkranz et al. 1999).
greater the rate, the greater the requirement and the Poor fetal growth is paralleled by reduced
more likely that deficiency will occur. Growth rates organ growth as well as altered structure and
are greater during infancy than later in life; i.e., the function (McCance and Widdowson 1974) but
624 R. J. Cooke
not all organ systems are affected equally. This is In this study, infants were stratified at birth and
well illustrated in the study of Myers et al. (1971). into those who were appropriate size for gesta-
In this study, 30% reduction in body weight in tional age (AGA weight 10th percentile) and
SGA monkeys was associated with an 8% reduc- SGA (weight <10th percentile). This process
tion in brain weight but 35% reduction in lung, was repeated at 2 years of age. Four groups
liver, pancreatic, and spleen weights when com- emerged: (a) AGA at birth and 2 years
pared to their AGA counterparts (Myers (AGA-AGA), (b) AGA at birth and SGA at
et al. 1971). Thus, the brain is “spared” at the 2 years (AGA-SGA), (c) SGA at birth and AGA
expense of other organs which, e.g., through the at 2 years (SGA-AGA), and (d) SGA at birth and
development of chronic lung disease, sepsis, etc., 2 years (SGA-SGA).
may amplify undernutrition by reducing intake No differences were noted in development
and/or increasing requirements. between the AGA-AGA and SGA-SGA infants.
In the late 1980s and early 1990s, studies After adjusting for co-variables, infants who
indicated that poor growth between birth- “caught up,” i.e., SGA-AGA, had greater Bayley
hospital discharge was associated with poorer PDIs than those who did not (SGA-SGA). Infants
neurodevelopment (Morley 1999; Ehrenkranz who “faltered” (AGA-SGA) had lower PDIs and
et al. 2006) and that better growth, as achieved MDIs than those who continued to thrive
by feeding a nutrient-enriched formula, was (AGA-AGA). These authors concluded that the
associated with better developmental outcomes course of postnatal growth primarily determined
(Lucas et al. 1998, 1990). More recently, early later development.
parenteral nutrition coupled with the early intro- To more closely examine this issue, Dharmaraj
duction and advancement of enteral feeds has et al. prospectively followed growth between birth
been associated with better growth but many and18 months corrected age (mca) and develop-
infants continue to be SGA at hospital discharge mental outcome at 18 mca (Dharmaraj et al. 2005).
(Evans and Thureen 2001; Dinerstein It was hypothesized that the greater the degree of
et al. 2006; Ibrahim et al. 2004; Donovan early growth failure (birth to 28 days), the poorer
et al. 2006). the development at 18 mca. Infants were stratified
While a clear relationship exists between at 28 days into those with mild (fall in weight
“catch-up” growth and development in preterm Z-score % 1.0; MGF) and severe (fall in weight
infants, the time frame within which it needs to Z-score >1.0; SGF) growth failure. This process
occur is not well delineated. In most studies, was repeated at 18 mca.
infants who “catch up” or “catch back” by The characteristics of the study infants are
6–9 m corrected age have better neurodeve- presented in Table 3. No differences were noted
lopmental outcome (Morley 1999; Scott and with the exception that gestational age was less
Usher 1966; Hack et al. 1982; Hack and Fanaroff (SGR-SGR < MGR-MGR, MGR-SGR,
1984; Latal-Hajnal et al. 2003). This is illustrated p < 0.05) and the frequency of cerebral palsy
in the study of Latal-Hajnal et al. (2003). tended to be greater (SGR-SGR > MGR-MGR,
Table 3 Characteristics of study infants (Dharmaraj et al. 2005)
Group (N) MGR-MGR (50) MGR-SGR (18) SGR-SGR (16) SGR-MGR (24)
Birth weight (g) 1,320 339 1,348 387 1,312 559 1,271 408
Gestation (w) 30 1.6a 30 1.8a 28 3.0a 29 2.3
BPD 13 (26 %) 3 (17 %) 6 (38 %) 10 (42 %)
Abnormal CUS 10 (20 %) 5 (28 %) 3 (19 %) 6 (25 %)
PVL 3 (6 %) 2 (11 %) 1 (6 %) 3 (13 %)
Cerebral palsy 4 (8 %) 3 (17 %) 5 (30 %)b 2 (8 %)
a
SGR-SGR < MGR-MGR, MGR-SGR, p < 0.05
b
SGR-SGR > MGR-MGR, SGR-MGR, p < 0.10
40 Postdischarge Nutrition in Preterm Infants 625
Fig. 3 Growth, i.e., change Postnatal Growth in Study Infants*
in weight Z-score between 1.0
Change In Weight Z-score From Birth
birth and 28 days, term and
one through 18 month 0.5 MGF-MGF
corrected age in infants in
the study of Dharmaraj et al. 0
SGF-MGF
−0.5
−1.0
−1.5 MGF-SGF
−2.0 SGF-SGF
Birth 28d Disc EDD +1m +2m +3m +6m + 9m + 12m +18m
* Dharmaraj et al60
Table 4 MDI and PDI in study infants (Dharmaraj et al. 2005)
Group (N) MGR-MGR MGR-SGR SGR-MGR SGR-SGR
MDIa 93 18 91 18 95 1 77 19
PDIa 90 17a 83 19 87 19b 77 22a
MDIb 96 15 93 20 98 16 88 11
PDIb 94 13 89 15 91 14 89 16
MDI ~ MGR-MGR, SGR-MGR > SGR-SGR. p < 0.05
a
PDI ~ MGR-MGR ( p < 0.05), SGR-MGR ( p < 0.10) > SGR-SGR
b
Infants with cerebral palsy excluded. MDI ~ MGR-MGR ( p < 0.05), SGR-MGR ( p < 0.10) > SGR-SGR
SGR-MGR, p < 0.10) in infants with severe Collectively, these data support the conclusions
growth failure at 28 days and 18 m corrected age. of Latal-Hajnal et al.; i.e., it is the course of postna-
Growth of these infants is presented in Fig. 3. tal growth that determines later developmental out-
Between birth and 28 days, Z-scores for weight come in preterm infants. The data of Dharmaraj
decreased and then recovered to some degree in et al. also indicate that a “critical window of oppor-
all groups. After 28 days, growth continued to tunity” exists between 28 days and 1–2 mca during
improve in infants with MGF at 28 days and which “recovery” or “catch-up” growth, to birth-
18 mca (MGF-MGF) and SGF at 28 days but weight percentile, is paralleled by better neurodeve-
mild growth failure (SGF-MGF) at 18 mca. How- lopmental outcome. If infants are to “recover,” this
ever, growth faltered in the other groups, that is, is the time frame within which to do it.
MGF-SGF and SGF-SGF.
The developmental outcome data are presented
in Table 4. MDI and PDI were less in SGF-SGF 40.5 Catch-Up Growth, Insulin
than MGF-MGF infants, supporting the primary Resistance, and Visceral
hypothesis that poor growth between birth and Obesity in Preterm Infants
28 days is a marker for poor development. MDI
and PDI were also greater in infants who recov- Despite the prevalence/severity of PGF that is
ered after 28 days (SGF-MGF) than those who did paralleled by an increased morbidity/mortality
not (SGF-SGF), indicating that “catch-up” growth before/after hospital discharge, concern has been
between 28 days and 18 mca is paralleled by expressed about measures taken to improve
markedly improved development. growth after hospital discharge. Concern largely
626 R. J. Cooke
relates to “catch-up” growth and the subsequent “catch-up” that is paralleled by increased fat depo-
development of insulin resistance (Singhal sition. A diet that better meets protein needs will be
et al. 2001, 2003) and metabolic syndrome X paralleled by increased lean mass accretion.
(Ong and Loos 2006) leading to the idea that Energy density is the prime determinant of vol-
“bigger might not be better,” even in preterm ume of intake in infants (Fomon 1993a; Cooke
VLBWI (Singhal et al. 2003). et al. 1998). Yet at borderline low protein intakes,
However, a certain amount of confusion exists volume/energy intake is increased to compensate
when the terms “rapid” and “catch-up” growth are and is associated with increased fat accretion
used; i.e., they are sometimes used interchangeably (Fomon 1993b). The energy cost of lean mass
(Ong and Loos 2006) but are not the same. “Rapid” accretion is ~13.4 kcal/g and that of fat accretion
growth is “an abnormal growth pattern that moves is 10.6 kcal/g (Roberts and Young 1988). At equiv-
upward beyond the original growth percentile on a alent energy intakes, therefore, the greater the rate
distance growth chart” (Hermanussen 2013a). of lean mass accretion, the lesser the tendency to fat
“Catch-up” is a physiologic condition of temporary accretion. A little more rather than less protein,
overgrowth that occurs after illness and/or starva- therefore, might be considered appropriate.
tion, and in the process, the original growth per- The relative roles of genetic, intrauterine, and
centile is reestablished (Hermanussen 2013b). environmental factors in the pathogenesis of insu-
The extent to which “catch-up” occurs depends lin resistance are unclear, but diet also plays a key
on many factors, including timing of the insult. role (Cornier et al. 2008). A high energy, i.e.,
Growth/development is thought to be glycemic or fat content, increases insulin needs,
programmed within a specific time frame or crit- fat synthesis, storage, etc. (Bremer et al. 2012).
ical epoch which if missed may not be recoverable Whether a “normal” infant diet, i.e., that appro-
(McCance and Widdowson 1974; Widdowson priate for a term infant, is likely to do so in
and McCance 1975). It also depends upon the VLBWI with PGF is unclear. What is clear is
severity and duration of the insult; the more severe that growth and nutritional need to be closely
and prolonged the insult, the greater the accrued monitored during the first 1–2 m after hospital
nutritional deficit. Intake, therefore, must not only discharge, with particular attention paid to ade-
replace the deficit but also meet needs for mainte- quacy of protein intake and protein-energy status,
nance and normal growth. i.e., monitoring linear growth and biochemical
With acute illness, infants develop a measures of status if needed, i.e., blood urea nitro-
hypermetabolic state, and there is an acute depletion gen, prealbumin, and albumin levels.
of body protein to meet energy needs (Lowry and To more closely examine this issue, body size
Perez 2006). With chronic protein-energy malnutri- and composition were measured in preterm
tion during infancy, visceral tissue is conserved at infants fed either a preterm formula (protein con-
the expense of protein and fat (Ashworth and tent = 2.7 g/100 kcal, discharge 6 m) (A), a term
Millward 1986). Nutritional rehabilitation in these formula (protein content 1.8 g/100 kcal, discharge
infants with high-energy intakes largely results in 6 m) (B), a preterm formula to term and then a
increased weight gain (MacLean and Graham 1980) term formula to 6 m (C), or unfortified breast milk
and body fat (MacLean and Graham 1980; Jackson (D) (Cooke et al. 1998, 1999). The results are
1990); i.e., the nature of the gain is dependent upon presented in Fig. 4.
the compositional nature of intake. “Rapid” growth was not noted in either treat-
At hospital discharge, all preterm VLBWI have ment group; i.e., Z-scores for weight did not exceed
accrued a significant protein and energy deficit birth percentile. Between discharge and term,
(Embleton et al. 2001) and are lighter and shorter “catch-up” growth in weight and length occurred
and have a reduced lean but greater fat mass than in the formula but not the breastfed infants. There-
the reference infant at the same body weight or after, “catch-up” occurred in all groups and was
gestation (Uthaya et al. 2005). Thereafter, a diet faster and more complete in infants fed the preterm
that is relatively high in energy will promote formula. Infants with the poorest growth were
40 Postdischarge Nutrition in Preterm Infants 627
Postnatal Growth in Study Infants* (c) Do not support the recommendation that a
0 preterm formula be fed to term and
-.5 discontinued thereafter (Aggett et al. 2006)
-.1
-1.5 40.6 Post-discharge Nutritional
-2 * Support in Preterm Infant
* *
-2.5
40.6.1 Overview
-3
Weight Z-score
-3.5 Before hospital discharge, it is important that
0 the method of feeding and growth patterns are
-.5 well established. Nutritional status of each
-1 infant should be closely evaluated, with the
-1.5 information communicated to the primary care
-2
* * * physician and arrangements for follow-up
-2.5 * * clearly defined.
-3 * Intake after discharge must not only meet
-3.5 needs for maintenance and normal growth but
-4 Length Z-score also “catch-up” growth. It is assumed that needs
-4.5 for normal growth are similar in preterm boys and
Group Preterm Term Cross-Over Breast girls. Yet, preterm boys grow faster in utero and
* Cooke et al 16,
accrete more lean mass than girls during the first
Discharge Term 12 w 6m 12 m 2–3 m of life (Rawlings et al. 1999). They are also
more susceptible to even marginal levels of intake
Fig. 4 Growth between discharge and 12 months in and benefit more when fed nutrient-enriched for-
infants fed a preterm infant formula, a term formula, or a
preterm formula (discharge-term)/term formula (after term,
mulas before (Lucas et al. 1989a, 1990, 1994;
crossover) or breastfed Morley and Lucas 1997) and after hospital dis-
charge (Cooke et al. 1999; Lucas et al. 2001; Car-
ver et al. 2001; Agosti et al. 2003).
those fed the preterm formula between discharge It is also assumed that needs for “recovery” are
and term and the term formula thereafter (Fig. 4). similar for all preterm infants. This is not the case.
More complete “catch-up” growth was paralleled Up to 40% of infants prematurely are small for
by an increase in fat-free mass and total fat mass but gestational age (SGA) at birth. Needs are likely to
not % fat mass (Table 5). No differences were differ between the AGA and SGA infants. At the
detected in central fat mass between the groups, same time, the severity of PGF not only varies
but leg fat mass was greater in infants fed the pre- widely between infants discharged from a given
term formula (Table 6). In effect, “catch-up” growth NICU (Embleton et al. 2001); i.e., the smaller and
was paralleled by an increase in linear growth, lean, more immature the infant, the greater the accrued
and fat mass accretion, the latter reflecting increased nutrient deficit, but also between NICUs (Olsen
peripheral not central fat mass accretion. et al. 2002; Cooke et al. 2004; Griffin et al. 2016;
Collectively, these data: Horbar et al. 2015). In effect, needs for “recovery”
are also highly variable.
(a) Do not support concerns about altered adipos- Collectively, these data emphasize the
ity in preterm infants fed a nutrient-enriched importance of individualized assessment before
formula after hospital discharge discharge and, irrespective of what an infant is
(b) Indicate that rate and composition of growth are fed, close nutritional monitoring after dis-
dependent upon the composition of the diet charge. Not surprisingly, many questions
628 R. J. Cooke
Table 5 Body composition of preterm infants fed either preterm formula, term formula, preterm formula (to term)/term
formula (after term, crossover), or breastfed (Cooke et al. 1999)
Term 12 weeks 6 months 12 months
Group (n = 148) (n = 141) (n = 145) (n = 138)
Fat-free Preterm 2,745 445 4,270 452 5,208 638 6,872 806 A>
mass (g) (A)
Term (B) 2,393 276 4,022 411 5,139 515 6,592 738 B
( p < 0.05)
Crossover 2,507 244 3,948 431 4,978 541 6,399 881 C
(C) ( p < 0.001)
Breastfed 2,171 296 3,762 1,051 5,063 568 6,451 746 D
(D) ( p < 0.005)
Fat mass (g) Preterm 570 256 1,455 461 2,033 686 2,332 679 A>
(A)
Term (B) 511 222 1,367 419 1,940 586 2,058 477 B
( p < 0.05)
Crossover 566 204 1,188 366 1,815 632 2,077 623 C
(C) ( p < 0.005)
Breastfed 331 128 1,365 527 1,934 658 2,153 645
(D)
Fat mass % Preterm 17 5.5 25 4.7 28 5.9 25 5.3
(A)
Term (B) 17 6.0 25 5.5 27 5.1 24 4.4
Crossover 18 4.7 23 4.1 26 5.8 24 4.5
(C)
Breastfed 13 3.2 25 8.2 27 6.8 25 4.8
(D)
Table 6 Regional body composition of preterm infants fed either preterm formula, term formula, preterm formula
(to term)/term formula (after term, crossover), or breastfed
G Group Term 12 weeks 6 months 12 months
Trunk Preterm (A) 172 65 532 168 651 218 699 249
Term (B) 182 71 485 154 635 170 613 160
Crossover (C) 186 67 394 136 579 221 573 162
Breastfed (D) 147 54 503 183 688 229 657 230
Legs Preterm (A) 159 58 500 155 736 270 975 354 A>
Term (B) 133 73 451 168 652 300 830 271 B ( p < 0.01)
Crossover (C) 129 75 458 133 602 247 822 409 C ( p < 0.001)
Breastfed (D) 98 58 454 183 654 289 897 254 D ( p < 0.10)
remain unanswered. How often should growth greater the degree of PGF, the greater the level
be monitored? of concern, until an acceptable growth pattern is
In the follow-up study of Dharmaraj achieved and maintained.
et al. (2005), growth velocity was greatest In the study of Cooke et al. (1998), significant
between discharge and term, continuing to growth faltering was noted:
1–2 mca, a time frame within which brain growth
velocity is also greatest and likely to be function- (a) In breastfed but not formula-fed infants
ally significant (Fig. 3). Growth monitoring dur- between discharge and term (Fig. 4)
ing this time frame should be done at least weekly, (b) When a dietary change was made, i.e., infants
if not more often in high-risk infants; i.e., the fed a preterm formula between discharge and
40 Postdischarge Nutrition in Preterm Infants 629
term and then the term formula thereafter or a term infant formula after hospital discharge
(Fig. 4) (Kitchen et al. 1992a, b; Ernst et al. 1990; Casey
et al. 1990; Fitzhardinge and Inwood 1989;
More frequent growth monitoring would also Fenton et al. 1990; Ross et al. 1990). Both feed-
appear prudent under these circumstances. ing regimens were designed to meet nutritional
Which growth parameters should be monitored needs of the term rather than the rapidly growing
and evaluated? Accurate measurement of body preterm infant. Infants, therefore, may have been
weight and head circumference, with subsequent partly underfed during the first 6–12 months
conversion to Z-scores, is necessary to determine of life.
whether or not an infant is “tracking” toward More recently, studies have examined the
original birth-weight centile. Accurate measure- effects of feeding nutrient-enriched formulas,i.e.,
ment of body length, while difficult and time- formulas with a greater nutrient density than a
consuming, is also important to ensure that the term infant formula, to preterm infants after hos-
composition of growth is also appropriate pital discharge (Cooke et al. 1998, 1999, 2001;
(Singhal et al. 2003). Lucas et al. 1992, 2001; Carver et al. 2001; Agosti
et al. 2003; Bishop et al. 1993; Chan et al. 1994;
Wheeler and Hall 1996; Lapillonne et al. 2004;
40.6.2 Studies Koo and Hockman 2006; De Curtis et al. 2002). In
this respect, two meta-analyses are relevant.
40.6.2.1 Formula Feeding Reviewing the results of studies published before
2005 Henderson et al. concluded that feeding with
Growth nutrient-enriched formulas had little effect on
Many studies have examined post-discharge growth (Henderson et al. 2005). As such, their
growth in preterm infants (Kitchen et al. 1992a, b; conclusions on growth merit examination.
Ernst et al. 1990; Casey et al. 1990; Fitzhardinge The first outcome variable evaluated was
and Inwood 1989; Fenton et al. 1990; Ross “growth during the trial period.” The results of
et al. 1990). Although some “catch-up” growth one study were used, i.e., de Curtis et al. (2002)
has been observed, preterm infants do not grow as wherein the sample size was 33 and the end point
well as their term counterparts and are smaller at was gain in weight and crown-heel length and
3 years (Casey et al. 1991), 8 years (Hack head circumference between 36 wca and 2 mca.
et al. 1993), and adulthood (Hack et al. 2003). Furthermore, growth velocity changes rapidly
There are several possible reasons for this. during this time frame (Fig. 5) and that which is
Current in-hospital feeding practices ensure averaged over a 12-week period may not reflect
that most, if not all, VLBWI are undernourished early but significant differences between the treat-
and growth retarded at initial hospital discharge ment groups (Cooke et al. 1998).
(Embleton et al. 2001; Cooke et al. 2004). A The second end point was “longer-term
“critical epoch” of growth may, therefore, have growth,” i.e., weight, length, and head circumfer-
been missed. Preterm infants also have greater ence at 6 m, 9 m, and 18 m corrected age. Data
morbidity than term infants during the first year from only one study was used at 6 mca
of life (McCormick et al. 1980; Hack et al. 1983; (Litmanovitz et al. 2004) and one at 9 mca
Navas et al. 1992; Thomas et al. 2000; Wang (Lucas et al. 2001), again not entirely representa-
et al. 1995a), and intercurrent illness will affect tive. The conclusions drawn by Henderson
growth, irrespective of whether infants are admit- et al. on growth, therefore, must be questioned.
ted to hospital or not. The more recent and more comprehensive
Until relatively recently, little attention had meta-analysis of Teller et al. is very informative
been paid to nutritional factors in the pathogen- (Teller et al. 2016). Thirty-one eligible studies
esis of this problem. For most early studies, were identified which were noted to differ signif-
infants were fed either unfortified human milk icantly in study design, i.e., (a) inclusion criteria,
630 R. J. Cooke
Weight Gain in Study Infants* formula with the highest protein content
55
Weight Gain (g/d) (2.5–3.0 g/100 ml) that consistent effects were
50
noted on growth, an effect that was more pro-
45
40
nounced in boys than girls. Yet, these studies
35 were not “powered” to control for the
30 confounding effect of sex on head growth and
25 development.
20 In the study of Lucas et al. (1989a, 1990), sex
15
Preterm ( ) > Term ( ), was a confounding variable but sample size
10 Cross-Over (x) (p <.001) (n = 219) was large enough, therefore adequately
5 “powered,” to detect differences in development
Disc - 38w - Term - 4w - 8w - 12w - 4m - 5m - 6m
between treatment groups. Such was not the case
* Cooke et al 16, for the studies of Agosti et al. (2003) (n = 121)
and Jeon et al. (2011) (n = 90) and Cooke
Fig. 5 Growth velocity in study infants fed either a pre- et al. (2001) (n = 113) where sample sizes are
term infant formula (closed circle), a term formula (open much smaller. In the latter study, boys fed the
circle) or a preterm infant formula (discharge-term), or
term infant formula (X)
term formula had the poorest head growth,
which in turn was paralleled by ten-point reduc-
tion in MDI when compared to girls fed the term
(b) point of enrolment, (c) nutrient content of formula, suggesting that boys are at a disadvan-
formula fed, (d) duration of intervention, and tage when fed a term infant formula.
(e) outcomes evaluated. An additional consideration is as follows.
In the main, no consistent differences were Brain growth is rapid during the last trimester
detected in body weight, length, or head circum- and first 2 years of life, a time when even minor
ference between treatment groups. What was insults may have significant effects (Dobbing
noted was a consistent dose-response effect, i.e., 1981). But not all parts of the brain are developing
protein-energy ratios of 2.5–3.0 g/100 ml were at the same rate, therefore not equally vulnerable
associated with increased linear growth as well as (Dobbing 1981). In effect global measures of
increased weight and head circumference noted at function, such as Bayley’s assessment, may not
3, 6, 9, and 12 mca (Teller et al. 2016). be sensitive enough to detect minor or focal dif-
Where body composition was measured using ferences in developmental outcome (Singer
dual-emission x-ray absorptiometry (DEXA), et al. 1994).
increased linear growth was associated with Dabydeen et al. prospectively randomized term
increased lean mass accretion, which was and preterm infants with perinatal brain injury to
paralleled by a reduced or increased fat mass but either a control or high-energy and high-protein diet
not increased adiposity (Cooke et al. 1999; after perinatal brain injury during the first year of
Lapillonne et al. 2004; Roggero et al. 2012). An life (Dabydeen et al. 2008). Infants fed the high-
exception to these observations was the study of energy and high-protein diet had a greater head
Koo et al. where reduced weight gain and linear growth and axonal diameters when compared to
growth were associated with reduced lean and fat the control group. It was concluded that infants
mass accretion (Koo and Hockman 2006). with significant perinatal brain injury had increased
nutritional requirements and that inadequate intake,
Development as is commonly noted in neurologically impaired
In the meta-analyses of Henderson et al. (2005) infants, may compromise subsequent brain growth
and of Teller et al. (2016), no consistent effects and development (Dabydeen et al. 2008).
were detected on neurodevelopment. This is not Collectively, these studies (Lucas et al. 2001;
entirely surprising. In the meta-analysis of Teller Agosti et al. 2003; Cooke et al. 2001; Dabydeen
et al., it was only in infants who were fed the et al. 2008) suggest that the feeding with a formula
40 Postdischarge Nutrition in Preterm Infants 631
with a protein-energy ratio of 2.5–3.0 g/100 ml and growth is poorer. Nonetheless, because of
is associated with better head growth and trends lower rates of morbidity, e.g., sepsis and necrotiz-
toward better post-developmental outcome. In the ing enterocolitis (Schanler et al. 1999), and
case of the otherwise “normal” preterm infant, improved developmental outcome (Morley
male infants are most likely to benefit. In infants et al. 1988a), it is recommended that fortified
with perinatal brain injury, both term and preterm human milk be fed whenever possible before hos-
infants may benefit. Further more appropriately pital discharge (Klein 2002).
“powered” studies are needed to address these After hospital discharge, breastfed infants also
issues. grow more poorly than those fed nutrient-
enriched formulas (Lucas et al. 2001; Chan
et al. 1994; Wauben et al. 1998). This again is
40.6.3 Breastfeeding not surprising. Before discharge, intake less ade-
quately meets requirements, the accrued nutri-
Human milk has been recommended as the pre- tional deficit, and, therefore, needs for
ferred method of feeding for preterm infants after “recovery” are greater. Mature human milk is
hospital discharge (Canada 2004; AAPCON designed to meet the needs of the term infant
2009; Agostoni et al. 2009; Lapillonne and not the preterm infant, and there are signifi-
et al. 2013). In a nutritional sense this, at first cant differences in nutrient content between
glance, is puzzling. Before hospital discharge, mature human milk and formulas used to feed
preterm infants fed human milk do not grow as infants before and after discharge (Table 7).
well as infants fed nutrient-enriched formulas Poorer growth after discharge is paralleled by
(Tyson et al. 1983; Gross 1983). It is, therefore, alterations in bone mineral metabolism and body
recommended that human milk be fortified with composition. Bone mineral accretion is less in
additional nutrients (Klein 2002). Growth infants fed un-supplemented human milk after
improves but it is still not as good as in infants discharge (Lucas et al. 2001; Chan et al. 1994;
fed a preterm infant formula (Carlson and Ziegler Wauben et al. 1998; Kurl et al. 2003; Schanler
1998). The reasons for this are not entirely clear. et al. 1992). This, in turn, can be related to out-
Fortifiers differ in nutrient composition and it come on a short-term, e.g., osteopenia (Lucas
is unclear which, if any, really meets require- et al. 1989b) and fractures (Koo et al. 1988), and
ments. The composition of human milk varies long-term, e.g., poorer linear growth (Fewtrell
widely (Atkinson et al. 1995), and because it is et al. 2000), basis. Interestingly, infants fed
not consistently measured, there is no way of human milk also have increased fat accretion
knowing what the infant is really receiving. In when compared to those fed a nutrient-enriched
effect, intake less adequately meets requirements formula (Wauben et al. 1998).
Table 7 A comparison of nutrient content of human milk with preterm, nutrient-enriched, and term infant formulas
Per liter Human milk Preterm Post-discharge Term
Energy kcal 670 810 730 67
Protein g 10 23 20 14
Fat g 35 42 40 36
Carbohydrate g 70 88 78 73
Calcium mg 260 1,400 850 530
Phosphorus mg 140 700 480 330
Sodium mmol 9 15 11 8
Chloride mmol 16 19 17 12
Zinc mg 3.2 12.1 9 6
Vitamin A mg 0.7 3 1 0.6
632 R. J. Cooke
Thus, infants grow as they are fed. When mineral The results of this much larger scale study are
intake is inadequate, bone mineral accretion is puzzling in that no significant differences were
decreased. Whether the latter in some way alters detected in growth between infants fed
“programming” and, therefore, health in adult life unfortified and fortified milk. One possibility
is unclear. What is clear is that the assessment of relates to the small sample size in the original
bone mineral status, i.e., serum phosphorus and study (O’Connor et al. 2008), n ~ 20/treatment
alkaline phosphatase, is also an important consider- group; i.e., the results are not generalizable.
ation during this critical time frame (Schanler 2005). Alternatively, the level of fortification used in
Several studies have examined the effect of the latter study may have been inadequate to
nutrient fortification of human milk after hospital consistently improve growth in such a heteroge-
discharge. In a randomized controlled pilot trial, neous population. It is notable that the timing of
preterm infants (750–1,800 g) were fed unfortified introduction of complementary foods was later
(n = 20) or fortified (n = 19) human milk after with nutrient enrichment, perhaps suggesting
hospital discharge-12 week (O’Connor that energy needs were more adequately met
et al. 2008). A multi-nutrient fortifier, estimated and infants satiated longer.
to ensure an energy and protein density of 80 kcal The results of these studies raise more ques-
and 2.2 g/100 ml, was added to 50% of feeds. tions than answers:
Weight tended to be greater (all infants), while
length (all infants) and head circumference, (a) Should all preterm VLBWI be fortified human
infants 1,250 g only, were greater in the fortified milk after hospital discharge? Since all
group. In a follow-up of the same infants, weight, VLBWI accrue a significant nutrient deficit
linear growth, bone mineral content, and head between birth and hospital discharge and
growth (infants <1,250 g only) but not Bayley’s mature human milk is designed for the needs
II developmental scores were greater in infants fed of “normal” infants, i.e., needs for mainte-
fortified human milk (Aimone et al. 2009). nance and normal growth, it seems prudent
In a larger more recent randomized controlled to fortify in all breastfed infants after
trial between hospital discharge and 4 m corrected discharge.
age, Zacharisson et al. fed preterm VLBWI (b) What is the best way to fortify human milk?
(24–32 weeks; 535–2,255 g) either unfortified The nutritional content of fortifiers differs. Is
(n = 102; group A) or fortified (n = 105; group one better than another? Further studies are
B) human milk and compared their growth to a needed to examine this issue. In the mean-
group of infants fed a preterm formula (n = 113; time, the level of fortification should be
group C, preterm formula) (Zachariassen adjusted to ensure that growth, in terms of
et al. 2011). No differences were detected in weight and length gain, is “tracking” in the
growth between groups A and B at 12 mca, and right direction (Arslanoglu et al. 2006; Cooke
it was concluded that while fortification did not 2006).
affect the durations of breastfeeding, it also did (c) How long should fortification be continued?
not influence growth at 1 year of age. There are no data in this area. Data in formula-
Yet, important and consistent differences were fed infants indicate that discontinuation of
noted in breastfed and the formula-fed infants. preterm formula and then feeding a term for-
Infants in C had a greater increase in weight mula at term is paralleled by a rapid deceler-
Z-score between discharge and term and in length ation in growth that is not entirely recovered
Z-score until 6 months CA. At 12 mca, boys in C by 6 or 12 m corrected age (Fig. 4; Cooke
were longer and heavier than in groups A and B, et al. 1998). At least, 1–2 mca, therefore,
while girls in group C were longer and heavier seems advisable since this is also the period
than in group A only. Greater protein intakes in C of greatest brain growth velocity and appears
were also related to increased serum urea nitrogen to be functionally significant (Dharmaraj
levels. et al. 2005).
40 Postdischarge Nutrition in Preterm Infants 633
40.7 Summary Arslanoglu S, Moro GE, Ziegler EE (2006) Adjustable
fortification of human milk fed to preterm infants:
does it make a difference? J Perinatol 26:614–621
Many questions remain unanswered about what to Ashworth A, Millward DJ (1986) Catch-up growth in
feed preterm, particularly VLBWI, infants after children. Nutr Rev 44:157–163
hospital discharge but several things are clear: Atkinson SA, Alston-Mills B, Lonnerdal B, Neville MC
(1995) Major minerals and ionic constituents of
human and bovine milks. In: Jensen RG
1. Nutritional status of all infants should be (ed) Handbook of milk composition. Academic, San
closely evaluated before discharge and the Diego, pp 593–622
information relayed to the primary care physi- Bedi KS (1987) Lasting neuroanatomical changes follow-
cian. Infants with the greatest degree of growth ing undernutrition during early life. In: Dobbing J
(ed) Early nutrition and later achievement. Academic,
failure at discharge are at greatest risk for fur- London, pp 1–49
ther “growth faltering.” Benitez-Bribiesca L, De la Rosa-Alvarez I, Mansilla-
2. Irrespective of what is fed, growth should be Olivares A (1999) Dendritic spine pathology in infants
closely monitored and intake adjusted with with severe protein-calorie malnutrition. Pediatrics
104:e21
the goal that birth centile, at least for weight, Bishop NJ, King FJ, Lucas A (1993) Increased bone min-
is reestablished between discharge and eral content of preterm infants fed with a nutrient
1–2 mca. enriched formula after discharge from hospital. Arch
3. Continuing and close communication between Dis Child 68:573–578
Bremer AA, Mietus-Snyder M, Lustig RH (2012) Toward
designated personnel in the neonatal intensive a unifying hypothesis of metabolic syndrome. Pediat-
care unit and the infant’s family as well as the rics 129:557–570
primary care providers is essential during this Carlson SJ, Ziegler EE (1998) Nutrient intakes and growth
critical “epoch” of growth and development. of very low birth weight infants. Perinatology
18:252–258
Carver JD, Wu PY, Hall RT et al (2001) Growth of preterm
infants fed nutrient-enriched or term formula after hos-
pital discharge. Pediatrics 107:683–689
References Casey PH, Kraemer HC, Bernbaum J et al (1990) Growth
patterns of low birth weight preterm infants: a longitu-
AAPCON (1998) Nutritional needs of preterm infants. In: dinal analysis of a large, varied sample. J Pediatr
Kleinman RE (ed) Pediatric nutrition handbook. Amer- 117:298–307
ican Academy of Pediatrics, Elk Grove Village, pp Casey PH, Kraemer HC, Bernbaum J, Yogman MW, Sells
55–88 JC (1991) Growth status and growth rates of a varied
AAPCON (2009) Nutritional needs of the preterm infant. sample of low birth weight, preterm infants: a longitu-
In: Kleinman RE (ed) Pediatric nutrition handbook, 6th dinal cohort from birth to three years of age. J Pediatr
edn. American Academy of Pediatrics, Elk Grove Vil- 119:599–605
lage, pp 79–104 Chan GM, Borschel MW, Jacobs JR (1994) Effects of
Aggett PJ, Agostoni C, Axelsson I et al (2006) Feeding human milk or formula feeding on the growth, behav-
preterm infants after hospital discharge: a commentary ior, and protein status of preterm infants discharged
by the ESPGHAN committee on nutrition. J Pediatr from the newborn intensive care unit. Am J Clin Nutr
Gastroenterol Nutr 42:596–603 60:710–716
Agosti M, Vegni C, Calciolari G, Marini A (2003) Post- Clark RH, Thomas P, Peabody J (2003) Extrauterine
discharge nutrition of the very low-birthweight infant: growth restriction remains a serious problem in prema-
interim results of the multicentric GAMMA study. Acta turely born neonates. Pediatrics 111:986–990
Paediatr Suppl 91:39–43 Cooke RJ (2006) Adjustable fortification of human milk
Agostoni C, Braegger C, Decsi T et al (2009) Breast- fed to preterm infants. J Perinatol 26:591–592
feeding: a commentary by the ESPGHAN committee Cooke RW, Foulder-Hughes L (2003) Growth impairment
on nutrition. J Pediatr Gastroenterol Nutr 49:112–125 in the very preterm and cognitive and motor perfor-
Aimone A, Rovet J, Ward W et al (2009) Growth and body mance at 7 years. Arch Dis Child 88:482–487
composition of human milk-fed premature infants pro- Cooke RJ, Griffin I (2009) Altered body composition in
vided with extra energy and nutrients early after hospi- preterm infants at hospital discharge. Acta Paediatr
tal discharge: 1-year follow-up. J Pediatr Gastroenterol 98:1269–1273
Nutr 49:456–466 Cooke RJ, Griffin IJ, McCormick K et al (1998) Feeding
Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M preterm infants after hospital discharge: effect of die-
(1996) A United States national reference for fetal tary manipulation on nutrient intake and growth.
growth. Obstet Gynecol 87:163–168 Pediatr Res 43:355–360
634 R. J. Cooke
Cooke RJ, McCormick K, Griffin IJ et al (1999) Feeding Embleton NE, Pang N, Cooke RJ (2001) Postnatal malnu-
preterm infants after hospital discharge: effect of diet trition and growth retardation: an inevitable conse-
on body composition. Pediatr Res 46:461–464 quence of current recommendations in preterm
Cooke RJ, Embleton ND, Griffin IJ, Wells JC, McCormick infants? Pediatrics 107:270–273
KP (2001) Feeding preterm infants after hospital dis- Ernst JA, Bull MJ, Rickard KA, Brady MS, Lemons
charge: growth and development at 18 months of age. JA (1990) Growth outcome and feeding practices of
Pediatr Res 49:719–722 the very low birth weight infant (less than 1500
Cooke RJ, Ainsworth SB, Fenton AC (2004) Postnatal grams) within the first year of life. J Pediatr 117:
growth retardation: a universal problem in preterm S156–S166
infants. Arch Dis Child Fetal Neonatal Ed 89: Evans RA, Thureen P (2001) Early feeding strategies in
F428–F430 preterm and critically ill neonates. Neonatal Netw
Cordero ME, D’Acuna E, Benveniste S, Prado R, Nunez 20:7–18
JA, Colombo M (1993) Dendritic development in neo- Fenton TR, McMillan DD, Sauve RS (1990) Nutrition and
cortex of infants with early postnatal life undernutri- growth analysis of very low birth weight infants. Pedi-
tion. Pediatr Neurol 9:457–464 atrics 86:378–383
Cornier MA, Dabelea D, Hernandez TL et al (2008) The Fewtrell PA, Cole TJ, Lucas A (2000) Effects of growth
metabolic syndrome. Endocr Rev 29:777–822 during infancy and childhood on bone mineralization
Dabydeen L, Thomas JE, Aston TJ, Hartley H, Sinha SK, and turnover in preterm children aged 8–12 years. Acta
Eyre JA (2008) High-energy and -protein diet increases Paediatr 89:148–153
brain and corticospinal tract growth in term and preterm Fitzhardinge PM, Inwood S (1989) Long-term growth in
infants after perinatal brain injury. Pediatrics small-for-date children. Acta Paediatr Scand – Suppl
121:148–156 349:27–33, discussion 4
De Curtis M, Pieltain C, Rigo J (2002) Body composition Fomon S (1993a) Energy. In: Fomon SJ, Bell EF (eds)
in preterm infants fed standard term or enriched for- Nutrition of normal infants, 2nd edn. Mosby, St
mula after hospital discharge. Eur J Nutr 41:177–182 Louis, pp 103–120
Dharmaraj ST, Henderson M, Embleton ND, Fenton AC, Fomon S (1993b) Protein. In: Fomon SJ (ed) Nutrition of
Cooke RJ (2005) Postnatal growth retardation, catch- normal infants, 2nd edn. Mosby, St Louis, pp 121–139
up growth and developmental outcome in preterm Galler J, Shumsky J, Morgane PJ (1996) Malnutrition and
infants. Arch Dis Child 90:11A brain development. In: Walker AW, Watkins J (eds)
Dinerstein A, Nieto RM, Solana CL, Perez GP, Otheguy Paediatric nutrition. Decker, New York, pp 196–212
LE, Larguia AM (2006) Early and aggressive nutri- Greisen G (1992) Estimation of fetal weight by ultrasound.
tional strategy (parenteral and enteral) decreases post- Horm Res 38:208–210
natal growth failure in very low birth weight infants. J Griffin IJ, Tancredi DJ, Bertino E, Lee HC, Profit J (2016)
Perinatol 26:436–442 Postnatal growth failure in very low birthweight infants
Dobbing J (1981) The later development of the brain and born between 2005 and 2012. Arch Dis Child Fetal
its vulnerability. In: Davis JA, Dobbing J (eds) Scien- Neonatal Ed 101:50–55
tific foundations of pediatrics. University Park Press, Gross SJ (1983) Growth and biochemical response of
Baltimore, pp 744–758 preterm infants fed human milk or modified infant
Dobbing J (1987) Early nutrition and later achievement. formula. N Engl J Med 308:237–241
Academic, London Gross SJ, Oehler JM, Eckerman CO (1983) Head growth
Dobbing J, Sands J (1971) Vulnerability of developing and developmental outcome in very low-birth-weight
brain. IX. The effect of nutritional growth retardation infants. Pediatrics 71:70–75
on the timing of the brain growth-spurt. Biol Neonate Hack M, Breslau N (1986) Very low birth weight infants:
19:363–378 effects of brain growth during infancy on intelligence
Dobbing J, Hopewell JW, Lynch A (1971) Vulnerability of quotient at 3 years of age. Pediatrics 77:196–202
developing brain. VII. Permanent deficit of neurons in Hack M, Fanaroff AA (1984) The outcome of growth
cerebral and cerebellar cortex following early mild failure associated with preterm birth. Clin Obstet
undernutrition. Exp Neurol 32:439–447 Gynecol 27:647–663
Donovan R, Puppala B, Angst D, Coyle BW (2006) Hack M, Merkatz IR, Gordon D, Jones PK, Fanaroff AA
Outcomes of early nutrition support in extremely (1982) The prognostic significance of postnatal growth
low-birth-weight infants. Nutr Clin Pract 21: in very low – birth weight infants. Am J Obstet Gynecol
395–400 143:693–699
Ehrenkranz RA, Younes N, Lemons JA et al (1999) Lon- Hack M, Caron B, Rivers A, Fanaroff AA (1983) The very
gitudinal growth of hospitalized very low birth weight low birth weight infant: the broader spectrum of mor-
infants. Pediatrics 104:280–289 bidity during infancy and early childhood. J Dev Behav
Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage Pediatr 4:243–249
LA, Poole WK (2006) Growth in the neonatal intensive Hack M, Breslau N, Weissman B, Aram D, Klein N,
care unit influences neurodevelopmental and growth Borawski E (1991) Effect of very low birth weight
outcomes of extremely low birth weight infants. Pedi- and subnormal head size on cognitive abilities at school
atrics 117:1253–1261 age [see comments]. N Engl J Med 325:231–237
40 Postdischarge Nutrition in Preterm Infants 635
Hack M, Weissman B, Breslau N, Klein N, Borawski- Kurl S, Heinonen K, Lansimies E (2003) Pre- and post-
Clark E, Fanaroff AA (1993) Health of very low birth discharge feeding of very preterm infants: impact on
weight children during their first eight years. J Pediatr growth and bone mineralization. Clin Physiol Funct
122:887–892 Imaging 23:182–189
Hack M, Schluchter M, Cartar L, Rahman M, Cuttler L, Lapillonne A, Salle BL, Glorieux FH, Claris O (2004)
Borawski E (2003) Growth of very low birth weight Bone mineralization and growth are enhanced in pre-
infants to age 20 years. Pediatrics 112:e30–e38 term infants fed an isocaloric, nutrient-enriched pre-
Health Canada (2004) Breast feeding duration term formula through term. Am J Clin Nutr
recommendations 80:1595–1603
Heird WC (2001) Determination of nutritional require- Lapillonne A, O’Connor DL, Wang D, Rigo J (2013)
ments in preterm infants, with special reference to Nutritional recommendations for the late-preterm
‘catch-up’ growth. Semin Neonatol 6:365–375 infant and the preterm infant after hospital discharge.
Henderson G, Fahey T, McGuire W (2005) Calorie and J Pediatr 162:S90–S100
protein-enriched formula versus standard term for- Larsen T, Petersen S, Greisen G, Larsen JF (1990) Normal
mula for improving growth and development in fetal growth evaluated by longitudinal ultrasound
preterm or low birth weight infants following hos- examinations. Early Hum Dev 24:37–45
pital discharge. Cochrane Database Syst Rev Latal-Hajnal B, von Siebenthal K, Kovari H, Bucher HU,
CD004696 Largo RH (2003) Postnatal growth in VLBW infants:
Hermanussen M (2013a) Basics. Rapid growth. In: significant association with neurodevelopmental out-
Hermanussen M (ed) Auxology studying human come. J Pediatr 143:163–170
growth and development. Schweizerbart’sche, Litmanovitz I, Dolfin T, Arnon S et al (2004) Bone strength
Stuttgaart, pp 18–19 and growth of preterm infants fed nutrient-enriched or
Hermanussen M (2013b) Basics. In: Hermanussen M term formula after hospital discharge. Pediatr Res
(ed) Auxology studying human growth and develop- 55:274A
ment. Schweizerbart’sche, Stuttgart Lowry S, Perez JM (2006) The hypercatabolic state. In:
Horbar JD, Ehrenkranz RA, Badger GJ et al (2015) Weight Shils M, Shike M, Ross CA, Caballero B, Cousins R
growth velocity and postnatal growth failure in infants (eds) Modern nutrition in health and disease, 10th edn.
501 to 1500 grams: 2000–2013. Pediatrics 136: Lippincott, Williams & Wilkins, Philadelphia, pp
e84–e92 1381–1400
Ibrahim HM, Jeroudi MA, Baier RJ, Dhanireddy R, Lucas A, Morley R, Cole TJ et al (1989a) Early diet in
Krouskop RW (2004) Aggressive early total parental preterm babies and developmental status in infancy
nutrition in low-birth-weight infants. J Perinatol [see comments]. Arch Dis Child 64:1570–1578
24:482–486 Lucas A, Brooke OG, Baker BA, Bishop N, Morley R
Jackson AA (1990) Protein requirements for catch-up (1989b) High alkaline phosphatase activity and growth
growth. Proc Nutr Soc 49:507–516 in preterm neonates. Arch Dis Child 64:902–909
Jeon GW, Jung YJ, Koh SY et al (2011) Preterm infants fed Lucas A, Morley R, Cole TJ et al (1990) Early diet in
nutrient-enriched formula until 6 months show preterm babies and developmental status at 18 months.
improved growth and development. Pediatr Int: Off J Lancet 335:1477–1481
Jpn Pediatr Soc 53:683–688 Lucas A, Bishop NJ, King FJ, Cole TJ (1992) Randomised
Kitchen WH, Doyle LW, Ford GW, Callanan C, Rickards trial of nutrition for preterm infants after discharge [see
AL, Kelly E (1992a) Very low birth weight and growth comments]. Arch Dis Child 67:324–327
to age 8 years. II: head dimensions and intelligence. Lucas A, Morley R, Cole TJ, Gore SM (1994) A
Am J Dis Child 146:46–50 randomised multicentre study of human milk versus
Kitchen WH, Doyle LW, Ford GW, Callanan C (1992b) formula and later development in preterm infants.
Very low birth weight and growth to age 8 years. I: Arch Dis Child Fetal Neonatal Ed 70:F141–F146
weight and height. Am J Dis Child 146:40–45 Lucas A, Morley R, Cole TJ (1998) Randomised trial of
Klein CJ (2002) Nutrient requirements for preterm infant early diet in preterm babies and later intelligence quo-
formulas. J Nutr 132:1395S–1577S tient. BMJ 317:1481–1487
Koo WW, Hockman EM (2006) Posthospital discharge Lucas A, Fewtrell MS, Morley R et al (2001) Randomized
feeding for preterm infants: effects of standard com- trial of nutrient-enriched formula versus standard for-
pared with enriched milk formula on growth, bone mula for postdischarge preterm infants. Pediatrics
mass, and body composition. Am J Clin Nutr 108:703–711
84:1357–1364 MacLean WC Jr, Graham GG (1980) The effect of energy
Koo WW, Sherman R, Succop P et al (1988) Sequential intake on nitrogen content of weight gained by recover-
bone mineral content in small preterm infants with and ing malnourished infants. Am J Clin Nutr 33:903–909
without fractures and rickets. J Bone Miner Res McCance RA, Widdowson EM (1974) The determinants of
3:193–197 growth and form. Proc R Soc Lond B Biol Sci 185:1–17
Krigman MR, Hogan EL (1976) Undernutrition in the McCormick MC, Shapiro S, Starfield BH (1980)
developing rat: effect upon myelination. Brain Res Rehospitalization in the first year of life for high-risk
107:239–255 survivors. Pediatrics 66:991–999
636 R. J. Cooke
Mehta NM, Corkins MR, Lyman B et al (2013) Defining Schanler RJ, Burns PA, Abrams SA, Garza C (1992) Bone
pediatric malnutrition: a paradigm shift toward mineralization outcomes in human milk-fed preterm
etiology-related definitions. JPEN J Parenter Enteral infants. Pediatr Res 31:583–586
Nutr 37:460–481 Schanler RJ, Shulman RJ, Lau C (1999) Feeding strategies
Morley R (1999) Early growth and later development. In: for premature infants: beneficial outcomes of feeding
Ziegler EE, Lucas A, Moro GE (eds) Nutrition of the fortified human milk versus preterm formula [com-
very low birth weight infant. Lippincott Williams and ment]. Pediatrics 103:1150–1157
Wilkins, Philadelphia, pp 19–32 Scott KE, Usher R (1966) Fetal malnutrition: its incidence,
Morley R, Lucas A (1997) Nutrition and cognitive devel- causes, and effects. Am J Obstet Gynecol 94:951–963
opment. Br Med Bull 53:123–134 Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ
Morley R, Cole TJ, Powell R, Lucas A (1988) Mother’s (2006) Modern nutrition in health and disease.
choice to provide breast milk and developmental out- Lippincott Williams and Wilkins, Philadelphia
come. Arch Dis Child 63:1382–1385 Singer L, Arendt R, Song LY, Warshawsky E, Kliegman R
Myers RE, Hill DE, Holt AB, Scott RE, Mellits ED, (1994) Direct and indirect interactions of cocaine with
Cheek DB (1971) Fetal growth retardation produced childbirth outcomes. Arch Pediatr Adolesc Med
by experimental placental insufficiency in the rhesus 148:959–964
monkey. I. Body weight, organ size. Biol Neonate Singhal A, Cole TJ, Lucas A (2001) Early nutrition in
18:379–394 preterm infants and later blood pressure: two cohorts
Navas L, Wang E, de Carvalho V, Robinson J, PICNIC after randomised trials. Lancet 357:413–419
(1992) Improved outcome of respiratory syncytial virus Singhal A, Fewtrell M, Cole TJ, Lucas A (2003) Low nutrient
infection in a high-risk hospitalized population of intake and early growth for later insulin resistance in
Canadian children. J Pediatr 121:348–354 adolescents born preterm. Lancet 361:1089–1097
O’Connor DL, Khan S, Weishuhn K et al (2008) Growth Stathis SL, O’Callaghan M, Harvey J, Rogers Y (1999)
and nutrient intakes of human milk-fed preterm infants Head circumference in ELBW babies is associated with
provided with extra energy and nutrients after hospital learning difficulties and cognition but not ADHD in the
discharge. Pediatrics 121:766–776 school-aged child. Dev Med Child Neurol 41:375–380
Olsen IE, Richardson DK, Schmid CH, Ausman LM, Stoch MB, Smythe PM, Moodie AD, Bradshaw D (1982)
Dwyer JT (2002) Intersite differences in weight growth Psychosocial outcome and CT findings after gross
velocity of extremely premature infants. Pediatrics undernourishment during infancy: a 20-year develop-
110:1125–1132 mental study. Dev Med Child Neurol 24:419–436
Ong KK, Loos RJ (2006) Rapid infancy weight gain and Teller IC, Embleton ND, Griffin IJ, van Elburg RM (2016)
subsequent obesity: systematic reviews and hopeful Post-discharge formula feeding in preterm infants: a
suggestions. Acta Paediatr 95:904–908 systematic review mapping evidence about the role of
Ounsted M, Moar VA, Scott A (1988) Head circumference macronutrient enrichment. Clin Nutr 35(4):791–801
and developmental ability at the age of seven years. Thomas M, Bedford-Russel A, Sharland M (2000)
Acta Paediatr Scand 77:374–379 Hospitalisation of RSV infection in ex-preterm infants
Peterson J, Taylor HG, Minich N, Klein N, Hack M (2006) – implications for RSV immune globulin. Arch Dis
Subnormal head circumference in very low birth Child 183:122–127
weight children: neonatal correlates and school-age Tyson JE, Lasky RE, Mize CE et al (1983) Growth, met-
consequences. Early Hum Dev 82:325–334 abolic response, and development in very-low-birth-
Pryor J, Silva PA, Brooke M (1995) Growth, develop- weight infants fed banked human milk or enriched
ment and behaviour in adolescents born small-for- formula. I. Neonatal findings. J Pediatr 103:95–104
gestational-age. J Paediatr Child Health 31: Uthaya S, Thomas EL, Hamilton G, Dore CJ, Bell J, Modi
403–407 N (2005) Altered adiposity after extremely preterm
Rawlings DJ, Cooke RJ, McCormick K et al (1999) Body birth. Pediatr Res 57:211–215
composition of preterm infants during infancy. Arch Volpe JJ (2008) Neurology of the newborn, 5th edn.
Dis Child Fetal Neonatal Ed 80:F188–F191 Saunders Elsevier, Philadelphia
Roberts SB, Young VR (1988) Energy costs of fat and Wang E, Law B, Stephens D, PICNIC (1995) Prospective
protein deposition in the human infant. Am J Clin study of risk factors and outcomes in patients
Nutr 48:951–955 hospitalised with respiratory syncytial viral lower
Roggero P, Gianni ML, Piemontese P, Amato O, Agosti M, respiratory tract infection. J Pediatr 126:212–219
Mosca F (2012) Effect of nutrition on growth and body Wauben IP, Atkinson SA, Shah JK, Paes B (1998) Growth
composition in infants born preterm. J Matern Fetal and body composition of preterm infants: influence of
Neonatal Med 25(Suppl 3):49–52 nutrient fortification of mother’s milk in hospital and
Ross G, Lipper EG, Auld PA (1990) Growth achievement breastfeeding post- hospital discharge (in process cita-
of very low birth weight premature children at school tion). Acta Paediatr 87:780–785
age. J Pediatr 117:307–309 Wheeler RE, Hall RT (1996) Feeding of premature infant
Schanler RJ (2005) Post-discharge nutrition for the preterm formula after hospital discharge of infants weighing
infant. Acta Paediatr Suppl 94:68–73 less than 1800 grams at birth. J Perinatol 16:111–116
40 Postdischarge Nutrition in Preterm Infants 637
Widdowson EM, McCance RA (1975) A review: new Yeung MY (2006) Postnatal growth, neurodevelopment
thoughts on growth. Pediatr Res 9:154–156 and altered adiposity after preterm birth – from a
Wilson DC, Cairns P, Halliday HL, Reid M, McClure G, clinical nutrition perspective. Acta Paediatr 95:
Dodge JA (1997) Randomised controlled trial of an 909–917
aggressive nutritional regimen in sick very low birthweight Zachariassen G, Faerk J, Grytter C et al (2011) Nutrient
infants. Arch Dis Child Fetal Neonatal Ed 77:F4–F11 enrichment of mother’s milk and growth of very pre-
Winick M, Rosso P (1969a) The effect of severe early term infants after hospital discharge. Pediatrics 127:
malnutrition on cellular growth of human brain. Pediatr e995–e1003
Res 3:181–184 Ziegler EE, Thureen PJ, Carlson SJ (2002) Aggressive
Winick M, Rosso P (1969b) Head circumference and cel- nutrition of the very low birthweight infant. Clin
lular growth of the brain in normal and marasmic chil- Perinatol 29:225–244
dren. J Pediatr 74:774–778
Calcium and Phosphorus Homeostasis:
Pathophysiology 41
Jacques Rigo, Catherine Pieltain, Renaud Viellevoye, and
Franco Bagnoli
Contents
41.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 640
41.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 640
41.3 Calcium and Phosphorus Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
41.3.1 Calcium Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
41.3.2 Phosphorus Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646
41.4 Hormonal Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649
41.4.1 Parathyroid Hormone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649
41.4.2 Vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650
41.4.3 Calcitonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652
41.4.4 FGF23 and Phosphatonin Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653
41.5 Clinical Conditions Associated with Calcium Disturbances . . . . . . . . . . . . . . 653
41.5.1 Neonatal Hypocalcemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653
41.5.2 Neonatal Hypercalcemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659
41.5.3 Neonatal Hyperparathyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659
41.5.4 Nephrocalcinosis in Preterm Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661
41.6 Disorders of Phosphate Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
41.6.1 Neonatal Hypophosphatemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
41.6.2 Neonatal Hyperphosphatemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
41.7 Bone Mineralization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
41.7.1 Factors Affecting Growth and Mineralization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
41.7.2 Osteopenia of Prematurity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
Abstract
The metabolic homeostasis of calcium, phos-
phorus, and magnesium and mineralization of
J. Rigo (*) · C. Pieltain · R. Viellevoye the skeleton are complex functions that require
Department of Neonatology, University of Liège, CHR de adequate supply of nutrients, the development
la Citadelle, Liège, Belgium of the intestinal absorption process, the inter-
F. Bagnoli
Department of Pediatrics, Obstetrics and Reproductive
Medicine, University of Siena, Siena, Italy
# Springer International Publishing AG, part of Springer Nature 2018 639
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_190
640 J. Rigo et al.
action of several hormones (such as parathy- 41.1 Salient Points
roid hormone, vitamin D, and calcitonin), and
optimum renal and skeletal control. Approx- • When calcium and phosphorus are provided
imately 50% of total serum calcium is in together as human milk fortifiers, calcium
ionized form at the normal serum protein retention and absorption rates are parallel,
concentration and represents the biologically reaching 60 mg/kg per day.
active component of the total serum calcium • The ESPGHAN Committee Nutrition
concentration. The fetus maintains higher recommended an adequate intake of calcium
blood calcium and phosphorus levels than 60–90 mg/kg/day (110–130 mg/100 Kcal),
the ambient maternal levels. This process is phosphate 65–90 mg/kg/day, Ca:P ratio 1.5–2.
the result of the active transport of calcium • Vitamin D recommendations differ signifi-
across the placenta. The role of vitamin D in cantly between North American (400 IU/day)
fetal physiology is not well understood. Cal- and European countries (800–1000 IU/day).
cium absorption is the main determinant of its • Iatrogenic hypercalcemia is the most common
retention in the small intestine by both active type of hypercalcemia.
and passive processes. Acid pH in the stom- • The measurement of calcium-regulating hor-
ach is a prerequisite for absorption. Reference mones is not routinely recommended unless
values of calcium retention calculated during hypocalcemia is prolonged, refractory, or
the last trimester of gestation (120–130 mg/ recurrent.
kg/day) are considered the target mineral • When available, DEXA is more sensitive than
accretion rates for infants with very low ultrasound for quantifying osteopenia in
birth weight. We should pay particular atten- VLBW infants.
tion to the dosage of total and ionized serum
calcium when some medications are used or
when there is acidosis/alkalosis, hypomagne- 41.2 Introduction
semia, prematurity, infant of a diabetic
mother, or birth asphyxia. In contrast to cal- Ninety-eight percent of the calcium and eighty per-
cium, the serum phosphorus concentration cent of the phosphorus in the body are in the skel-
varies widely depending mainly on intake eton; these elements are also constituents of the
and renal excretion but is also influenced by intracellular and extracellular spaces. The metabolic
age, gender, pH, and a variety of hormones. homeostasis of calcium, phosphorus, and magne-
Premature infants, particularly those born at sium and mineralization of the skeleton are com-
<28 weeks’ gestation, are at significant risk plex functions that require the intervention of
for reduced bone mineral content (BMC) and various parameters; an adequate supply of nutrients;
subsequent bone disease, variably termed the development of the intestinal absorption pro-
metabolic bone disease (MBD), osteomala- cess; and the effects of several hormones, such as
cia, osteopenia, or neonatal rickets. Several parathyroid hormone, vitamin D, and calcitonin, as
factors increase the risk for severe MBD well as optimum renal and skeletal controls (Rigo
among VLBW infants, with the most impor- et al. 2000). Bone formation requires protein and
tant appearing to be an inadequate supply of energy for collagen matrix synthesis, and an ade-
calcium and phosphorus associated with the quate intake of calcium and phosphorus is
use of an enteral vs. transplacental route. necessary for correct mineralization. During
Early optimal parenteral and oral nutritional development, nutrients are transferred mainly
support, combined with biologic neonatal across the placenta. It has been calculated that
screening and biomarker measurements, during the last trimester of gestation the daily
appears to be helpful for the prevention of accretion per kilogram of body weight represents
MBD. around 120 mg of calcium and 70 mg of
41 Calcium and Phosphorus Homeostasis: Pathophysiology 641
phosphorus. Therefore, at birth the whole-body calcium concentration is tightly regulated by para-
content of a term infant represents approximately thyroid hormone (PTH) and calcitriol (1,25-
30 g of calcium and 16 g of phosphorus. After dihydroxy vitamin D3; 1,25[OH]2D3), which
birth, the use of the gastrointestinal tract to pro- increase serum calcium (Fig. 1), and by calcitonin,
vide nutrients for growth causes a reduction in which decreases serum calcium.
calcium availability for bone accretion promot-
ing the occurrence of relative osteopenia in pre- 41.3.1.2 Placental Transport
term infants and to a lesser extent in term infants During pregnancy there is an active calcium trans-
during the first weeks of life. In addition to their fer from the mother to the fetus, reaching a peak of
roles in bone formation, calcium and phosphorus 120–150 mg/kg of fetal weight per day during the
play important roles in many physiologic pro- third trimester.
cesses, such as transport across membranes, acti- To meet the high demand for mineral require-
vation and inhibition of enzymes, intracellular ments of the developing skeleton, the fetus main-
regulation of metabolic pathways, secretion and tains higher blood calcium and phosphorus levels
action of hormones, blood coagulation, muscle than the ambient maternal levels. This process is
contractility, and nerve conduction. The 20% of the result of the active transport of calcium across
phosphorus not complexed within bone is pre- the placenta by a calcium pump in the basal mem-
sent mainly as adenosine triphosphate, nucleic brane that maintains a gradient of maternal to fetal
acids, and cell and organelle membranes. calcium of 1:1.4. PTH has no effect on placental
calcium transport.
By contrast, the main regulator of fetal ionized
41.3 Calcium and Phosphorus calcium appears to be the parathyroid hormone-
Physiology related protein (PTHrP) produced by the placenta.
PTHrP(1–141) or its midmolecule fragment,
41.3.1 Calcium Physiology PTHrP(67–86), is the active form contrary to
PTH (1–34) or PTHrP(1.34), suggesting that
41.3.1.1 Serum Calcium PTHrP stimulates receptor(s) distinct from the
Serum calcium is a fraction of total body calcium PTH/PTHrP receptor (Sato 2008).
because only about 2% of calcium is present in The role of vitamin D in fetal physiology is not
extracellular fluid and soft tissues. Approximately well understood. Cord concentrations of
50% of total serum calcium is in ionized form at 25-hydroxyvitamin D and 1,25-dihydroxyvitamin
the normal serum protein concentration and repre- D correlate significantly with those found in the
sents the biologically active component of the total maternal circulation, suggesting that the vitamin
serum calcium concentration. Another 8–10% is D pool of the fetus depends entirely on that of the
complexed to organic and inorganic acids (e.g., mother. Fetomaternal relationships of 1,25-
citrate, lactate, bicarbonate, sulfate, and phos- dihydroxyvitamin D concentrations are still
phate); together, the ionized and complexed cal- debated.
cium fractions represent the diffusible portion of Nevertheless, it has been demontrated that the
circulating calcium. Approximately 40% of placenta is able to synthethise and metabolize
serum calcium is protein bound, primarily to 1,25-dihydroxyvitamin D through the activity of
albumin (80%) but also to globulins (20%) 25-hydroxyvitamin D-1α-hydroxylase and 1,25-
(Rigo et al. 2010; Hsu and Levine 2004). Ionized dihydroxyvitamin D-24 hydroxylase, two key
calcium is the only physiologically active enzymes for vitamin D metabolism (Avila et al.
fraction. 2006). In addition, it has been suggested that meth-
The protein-bound calcium is not biologically ylation of the vitamin D-24-hydroxylase gene
active but provides a rapidly available reserve of plays an important role in maximizing active vita-
calcium. Under normal circumstances the serum min D bioavailability at the fetomaternal interface
642 J. Rigo et al.
Fig. 1 Regulation of calcium and phosphate homeostasis. stimulated by high PTH and low PO4. FGF23 production
Parathyroid hormone (PTH) increases Ca release from and release is stimulated by serum phosphate independent
bone, Ca resorption in the kidney, and 1,25(OH)2D3 secre- of PTH axis. FGF23 lowers phosphate concentration by
tion from the kidney. PTH production is stimulated by low inhibiting renal and intestinal phosphate transport as well
Ca and inhibited by low Mg and high 1,25(OH)2D3. Vita- as preventing activation of 1,25(OH)2D3 which in turn
min D increases Ca release from bone and Ca and PO4 controls levels of bone synthesis of FGF23. CaSR
absorption from the intestine. Vitamin D production is calcium-stimulating response, UV ultraviolet light
(Novakovic et al. 2009) and that active transpla- active absorption of calcium, which involves car-
cental calcium and phosphate transfers are at least riers such as calcium-binding proteins.
partly dependent on insulin-like growth factor-1 After birth calcium absorption limits the rate of
(IGF-1), itself a stimulating factor of fetal and bone mineralization for growth although the
placental 1,25-dihydroxyvitamin D synthesis. absorption rate is higher than that during all
Bone mass of the newborn may be related to the other periods of life. The absorption of calcium
vitamin D status of the mother and studies of occurs in the small intestine by two main routes –
particular populations show that infants of mothers either through or between cells. Movement
severely deficient in vitamin D may be born with through the cell takes place by active transport
rickets and can suffer fractures in the neonatal dependent on vitamin D bound to a cytosolic
period (Salle et al. 2000; Bassir et al. 2001). calcium-binding protein (calbindin D9k). The
major role of vitamin D in transcellular calcium
41.3.1.3 Intestinal Absorption transport involves the biosynthesis of calcium-
Calcium absorption is the main determinant of its binding protein. Passive calcium transport is
retention; consequently, it has a significant impact driven by chemical gradients that represent move-
on bone mineral content. Calcium absorption ment of calcium among the cells (paracellular
occurs in the small intestine by both active and transport). In addition to vitamin D status, various
passive processes. Vitamin D is essential for the other factors affect calcium absorption (Rigo et al.
41 Calcium and Phosphorus Homeostasis: Pathophysiology 643
2010; Atkinson and Tsang 2005). Ionization of endogenous fecal calcium excretion and true cal-
calcium compounds, which requires an acid pH, cium absorption may be evaluated. Considering
occurs in the stomach and is a prerequisite for that fecal calcium excretion may represent about
absorption. Therefore, low availability could be 15 mg/kg per day in preterm infants, the true
the result of an insoluble fraction of calcium calcium absorption rate is significantly higher
intake or the precipitation of calcium in the gut. than the apparent rate measured by conventional
Calcium chloride, citrate, and carbonate have metabolic balances.
higher solubilities than calcium phosphate, Numerous metabolic balance studies have
which should be avoided in formulas. By contrast, been performed in preterm infants fed human
the higher solubility of organic calcium, such milk or a formula (Fig. 2) (Rigo et al. 2000,
as that found in calcium gluconate or glyc- 2007; Rigo and Senterre 2006) to evaluate appar-
erophosphate, improves its absorption. Fat intake ent calcium absorption. In preterm infants fed
and LCSFA (long-chain saturated fat acids) intake human milk, calcium absorption ranges from
may also influence calcium absorption through 60% to 70% depending on the calcium intake,
the formation of calcium soap. It has been showed whereas calcium retention is related to the phos-
that the free palmitate content in the gastrointesti- phorus supply. Supplementation of human milk
nal tract after the hydrolysis of triglyceride may with phosphorus alone normalizes calciuria and
impair calcium absorption. The higher bioavail- allows calcium retention to reach about 35 mg/kg
ability of calcium in human milk would be partly per day. When calcium and phosphorus are pro-
due to palmitate, which is predominantly esteri- vided together or as human milk fortifiers, cal-
fied at the glycerol 2 positions (Sn-2), but also to cium retention and absorption rates parallel that
the human milk bile salt-stimulated lipase that is of human milk, reaching 60 mg/kg per day.
not specific to the Sn-1 and Sn-3 positions. The The use of new human milk fortifiers containing
improvement of calcium absorption with the use highly soluble calcium glycerophosphate im-
of medium-chain triglycerides is probably the proves calcium retention to 90 mg/kg per day
result of the reduction of total LCSFA content in (Fig. 2) (Rigo et al. 2000). In formula-fed infants,
formula. At present, with the use of a well the percentage of net calcium absorption is less
absorbed fat combination (85% fat absorption), than that with human milk, ranging from 35% to
the influence of calcium soap formation and the 60%. Most of the difference probably results
B-palmitate content formula could be relatively from the various factors affecting calcium solu-
minimal in clinical practice. A relatively low gas- bility and absorption. At present, the use of a
trointestinal pH content or the lactose and casein preterm formula with a high mineral content
content of the formula may also have an additional does not necessarily improve mineral retention
positive effect on calcium absorption. In light of (Rigo and Senterre 2006). Indeed, due to the
the considerable requirements of preterm infants, poor solubility of calcium salts, especially cal-
all of these factors probably play a significant role cium phosphate, the calcium content measured
in the amount of calcium retained and deposited in in formulas may be significantly lower than the
the skeleton. claimed value, and an additional loss due to pre-
Medications also interfere with calcium cipitation may occur before feeding (Rigo and
absorption; for example, glucocorticoids inhibit Senterre 2006). In metabolic studies, the actual
intestinal transfer. Some anticonvulsants can also amount of calcium provided by feeding needs to
inhibit calcium absorption either directly (phenyt- be measured. As shown in Fig. 2, calcium reten-
oin) or indirectly through interference with vita- tion limited to 90 mg/kg per day could presently
min D metabolism (phenobarbital and phenytoin). be expected in preterm infants fed a preterm for-
In newborn infants, a significant amount of cal- mula with a highly soluble calcium content. Nev-
cium is secreted in the intestinal lumen through ertheless, those values are still relatively far from
digestive fluid. With the use of stable isotopes, the reference values calculated during the last
644 J. Rigo et al.
200 100 120 120
Ca intake Ca absorbed
P intake P absorbed
Ca retention Absorption % 110
180 90 P retention Absorption %
100 100
160 80
Phosphorus (mg/kg/d)
90
Calcium (mg/kg/d)
140 70
Absorption (%)
80 80
Absorption (%)
120 60 70
100 50 60 60
50
80 40
40 40
60 30
30
40 20
20 20
20 10 10
0 0 0 0
HMF1 (n=36) HMF2 (n=22) HMF3 (n=23) HMF1(n=36) HMF2(n=22) HMF3(n=23)
200 100 120 120
Ca intake Ca absorbed P intake P absorbed
180 90 110 110
Ca retention Absorption % P retention Absorption %
100 100
160 80
Phosphorus (mg/kg/d)
90 90
Calcium (mg/kg/d)
140 70
Absorption (%)
80 80
Absorption (%)
120 60
70 70
100 50 60 60
80 40 50 50
40 40
60 30
30 30
40 20
20 20
20 10
10 10
0 0 0 0
PF1 (n=31) PF2 (n=37) PF3 (n=27) PF4 (n=20) PF1 (n=31) PF2 (n=37) PF3 (n=27) PF4 (n=20)
Fig. 2 Calcium and phosphorus absorption and retention retention are related to intake, in contrast to formula
in preterm infants fed human milk (without or with a groups, in which a plateau is reached rapidly due to a
human milk fortifier) and preterm formulas. In human decrease in net absorption (%). HMF human milk fortifier,
milk groups, calcium and phosphorus absorption and PF preterm formula
trimester of gestation (120–130 mg/kg per day), tubule by a mechanism independent of Na+
which is still considered the target mineral accre- reabsorption but regulated by PTH and 1,25
tion rate for infants with very low birth weight (OH)2D3. Calcium reabsorption is increased by
(VLBW). both PTH and 1,25(OH)2D3. It is also regulated
by ionized calcium concentration, phosphate con-
41.3.1.4 Renal Excretion centration, and acid-base status and increases with
Under normal circumstances, calcium status is Ca2+ depletion and alkalosis but decreases with
maintained by a balance between its intestinal hypercalcemia, phosphate depletion, and acidosis.
absorption and renal excretion. Urinary excretion The effects of diuretics on renal calcium excretion
is the result of glomerular filtration followed by vary considerably. Furosemide markedly
the sum of the processes of tubular reabsorption increases renal calcium losses and is a risk factor
and secretion. Approximately 70% of the filtered for neonatal nephrocalcinosis. Thiazides increase
load of calcium is reabsorbed in the proximal renal tubular calcium reabsorption, thereby reduc-
tubule and 20% in the thick ascending limb of ing calciuria (Portal 2004).
Henle’s loop in association with Na+ reabsorption. The ability of the kidney to dispose of excess
Although it is responsible for only 5–10% of Ca2+ calcium represents a major homeostatic mech-
reabsorption, the major regulation of Ca2+ anism. Under normal circumstancs nearly all
reabsorption occurs in the distal convoluted filtered calcium (98%) is reabsorbed in the
41 Calcium and Phosphorus Homeostasis: Pathophysiology 645
Intestinal absorption
Absorption of 90% of the phosphorus intakes Soft tissue accretion
in the small intestine.
Absorption of 36–60% of the calcium intakes Retention of 10 mg of phosphorus
in the small intestine under dependence for each gram of the protein retention
of vitamin D and diet (human milk or formula) with a N/P ratio = 15/1.
Calcium soft tissue retention
is negligible
Renal excretion
Renal excretion is the main
mechanism of phosphorus
regulation.
only in case of phosphorus
depletion
Plasma regulation
50% of the plasma Ca Bone mineralization
is ionized and biologically active.
Regulation depends on PTH, vitamin D Calcium deposition associated
Calcium and calcitonin. Two third of serum phosphorus with phosphorus in the form of
hydroxyapatite [Ca10(PO4)6(OH)2]
Phosphorus is inorganic, while one third is organic. Molar Ca/P ratio 1.67 (2.15 wt/wt)
Regulation depends on PTH, vitamin D and
Protein phosphatonins (FGF23)
Fig. 3 Metabolism of calcium and phosphorus in term infants with feeding
renal tubule. However, preterm and term urinary phosphate excretion. In contrast, when
infants differ from the adult in three main human milk is supplemented with phosphate,
aspects: (1) Renal function is far from being significant phosphaturia appears at the same
completely developed, (2) Mineral require- time that calciuria decreases to a minimum
ments for growth are very high and (3) Renal level. Therefore, hypercalciuria can be
calcium load results solely in the difference explained by a relative phosphate depletion
between net absorption and net bone and soft that cannot meet the phosphate demand neces-
tissue retention. Considering that calcium soft sary for skeletal mineralization (Fig. 3).
tissue retention is negligible, renal calcium load
is highly dependent on bone calcium deposition 41.3.1.5 Requirement
associated with phosphorus in the form of For preterm infants, recommendations are based
hydroxyapatite [Ca10(PO4)6(OH) 2] containing on fetal accretion rates. In 1985 the American
a molar calcium:phosphorus ratio of 1.67 Academy of Pediatrics recommended that formu-
(2.15 wt/wt). Therefore, the main determinant las contain 140–160 mg of calcium per 100 kcal
of the urinary loss of calcium in preterm and (American Academy of Pediatric 1985). More
term neonates is relative to phosphorus deple- recently, the Life Sciences Research Office
tion, which has been illustrated in balance stud- recommended a calcium content of 123–185 mg/
ies performed in growing preterm infants fed 100 kcal for preterm infant formula, and an inter-
human milk. When human milk is provided national expert panel suggested a similar value of
exclusively, there is an increase in the urinary 90–180 mg/100 kcal (Klein 2002). However, the
excretion of calcium associated with very low ESPGHAN (European Society for Pediatric
646 J. Rigo et al.
Gastroenterology, Hepatology, and Nutrition) as the mass of the elemental phosphorus (mmol/L
committee of nutrition considers that those cal- or mg/dL). In contrast to calcium, the serum phos-
cium needs are based on data obtained in infants phorus concentration varies widely depending
fed preterm formulas with low calcium bioavail- mainly on intake and renal excretion but is also
ability. It suggests that after birth, bone metabo- influenced by age, gender, pH, and a variety of
lism is designed to accelerate bone turnover, hormones. At birth, the mean serum phosphorus
reducing calcium requirements and that the rela- concentration is relatively low (2.6 mmol/L, or
tive osteopenia observed in preterm infants could 6.2 mg/dL) but thereafter rises rapidly to reach
be considered at least partially physiologic. As a 3.4 mmol/L, or 8.1 mg/dL, owing to both endog-
calcium retention level ranging from 60 to 90 mg/ enous phosphorus release and low renal excretion.
kg/day assures appropriate mineralization and Serum phosphorus subsequently varies. The diet
decreases the risk of fracture in VLBW infants, partially determines the serum phosphorus con-
the ESPGHAN CoN recommended the use of tent: it is higher in formula-fed than breast-fed
highly bioavailable calcium salts providing a cal- infants. Serum phosphorus is inversely related to
cium content of 110–130 mg/100 kcal (Agostoni serum calcium concentration. After the neonatal
et al. 2010). period, the serum phosphorus concentration pro-
gressively decreases to 2.1 mmol/L, or 5 mg/dL,
at the age of 1–2 years; 1.8 mmol/L, or 4.4 mg/dL,
41.3.2 Phosphorus Physiology in middle childhood; and 1.5 mmol/L, or 3.5 mg/
dL, at the end of adolescence (Portal 2004).
Unlike calcium, phosphorus remains in the soft
tissues, mainly in the form of phosphate esters, 41.3.2.2 Placental Transport
and in extracellular fluid in the form of inorganic During pregnancy there is transfer of phosphorus
phosphate ions. It represents approximately from the mother to the fetus that reaches a peak of
15% of the whole-body content. Given its wide- 60–75 mg/kg per day during the third trimester;
spread distribution, phosphorus plays a critical 75% is retained for bone mineralization, and 25%
role in many biological processes, including is retained in other tissues. The transplacental
energy metabolism, membrane composition, transport of phosphorus is an active process
nucleotide structure, cellular signaling and against a concentration gradient and is sodium
bone mineralization. It is, therefore, not surpris- dependent. Both 1,25(OH)2D3 and fetal PTH
ing that a deficiency of phosphorus results in may be involved in the regulation of placental
clinical disease, including muscle weakness, phosphorus transfer.
impaired leukocyte function, and abnormal
bone metabolization. 41.3.2.3 Intestinal Absorption
Intestinal phosphorus absorption takes place pri-
41.3.2.1 Serum Phosphorus marily in the duodenum, jejunum, and to a lesser
In serum about two thirds of phosphorus is extent in the ileum and colon. It occurs via two
organic (lipid phosphorus and phosphoric ester mechanisms: an active, sodium-dependent trans-
phosphorus) and one third inorganic. In routine cellular process localized to the mucosal surface
clinical practice only inorganic phosphorus is and passive diffusion through the paracellular
measured. About 85% of the inorganic phospho- pathway. It depends on both the absolute amount
rus is ionized, circulating as monohydrogen or of dietary phosphorus and the relative concentra-
dihydrogen phosphate; 5% is complexed with tions of calcium and phosphorus (an excessive
sodium, magnesium, or calcium; and 10% is pro- amount of either can decrease the absorption of
tein bound (Rigo et al. 2010). the other). Vitamin D may stimulate active phos-
Because so many phosphorus species are pre- phorus absorption, although it is largely indepen-
sent, depending on pH and other factors, the dent of vitamin D intake. The efficiency of this
serum concentration is conventionally expressed absorption is high (close to 90% of intake)
41 Calcium and Phosphorus Homeostasis: Pathophysiology 647
regardless of the type of milk given (Rigo et al. period appears to be correlated with the smaller
2000, 2010). However, the use of poorly soluble phosphate needs of adult and older animals than
phosphate salt such as calcium triphosphate in those of growing animals and is associated with a
formulas is associated with a significant reduction rapid downregulation of Na+-phosphate
in phosphorus absorption (Rigo et al. 2000). In cotransporter-2 mRNA and protein in the brush
contrast to calcium, only a small amount of phos- border membrane (Holtback and Aperia 2003).
phate is secreted in the intestinal lumen through The kidney is the major determinant of the plasma
digestive fluid. phosphate concentration. Filtered load depends
on the plasma phosphorus level and glomerular
41.3.2.4 Renal Excretion filtration rate (GFR).
The kidney contributes to a positive phosphate Tubular reabsorption is an active and saturable
balance during growth by the reabsorption of a process that gives rise to a maximum rate of
relatively high fraction of filtered inorganic phos- tubular reabsorption (Tm). There is a plasma min-
phate (99% in newborns, 95% in infants fed imum threshold below which phosphorus
human milk, and 80% in adults). reabsorption is almost complete and urinary
Preterm infants have an increased fractional excretion close to zero and a maximum threshold
excretion of phosphate and are at a greater risk above which all tubular reabsorptive systems are
of developing signs and symptoms of phosphate saturated, so each additional increment in filtered
deficiency. The bulk of filtered phosphate is load is associated with a parallel increment in
reabsorbed in the proximal tubule via a sodium- excretion (Rigo et al. 2010). In preterm infants,
dependent transporter, the Na+-phosphate the minimum and maximum threshold levels are
cotransporter. The age-related decrease in phos- 1.75 mmol/L (5.4 mg/dL) and 2.45 mmol/L
phate reabsorption observed after the weaning (7.6 mg/dL), respectively (Fig. 4).
Fig. 4 Relationship 70
between urinary excretion
of phosphorus and serum
phosphate level (n = 198) in
preterm infants. Regression 60
lines represent the
minimum, mean, and
maximum plasma
50
Urinary phosphorus excretion (mg/kg/d)
phosphate concentration
thresholds for tubular
reabsorption of phosphate.
Points to the left of the 40
minimum threshold were
considered
hypophosphatemia
associated with phosphorus 30
depletion. Points to the right
of the maximum threshold
were considered
hyperphosphatemia due to 20
low glomerular filtration
rates and relative
phosphorus overload
10
0
0 1 2 3 4 5 6 7 8 9 10 11
Serum phosphorus concentration (mg/dL)
648 J. Rigo et al.
In the intermediate zone, there is a functional regulation of phosphorus excretion during the
relationship between GFR and Tm, known as the early life remain to be established. FGF23 princi-
glomerulotubular balance, in which a change in pally functions as a phosphaturic factor and
GFR is compensated for by a change in Tm in counter-regulatory hormone for 1,25(OH)2 vita-
order to regulate phosphorus excretion. The total min D production (Quarles 2008).
body phosphate metabolism is tightly regulated by Absorbed phosphate enters the extracellular
three hormones, namely PTH, 1,25(OH)2 vitamin phosphate pool, which is in equilibrium with
D and fibroblast growth factor 23 (FGF23) bone and soft tissue. In adults with neutral phos-
(Quarles 2008). The level of PTH activity in phorus balance, the amount of phosphorus
plasma is an important physiologic regulator of excreted by the kidney is equal to the net amount
phosphorus excretion. PTH inhibits phosphorus absorbed by the intestine; in growing infants, it is
reabsorption, but its activity appears to be limited less than the net amount absorbed due to the
to the intermediate zone between the minimum and deposition of phosphorus in soft tissues and bone.
maximum plasma threshold levels. In contrast, In growing infants, phosphorus will preferen-
1,25(OH)2 vitamin D synthesis, stimulated by a tially go to soft tissue with a weight-to-weight
decrease in plasma phosphorus concentration, has nitrogen:phosphorus ratio of 15:1 and to bone
an indirect effect on phosphorus reabsorption by its with a weight-to-weight calcium:phosphorus
effect on mineral absorption and mobilization from ratio of 2.15:1. The residual phosphorus consti-
bone, resulting in an increase in plasma calcium tutes the renal phosphorus load influencing
concentration and the suppression of PTH release. plasma concentration and urinary excretion. In
During early postnatal life the phosphate response the face of a limited total phosphorus supply,
to PTH is blunted, whereas PTH increases tubular bone mineral accretion may be limited, leading
calcium reabsorption. to significant calcium excretion associated with
Together, these actions result in the retention of very low urinary excretion of phosphorus
both calcium and phosphate in infants, which is (Fig. 5). This particular situation is illustrated in
favorable for growth. The role of newly discov- Fig. 3, showing calcium and phosphorus metabo-
ered phosphatonin peptides such as FGF23 in the lism in term infants.
Fig. 5 Relationship 35
between urinary excretion
of calcium and urinary
excretion of phosphorus in 30
preterm infants (n = 198).
Urinary excretion of calcium mg/kg/d)
Hypercalciuria (>8 mg/kg/
day) is related to low 25
phosphate excretion
(<3 mg/kg/day).
Conversely, urinary 20
excretion of calcium below
8 mg/kg/day is usually
observed in preterm infants 15
with phosphorus excretion
over 4 mg/kg/day
10
0
0 5 10 15 20 25 30 35 40 45
Urinary excretion of phosphorus (mg/kg/d)
41 Calcium and Phosphorus Homeostasis: Pathophysiology 649
41.3.2.5 Requirement Slower regulation of PTH secretion occurs over
For preterm infants the recommendations are a period of hours as a result of cellular changes in
based on fetal accretion rates. The 1985 American PTH messenger RNA (mRNA). Vitamin D and its
Academy of Pediatrics recommended 95–108 mg metabolites 25-hydroxyvitamin D and 1,25-
of phosphorus per 100 kcal for preterm formulas dihydroxyvitamin D, acting through vitamin D
(American Academy of Pediatric 1985), whereas receptors, decrease the level of PTH mRNA and
more recently, the Life Sciences Research Office hypocalcemia increase it. The slowest regulation
and the International Expert Panel recommended of PTH secretion occurs over days or even months
similar values, with a calcium-to-phosphorus ratio and reflects changes in the growth of the parathy-
maintained over 1.7:1 but less than 2.0:1 (Klein roid glands. Metabolites of vitamin D directly
2002). Considering a nitrogen retention ranging inhibit the mass of parathyroid cells; hypocalce-
from 350 to 450 mg/kg/day and a calcium reten- mia stimulates the growth of parathyroid cells
tion from 60 to 90 mg/kg/day. The ESPGHAN independent of the contrary action of vitamin D
CoN recommended an adequate intake of metabolites. In the kidney, the calcium-sensing
65–90 mg/kg/day of a highly absorbable source receptor (CaSR) mediates the direct inhibition of
of phosphate (90%) with a Ca to P ratio between the reabsorption of divalent cations in the thick
1.5 and 2.0 (Agostoni et al. 2010). cortical ascending limb of Henle’s loop
(Rodriguez 2003).
41.4 Hormonal Regulation 41.4.1.2 Fetal Parathyroid Function
Human parathyroid glands are functionally active
41.4.1 Parathyroid Hormone as early as 12 weeks of gestation. However, fetal
parathyroid glands are functionally suppressed by
PTH is synthesized as a larger (115-amino acid) high intrauterine calcium concentrations, and
precursor (prepro-PTH) but is stored and secreted PTH levels in cord blood are frequently below
mainly as an 84-amino acid peptide, with the the detection limit. PTH does not appear to cross
1–34,N-terminal portion conferring bioactivity. the placenta in either direction, and the role of
PTH regulates large calcium fluxes across bone, PTH in maternal-fetal calcium transport is limited.
kidneys, and intestine (Fig. 1). PTH increases In contrast, PTHrP acts during fetal life to pro-
serum calcium concentrations directly by increas- mote calcium transfer, high blood calcium con-
ing bone resorption and renal calcium centration, bone development, and matrix
reabsorption and indirectly by increasing renal mineralization.
synthesis of 1,25(OH)2D3, thereby increasing Maternal hyperparathyroidism results in mater-
intestinal calcium absorption. PTH also lowers nal hypercalcemia, which leads to fetal hypercal-
serum phosphorus concentrations through its cemia and suppression of fetal and neonatal
phosphaturic action on the renal proximal tubule. parathyroid glands. Conversely, untreated mater-
This action minimizes the possibly adverse effect nal hypoparathyroidism leads to maternal hypo-
of hyperphosphatemia related to bone resorption calcemia, fetal hypocalcemia, and secondary fetal
on calcium homeostasis. and neonatal hyperparathyroidism.
41.4.1.1 Regulation 41.4.1.3 Neonatal Parathyroid Function
Serum calcium concentration regulates PTH After birth, with the abrupt termination of the
secretion; high concentrations inhibit the secre- maternal calcium supply, serum calcium in the
tion of PTH and low concentrations stimulate newborn decreases and serum PTH increases cor-
it. Low or falling serum calcium concentrations respondingly. Both term and preterm infants may
act within seconds to stimulate PTH secretion, show a PTH response to falling serum calcium.
initiated by means of a calcium-sensing receptor Nevertheless, plasma PTH levels are relatively
(CaSR) on the surfaces of parathyroid cells. low in the neonatal period and are minimally
650 J. Rigo et al.
responsive to hypocalcemia during the first exposure or is absorbed from dietary sources as
2–3 days of life leading to transient neonatal either vitamin D3 (from animal sources) or vita-
hypocalcemia. Infants with VLBW have a min D2 (ergocalciferol [from vegetable sources]).
decreased PTH surge compared with full-term Regardless of its origin, vitamin D2 and D3 are
infants. Infants of diabetic mothers may have transported bound to the vitamin D binding pro-
impaired PTH production during the beginning tein to the liver, where it is hydroxylated at carbon
days of life. Infants with birth asphyxia may also 25 to form vitamin D3 (25[OH]D3, or calcidiol),
have decreased PTH responses to hypocalcemia. the most abundant vitamin D metabolite. The
circulating concentrations of 25[OH]D3 provide
41.4.1.4 Parathyroid Hormone a useful index of vitamin D status (reflecting both
Reference Values dietary intake and sunshine exposure). Subse-
In full-term newborns, serum PTH concentrations quently in the kidney, 25[OH]D3 is further
tend to be low in cord blood but increase within hydroxylated at carbon 1 to form the final active
the first 48 h of life in response to the decrease in metabolite, 1,25(OH)2D3, or calcitriol. This last
serum calcium. In preterm infants the serum transformation is tightly regulated and is the rate-
immunoreactive, intact PTH (1–84) concentra- limiting step in vitamin D metabolism. 1,25
tions increase immediately after birth, indicating (OH)2D3 can also be synthesized by various
that the secretion of the hormone responds phys- cells as well as by the placenta during pregnancy.
iologically to the hypocalcemic stimulus. This However, this local production of 1,25(OH)2D3 is
increase in immunoreactive PTH concentration not associated with calcium homeostasis but
could be blunted when premature infants receive could contribute to regulating cell growth.
calcium by infusion, with the calcium load buff-
ering the postnatal depression of serum calcium. 41.4.2.2 Effects
By day 10, the serum concentrations of intact PTH Normal vitamin D status is necessary to maintain
return to euparathyroid values (Table 1) (Salle calcium and phosphorus homeostasis. The effects
et al. 2000). The multiplication factor for serum of 1,25(OH)2D3 (calcitriol) on target tissues are
PTH from picograms per deciliter to picomoles initiated by its binding to a steroid receptor (vita-
per liter (pg/dL to pmol/L) is 0.11. min D receptor) distributed in numerous tissues,
leading to the synthesis of a variety of proteins.
Therefore, 1,25(OH)2D3 acts on the small intes-
41.4.2 Vitamin D tine, increasing the absorption of calcium and
phosphorus by the synthesis of calcium-binding
41.4.2.1 Synthesis and Metabolism (calbindin-D) proteins; on bone, mobilizing cal-
Vitamin D is synthesized endogenously in the cium and phosphorus by increasing the number of
skin (cholecalciferol or vitamin D3) after sunshine osteoclasts; and on the kidney, increasing calcium
Table 1 Evolution of PTH(1–84) cPTH DBP
intact PTH (1–84), carboxy
(pmol/L) (pmol/L) (μmol/L)
terminal PTH, and vitamin
D binding protein Cord Serum 11 3 48 8 4.43 0.37
concentrations in Day 1 66 11a 125 15a 4.40 0.34
15 preterm infants Day 2 87 11a 168 5a 4.96 0.23
Day 5 67 9a 152 16a 6.21 0.26a
Day 10 23 4 69 6 6.03 0.30a
Day 30 38 7 80 11 5.16 0.23
From (Salle et al. 2000), with permission
PTH parathyroid hormone, cPTH carboxy terminal PTH, DBP vitamin D binding
protein
a
Significantly different from cord serum, P < 0.05
41 Calcium and Phosphorus Homeostasis: Pathophysiology 651
reabsorption in the distal nephron segments by 1,25-dihydroxyvitamin D concentrations are more
increasing the expression of the epithelial calcium complex, most of the 1,25-dihydroxyvitamin D in
influx channel. There is a natural polymorphism fetal plasma is due to fetal kidney activity, as
in the genotype of the vitamin D receptor that suggested by studies in fetal plasma from infants
contributes to skeletal metabolism in early child- with renal agenesis. Actually, the precise role of the
hood and to the genetic determinant of the peak placental 1,25-dihydroxyvitamin D activity in the
bone mass. mineral homeostasis during the fetal life remains to
be evaluated.
41.4.2.3 Regulation of Secretion Bone mass of the newborn may be related to
In contrast to hepatic 25-hydroxylation, renal the vitamin D status of the mother (Pawley and
1-hydroxylation, which leads to the active metab- Bishop 2004). Comparison of the results of dual-
olite, appears to be tightly regulated. The main energy X-ray absorptiometry from different coun-
factors increasing the synthesis of calcitriol via tries shows that infant whole-body bone mineral
stimulation of renal 25(OH)D3-1α-hydroxylase content values are lower in countries in which
are PTH, PTHrP, hypocalcemia, hypo- milk products are not supplemented with vitamin
phosphatemia, and other hormonal factors, such D than in those where milk products are
as insulin-like growth factor-1, estrogen, prolac- supplemented. In contrast, vitamin D supplemen-
tin, and growth hormone. The production of tation of malnourished mothers results in
calcitriol is inhibited by elevated serum levels of improved growth of the fetus and child in terms
calcium and phosphorus, but also by the newly of both birth weight and subsequent linear growth
discovered phosphatonin peptides implicated in during infancy.
phosphorus homeostasis. Thus, an increase in Therefore, during pregnancy a daily vitamin D
FGF23 production suppresses 1,25(OH)2 vitamin supplement of at least 400 IU/day (10 μg/day)
D via inhibition of 25-hydroxyvitamin D-1- need to be administered, whereas for at-risk
α-hydroxylase and stimulation of 24-hydroxylase populations an increased supply to 1000 IU/day
inactivating 1,25(OH)2 vitamin D in the proximal [25 μg/day]) should be given at least during the
tubule of the kidney (Quarles 2008). last 3 months of pregnancy.
41.4.2.4 Fetal Vitamin D Function 41.4.2.5 Neonatal Vitamin D: Function
Serum 25-hydroxyvitamin D concentration and Recommendations
depends on vitamin D intake and production. Plasma 25(OH) D3 concentration is a useful vita-
The production of vitamin D is influenced by min D biomarker reflecting vitamin D supply and
geographic location, season and latitude, and usage over a period of time. Unfortunately, the
skin pigmentation. Vitamin D deficiency is very cut-off used for serum 25(OH) D3 concentrations
common during pregnancy, not only in areas with varies among researchers, leading to various prev-
a prolonged winter season. In Belgium, vitamin D alence of vitamin D deficiency and/or insuffi-
deficiency, <50 and 80 nmol/L, represent respec- ciency. Nevertheless, several surveys show a
tively 80% and 90% of the pregnant women high rate of poor maternal vitamin D status
(Pieltain et al. 2009). throughout the world, particularly in countries
Cord concentrations of the major vitamin D without vitamin D supplementation, with poor
metabolites are consistently lower than those mea- sun exposure, extensive clothing, or with deeply
sured in the mother’s serum. Placental vein pigmented skin. Thus, the rate of cord blood vita-
25-hydroxyvitamin D concentrations correlate min D severe insufficiency (<20 nmol/L;
significantly with those found in the maternal <8.3 ng/mL) may reach up to 70% in European
circulation, suggesting that calcidiol easily dif- populations (Pieltain et al. 2009; Pawley and
fuses across the placental barrier and that the Bishop 2004).
vitamin D pool of the fetus depends entirely on The concentrations of vitamin D are low in
that of the mother. The fetomaternal relations of human milk (20–60 IU/L) and lower than that in
652 J. Rigo et al.
regular formulas (400–600 IU/L). In breast-fed concentrations of total 1,25-dihydroxyvitamin D by
infants not receiving vitamin D supplements, vita- 5 days of age, promoting calcium absorption and
min D stores could be depleted within 8 weeks of mineral accretion rates during the neonatal period.
delivery, suggesting the need for vitamin D sup- Therefore, vitamin D recommendations may differ
plementation (Greer 2003). A minimum daily significantly between North American (400 IU/day,
intake of 400 IU (10 μg/day) of vitamin D is 10 μg/day) and European countries (800–1000 IU/
recommended by the AAP for all infants begin- day, 10–25 μg/day) (Agostoni et al. 2010).
ning soon after birth, including those who are
exclusively breastfed (Wagner et al. 2008). More- 41.4.2.6 Reference Values
over, in breastfed full-term infants born to mothers New informations on the additional role of vita-
who are vitamin D deficient, maternal supplemen- min D on glucose homeostasis, immune system,
tation with vitamin D could be required to cardiovascular disease, and cancer has resulted in
increase the human milk vitamin D concentration defining vitamin D deficiency in adults as a
and in turn improve infant vitamin D status. In 25-OH-D concentration < 50 nmol/L and vitamin
addition, vitamin D is metabolized in the liver, D insufficiency as a 25-OH-D concentration of
and anticonvulsants such as phenobarbital and 50–80 nmol/L. At the present time, however, con-
diphenylhydantoin increase its hepatic catabolism sensus has not been reached with regard to the
and requirements. concentration of 25-OH-D to define vitamin D
In preterm infants, as a result of the decrease in insufficiency for infants and children (Holick
serum calcium during the first days of age, the 2007). Universal units of measure for 25-OH-D
postnatal surge in PTH induces increased synthe- and 1,25-OH2-D are nmol/L. Conversion to
sis of 1,25(OH)2D3 during the first days day of ng/mL is made by dividing the value expressed
life. Provision of 1000 IU of vitamin D3 increases in nmol/L by 2.496. Thus, 80 nmol/L becomes
the 25-hydroxyvitamin D pool of the newborn at 32 ng/mL.
birth, followed by rapid renal synthesis of 1,25-
dihydroxyvitamin D during the early postnatal
days. In very low birth weight infants 41.4.3 Calcitonin
(<1500 g), immaturity of the vitamin D activation
pathway, either alone or in combination with other Calcitonin (CT) is a 32-amino acid peptide secreted
abnormalities, particularly transient hypoparathy- by the thyroidal C cells. In addition, a group of
roidism, hypercalcitoninemia, and end-organ peptide hormones, the “calcitonin family”, includ-
resistance to hormonal effects, may promote late ing the calcitonin gene-related protein (CGRP),
neonatal hypocalcemia. However, after 28 weeks with structural similarities to calcitonin are also
of gestation, activation of vitamin D is operative produced by several tissues. Although calcitonin
as early as 24 h after birth. Vitamin D supplemen- has often been considered to be a vestigial hormone
tation just after birth improves its nutritional sta- with no certain role in mammalian calcium and
tus, as evidenced by rises in both plasma 1,25- and bone homeostasis, recent studies indicate that calci-
25-hydroxyvitamin D concentrations. tonin has important roles in calcium and bone
In countries with high vitamin D status, plasma homeostasis that have not been previously recog-
25-hydroxyvitamin D remained normal for nized. It has been established that the major action
6 months while infants received around 400 IU/ of CT is the inhibition of bone resorption, and
day (<10 μg/day). By contrast, in Europe and osteoclasts (Karsdal et al. 2008). The regulation of
other countries where dairy products are not calcitonin is opposite to that of PTH. Mediated by
enriched with vitamin D, sunshine exposure is the CaSR, an increase in ionized calcium stimulates
restricted (Salle et al. 2000), and mean cord con- calcitonin secretion, whereas a decrease in ionized
centrations of 25-hydroxyvitamin D are low, the calcium leads to a fall in calcitonin. Thus, the CaSR
administration of vitamin D (from 1000 IU/day, or has a dual physiological response to regulate PTH
25 μg/day) results in a rapid increase in circulating and calcitonin that in the long-term will influence
41 Calcium and Phosphorus Homeostasis: Pathophysiology 653
the maintenance of skeletal mineral content (Fudge enhances tubular phosphorus avidity and increases
and Kovacs 2004). 1,25D production. A down regulation of FGF-23
At birth, serum calcitonin concentrations are could promote the relative hyperphosphatemia and
higher in cord blood than maternal blood, and they the relative increase in 1,25(OH)2 vitamin D pro-
increase further in the first 24 h of life. The phys- moting bone mineralization during early rapid
iologic importance of the postnatal increase of growth in the neonatal period (Quarles 2008).
calcitonin is unclear and it is uncertain whether The targeting of FGF23 to the kidney is mediated
calcitonin plays any specific role in calcium by a coreceptor (klotho) that enhances the binding
homeostasis and skeletal metabolism during the affinity of FGF23 to the widely expressed FGF
fetal and neonatal period (Fudge and Kovacs receptor 1c (Quarles 2008).
2004). In contrast, CT has an important physio- Phosphatonins have been implicated in the
logical role during lactation protecting the mater- pathophysiology of disorders of phosphate
nal skeleton against excessive resorption and homeostasis such as Tumor-induced osteomalacia
attendant fragility. (TIO), X-linked hypophosphatemic rickets
(XLH), autosomal dominant hypophosphatemic
rickets (ADHR), autosomal recessive hypo-
41.4.4 FGF23 and Phosphatonin phosphatemia (ARHP), tumoral calcinosis and
Peptides renal failure (Shaikh et al. 2008). However, the
role of newly discovered phosphatonin peptides,
“Phosphatonins” represent a number of peptides such as FGF 23 in the regulation of phosphorus
which have been recently identified as a result of excretion during the early life, remain to be
the study of various diseases associated with established.
hypophosphatemia: fibroblast growth factor
23 [FGF23], secreted frizzled-related protein
4 [sFRP-4], fibroblast growth factor 7 [FGF7] 41.5 Clinical Conditions Associated
and matrix extracellular phosphoglycoprotein with Calcium Disturbances
[MEPE] (Quarles 2008; Liu et al. 2007; Shaikh
et al. 2008). FGF23 is predominantly produced by 41.5.1 Neonatal Hypocalcemia
osteocytes in bone, and its principal actions are to
inhibit sodium-dependent phosphate reabsorption Serum total and ionized calcium concentrations
and 1α-hydroxylase activity in the proximal are relatively high at birth but decrease sharply
tubule of the kidney, leading to phosphaturia and during the first hours of life to reach a nadir at 24 h
suppression of circulating 1,25(OH)2D levels. and increase progressively thereafter up to the end
Evidence that FGF23 is the principle phosphaturic of the first week of life (Table 2). Sudden changes
factor comes from a variety of observations
(Shaikh et al. 2008).
Fibroblast growth factor 23 regulates serum Table 2 Evolution of serum calcium concentrations
(mmol/La) during the first 10 days of life in term and
phosphate levels within a narrow range despite preterm infants
wide fluctuation in dietary intake via a series of
Term Preterm
classic negative endocrine feedback loops involv-
Age Mean 95% CI Mean 95% CI
ing 1,25-dihydroxyvitamin D, parathyroid hor- Birth 2.55 2.25–2.85 2.24 1.58–2.90
mone, urinary phosphate excretion, and dietary (cord
phosphorus absorption. A sustained increase in blood)
dietary phosphorus intake stimulates FGF23 24 h 2.25 1.95–2.55 1.94 1.64–2.24
secretion that increases phosphaturia. At the 48 h 2.39 2.14–2.64 1.85 1.47–2.23
same time, FGF23 inhibits renal synthesis of 120 h 2.46 2.25–2.68 2.22 1.84–2.60
1,25D. By contrast, a sustained reduction in phos- 240 h 2.48 2.26–2.69 2.45 2.45–2.89
phorus intake lowers FGF23 secretion, which
a
Conversion to mg/dL: mmol/L 0.2495
654 J. Rigo et al.
Table 3 Causes of neonatal calcium disorders
Hypocalcemia Hypercalcemia
Early Hypocalcemia (1–4 days of age) Iatrogenic
Prematurity Calcium salts, vitamin A
Maternal diabetes Hypophosphatemia (prematurity)
Perinatal stress/asphyxia Hypervitaminosis D
Intrauterine growth restriction Thiazide diuretics
Maternal anticonvulsants
Disorders of Parathyroid Function
Late Hypocalcemia (5–10 days of age) Maternal hypocalcemia,
hypoparathyroidism
Hyperphosphatemia (high phosphate load, advanced renal insufficiency) Mutation of the parathyroid hormone-
related protein receptor
Hypomagnesemia Jansen metaphyseal chondrodysplasia
Vitamin D deficiency Calcium-sensing receptor defects
PTH resistance (transient neonatal pseudohypoparathyroidism) Familial hypocalciuric hypercalcemia
Hypoparathyroidism Neonatal severe hyperparathyroidism
Primary: parathyroid agenesis, 22q11 deletion, parathyroid hormone
gene mutation
Idiopathic Infantile Hypercalcemia
Secondary: maternal hyperparathyroidism Hyperprostaglandin E Syndrome
Calcium-sensing receptor defects; autosomal dominant hypocalcemic Severe Infantile Hypophosphatasia
hypercalciuria Other Causes
Acquired or inherited disorders of vitamin D metabolism Congenital carbohydrate malabsorption
Neonatal hypocalcemia associated with skeletal dysplasia Distal renal tubular acidosis
Other causes (alkalosis, citrated blood transfusions, phototherapy, viral Tumor-related hypercalcemia
gastroenteritis, lipid infusions) Congenital hypothyroidism
Williams syndrome
Subcutaneous fat necrosis
Blue diaper syndrome
in the distribution of calcium between ionized and concentration. This measurement is particularly
bound fractions may cause symptoms of hypocal- important when evaluating patients who have
cemia even in children with functioning hormonal abnormal circulating proteins and after blood
mechanisms for the regulation of the ionized cal- transfusion for the correction of acidosis and
cium concentration (Table 3). Increases in the hyperventilation. For example, total serum cal-
extracellular fluid concentration of anions such cium decreases approximately 1 mg/dL, or
as phosphate, citrate, or bicarbonate increase the 0.25 mmol/L, for each 1 g/dL of decrease in
proportion of bound calcium and decrease ionized serum albumin, without any change in ionized
calcium. Alkalosis increases the affinity of albu- calcium.
min for calcium and thereby decreases the con- Neonates at the greatest risk for symptomatic
centration of ionized calcium. In contrast, acidosis or asymptomatic neonatal hypocalcemia, such as
increases the ionized calcium concentration by the infants of diabetic mothers or preterm or
decreasing the binding of calcium to albumin. asphyxiated neonates, are frequently sick for a
Although it is conventional to measure the total multitude of reasons, and the contribution of neo-
serum calcium concentration, more physiologi- natal hypocalcemia to signs related to their pri-
cally relevant information is obtained by direct mary illness can be easily obscured. From a
measurement of the ionized calcium clinical viewpoint, because Ca2+ concentrations
41 Calcium and Phosphorus Homeostasis: Pathophysiology 655
are maintained within narrow ranges under nor- increased calcium intake with feedings, increased
mal circumstances, the potential risk for distur- renal phosphorus excretion, and improved para-
bances of physiologic function increases as the thyroid function. Calcium supplementation may
Ca2+ concentration decreases. A useful approach hasten the restorative process.
to the classification of neonatal hypocalcemia is
by time of onset. The early and late forms of 41.5.1.2 Early Hypocalcemia: Preterm
hypocalcemia have different causes and occur in Infants
different clinical settings. The frequency of hypocalcemia varies inversely
with birth-weight and gestational age. In preterm
41.5.1.1 Early Hypocalcemia: Term infants, the postnatal decrease in the serum cal-
Infants cium level typically occurs more rapidly than it
Early neonatal hypocalcemia occurs during the does in term infants, the magnitude of the depres-
first 4 days of life and represents an exaggeration sion being inversely proportional to gestation.
of the normal fall in serum calcium concentration Before routine calcium supplementation and the
that occurs during the first 24–48 h of life. At birth use of parenteral nutrition from the first day of
there is an interruption of maternal calcium sup- age, many LBW infants and nearly all those with
ply, and the serum calcium concentration in extremely low birth weight (ELBW) exhibited
infants is maintained by either the increased cal- total calcium levels of less than 7.0 mg/dL by
cium flux from bone or sufficient exogenous cal- day 2. However, the fall in Ca2+ is not propor-
cium intake. Because intestinal calcium tional to that in total calcium concentration, and
absorption is correlated with intake and dietary the ratio of ionized to total calcium is higher in
calcium is usually low on the first day of life, the these infants. The reason for the maintenance of
serum calcium concentration decreases on the first Ca2+ is uncertain but is probably related to low
day of life (Hsu and Levine 2004). serum protein concentration and pH associated
Normal serum concentrations for Ca2+ in full- with prematurity. The sparing effect of Ca2+ may
term newborns reach a nadir at about 24 h of age partially explain the frequent lack of signs in
(1.10–1.36 mmol/L, or 4.4–5.4 mg/dL) and rise preterm infants with low total calcium levels. In
slowly thereafter. Nenatal hypocalcemia could be preterm infants the reference values for ionized
reasonnably defined as a serum total calcium calcium are available only for large, moderately
below 2 mmol/L or a an ionized calcium of less premature infants who show values very similar to
than 0.9–1.1 mmol/L. those for full-term infants. These cutoff values
Early neonatal hypocalcemia apparently might not apply to smaller infants, given insuffi-
results from the abrupt interruption of the placen- cient physiologic data on ionized calcium. At
tal supply and the low intake provided by oral and present, the traditional cutoff point, a total calcium
parenteral nutrition and also by the slow release of content of less than 1.75 mmol/L (7.0 mg/dL) and
PTH by immature parathyroid glands or the inad- an ionized calcium of less than 0.9–1.1 mmol/L,
equate responsiveness of the renal tubular cells remains reasonable in VLBW infants.
to PTH.
By contrast, exaggerated rise in calcitonin 41.5.1.3 Perinatal Asphyxia
secretion may not play a contributory role in pre- In asphyxiated infants, the following factors may
mature infants. In infants with VLBW the high contribute to early hypocalcemia: a decreased cal-
renal sodium excretion probably aggravates cium intake due to delayed feedings and an
calciuric losses, and relative end-organ resistance increased endogenous phosphorus load resulting
to 1,25(OH)2D3 may exist additionally to an 25 from the reduction of the glomerular filtration
(OH)D3 deficiency. Hypocalcemia is temporary, rate. Hyperphosphatemia may induce relative
and the serum calcium concentration gradually PTH resistance and a stimulation of FGF23 secre-
reverts to normal after 1–3 days. Factors contrib- tion. Theoretically, the correction of acidosis with
uting to serum calcium normalization include alkali may further aggravate hypocalcemia by
656 J. Rigo et al.
inducing decreased calcium flux from bone to the In some instances the clinical distinction between
extracellular fluid and by lowering the ionized early and late hypocalcemia may not be clear.
calcium concentration.
Phosphate Loading
41.5.1.4 Maternal Conditions Hypocalcemia induced by an elevated phosphorus
and Treatments supply usually occurs at the end of the first week
of life. Late-onset hypocalcemia is considered to
Maternal Diabetes be a manifestation of relative resistance of the
Infants of diabetic mothers (IDMs) demonstrate immature kidney to PTH. In these infants the
an exaggerated postnatal drop in circulating cal- renal tubular cells are unable to respond appropri-
cium levels when compared with controls of ges- ately to PTH, leading to renal retention of phos-
tational age. Prematurity and birth asphyxia are phorus and hypocalcemia. These biochemical
frequently associated problems that indepen- features strongly resemble those of pseudo-
dently increase the risk for hypocalcemia. In hypoparathyroidism (Hsu and Levine 2004). The
IDMs, hypocalcemia appears to be related to normally low neonatal glomerular filtration rate
hypomagnesemia, the maternal form of which is may also play a role in limiting the ability to
caused by urinary magnesium losses with diabetes excrete the phosphorus load.
and leads to fetal magnesium deficiency and sec- Late hypocalcemia was frequently observed in
ondary functional hypoparathyroidism in the fetus infants fed cow’s milk or evaporated milk because
and newborn. Hypocalcemia in IDMs is also cor- of their high phosphorus content. With the intro-
related with the severity of maternal diabetes, duction of adapted infant formulas, late hypocal-
which is classified by White’s criteria. The natural cemia, though not abolished, has become
history is usually similar to that of early neonatal uncommon. However, even with current formulas
hypocalcemia in preterm infants, but hypocalce- the formula-fed infants have lower serum ionized
mia sometimes persists for several additional calcium and higher serum phosphorus in the first
days. Improved metabolic control for pregnant week of life than those of breastfed infants.
diabetic women has markedly diminished the These differences correlate with the absolute
occurrence and severity of early neonatal hypo- phosphorus amount but not with the different
calcemia in IDMs. The incidence of hypocalcemia calcium:phosphorus ratios in formulas. The phos-
is also increased in the infants of gestational dia- phate load increases calcium bone deposition,
betic mothers (IGDMs), and the role of hypomag- leading to hypocalcemia. The normal response to
nesemia has recently been demonstrated hypocalcemia is an increase in PTH secretion,
(Banerjee et al. 2003). inducing an increase in both the urinary excretion
Maternal hyperparathyroidism with hypercal- of phosphate and tubular resorption of calcium.
cemia, maternal chronic renal failure with second- The pathogenesis of this “transient hypoparathy-
ary hyperparathyroidism, mothers with abnormal roidism” in late neonatal hypocalcemia is poorly
vitamin D homeostasis and mothers receiving understood. The inadequate secretion of PTH,
anticonvulsants are additional factors increasing immaturity of PTH receptors, or transient change
risk for neonatal hypocalcemia (Table 3). in the threshold of CaSR may play an important
role (Stewart 2004). In these infants, serum cal-
41.5.1.5 Late Hypocalcemia cium levels frequently increase when they are
Hypocalcemia is conventionally defined as late given human milk, lower-phosphate formulas,
when it occurs after the first 4 days of life. Late and calcium supplements. After several days to
neonatal hypocalcemia usually develops at about weeks, serum PTH usually increases and
1 week of age (Table 3) and more frequently in the infants are able to tolerate a higher dietary
term than preterm infants and is not correlated phosphate load. Some of these infants have a
with maternal diabetes, birth trauma, or asphyxia. persistent or recurrent inability to mount an
41 Calcium and Phosphorus Homeostasis: Pathophysiology 657
adequate PTH response to a hypocalcemic nephrolithiasis. Phototherapy appears to be an
challenge and may have a form of congenital additional possible cause of neonatal hypocalce-
hypoparathyroidism. mia, although the mechanism is still uncertain.
Lipid infusions may increase serum free fatty
Hypocalcemia Resulting from Vitamin D acid levels, which form insoluble complexes
Disorder with calcium. Most of these effects are transient,
Maternal vitamin D deficiency is the major risk and cessation of therapy is associated with a return
for neonatal vitamin D deficiency presenting as to normal serum calcium levels.
hypocalcemia. Vitamin D deficiency is unusual
in countries where it is common practice to 41.5.1.7 Clinical Manifestations
supplement the diet with vitamin D dairy prod- of Hypocalcemia
ucts and other foods. However, it occurs in The clinical manifestations of neonatal hypocal-
women in whom both sunlight exposure and cemia in infants may be easily confused with other
the dietary intake of vitamin D are inadequate neonatal disorders (e.g., hypoglycemia, sepsis,
and high incidence has been reported in most of meningitis, asphyxia, intracranial bleeding, nar-
the european countries (Pieltain et al. 2009). There- cotic withdrawal). The neonate with hypocalce-
fore, if daily vitamin D supplementation during the mia may be asymptomatic; the less mature the
whole pregnancy can be undertaken, the amount infant, the more subtle and varied the clinical
given should be at least 400 IU/day (10 μg/day). In manifestations. In the neonatal period the main
countries where dairy products are not clinical signs of hypocalcemia are jitteriness
supplemented with vitamin D and sunshine expo- (increased neuromuscular irritability and activity)
sure is low, 1000 IU/day (25 μg/day) should be and generalized convulsions, although focal sei-
given during the last 3 months of pregnancy (Salle zures have also been reported. Infants may also be
et al. 2000). lethargic, eat poorly, vomit, and have abdominal
Breastfed infants of strictly vegetarian mothers distention. The degree of irritability does not
are also susceptible to vitamin D deficiency and appear to correlate with serum calcium values.
early-onset hypocalcemic rickets. Furthermore, hypocalcemia may be asymptom-
atic. Therefore, suspicion of hypocalcemia should
Hypomagnesemia be confirmed by the measurement of total serum
Neonatal hypocalcemia usually accompanies calcium and Ca2+.
hypomagnesemia because magnesium deficiency The diagnostic workup for hypocalcemia
inhibits the secretion of PTH and reduces respon- includes a history, physical examination, and rel-
siveness to its action. Depression of the serum evant investigations. In clinical practice, the diag-
magnesium levels in newborns is mainly due to nosis of hypocalcemia is based on the
transient hypomagnesemia or exceptionally to pri- determination of ionized or total calcium. Serum
mary hypomagnesemia with secondary hypocal- magnesium should also be measured because
cemia (Hsu and Levine 2004). hypomagnesemia may coexist and cause identical
signs. The measurement of calcium-regulating
41.5.1.6 Other Causes of Neonatal hormones is not routinely recommended unless
Hypocalcemia hypocalcemia is prolonged, refractory, or recur-
Bicarbonate therapy, as well as any form of rent. Assays of calciotropic hormones and 25(OH)
metabolic or respiratory alkalosis, decreases ion- D may be useful in the diagnosis of uncommon
ized calcium levels and bone resorption of cal- causes of neonatal hypocalcemia, such as primary
cium. Transfusion and plasmapheresis with hypoparathyroidism, malabsorption, and disor-
citrated blood can form nonionized calcium com- ders of vitamin D metabolism. If DiGeorge syn-
plexes, thus decreasing Ca2+. Furosemide and drome is suspected chest X-ray examination for a
xanthine therapy promotes calciuresis as well as thymic silhouette is indicated and molecular
658 J. Rigo et al.
genetic studies may be needed to confirm a micro- calcium therapy varies with the course of hypo-
deletion of chromosome 22q11.2. calcemia. As few as 2 or 3 days of therapy are
usually required.
41.5.1.8 Treatment
Late Neonatal Hypocalcemia
Early Neonatal Hypocalcemia There is usually little debate regarding the treat-
In asymptomatic newborns, treatment generally ment of late hypocalcemia. Because serum calcium
is indicated when the total serum calcium con- is not routinely measured after the first few days of
centration is less than 1.5 mol/L (6 mg/dL) in the life, late hypocalcemia is usually symptomatic
preterm infant and less than 1.75 mol/L (7 mg/ when diagnosed and the requirement for calcium
dL) in the term infant. Calcium supplementation therapy may be prolonged in the case of hypocal-
can be given either by the intravenous or oral cemia caused by malabsorption or hypoparathy-
route. Depending on the clinical status of the roidism. In phosphorus-induced hypocalcemia, a
infant, treatment of newborns who have acute low-phosphorus formula (or human milk) and
or symptomatic hypocalcemia is accomplished oral calcium supplementation are indicated to
best by the intravenous infusion of calcium salts; decrease phosphorus absorption and increase cal-
10% calcium gluconate (9.3 mg/mL of elemental cium absorption. In hypomagnesemia, the magne-
calcium, maximum 2 mL/kg over 15 min sium deficiency usually has to be corrected before
followed by 75 mg/kg per day up to normal hypocalcemia can be treated successfully.
range) is used most commonly. Effective oral Hypoparathyroidism requires therapy with vita-
therapy involves adding calcium glucobionate min D or one of its metabolites; 1,25(OH)2D3 (or 1
or calcium carbonate to human milk or a low α-hydroxyvitamin D3, a synthetic analogue that
phosphate formula (calcium to phosphate ratio undergoes hepatic 25-hydroxylation) has the advan-
of 2:1). tage f a shorter half-life, and treatment may be more
Additional therapy depends on the cause of easily tailored to the individual patient. Attention
hypocalcemia. Infants who have hypoparathy- should be directed toward a number of concomitant
roidism require calcitriol in addition to calcium treatments. Because thiazide diuretics can increase
supplementation to restore and maintain renal calcium reabsorption, the inadvertent institu-
eucalcemia. Infants who have vitamin D defi- tion or discontinuation of these drugs may increase
ciency will benefit from vitamin D supplementa- or decrease, respectively, the plasma calcium level.
tion. If magnesium concentrations are low, In contrast, furosemide and other loop diuretics can
treatment with intravenous or intramuscular mag- increase the renal clearance of calcium and depress
nesium sulfate is essential for correction as a 50% serum calcium levels. The administration of gluco-
solution of magnesium sulfate in a dose of corticoids antagonizes the action of vitamin D
0.1–0.2 mL/kg. (and the analogues) and may also precipitate hypo-
Complications of intravenous calcium therapy calcemia. The development of hypomagnesemia
include extravasation into soft tissues (with cal- may also interfere with the effectiveness of treat-
cium deposition and sometimes cutaneous necro- ment with calcium and vitamin D (Rigo et al. 2010).
sis) and bradycardia. Because of the many
potential risks, arterial infusions of calcium in 41.5.1.9 Prevention of Neonatal
high concentrations should be avoided. However, Hypocalcemia
parenteral nutrition solutions containing standard The most effective prevention of neonatal hypo-
mineral (including calcium) content can be safely calcemia includes the prevention of prematurity
infused through appropriately positioned umbili- and birth asphyxia, the judicious use of bicarbon-
cal venous or arterial catheters. The direct admin- ate therapy, and mechanical ventilation to avoid
istration of calcium preparations with bicarbonate secondary metabolic alkalosis. Whereas, the phar-
or phosphate solution results in precipitation and macologic prevention of neonatal hypocalcemia,
must be avoided. The duration of supplemental especially in VLBW infants, is based on the
41 Calcium and Phosphorus Homeostasis: Pathophysiology 659
prophylactic use of calcium salts, phosphorus in the oral or parenteral diet. Moderate hypercal-
salts, and vitamin D supplementation from the cemia may also be the result of phosphorus defi-
first day of life, with a regular survey of serum ciency in premature infants receiving
concentrations and urinary excretion. unbalanced calcium and phosphorus regimens
in oral and parenteral nutrition. In this situation,
hypercalcemia is accompanied by hypo-
41.5.2 Neonatal Hypercalcemia phosphoremia. Infants with VLBW who are fed
mineral-unsupplemented human milk may
Hypercalcemia is defined as a pathologic eleva- develop hypophosphatemic hypercalcemia. The
tion in plasma ionized Ca2+ concentration greater low phosphorus concentration in human milk
than 1.35 mmol/L (5.4 mg/dL) with or without a causes phosphorus deficiency, leading to an
simultaneous elevation in total calcium concen- increased calcium concentration and hyper-
tration of greater than 2.75 mmol/L (11.0 mg/dL) calciuria. Hypophosphatemia stimulates renal
as total calcium is more related to serum albumin synthesis of calcitriol, which activates the intes-
concentration (Rigo et al. 2010; Rodriguez 2003). tinal absorption and skeletal resorption of cal-
Neonatal hypercalcemia (Table 3) is relatively cium and phosphorus. The absorbed phosphorus
uncommon, but it needs to be recognized because is preferentially oriented for soft tissue forma-
it can result in significant morbidity or mortality. tion, whereas the remaining phosphorus is insuf-
The clinical symptoms of sustained hypercalce- ficient to allow calcium deposition. Phosphorus
mia are not specific. Infants with mild increases in supplementation and the use of human milk for-
serum calcium (2.75–3.25 mmol/L, or 11–13 mg/ tifiers can prevent hypophosphatemia and
dL) often fail to manifest specific symptoms of hypercalcemia. Similar situations have been
hypercalcemia. Nonspecific signs and symptoms reported in infants on parenteral nutrition, pro-
such as anorexia, vomiting, and constipation (but viding an unbalanced calcium:phosphorus ratio.
rarely diarrhea) may occur with moderate to Additionally, thiazide diuretics reduce renal cal-
severe hypercalcemia. Seizures, bradycardia, or cium excretion and may represent a contributing
arterial hypertension is very exceptional. On factor. Other causes of iatrogenic hypercalcemia
physical examination infants may appear are the use of extracorporeal membrane oxygen-
dehydrated, lethargic, and hypotonic. Those with ation, which can cause transient hypercalcemia
chronic hypercalcemia may present with failure to in up to 30% of infants, and vitamin D intoxica-
thrive as the principal source of physical distress. tion from the administration of excessive vita-
Renal function is generally impaired, and polyuria min D supplements. Vitamin A toxicity
and hypercalciuria are observed. However, increasing bone resorption is rare and can
renal complications such as nephrocalcinosis, cause severe hypercalcemia.
nephrolithiasis, and hematuria may be the earliest
clinical manifestations of hypercalcemia.
41.5.3 Neonatal Hyperparathyroidism
41.5.2.1 Iatrogenic Hypercalcemia
Hypercalcemia may result from increased intes- Neonatal hyperparathyroidism frequently results
tinal or renal calcium absorption, increased bone in severe hypercalcemia. It may be hereditary
turnover or iatrogenic causes. Iatrogenic hyper- primary hyperparathyroidism or be secondary to
calcemia is the most common type of hypercal- maternal hypocalcemia and is summarized in
cemia in the newborn and should be considered Table 3 with other more unusual causes of
before starting extensive investigation of rare hypercalcemia.
syndromes. It may result from excessive intra-
venous calcium administration during total par- 41.5.3.1 Primary Hyperparathyroidism
enteral nutrition or exchange transfusion but Hereditary primary hyperparathyroidism
also of unbalanced calcium to phosphorus ratio manifested in neonates is associated with
660 J. Rigo et al.
inactivating mutation of CaR. The serverity of necrosis, Williams syndrome, Jansen metaphyseal
hypercalcemia is related to the extent of CaR chondrodysplasia, and hypophosphatasia.
mutation, moderate with heterozygous mutation In clinical practice the practical approach is
in patients with familial hypocalciuric hypercal- first to exclude the possibility of iatrogenic hyper-
cemia. It is an autosomal-dominant trait with a calcemia. Secondly, a maternal history of
high degree of penetrance. More severe hypercal- calcium-phosphorus disease or excessive vitamin
cemia occurs in neonatal hyperparathyroidism D intake during pregnancy should be investi-
with homozygous inactivating germline muta- gated. Thirdly, the signs of clinical syndromes
tions of the CaR gene (Toke et al. 2009). associated with hypercalcemia, such as blue dia-
pers, fat necrosis, and elfin facies, should be
41.5.3.2 Secondary sought. Finally, the initial laboratory evaluation
Hyperparathyroidism should include serum calcium, phosphorus, alka-
In many cases of secondary hyperparathyroidism, line phosphatase, PTH, the urinary calcium:cre-
a thorough investigation of the infant’s mother atinine ratio, and tubular reabsorption of
will disclose previously known but poorly treated phosphorus. In most cases, these tests allow the
hypoparathyroidism, pseudohypoparathyroidism, differentiation of hypercalcemia caused by para-
or clinically unsuspected hypocalcemia, as seen in thyroid disorders from nonparathyroid condi-
mothers with renal tubular acidosis that had tions. In hyperparathyroidism the serum
induced severe secondary hyperparathyroidism phosphorus concentration is low; renal tubular
in the developing fetus during pregnancy. The phosphorus reabsorption is decreased, usually to
clinical presentation is variable and may depend less than 85%; and the serum PTH concentration
on the severity of maternal hypocalcemia. Sec- is elevated. Finally, additional tests may be
ondary hyperparathyroidism and neonatal hyper- performed: a serum 25(OH)D3 determination
calcemia are transient conditions with a good may be useful when an excess of vitamin D is
prognosis provided that supportive measures are suspected; long-bone X-ray films identify demin-
instituted. eralization, osteolytic lesions, or both (hyperpara-
thyroidism) or osteosclerotic lesions
41.5.3.3 Clinical Manifestations (occasionally with vitamin D excess); measure-
Most infants are asymptomatic when diagnosed. ments of serum and urinary calcium in parents
Those with mildly elevated levels of calcium allow a diagnosis of familial hypocalciuric hyper-
often fail to manifest specific symptoms of hyper- calcemia; and renal sonography detects
calcemia. Infants with chronic hypercalcemia may nephrocalcinosis.
present with failure to thrive as the principal
source of physical distress. 41.5.3.4 Treatment
There are nonspecific signs and symptoms such The treatment of neonatal hypercalcemia
as anorexia, vomiting, and constipation (but rarely depends on the severity of the presentation. Con-
diarrhea); polyuria may occur with moderate to servative management is appropriate in the case
severe hypercalcemia. In severe hypercalcemia of mild hypercalcemia in a preterm infant
infants are often dehydrated, lethargic, and hypo- resulting from an inappropriate mineral supply,
tonic. Alternatively, they may present with seizures. hypoalbuminemia, or chronic acidosis, with spe-
Clinically, these infants can have bradycardia, a cial emphasis on the phosphorus supply when
short QT interval, and hypertension. However, hypercalcemia is associated with hypo-
renal complications such as nephrocalcinosis, phosphatemia. Hypercalcemia seen in newborns
nephrolithiasis, and hematuria may be the earliest exposed to maternal hypocalcemia is usually
clinical manifestations of hyper- calcemia. Other- mild and transient, and treatment consists of no
wise, the physical examination is usually normal more than supplying the appropriate amounts of
except for the infants with subcutaneous fat calcium and phosphorus in the milk.
41 Calcium and Phosphorus Homeostasis: Pathophysiology 661
Infants with moderate to severe hypercalcemia experience in neonates and they may contain
need more aggressive treatment. The initial steps unwanted free phosphate.
are not specific: (1) Discontinue oral and intrave-
nous calcium and vitamin D supplementation and
dietary restriction; (2) increase the urinary excre- 41.5.4 Nephrocalcinosis in Preterm
tion of calcium by maximizing glomerular filtra- Infants
tion with the administration of intravenous fluids,
which consist of standard saline at about twice the Nephrocalcinosis is defined as ultrasound evi-
maintenance requirements; and (3) encourage cal- dence of bright reflections with or without acous-
cium excretion with furosemide after rehydration tic shadowing, small flecks across to completely
but with particular attention to maintaining elec- echodense pyramids which are reproducible in
trolyte homeostasis. both the longitudinal and transverse direction,
More specific therapy comprises the use of found within the cortex or medulla. Initially,
glucocorticoids, calcitonin, bisphosphonate, dial- nephrocalcinosis was attributed to long-term furo-
ysis, and total parathyroidectomy. Glucocorti- semide therapy. It is now known to be multifacto-
coids (2 mg/kg of prednisone) decrease rial and has been associated with low gestational age
intestinal calcium absorption, decrease bone and birth weight; severe respiratory disease, tran-
resorption, and increase renal excretion. They sient renal failure; imbalance intakes of calcium and
may be useful during a short period, mainly in phosphate; long duration of total parenteral nutri-
cases of an excess of vitamin D, but are relatively tion; as well as pro-calciuric medications such as
ineffective in cases of hyperparathyroidism. Cal- furosemide, corticosteroids, aminoglycosides, and
citonin (4–6 IU/kg subcutaneously every 6 h) xanthines. In addition, in analogy to the pathogene-
reduces the serum calcium concentration, but its sis of stone formation, nephrocalcinosis is considered
effectiveness declines after a few days. to result from a spontaneous or therapy-induced
Bisphosphonate therapy is limited in newborn imbalance between promoters (e.g., calcium, oxa-
infants. However, pamidronate (0.5–2.0 mg/kg) late, uric acid, ascorbic acid) and inhibitors (e.g.,
has been used in the treatment of subcutaneous fat citrate, magnesium) of crystallization in urine.
necrosis and could be an ideal agent to stabilize The prevalence of nephrocalcinosis varies
cases of neonatal severe hyperparathyroidism, as between studies from 7% to 41% in recent reports
recently suggested. A calcimimetic drug that (Schell-Feith et al. 2010).
reduces PTH secretion, recently approved by the The short- and long-term evolution of
FDA for chronic secondary hyperparathyroidism nephrocalcinosis has not been clearly defined.
in dialyzed patients, could be of major interest in Ultrasonographic abnormalities that develop during
primary hyperparathyroidism but needs to be the first months of life disappear in the majority of
evaluated during infancy (Stewart 2004). Dialy- patients within months to years. Earlier studies had
sis could be prescribed with a lowcalcium dialy- raised concerns regarding tubular function in
sate (1.25 mmol/L) in the face of severe and affected patients. This has not clearly been substan-
unremitting hypercalcemia. Total parathyroidec- tiated in more recent larger studies where an unfa-
tomy with partial autotransplantation could be a vorable effect on renal function is seen in a small
rescue treatment in the severe form of neonatal number of children (Schell-Feith et al. 2010). Nev-
severe hyperparathyroidism. In the chronic ertheless, premature children with or without
phase, dietary restriction with the use of a special nephrocalcinosis when compared with non-
formula without vitamin D supplementation is the premature children had lower kidney size and bor-
mainstay of treatment. If the dietary regimen is derline blood pressure. In addition, children with
insufficient, corticosteroids can be used with cau- intra- or extrauterine growth retardation had an
tion. Cellulose phosphate binders have been impaired GFR compared to children with appropri-
occasionally used in children, but there is limited ate pre- and postnatal growth (Bachetta et al. 2009).
662 J. Rigo et al.
In summary, nephrocalcinosis is a high inci- Table 4 Causes of neonatal phosphorus disorders
dence disease in VLBW and ELBW infants but Hypophosphatemia Hyperphosphatemia
associated with a good renal outcome and a high Endocrine Endocrine
resolution rate. However, it has been highlighted Hyperparathyroidism Hypoparathyroidism
that there could be long-term sequelae in tubular VitaminD deficiency or Hyperthyroidism
dysfunction and hypertension. This warrants close resistance
monitoring in ex-premature babies. Renal losses Growth hormone
excess
Congenital tubular Vitamin D toxicity
disorders
41.6 Disorders of Phosphate Secondary tubular Renal
Homeostasis disorders
Diuretics Renal failure
41.6.1 Neonatal Hypophosphatemia Volume expanders Volume depletion
Hypercalciuria Increased load
In adults, moderate hypophosphatemia is defined as Glucosuria Enteral, Cow milk
feeding
a serum phosphorus concentration between 3.0 and
Hypomagnesemia Rectal enema
1 mg dL 1, and is usually asymptomatic. Severe
Gastrointestinal Parenteral
hypophosphatemia is defined as serum inorganic
Decrease of intake Blood transfusion
phosphorus concentration below 1.0 mg dL 1. In
Decrease of absorption
children, serum phosphorus concentrations below Calcium salt
5 mg dL 1 are often considered abnormal. This Malabsorption
level corresponds to the threshold level of tubular Antacid
resorption capacity and potential increase in urinary Gene mutation
calcium excretion (Fig. 5). Hypophosphatemia may Others
be caused by decreased intestinal absorption of phos- Metabolic acidosis
phate, increased urine losses of phosphate, and an Respiratory alkalosis
endogenous shift of inorganic phosphorus from Gram-negative sepsis
extracellular to intracellular fluid compartments. It Refeeding syndrome
has also been reported in various rare hereditary Hypercalcemia
diseases associated or not with neonatal hyperpara- Carbonic anhydrase
thyroidism (Table 4). Early hypophosphatemia was inhibitors
Dopamine
observed in IUGR. Within the 1st week of life, a
significant correlation between pre eclampsia and 1st
week inorganic phosphate deficiency was related in A high incidence (i.e., 28%) of hypo-
VLBW babies, whereas, the occurrence of hyper- phosphoremia associated with a double mortality
calciuria and low urinary phosphate was also rate related to myocardial dysfunction is reported
observed in small-for gestational age (SGA) infants. in adult intensive care patients. A short course of
These studies suggest that infants with extrinsic phosphotherapy improved the left ventricular
IUGR are probably insufficiently provided with function rapidly in inorganic phosphate depleted
phosphorus in utero and hence postnatally may suf- adults (Zazzo et al. 1995). Therefore it is tempting
fer early-onset inorganic phosphate depletion from to speculate that early-onset inorganic phosphate
prenatal origin. This mineral imbalance has been depletion could be an etiologic factor in myocar-
delineated in newborns with chronic fetal hypoxia dial dysfunction, leading postnatally to left heart
and malnutrition leading to disproportionate or failure and ensuing pulmonary hemorrhage in the
type II IUGR. In those infants, hypophosphatemia most severely growth retarded VLBW-infants.
as well as platelet count and high nucleated red During the first weeks of life, hypo-
blood cell count were closely correlated with the phosphatemia related to low phosphorus intake
severity of IUGR in SGA type II. occurs in low birth weight babies who were fed
41 Calcium and Phosphorus Homeostasis: Pathophysiology 663
soy formulas and more frequently exclusive body phosphate load from blood transfusions and
unsupplemented human milk (Putet et al. 1987). hyperalimentation. Increased renal tubular
With human milk addition of 5–10 mg/100 mL of reabsorption of phosphate is responsible for hyper-
inorganic phosphate equivalent corrects plasma phosphatemia seen in neonatal hypoparathyroid-
concentration, reduces calcium excretion and ism and associated disorders such as infants of
improves calcium retention. In formula fed diabetic mothers, transient neonatal hypoparathy
infants, similar hypophosphatemia is also roidism, neonatal pseudohypoparathyroidism or in
observed in relation to an inadequate calcium babies born to mothers with hyperparathyroidism
phosphorus ratio resulting either from a relative (Table 4). Hyperphosphatemia and secondary
phosphorus malabsorption or a relatively higher hyperparathyroidism have been extensively inves-
calcium absorption rate. In that situation, tigated as inducing factors in cardiovascular calci-
absorbed phosphorus is lower than that required fication. Together with passive deposition of
for deposition in soft tissues and bone according calciumphosphate in extraskeletal tissues, it has
to nitrogen retention and calcium absorption. recently been demonstrated that inorganic phos-
An inadequate calcium to phosphorus ratio is phate induces arterial calcification directly through
also observed in preterm infants with persistent a real “ossification” of the tunica media
metabolic acidosis or prolonged respiratory dis- (Caudarella et al. 2007).
tress syndrome. In that situation, the acid-base
disturbance, increased bicarbonate or hypercapnia
reduced phosphorus tubular reabsorption induc- 41.7 Bone Mineralization
ing a relative hypophosphatemia and hyper-
calciemia associated with a concomitant urinary 41.7.1 Factors Affecting Growth
excretion of phosphorus and calcium increasing and Mineralization
the risk of nephrocalcinosis.
Given its widespread distribution and critical During gestation, the fetus receives an ample pro-
role in vital cellular processes, it is not surprising vision of nutritional supply through the placenta.
that a deficiency of phosphorus results in various Nitrogen, energy, minerals, and vitamins allow a
clinical symptoms including hypotension and high velocity of body length growth, representing
decreased stroke volume, impaired diaphragm con- around 1.2 cm/week during the last trimester of
tractility, dyspnea and respiratory failure, paresthe- gestation. The fetus maintains its hypercalcemic
sia, weakness, confusion, disorientation, lethargy, state in a high calcitonin and estrogen environ-
areflexic paralysis, seizures and coma, leukocyte ment, promoting the modeling/remodeling ratio in
dysfunction hemolysis and thrombocytopenia, as favor of modeling and thus increasing endo-
well as rickets or osteomalacia as reported in cortical bone. In addition, according to the
refeeding syndrome (Fuentebella and Korner 2009). mechanostat theory of bone development, fetal
bone is also driven by the mechanical force
applied to the fetal skeleton during the intrauterine
41.6.2 Neonatal Hyperphosphatemia resistance training provided by regular fetal kicks
against the uterine wall (Rauch and Schoenau
Hyperphospatemia is usually due to a decrease in 2001, 2002). Consequently, at term the newborn
renal function or a PTH absence (primary or sec- skeleton has a high physical density (bone mass
ondary hypoparathyroidism) or phosphatonin defi- divided by bone volume), with elevated cortical
ciency. Hyperphosphatemia is most often the thickness and relatively small marrow cavities.
result of decreased renal excretion of phosphate Various factors influence the processes of
anions as encountered in acute or chronic renal growth, mineralization, and bone structure.
failure, particularly when glomerular filtration Growth is directly related to protein and energy
rate is reduced to less than 25% of normal. Hyper- supplies but also to the hormonal environment
phosphatemia could also be the result of increased comprising insulin, IGF1, and IGF2, among
664 J. Rigo et al.
others. Bone formation, mineralization, and struc- fractures among VLBW infants are still lacking,
ture are related to mineral supply and hormonal but some clinical evidence suggests that the risk
factors such as PTH, PTHrP, vitamin D, and cal- for fracture is greatly reduced with the use of
citonin as well as others, such as genetics and parenteral and enteral nutrition adapted to the
physical activity. Several factors have been special nutritional needs of the premature infant.
found to have a significant impact on newborn Risk factors for MBD are commonly encoun-
bone mineral content and developing fetal bone. tered in the preterm infant. The majority of bone
Reduced calcium supply, vitamin D deficiency, mineralization, along with calcium and phosphorus
alcohol consumption, and smoking during preg- accretion, occurs during the third trimester of preg-
nancy are all factors affecting fetal skeletal devel- nancy. Infants born before this time thus have
opment in addition to low weight related to depleted stores of these minerals (Harrison et al.
gestation and diabetes in the mother. 2008). Data from bone density scans (dual-energy
X-ray absorptiometry [DEXA]) performed at birth
in preterm and term infants suggest that bone min-
41.7.2 Osteopenia of Prematurity eral accretion during the last trimester of gestation
is higher than needed, with growth in bone volume
Premature infants, particularly those born at leading to a continuous increase in skeletal density.
<28 weeks’ gestation, are at significant risk for Preterm infants therefore have a large mineral def-
reduced bone mineral content (BMC) and subse- icit compared with term infants. Several factors
quent bone disease, variably termed metabolic increase the risk for severe MBD among VLBW
bone disease (MBD), osteomalacia, osteopenia, infants, with the most important appearing to be an
or neonatal rickets (Rigo et al. 2007; Land and inadequate supply of calcium and phosphorus
Schoenau 2008; Rigo 2008). Reduction in BMC associated with the use of an enteral vs transpla-
and the development of MBD of prematurity are cental route. Newborn premature infants experi-
quite common among VLBW infants. However, ence a diminished mineral uptake required for
due to the lack of widely adopted diagnostic proper bone accretion, due, in part, to the reduced
criteria, the true incidence has not been deter- availability and to their compromised gastrointes-
mined. Fractures in premature infants typically tinal (GI) absorption. Metabolic balance studies in
occur several weeks after delivery and prior to preterm infants fed fortified human milk and for-
the postnatal age of 6 months (Bishop et al. mulas (Rigo et al. 2000, 2010) have reported that
2007; Harrison et al. 2008). Rib fractures, the maximal calcium retention values may reach
most common type, usually occur silently and 60–90 mg/kg/day and maximal inorganic phos-
are diagnosed only if X-rays are performed. phate retention values may reach 50–75 mg/kg/
Therefore, the true incidence of fractures is diffi- day. The retention rates are relatively low com-
cult to determine, varying between 2.1% and 25% pared with the fetal accretion rates. In total paren-
in 3 previous studies (Bishop et al. 2007) teral nutrition, similar data could be obtained with
conducted without the use of prospective, system- the use of organic phosphate supply and highly
atic skeletal surveys. soluble calcium salt. In our unit, using calcium
The risk factors commonly associated with glycerophosphate, we provide up to 105 mg of
fractures include extremely low birth weight, late calcium and 80 mg of inorganic phosphate/kg/day
(> 30 days) establishment of full enteral feeds or with a retention rate close to 95%.
prolonged parenteral nutrition, exclusive use of Decreased bone mineralization and the devel-
unfortified human milk, necrotizing enterocolitis, opment of osteopenia are the balanced result
conjugated hyperbilirubinemia, chronic lung dis- between two different factors, bone matrix growth
ease, use of various medications, utilization of directly related to energy balance and nitrogen
passive respiratory physiotherapy (i.e., chest per- retention on the one hand, and mineral accretion
cussion), and lack of physical activity, which may on the other hand (Rigo et al. 2010; Rigo and
be enhanced by sedatives. Recent data on Senterre 2006). Data from DEXA scans (Rigo
41 Calcium and Phosphorus Homeostasis: Pathophysiology 665
16
Volumetric BMD (arbitrary units)
mature
premature
BMAD (BMC/BA1.5) (mg/cm3) 14
12
term
10
Preterm reference at birth n = 106
8 Term reference up to 1 year n = 165
Term: growth up to 2 months n = 97
6 <1500 g: growth up to discharge n = 108
Preterm: follow-up n = 18
4
24 32 40 48 56 64 72 80 88
Post-conceptional age (wks)
Fig. 6 Physiological evolution of DEXA apparent Bone symbols) compared to that observed in premature infants
Mineral Density during the last trimester of gestation and (open symbols). Comparison to the evolution suggested by
during the first year of life in healthy term infants (dark the mechanostat theory ( frame)
et al. 2010; Rigo and Senterre 2006) performed stimulation during their stay. In order to obviate the
during the first weeks after birth in both preterm effects of reduced mechanical stimulation, system-
and term infants suggest that bone growth, esti- atic physical activity programs administered sev-
mated by increase in bone area, is relatively higher eral times a week by nurses, therapists, and parents
than bone mineral accretion, leading to a continu- have been evaluated. A number of recent studies,
ous decrease in skeletal density (Fig. 6). Neverthe- agree that physical activity either improves bone
less, after a few weeks or months, with the mineralization, as determined by single-photon
continuous reduction in growth velocity, the bal- absorptiometry, or increases bone formation, as
ance is progressively reversed and the bone mass estimated by the measure of serum collagen
accrual compensates slowly for the early peak bone C-terminal propeptide (Schulzke et al. 2007).
growth during the first few months of life. Physical These regimens either increased bone strength or
activity appears to play a significant role in bone attenuated its decrease, as evaluated by quantitative
mineralization. During the neonatal period, measurement of bone ultrasound transmission
mechanical strain on bone and joints stimulates speed. Nevertheless, the last Cochrane review of
bone formation and growth, whereas inactivity this subject concluded that additional studies are
leads to bone resorption (Rauch and Schoenau needed before the general use of such physical
2001, 2002). This might be equally valid for pre- activity programs can be promoted (Schulzke
term infants in incubators during the first weeks of et al. 2007). A number of other factors may also
life, who lack the in utero mechanical stimulation play a significant role in bone mineralization,
associated with regular kicks against the confining including genetic polymorphism, mechanical stim-
uterine wall (Schulzke et al. 2007). During the ulation, or the use of various medications that
initial hospitalization, the movements of preterm interfere with mineral absorption or retention,
infants usually occur without much resistance. such as diuretics, caffeine, and corticosteroids.
While in the NICU, these infants are handled Neonatal screening for MBD in preterm infants
with little tactile stimulation in order to reduce is still controversial (Rigo 2008). Serum calcium
stressful events. Moreover, the use of drugs to levels are carefully regulated by hormonal secre-
reduce pain aggravates the reduction in mechanical tion and are not a useful screening tool. However,
666 J. Rigo et al.
a low serum phosphorus concentra- These results are in agreement with the predicted
tion < 1.8 mmol/L) that is below the renal phos- time course of volumetric bone mineral density
phate threshold has been related to insufficient in mature newborns and premature babies,
phosphorus intake and to an increased risk for according to mechanostat theory (Land and
osteopenia. Urinary excretion of calcium and Schoenau 2008).
phosphorus has been proposed as a marker of The use of ultrasound has been proposed for
adequate postnatal mineralization when doses the evaluation of bone mineralization in newborn
>1.2 mmol/L of calcium and >0.4 mmol/L of infants (Rigo 2008). It is a simple, non-invasive,
inorganic phosphorus are excreted simulta- relatively inexpensive bedside procedure. Some
neously. However, these values are more appro- machines have been designed to measure broad-
priate for estimating the adequacy of the calcium band ultrasound attenuation or SOS, commonly
to phosphate ratio than for estimating mineral on the tibia. The propagation of sound waves in
accretion, especially when data on the mineral bone is determined by a number of factors, includ-
absorption rate are lacking. ing mineral density, cortical thickness, elasticity,
In infants, 90% of alkaline phosphatase (ALP) and micro-architecture, possibly providing a more
is of bone origin and thought to reflect bone turn- complete picture of bone strength than measure-
over. ALP concentrations usually increase during ments of BMD alone. In preterm and term infants
the first 2–3 weeks of life and may peak further if at birth, there is a significant correlation among
there are insufficient mineral supplies. Elevated tibial SOS and gestational age, birth weight, birth
levels of ALP have been reported in association length, and tibial length. However, the changes in
with severe under mineralization based on radio- SOS values during the last trimester of gestation
logic evidence, low bone speed of sound (SOS) are relatively small, accounting for only about
using quantitative ultrasound, or severe bone min- 130 m/s. This value is only 1.5 times higher
eral density (BMD) deficit revealed on DEXA than the interindividual variability (standard devi-
scans. Nevertheless, ALP is probably more sensi- ation [SD] = 95 m/s). After birth, a rapid decline
tive for evaluating fracture risk than for assessing in bone SOS occurs during the first days of life
MBD or osteopenia. that cannot be completely explained by a nutri-
Various radiologic investigations have been tional deficit. Therefore, these data suggest that
proposed for assessing bone mineralization and measurement of bone SOS has a lower sensitivity
osteopenia among preterm infants. Plain radiog- than DEXA for evaluating the various factors
raphy is poorly sensitive, detecting only a influencing bone mineralization during the neona-
decrease of >20–40% of bone mineralization tal period (Fig. 6).
(Harrison et al. 2008). By contrast, DEXA tech- In contrast to fetal bone metabolism, in which
nology, is sensitive, accurate, and precise, and modeling is the main process inducing high net
its use has been validated in both preterm and bone formation, with a rapid increase in trabecular
term infants (Rigo et al. 2000, 2010; Avila-Díaz thickness, neonatal bone metabolism is the result
et al. 2001). Normative data on bone mineral of a prevailing remodeling activity, defined as the
content, projected bone area, and BMD in cyclical succession of bone resorption and forma-
healthy preterm and term infants close to birth tion on the same bone surface (Land and
were established in order to obtain surrogate Schoenau 2008; Rigo 2008). Therefore, the rela-
intrauterine reference values. In addition, vari- tive MBD of prematurity could be the result of a
ous indices have been proposed for reducing the postnatal physiologic metabolic adaptation
anthropometric dependency of the various instead of the expression of a transitory MBD.
parameters and for facilitating group or individ- Indeed, the relative osteopenia observed in pre-
ual comparison. Thus, data obtained from vari- term infants appears to be similar to that observed
ous groups allow for the determination of major in healthy term infants during the first weeks after
changes in bone mineralization during the fetal delivery or to that observed in early adolescence at
life and postnatally in preterm and term infants. the time of a growth spurt.
41 Calcium and Phosphorus Homeostasis: Pathophysiology 667
After discharge, catch-up mineralization is rap- available, DEXA is more sensitive than ultra-
idly observed in VLBW infants (Avila-Díaz et al. sound for quantifying osteopenia in VLBW
2001). At 6 months of corrected age, spine and infants (Rigo 2008).
total bone mineral density, corrected for anthro-
pometric values, are in the range of normal term
newborn infants. In fact, the catch-up mineraliza-
tion observed after discharge is quite similar to References
that observed after the initial acceleration of
growth during adolescence. Nevertheless, peak Agostoni C, Buonocore G, Carnielli VP et al (2010)
Enteral nutrient supply for preterm infants. J Pediatr
bone mass may be less during adulthood (Zamora Gastroenterol Nutr 50:85–91
et al. 2001). As suggested by Fewtrell and American Academy of Pediatric (1985) Committee on
coworkers, at 8–12 years of age, formerly preterm nutrition: nutritional needs of low birth weight infants.
infants were shorter, lighter, and had lower BMCs Pediatrics 75:976
Atkinson SA, Tsang RC (2005) Calcium, magnesium,
than controls. However, BMC was appropriate for phosphorus, and vitamin D. In: Tsang R et al (eds)
the body size achieved and was not affected by Nutrition of the preterm infant, 2nd edn. Digital Edu-
early dieting or human milk feeding (Fewtrell cational Publishing, Cincinnati, p 245
et al. 2000). Avila E, Diaz L, Barrera D et al (2006) Regulation of
vitamin D hydroxylaxses gene expression by 1,25-
Thus, osteopenia or rickets of prematurity dihydroxyvitamin D3 and cyclic AMP in cultured
seems to be a self-resolving disease, although human syncytiotrophoblasts. J Steroid Biochem Mol
the potential long-term consequences on the Biol 103:90–96
attainment of peak bone mass are not clearly Avila-Díaz M, Flores-Huerta S, Martínez-Muñiz I, Amato
D (2001) Increments in whole body bone mineral con-
known. Even if BMC improves spontaneously in tent associated with weight and length in pre-term and
most infants, this discovery does not imply that a full-term infants during the first 6 months of life. Arch
period of demineralization is acceptable. Med Res 32:288–292
Although the long-term consequences are unclear, Bachetta J, Harambat Jr, Dubourg L et al (2009) Both
extrauerine and intrauterine growth restriction impair
the benefits of prevention and treatment include renal function in children born very preterm. Kidney Int
avoidance of fractures and possibly improved lin- 76:445–452
ear growth and peak bone mass. Banerjee S, Mimouni FB, Mehta R (2003) Lower whole
In summary, after birth, the development of blood ionized magnesium concentrations in hypocalce-
mic infants of gestational diabetic mothers. Magnes
relative osteomalacia or osteopenia is a physio- Res 16:127–130
logic event resulting from a mismatch of the Bassir M, Laborie S, Lapillonne A et al (2001) Vitamin D
mineral supply and the persistent growth veloc- deficiency in Iranian mothers and their neonates: a pilot
ity on the one hand, and from the stimulation of study. Acta Paediatr 90:577–579
Bishop N, Sprigg A, Dalton A (2007) Unexplained frac-
bone turnover as an adaptation to extrauterine tures in infancy: looking for fragile bones. Arch Dis
life on the other. This phenomenon is enhanced Child 92:251–256
in preterm infants born with low mineral stores, Caudarella R, Vescini F, Buffa A, Francucci CM (2007)
an immature GI tract, and reduced physical Hyperphosphatemia: effects on bone metabolism and
cardiovascular risk. J Endocrinol Investig 30(Suppl
activity, who demonstrate higher growth rates 6):29–34
than do term infants. Several of the conditions Fewtrell MS et al (2000) Neonatal factors predicting child-
discussed above and in the articles reviewed in hood height in preterm infants: evidence for a persisting
this chapter might increase the severity of MBD, effect of early metabolic bone disease? J Pediatr
137:668–673
leading to the development of severe osteopenia Fudge NJ, Kovacs CS (2004) Physiological studies in
and the risk for fracture. Early optimal parenteral heterozygous calcium sensing receptor (CaSR) gene-
and oral nutritional support, combined with bio- ablated mice confirm that the CaSR regulates calcitonin
logic neonatal screening and measurement of release in vivo. BMC Physiol 20:5
Fuentebella J, Korner JA (2009) Refeeding syndrome.
serum phosphorus and ALP concentrations, as Pediatr Clin N Am 56:1201–1210
well as mineral urinary excretion, appears to be Greer FR (2003) Vitamin D deficiency-it’s more than rick-
helpful for the prevention of MBD. When ets. J Pediatr 143:422–423
668 J. Rigo et al.
Harrison CM, Johnson K, McKechnie E (2008) nutritional aspects. Arch Dis Child Fetal Neonatal Ed
Osteopenia of prematurity: a national survey and 86:F82–F85
review of practice. Acta Paediatr 97:407–413 Rigo J (2008) Neonatal osteopenia and bone mineraliza-
Holick MF (2007) Vitamin deficiency. N Engl J Med tion. eNeonatal Rev 6:4
357:266–281 Rigo J, Senterre J (2006) Nutritional needs of premature
Holtback U, Aperia AC (2003) Molecular determinants of infants: current issues. J Pediatr 149:S80–S88
sodium and water balance during early human devel- Rigo J, De Curtis M, Pieltain C et al (2000) Bone mineral
opment. Semin Neonatol 8:291–299 metabolism in the micropremie. Clin Perinatol
Hsu SC, Levine MA (2004) Perinatal calcium metabolism: 27:147–170
physiology and pathophysiology. Semin Neonatol Rigo J, Pieltain C, Salle B, Senterre J (2007) Enteral
9:23–36 calcium, phosphate and vitamin D requirements and
Karsdal MA, Henriksen K, Arnold M, Christiansen C bone mineralization in preterm infants. Acta Paediatr
(2008) Calcitonin: a drug of the past or for the future? 96:969–974
Physiologic inhibition of bone resorption while sustain- Rigo J, Mohamed MW, De Curtis M (2010) Disorders of
ing osteoclast numbers improves bone quality. calcium, phosphorus, and magnesium metabolism. In:
BioDrugs 22:137–144 Martin R, Fanaroff A, Walsh M (eds) Neonatal-
Klein CJ (2002) Nutrient requirements for preterm infant perinatal medicine, 9th edn. Elsevier Mosby,
formulas. J Nutr 132:1395S–1577S Philadelphia
Land C, Schoenau E (2008) Fetal and postnatal bone Rodriguez SJ (2003) Neonatal hypercalcemia. J Nephrol
development: reviewing the role of mechanical stimuli 16:606–608
and nutrition. Best Pract Res Clin Endocrinol Metab Salle BL, Delvin EE, Lapillonne A et al (2000) Perinatal
22:107–118 metabolism of vitamin D. Am J Clin Nutr
Liu S, Gupta A, Quarles LD (2007) Emerging role of 71:1317S–1324S
fibroblast growth factor 23 in a bone-kidney axis regu- Sato K (2008) Hypercalcemia during pregnancy, puerpe-
lating systemic phosphate homeostasis and extracellu- rium, and lactation: review and a case report of hyper-
lar matrix mineralization. Curr Opin Nephrol calcemic crisis after delivery due to excessive
Hypertens 16:329–335 production of PTH-related protein (PTHrP) without
Novakovic B, Sibson M, Hg HK et al (2009) Placenta- malignancy (humoral hypercalcemia of pregnancy).
specific methylation of the vitamin D 24-hydroxylase ocr J 55:959–966
gene: implications for feedback autoregulation of Schell-Feith EA, Kist-van Holthe JE, van der Heijden AJ
active vitamin D levels at the fetomaternal interface. J (2010) Nephrocalcinosis in preterm neonates. Pediatr
Biol Chem 284:14838–14848 Nephrol 25:221–230
Pawley N, Bishop NJ (2004) Prenatal and infant predictors Schulzke SM, Trachsel D, Patole SK (2007) Physical
of bone health the influence of vitamin D. Am J Clin activity programs for promoting bone mineralization
Nutr 80(Suppl 6):1748S–1751S and growth in preterm infants. Cochrane Database
Pieltain C, Vervoort A, Senterre T, Rigo J (2009) Intérêt de Syst Rev (18):CD005387
la consommation de produits laitiers et de la supplé- Shaikh A, Berndt T, Kumar R (2008) Regulation of phos-
mentation en vitamine D au cours de la croissance. J phate homeostasis by the phosphatonins and other
Pédiatr Belge 11:24–27 novel mediators. Pediatr Nephrol 23:1203–1210
Portal AA (2004) Calcium and phosphorus. In: Avner ED, Stewart AF (2004) Translational implications of the para-
Harmon WE, Niaudet P et al (eds) Pediatric nephrol- thyroid calcium receptor. N Engl J Med 351:324–326
ogy, 5th edn. Lieppincott, Williams and Wilkins, Phil- Toke J, Patocs A, Balogh K (2009) Parathyroid hormone-
adelphia, p 209 dependent hypercalcemia. Wien Klin Wochenschr
Putet G, Rigo J, Salle B, Senterre J (1987) Supplementa- 121:236–245
tion of pooled human milk with casein hydrolysate: Wagner CL, Greer FR, American Academy of Pediatrics
energy and nitrogen balance and weight gain composi- Section on Breastfeeding, American Academy of Pedi-
tion in very low birth weight infants. Pediatr Res atrics Committee on Nutrition (2008) Prevention of
21:458–461 rickets and vitamin D deficiency in infants, children,
Quarles LD (2008) Endocrine functions of bone in min- and adolescents. Pediatrics 122:1142–1152
eral metabolism regulation. J Clin Invest Zamora SA, Belli DC, Rizzoli R et al (2001) Lower fem-
118:3820–3828 oral neck bone mineral density in prepubertal former
Rauch F, Schoenau E (2001) The developing bone: slave or preterm girls. Bone 29:424–427
master of its cells and molecules? Pediatr Res Zazzo JF, Troche G, Ruel P, Maintenant J (1995) High
50:309–314 incidence of hypophosphatemia in surgical intensive
Rauch F, Schoenau E (2002) Skeletal development in care patients: efficacy of phosphorus therapy on myo-
premature infants: a review of bone physiology beyond cardial function. Intensive Care Med 21:826–831
Micronutrients and Vitamins
42
Olivier Claris and Guy Putet
Contents
42.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669
42.2 Micronutrients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670
42.3 Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674
Abstract intellectual performance. Thiamin deficiency
Vitamins and micronutrients are essential for is known as “beriberi,” while Niacin deficiency
many cellular processes, but excessive intake is known as pellagra. This chapter summarizes
may also be toxic. Iron, zinc, and copper com- the most recent recommendations for vitamin
pete for intestinal absorption. The first sign of and micronutrient intake.
iron deficiency is anemia, while an excessive
intake may cause oxidative stress and may also
impact on cardiac and liver function. Zinc defi- 42.1 Salient Points
ciency may cause growth arrest, irritability,
anorexia, alopecia, esophagitis, and diarrhea. • Iron is mainly involved in erythropoiesis, but
Copper deficiency is associated with hypo- also in neurodevelopment, cardiac, and skele-
chromic anemia, hypotonia, failure to grow, tal muscle function.
diarrhea, bone abnormalities, and neutropenia. • Zinc participates in carbohydrate and protein
Iodine deficiency may impair growth and metabolism.
• Copper is involved in oxidation and reduction.
• Iodine intervenes in thyroid function.
• Thiamine is essential for carbohydrate metab-
O. Claris (*) olism and lipid synthesis.
Department of Neonatology, Hôpital Femme Mère Enfant,
• Riboflavin is implicated in energy metabolism.
Bron, France
• Niacin is a cofactor for electron transport and
Hospices Civils de Lyon and Université Claude Bernard,
energy metabolism.
Lyon, France
• Pyridoxine has a role in the metabolism of
G. Putet
aminoacids, prostaglandins, carbohydrate, in
Department of Neonatology, Hopital de la Croix-Rousse,
Hospices Civils de Lyon and Universite Claude Bernard, the development of the immune system and
Lyon, France neurologic function.
# Springer International Publishing AG, part of Springer Nature 2018 669
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_191
670 O. Claris and G. Putet
• Folate is active in the biosynthesis of purines, Iron Iron (Fe) is an important micronutrient
pyrimidine, and amino acid metabolism. implicated in DNA replication, cellular metabo-
• Cobalamin is involved in DNA nucleotide lism and oxygen delivery. It is mainly involved in
synthesis. erythropoesis and is the first sign of deficiency in
• Pantothenic acid is a precursor of Coenzyme A anemia, it is also implicated in neurodevelopment,
(energy metabolism). and cardiac and skeletal muscle function. On the
• Ascorbic acid has a role in hydroxylation and otherhand, it is a potentially toxic nutrient and, as
as an antioxidant. a powerful prooxidant, it may play a major role in
• Vitamin A is implicated in protein synthesis the oxidative stress. Furthermore, iron overload
and epithelial cell function, growth, and has a direct impact on cardiac and liver function.
immune function; it is also a strong For all these reasons, the range between require-
antioxidant. ments and toxicity is narrow.
• Vitamin E is an antioxidant that prevents lipid Iron is absorbed in the duodenum as ferrous.
peroxidation. Absorption rates depend on the iron status, the
• Vitamin K is essential for hepatic synthesis of form of iron given and the age of preterm
coagulation factors. (PT) infants. Iron absorption is particularly
• Vitamin D plays a physiologic role in neuro- enhanced by human milk feeding and vitamin
muscular function and cell growth and C status, and is decreased after erythrocyte
differentiation. transfusion and competes with zinc and copper
absorption.
Iron supplementation may be started as soon as
42.2 Micronutrients 2 weeks of age, at a dose of 2–3 mg/kg/day
(Agostini et al. 2010). Infants receiving erythro-
Table 1 summarizes the most recent recommen- poietin treatment require higher intake, but too
dations (Agostini et al. 2010; Tsang et al. 2005; high an intake may cause intestinal side effects
Koletzko et al. 2005a, b). and increase retinopathy of prematurity. It is
Table 1 Micronutrients: Human milk (HM) content and intake recommendations (Agostini et al. 2010; Tsang et al. 2005;
Koletzko et al. 2005a, b)
Requirements (Agostini et al. 2010; Koletzko
Requirements (Tsang et al. 2005) et al. 2005a, b)
HM content Parenteral Parenteral
FT Enteral PT Parenteral PT Enteral PT FT PT
Iron 0.5–1 mg/L 2–4 mg/kg 0.25–0.67 mg/kga 2–3 mg/kg 0.5–1 0.2 mg/kgb
mg/kg
Zinc 0.5–2.5 mg/Lc 1–2 mg/kg 0.4 mg/kg 1.1–2 mg/kg 0.25 mg/kg 0.45–0.5
mg/kg
Copper 600–800 μg/L 120–150 μg/kg 20 μg/kg 100–132 μg/kg 20 μg/kg
Selenium 15–20 μg/L 1.3–4.5 μg/kg 1.5–4.5 μg/kg 5–10 μg/kg 2–3 μg/kg
Iodine 70–90 μg/L 10–80 μg/kg 1 μg/kg 11–55 μg/kg 1 μg/day
Chromium 0.3–0.5 μg/L 0.1–2.25 μg/kg 0.05–0.3 μg/kg 0.03–1.23 μg/kg not
necessary
Manganese 5 μg/L 0.75–75 μg/kg 1 μg/kg <27 μg/kg 1 μg/kg <50 μg/day
Molybdenum 2 μg/L 0.3–4 μg/kg 0.25–1 μg/kg 0.3–5 μg/kg 0.25 μg/kg 1 μg/kg
<5 μg/day
Fluorine 1.5–60 μg/kg
a
After 2 weeks of life
b
Unnecessary before 3 weeks
c
Decrease with postnatal days
42 Micronutrients and Vitamins 671
therefore why intakes above 5 mg/kg/d are not control iodine levels are immature (Rogahn et al.
recommended (Franz et al. 2000). 2000). Based on the mean content of iodine in HM
Zinc Zinc (Zn) is an ubiquitous trace metal some PT infants may be on negative iodine bal-
present in numerous enzymes and participates in ance. Toxicity is more often due to percutaneous
carbohydrate (CHO) and protein metabolism. It is intake (antiseptic solution).
required for replication, transcription and repair of Chromium (Cr) It has a role in glucose
DNA, and plays an important role during embryo- homesostasis. Hyperglycemia and insulin resis-
genesis and growth. Zn is absorbed in the distal tance are part of Cr deficiency, never described
duodenum and proximal jejunum, and this is in infants either breast or formula fed.
impaired by high casein intake. Manganese (Mn) It is a component of several
Zn deficiency is characterized by growth enzymes acting in gluconeogenesis, mitochon-
arrest, irritability, anorexia, alopecia, esophagitis, drial membrane maintenance and in mucopoly-
diarrhea and functional recommendations in saccharide synthesis. Mn deficiency has not been
immunity, skin lesions of the hands and feet and described in human conclusively, however Mn
poor healing. True acrodermatitis enteropathica is toxicity has been seen in adults with extrapyrami-
rarely seen in PT infants but ELBW infants on dal symptoms. Advisable intakes are based on
TPN without Zn, SGA, and growing PT infants what is contained in human milk.
fed unfortified HM are at risk of Zn deficiency Molybdenum (Mo) It intervenes in the func-
(Friel et al. 1988). tion of xanthine, aldehyde and sulfite involved in
Copper (Cu) It is a component of numerous purine metabolism and sulfur excretion. Defi-
enzymes (superoxide dismutase) involved in ciency is only described in adults on very long
oxidation and reduction. It helps to protect cell term TPN. Advisable intakes are based on what is
membranes from oxidative damage. Copper contained in HM.
competes with Zn and iron for intestinal absorp- Fluorine (F) It is found in bones and teeth
tion. It is absorbed in the upper part of the mainly. There are no data to make any recommen-
intestine, and this decreases by high Zn and dation except that it is found in human milk and
iron intakes. Deficiency is associated with crosses the placenta.
hypochromic anemia not responding to iron
supplementation, hypotonia, failure to grow,
diarrhea, bone abnormalities, neutropenia. In 42.3 Vitamins
the case of hepatic cholestasis, intake has to
be reduced or stopped because of potential Table 2 summarizes the most recent recommenda-
toxicity. tions for vitamin intake (Tables 3, 4, and 5).
Selenium (Se) It is a glutathione peroxidase Vitamin B1 (thiamine) Vit B1 is a coenzyme
component, which protects cell membranes essential for CHO metabolism and lipids synthesis
against peroxide induced drainage. Deficiency once transformed by the liver into thiamine pyro
is only seen in infants on TPN without or with phosphate. It is absorbed in the proximal small
too little Se, or in Keshan disease (cardiomyop- intestine. Deficiency is known as “beriberi”. A
athy) areas where soil is Se deficient. Addition of thiamine deficient total parenteral nutrition (TPN)
Se to food or TPN must be cautious as most Se may induce severe lactic acidosis and death.
compounds are toxic if given in excess (Aggett Vitamin B2 (riboflavine) Vit B2 is implicated
et al. 1991). in energy metabolism (it forms flavin, adenine,
Iodine (I) It intervenes in thyroid function dinucleotides). It is absorbed in the small intes-
(T3 and T4 synthesis), and iodine deficiency tine. Deficiency leads to stomatitis, dermatitis and
(before or after birth) may impair growth and anemia. Requirements are based on HM content
intellectual performance. Excess iodine may also and are related to protein intake. If protein supply
create hypothyroidism. PT infants often have tran- is given without Vit supplementation, a deficit can
sitory hypothyroidism as their mechanisms to occur (Lucas and Bates 1984).
672 O. Claris and G. Putet
Table 2 Vitamins: human milk (HM) content and intake recommendations (Agostini et al. 2010; Tsang et al. 2005)
Requirements
(Agostini et al.
Requirements (Tsang et al. 2005) 2010)
HM content FT Enteral PT Parenteral PT Enteral PT Equivalents
Vit A 660–1000 IU/L 750–1500 IU/kg 750–1500 IU/kg 400–1000 μg RE/kg 1 RE = 1 μg all trans
retinol
1 RE = 3.33 IU Vit A
1 RE = 6 μg β carotene
1 RE = 12 μg other
carotenoids
Vit D 20–30 IU/L 200–1000 IU/day 60–400 IU/day 800–1000 IU/day 1 μg
cholecalciferol = 40 IU
Vit D
Vit E 3–4 IU/L 6–12 IU/kg 2.8–3.5 IU/kg 2.2–11 mg/kg TE 1 IU = 1 TE
1 IU = 0.67 mg
α-tocopherol
1 IU = 1 mg dl-α-TA
Vit K 5–10 μg/L 8–10 μg/kg 10 μg/kg 4.4–28 μg/kg
IU international units, RE retinol equivalent, TE tocopherol equivalent, TA tocopherol acetate
Vitamin B3 (niacin) Vit B3 can be synthesized Table 3 Vitamins: effect of temperature and light, and
from tryptophane (Try) in the presence of B6, toxicity
once this amino acid (AA) exceeds minimal Temperature Light Toxicity
intake (60 mg of Try !1 mg of niacin expressed Vit A # Photodegraded Intra cranial
as Niacin Equivalent). It is also a cofactor for hypertension if
electron transport and energy metabolism. >5000 IU/day
Absorption is effective in the small intestine. Defi- Vit D Stable Stable Hypercalcemia,
ciency is known as pellagra (dermatitis, diarrhea hypercalciuria,
anorexia,
and neurological symptoms). It usually results vomiting,
from multiple deficiency and poor protein intake failure to thrive,
not observed in newborn infants. calcifications
Vitamin B6 (pyridoxine) Vit B6 has a role in Vit E Stable Slightly Large doses
affected associated with
the metabolism of AA, prostaglandins, CHO, in
sepsis, NEC
the development of immune system and neuro- Vit K Stable # Not reported
logic function. Its requirement is related to protein
intake (15 μg of B6 should be available per g of
protein). It is absorbed in the small intestine. Defi-
ciency leads to vomiting, irritability, dermatitis, Vitamin B12 (cobalamin) Vit B12 is involved
failure to thrive, hypochromic anemia and neuro- in DNA nucleotides synthesis. Absorption
logical symptoms as convulsions. depends on gastric pH and occurs in the small
Vitamin B9 (folate) Vit B9 is active in the intestine. Deficiency of cobalamin is known as
biosynthesis of purines, pyrimidine and AA metab- leading to megaloblastic anemia, glossitis and
olism. Its activity decreases by Zn deficiency. Defi- neurologic signs, but although this is not seen in
ciency is associated with megaloblastic anemia, FT breast fed infants, it is well established in
leucopenia, thrombocytopenia, growth insuffi- infants of vegetarian mothers.
ciency, and lesions in small intestine, mostly in Vitamin B5 (pantothenic acid) It is a precursor
context of malabsorption syndromes. of Coenzyme A (energy metabolism). It is absorbed
42 Micronutrients and Vitamins 673
Table 4 Vitamins: daily intake recommendations (Agostini et al. 2010; Tsang et al. 2005)
Requirements Requirements
(Tsang et al. (Agostini et al.
2005) 2010)
Enteral FT Enteral PT Parenteral FT Parenteral PT Enteral PT Parenteral FT
B1 30 μg/kg 300 μg/kg 1–2 mg/day 350 μg/kg 140–300 μg/kg 350–500 μg/kg
B2 40 μg/kg 450 μg/kg 150 μg/kg 150 μg/kg 200–400 μg/kg 150–200 μg/kg
B3 0.2 mg/kg 4.5–6 mg/kg 17 mg/day 5 mg/kg 0.3–5 mg/kg 4–6.8 mg/kg
B6 14 μg/kg 180–300 μg/kg 1000 μg/day 180 μg/kg 45–300 μg/kg 150–200 μg/kg
B9 9.4 μg/kg 45–50 μg/kg 140 μg/day 56 μg/kg 35–100 μg/kg
B12 0.05 μg/kg 0.3 μg/kg 0.75 μg/day 0.3 μg/kg 0.1–0.77 μg/kg 0.3 μg/kg
B5 1.7 mg/day 2 mg/day 5 mg/day 2 mg/kg 0.33–2.1 mg/kg 1–2 mg/kg
B8 0.7 μg/kg 4–40 μg/kg 20 μg/day 6 μg/kg 1.7–1.65 μg/kg 5–8 μg/kg
Vit C 6 mg/kg 30–40 mg/kg 80 mg/day 25 mg/kg 11–46 mg/kg 15–25 mg/kg
Table 5 Vitamins: human milk (HM) content, effects of temperature and light, and toxicity
HM Temperature Light Toxicity
B1 165–220 μg/L # Photo Only in adults
degraded
B2 350–575 μg/L # Not clearly defined
B3 1.8–2.5 μg/L No side effect with nicotinamide
B6 130–310 μg/L Inactivated Very rare only in adults
B9 80–135 μg/L Destroyed Inactivated Very rare may mask Vit B12 deficit. May depress Zn
absorption
B12 0.2–1 μg/L Not reported
B5 2.2–5 mg/L Not reported
B8 5–9 μg/L Not reported
Vit C 35–85 mg/L Inactivated Rebound scurvy in newborn only after large doses
during pregnancy
in the small intestine. Deficiency has not yet been in the small intestine. Deficiency is known as
reported as diet provides sufficient amounts. scurvy. A transient elevation of plasma Tyr and
Vitamin B8 (biotin) Except in some metabolic Phenylalanine has been reported in VLBW infants
diseases, deficiency is not seen in enterally fed fed high protein casein formulae.
infants as it is synthesized in gut, but is seen in Vitamin A This term refers to compounds (ret-
TPN (pallor, anemia, dermatitis, lethargy, EEG inoids) having similar activities and structure as
abnormalities). It is also absorbed in the small retinol (natural molecule derived from beta-
intestine. carotene). Vit A activity is expressed as RE (reti-
Vitamin C (ascorbic acid) Vit C has a role as a nol equivalent), 1 RE = 1 μg retinol = 3.3 IU Vit
cofactor in hydroxylation reactions (proline, lysine, A. Vit A is mainly stored in liver and circulates in
norepinephrin synthesis and Try) and as an antiox- blood linked to retinol binding protein (RBP), and
idant. It also has a role in folic acid conversion to is implicated in protein synthesis and epithelial
folinic acid (active form) and in the oxidation of cell functions, growth and immune functions. It
tyrosine (Tyr), and in iron absorption. 1 IU of L has also strong antioxidant properties. It is
Ascorbic Acid corresponds to 50 μg. It is absorbed absorbed in the upper part of the small intestine.
674 O. Claris and G. Putet
No clinical deficiency is described in FT breastfed in pregnant women is still frequent, recommended
infants and precise requirements for PT infants are supply for neonates needs to be given as soon as
still unknown with recommended intakes are enteral feeding is established (Salle et al. 1982).
based mainly on biological data. Vit A supple-
mentation may play a role as an antioxidant factor,
and as a protective factor for bronchopulmonary References
dysplasia (BPD) (Greer 2005).
Vitamin E The term of Vit E refers to eight Aggett PJ, Haschke F, Heine W et al (1991) Comment on
compounds having similar activities. The most the content and composition of lipids in infant formu-
las. ESPGAN Committee on Nutrition. Acta Paediatr
active compound is α-tocopherol, which shows a Scand 80:887–896
strong antioxidant capability by protecting from Agostini C, Buonocore G, Carnielli VP et al (2010) Enteral
lipid peroxidation. Vit E is entirely expressed as supply for preterm infants. A comment of the
α-tocopherol equivalent (αTE), 1 mg αTE = 1 mg ESPGHAN Committee on Nutrition. J Pediatr
Gastroenterol Nutr 50:1–9
d-α-tocopherol = 1.49 IU, and 1 IU = 1 mg Franz AR, Mihatsch WA, Sander S et al (2000) Prospective
dl-α-tocopherol acetate. Vit E requirements randomized trial of early versus late enteral iron sup-
depend on polyunsaturated fatty acid intake. It is plementation in infants with a birth weight of less than
absorbed in the small intestine. Hemolytic anemia 1301 grams. Pediatrics 106:700–706
Friel JK, Penneys S, Reid DW, Andrews WL (1988) Zinc,
is the main consequence of Vit E deficiency. Some copper, manganese, and iron balance of parenterally fed
controversy still persists upon the role of Vit E in VLBW preterm infants receiving a trace element sup-
BPD and retinopathy of prematurity. Large plement. J Parenter Enter Nutr 12:382–386
intakes of Vit E (above 50 mg/kg) have been Greer FR (2005) Vit A, E and K. In: Tsang RC, Uauy R,
Koletzko B, Zlotkin SH (eds) Nutrition of the preterm
implicated in gastro intestinal adverse effects and infant. Scientific basis and practical application, 2nd edn.
sepsis (Raju et al. 1997). Digital Educational Publishing, Cincinnati, pp 141–172
Vitamin K There are to two forms: Vit K1 Koletzko B, Goulet O, Hunt J et al (2005a) Iron, mineral and
(phyloquinone: plant form) and Vit K2 trace elements. J Pediatr Gastroenterol Nutr 41:S39–S46
Koletzko B, Goulet O, Hunt J et al (2005b) Vitamines. J
(menaquinone: synthesized by bacteria). Vit K is Pediatr Gastroenterol Nutr 41:S47–S53
necessary for hepatic synthesis of coagulation Lucas A, Bates C (1984) Transient riboflavin depletion in
factors (II, VII, IX, X, protein C and protein S). preterm infants. Arch Dis Child 59:837–841
It is absorbed in the small intestine. It is needed in Raju TNK, Langenberg P, Bhutani V, Quinn GE (1997)
Vitamin E prophylaxis to reduce retinopathy of prema-
a very small amount and, as it is synthesized partly turity: a reappraisal of published trials. J Pediatr
in the gut, synthesis is less pronounced with HM, 131:844–850
and deficiency is seldomly seen, except in neo- Rogahn J, Ryan S, Wells J et al (2000) Randomised trial of
nates and in cases of malabsorption or hepatic iodine intake an thyroid status in preterm infants. Arch
Dis Child Fetal Neonatal Ed 83:F86–F90
disease (Greer 2005). Salle B, David L, Glorieux FH et al (1982) Early oral
Vitamin D Along with calcium and phospho- administration of vitamin D and its metabolites in pre-
rus homeostasis (see also ▶ Chap. 41, “Calcium mature neonates. Effects on mineral homeostasis.
and Phosphorus Homeostasis: Pathophysiology”), Pediatr Res 16:75–78
Tsang RC, Uauy R, Koletzko B, Zlotkin SH (eds) (2005)
Vit D plays a physiologic role in neuromuscular Nutrition of the preterm infant. Scientific basis and
function and cell growth and differentiation. It is practical application, 2nd edn. Digital Educational Pub-
absorbed in the small intestine. As Vit D deficiency lishing, Cincinnati
Part IV
Pharmacology and Infants of Smoking,
Addicted, and Diabetic Mother
Safety of Medications During
Pregnancy and Breastfeeding: Infants 43
of Drug-Addicted Mothers
Karel Allegaert, Tim van Mieghem, and John N. van den Anker
Contents
43.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678
43.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678
43.3 Maternal–Fetal Pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680
43.4 Breastfeeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681
43.4.1 Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683
43.4.2 Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 684
43.4.3 Antiepileptic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 684
43.5 Neonatal Withdrawal Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 686
43.5.1 Opioid-Related Neonatal Abstinence Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 686
43.5.2 Antidepressants/SSRI-Related Withdrawal Syndromes . . . . . . . . . . . . . . . . . . . . . . . 688
43.6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689
43.7 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 690
K. Allegaert (*)
Neonatal Intensive Care Unit, University Hospitals
Leuven, Leuven, Belgium
Department of Development and Regeneration, KU
J. N. van den Anker
Leuven, Leuven, Belgium
Division of Pediatric Clinical Pharmacology,
Intensive Care and Department of Pediatric Surgery, Children’s National Health System, Washington, DC,
Erasmus MC – Sophia Children’s Hospital, Rotterdam, USA
The Netherlands
Departments of Pediatrics, Integrative Systems Biology,
e-mail: [email protected]
Pharmacology and Physiology, George Washington
T. van Mieghem University, School of Medicine and Health Sciences,
Department of Development and Regeneration, KU Washington, DC, USA
Leuven, Leuven, Belgium
Intensive Care and Department of Pediatric Surgery,
Obstetrics and Gynecology, University Hospitals Leuven, Erasmus MC – Sophia Children’s Hospital, Rotterdam,
Leuven, Belgium The Netherlands
e-mail: [email protected] e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 677
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_192
678 K. Allegaert et al.
Abstract • The same rationale holds true for
Any decision on maternal pharmacotherapy breastfeeding. The goal of maternal medica-
should be balanced, comparing maternal and tions during breastfeeding should fulfill two
fetal/neonatal outcome to withholding any criteria: (1) provide safe and effective pharma-
treatment. This is because there is a relevant cotherapy for maternal condition(s) and (2)
body of evidence that uncontrolled maternal assure safety or tolerance of the nursing infant
conditions also affect fetal outcome. The from adverse events related to the maternal
same holds true for breastfeeding. pharmacotherapy.
Drugs are not thoroughly evaluated for use • A common misconception about drug safety is
during pregnancy or breastfeeding. Knowledge “when in doubt, do not provide breastfeeding,”
on safety of drugs exposure during fetal and since breastfeeding itself provides benefits to
neonatal (breastfeeding) life is limited. Preg- both infant and mother.
nancy category classifications for drugs are • Suggestive indicators of “likely safe during
currently used, but have their limitations. Preg- breastfeeding” are (i) a drug commonly admin-
nancy exposure registries to build knowledge istered to infants (e.g., antibiotics), (ii) a drug
have been implemented in the recently revised that is not absorbed following oral administra-
version of the FDA labelling guidelines (Preg- tion (e.g., aminoglycosides, propofol), (iii) a
nancy and Lactation Labeling Final Rule). drug that is not excreted into human milk
Suggestive indicators of “likely safe during (e.g., insulin, heparin), and (iv) a drug consid-
breastfeeding” are (i) drugs commonly admin- ered safe during pregnancy since fetal expo-
istered to infants, (ii) drugs that are not absorbed sure is generally longer and more extensive.
following oral administration, (iii) not excreted • Breastfeeding rarely needs to be discouraged,
into human milk, and finally (iv) drug consid- discontinued, or interrupted when the mother
ered safe during pregnancy, since fetal exposure needs drug therapy, but some caution should be
is generally longer and more extensive. Aspects taken with analgosedatives (opioids, benzodi-
of opioids, benzodiazepines, and anti-epileptics azepines). Radioactive-labeled diagnostic
use during fetal life or via breastfeeding have drugs such as lithium, iodine, gold, and ergot-
been discussed to illustrate the concepts of preg- amine alkaloids are high-risk drugs and are
nancy-related clinical pharmacology, followed likely not to be compatible with breastfeeding.
by a focused discussion on neonatal abstinence • The Pregnancy and Lactation Labeling Final
syndromes. We hereby aim to provide the prac- Rule should provide the tool to generate and
ticing clinician with some guidance and sources collect reliable information on maternal drug
of information. use during breastfeeding.
43.2 Introduction
43.1 Salient Points
Drug labeling rarely includes information about
• Drugs administered to the mother may have dosing, efficacy, and maternal, fetal, or newborn
harmful effects on the fetus at any time during safety and commonly states that “the drug has not
pregnancy. Decisions on maternal pharmaco- been studied during pregnancy or breastfeeding.”
therapy should always take account of the In general, drugs are not thoroughly evaluated for
effects of withholding maternal treatment on use during pregnancy. This is neither the case for
maternal, fetal, and neonatal outcomes. specific pregnancy-related diseases (e.g., gesta-
• The placenta should not be considered as a tional diabetes, nausea and vomiting of preg-
perfect, absolute barrier and neither is the nancy) nor for the impact of pregnancy, delivery,
fetus an inactive bystander following maternal or the postpartum period (e.g., breastfeeding)
and consequent fetal drug exposure. on pharmacotherapy of nonpregnancy-related
43 Safety of Medications During Pregnancy and Breastfeeding: Infants of Drug-Addicted Mothers 679
comorbidities (e.g., epilepsy, depression, pain simplistic approach to discontinue drugs due to a
syndromes, posttransplant, asthma, oncological perceived, association related risk, while ignoring
diseases) (Zaijcek and Giacoia 2007; Pavek the risks of discontinuation, is unwarranted and
et al. 2009). A similar case can be built for early often dangerous (e.g., epilepsy, depression, pain
infancy and results in extensive off-label and syndromes, posttransplant, asthma, or oncological
unlicensed pharmacotherapy in both subpopula- diseases) (Briggs et al. 2015; Gadot and Koren
tions (▶ Chap. 44, “Developmental Pharmacol- 2015; Amant et al. 2015).
ogy and Therapeutics in Neonatal Medicine”) The same rationale holds true for
and hence patient anxiety and prescriber liability. breastfeeding. Human milk is the obvious golden
Simple extrapolation from data in adults is reference and the normative standard feeding for
hazardous, since pregnancy itself affects pharma- newborns and infants, but may result in
cokinetics (PK, concentration-time profile) in part breastfeeding associated drug exposure. As exten-
driven by the hormonal (e.g., estradiol) and phys- sively discussed in another chapter of this text-
iological (e.g., cardiac output, renal function, book, drug disposition [absorption, distribution,
plasma volume, and protein-binding capacity) and subsequent elimination, either through meta-
changes. This results in extensive variability in bolic elimination or through primary renal elimi-
drug response. In general, renal elimination nation (ADME) pharmacokinetics] in early
capacity is increased throughout pregnancy (i.e., infancy also differs substantially between children
higher glomerular filtration rate, higher active and adults. In general, neonates have an overall
tubular transport). Similarly, basal metabolic low clearance capacity with an importance
activity is also increased. This commonly results between the subject explained by covariates
in higher drug metabolism (phase I and phase II such as organ weight and function, body compo-
processes), although these changes are in part also sition, size, co-administration of drugs, genetic
isoenzyme specific. This – although rare – may polymorphisms, growth restriction, or disease
even result in reduced enzymatic activity during characteristics.
pregnancy (Ramoz and Patel-Shori 2014; Thomas As a consequence, the ultimate goal of maternal
and Yates 2012). Finally, changes in body weight medications during breastfeeding should fulfill two
or protein-binding capacity can affect the volume criteria: (1) provide safe and effective pharmaco-
of distribution. Protein-binding capacity and the therapy for the maternal condition(s) and (2) still
subsequent free fraction may also have an impact assure safety or tolerance of the nursing infant
on the amount of drug that will be transferred from from adverse events related to the maternal phar-
the maternal plasma to the human milk compart- macotherapy (Sachs and Committee on Drugs
ment (Ramoz and Patel-Shori 2014; Thomas and 2013). As a geneal comment before we discuss
Yates 2012; Feghali and Mattison 2011). Despite more in detail some aspects of maternal–fetal
the limited available knowledge, women during pharmacotherapy, pharmacotherapy during
pregnancy as well as in the postpartum period breastfeeding, and the neonatal abstinence syn-
need pharmacotherapy for different medical rele- dromes, we would like to make the point that
vant conditions, either or not pregnancy related compound or class-specific information on drug
(Thomas and Yates 2012). use during pregnancy, postpartum, and
Drugs may have harmful effects on the fetus at breastfeeding is evolving and has become a field
any time during pregnancy. However, any deci- of active clinical research.
sion on pharmacotherapy should always be bal- This means that updated, reliable information
anced, comparing maternal and fetal/neonatal should be easy accessible for caregivers. Besides
outcome to withholding maternal treatment. This textbooks, LactMed is a free online database with
is because there is also a relevant body of evidence information on drugs and lactation as one of
that uncontrolled or suboptimal controlled mater- the newest additions to the National Library of
nal conditions in themselves also affect fetal well- Medicine’s TOXNET system. The Motherisk pro-
being and perinatal outcome. A linear, too gram has also an updated and useful website
680 K. Allegaert et al.
(www.motherisk.org) that can be searched and is a prescription in any female patient of childbear-
open for advices. Another source of information ing age (e.g., angiotensin-converting enzyme
with specific emphasis on teratology is the www. inhibitors, coumarins, antiepileptics, isotretinoin).
mothertobaby.org website. More recently In contrast, drug exposure during the second
(cf. infra), pregnancy exposure registries have and third trimester of pregnancy more generally
been introduced in the FDA labeling concept, affects either fetal growth or functional develop-
aiming to improve the available knowledge and ment (e.g., illicit drugs). Finally, perinatal
access to knowledge on drugs and pregnancy. exposure (e.g., opioids, benzodiazepines, antide-
Also the National Center on Birth Defects and pressants) may affect neonatal adaptation.
Developmental disabilities, integrated in the Cen- Studying the safety and the efficacy of drugs in
ters for Disease Control (CDC), provides informa- pregnancy is obviously more limited, since it is
tion on the safety of maternal drug use (www.cdc. ethically inacceptable to subject pregnant women
gov/pregnancy/meds/treatingfortwo). Supported to drugs for the sake of studying fetal and maternal
by the National Health Services (NHS) (www. safety (Briggs et al. 2015). However, capturing
rdtc.nhs.uk/services/teratology), the UK Teratol- observations on human exposure in a structured
ogy Information Service (UKTIS) website pro- approach may also provide relevant information
vides information, including monographs. despite the fact that such information may be
Through the same group, the Best Use of Medi- confounded by maternal disease state.
cines in Pregnancy (BUMPS, www.medicinesin Case–control studies, observational studies and
pregnancy.org) aims to inform and be informed by the use of prospective registration during preg-
the public. nancy may provide more robust information.
Such methods facilitate comparison of exposure
rates to a specific compound in mothers who
43.3 Maternal–Fetal deliver a newborn with a specific malformation
Pharmacotherapy versus those who delivered a healthy baby
(http://www.fda.gov/Drugs/DevelopmentApproval
Maternal pharmacotherapy may sometimes have Process/DevelopmentResources/Labeling/ucm093
a primary fetal indication, with maternal adminis- 307.html).
tration of steroids for fetal lung maturation as Largely because of these limitations, the
the best known maternal exposure, aimed for assessment of risks and how to handle the avail-
improved fetal and neonatal outcome. able evidence, association, or likelihood of fetal
Transmaternal fetal therapy clearly reflects the harm related to maternal pharmacotherapy
fact that the placenta should not be considered to remains a difficult, balanced decision. This is
be a perfect, absolute barrier and neither is the also reflected by the different and evolving applied
fetus an inactive bystander following maternal approaches: strategies evolve, but also vary.
and subsequent fetal drug exposure (Rowe Pregnancy category classifications are one
et al. 2013). Consequently, effects (e.g., lung mat- approach, but classifications vary somewhat
uration, conversion of supraventricular tachycar- between different authorities, and these categories
dia) but also harmful drug-related fetal side effects do not include risks related to drugs or their
may occur at any time throughout pregnancy. metabolites transferred through breast milk. The
Structural, teratogenic effects, i.e., prenatal concept of pregnancy exposure registries to build
toxicity characterized by structural defects (e.g., knowledge has been integrated in the recently
mono-organ like cardiac, central nervous system, revised version of the Food and Drug Administra-
or renal, but sometimes also multi-organ) in the tion (FDA) labeling guidelines on medication
developing embryo or fetus, are the most com- guidelines during pregnancy and lactation. FDA
monly seen between (already) the 3rd and 11th defines a pregnancy exposure registry as a study
week of pregnancy (Thomas and Yates 2012). that collects information from women who take
This is of relevance when a physician considers prescription medicines or vaccines during
43 Safety of Medications During Pregnancy and Breastfeeding: Infants of Drug-Addicted Mothers 681
pregnancy. This information includes data on the (http://www.fda.gov/Drugs/DevelopmentApproval-
newborn and is compared with women not taken Process/DevelopmentResources/Labeling/ucm0
drugs during pregnancy (http://www.fda.gov/ 93307.html). Already two decades ago, Ito
Drugs/DevelopmentApprovalProcess/Develop- et al. quantified the incidence of adverse reac-
mentResources/Labeling/ucm093307.html). tions (11.2%) in a cohort of 838 nursing infants
The FDA medication classification system ini- with mothers on drugs (Ito et al. 1993). More
tially applied a category A, B, C, D, X, and N for importantly, all events were classified as minor
each compound and required a quite large amount and were most commonly associated with antibi-
of high-quality data to be defined as pregnancy otics, analgesics/narcotics, antihistamines, seda-
category A (i.e., safe to the fetus). In the mean- tives, antidepressants, or antiepileptics. In 2003,
while, the FDA requests a more narrative descrip- this overall pattern was confirmed by Anderson
tion of the evidence available for use of the drug in et al., following a systematic review of 100
pregnancy in three subsections, “pregnancy,” published case reports. None of the cases were
“lactation,” and “females and males of reproduc- “definite,” 47% “probable,” and 53% “possible”
tive potentials.” The “pregnancy” subsection pro- related to breastfeeding. Central nervous system-
vides information to the use of the drug in related drugs accounted for about 50% of the
pregnant women, including dosing and potential events and also included three fatalities. These
fetal risks, and will be based on the earlier- observations suggest that when a few simple pre-
mentioned registries. The “lactation” section will cautions are taken in drug selection and when the
provide information about the use of the drug infant’s age is taken into account, breastfeeding
while breastfeeding, such as the amount of drug rarely needs to be discontinued when the mother
in human milk and potential effects on the nursing needs pharmacotherapy: adverse drug reactions
infant. This new Pregnancy and Lactation Label- in breastfed infants are less than imagined
ing Final Rule became effective by June 30, 2015 (Anderson et al. 2003).
(http://www.fda.gov/Drugs/DevelopmentAppro- Maternal absorption of a given dose of drug
valProcess/DevelopmentResources/Labeling/ucm (Dm) will result in compound-specific, variable
093307.html). transfer of the drug into the human milk (Di).
However, concentrations in human milk usually
are quite low, and the oral bioavailability follow-
43.4 Breastfeeding ing oral ingestion by the infant is also a very
relevant and often forgotten covariate to estimate
Lactating women are regular users of medications the subsequent exposure (RID = relative infant
and are often advised to either discontinue or even dose, Dm/Di * absorption) (Fig. 1). In Fig. 1, the
stop nursing while taking drugs, despite the fact differences in drug concentrations in the infant
that there are only a limited number of drugs that (1 vs. 2) can be explained by the presence (a) or
have been identified as potentially harmful to the absence (b) of “an initial concentration following
newborn. fetal exposure to the drug” since accumulation in
A common misconception about drug safety is the infant relates to dose and duration, body com-
“when in doubt, do not provide breastfeeding,” position, the clearance capacity of the infant, but
since breastfeeding itself provides relevant bene- also the initial concentration in the newborn’s
fits to both the infant and the mother (Genung compartments.
2013). The earlier-described Pregnancy and Lac- In the clinical setting, suggestive indicators of
tation Labeling Final Rule should provide the tool “likely safe during breastfeeding” are (i) a drug
to generate and collect more reliable information commonly administered to infants (e.g., antibiotics),
on this topic. At present, there are still a limited (ii) a drug that is not absorbed following oral
number of prospective population-based studies administration (e.g., aminoglycosides, propofol),
or systematic reviews that provide some insight (iii) not excreted into human milk (e.g., insulin,
in the extent and the relevance of the problem heparin), and finally (iv) a drug considered safe
682 K. Allegaert et al.
maternal exposure infant dose infant exposure
maternal pharmacokinetics conc x amount absorption + pre-existing exposure
Dmaternal, exposure Dinfant, intake Dinfant, exposure
Infant plasma a,b
maternal plasma Milk
Conc
Conc
Conc
Dose a
(Di)
b
h h h
Mauc/Pauc milk/plasma ratio
to what extent does the compound appear in human milk?
Dinfant, intake estimated infant dose = concentrationm x M/P x Volumemilk
to what extent is the baby exposed to the compound (oral intake) ?
Dinfant, exposure relative infant dose: Dm (mg/kg/day ) / Di (mg/kg/day) x absorption
to what extent does oral intake result in exposure ?
(a = pre-existing exposure, eg fetal, b = new exposure)
Fig. 1 Pharmacokinetics of mother–infant pairs as it (RID = relative infant dose, Dm/Di * absorption). The
relates to drug exposure through breastfeeding. Maternal differences in drug concentrations in the infant (1 vs. 2)
absorption of a given dose of drug (Dm) will result in can be explained by the presence (a) or absence (b) of an
compound-specific, variable transfer of the drug into the initial concentration following fetal exposure to the drug
human milk (Di). However, concentrations in human milk since accumulation in the infant relates to dose and dura-
usually are quite low, and the oral bioavailability following tion, body composition, the clearance capacity of the
oral ingestion by the infant is also a very relevant and often infant, but also the initial concentration in the newborn’s
forgotten covariate to estimate the subsequent exposure compartments
during pregnancy, since fetal exposure is gener- morphine intoxication in a breastfed neonate of a
ally longer and more extensive. In contrast, e.g., codeine-prescribed mother (Koren et al. 2006).
radioactive-labeled diagnostics, lithium, iodine, Subsequent guidelines (lowest codeine dose pos-
gold, and ergotamine alkaloids are high-risk sible, maternal exposure <4 days, and switch to
drugs, more likely not compatible with non-opioids as soon as possible, monitor maternal
breastfeeding. The available data suggest that and neonatal sedation) resulted in an eightfold
breastfeeding rarely needs to be discouraged, reduction (5/238, 2.1%) in the incidence of neo-
discontinued, or interrupted when the mother natal sedation and were only associated with
needs drug therapy, but some caution may be prolonged (>4 days) maternal codeine intake.
warranted with analgosedatives (opioids, benzo- As part of analgosedative treatment options,
diazepines) (Van den Anker 2012; Berlin and van mothers after delivery (e.g., post-caesarean,
den Anker 2013; Hendrickson and McKeown birth-related injuries, but also preexisting pain
2012). In contrast, local anesthetics, systemic syndromes) can be exposed to different
non-opioid analgesics, and intravenous or inhala- analgosedatives that may also have impact of the
tional anesthetics are safe in the setting of breastfed infant (Van den Anker 2012; Allegaert
breastfeeding (Allegaert and van den Anker and van den Anker 2015). This will be followed
2015). by some guidance on the use of antiepileptic drugs
Peripartum opioid exposure became a specific and breastfeeding. Aspects related to antidepres-
focus of interest, following a case report of sants will be covered in the section on neonatal
43 Safety of Medications During Pregnancy and Breastfeeding: Infants of Drug-Addicted Mothers 683
abstinence syndrome. We hereby also cover some The incidence of central nervous system
aspects of fetal exposure, since for some drugs, e.g., depression in breastfed neonates following mater-
antiepileptic drugs, neonates are exposed both nal exposure to oxycodone, codeine, or paraceta-
intrauterine and during breastfeeding. mol was retrospectively compared in
533 mother–infant pairs. Lam et al. hereby clearly
showed that there was a 20.1% rate of depression
43.4.1 Opioids in infants of nursing mothers on oxycodone, as
compared with 16.7% and 0.5% when treated
The breastfeeding rate increased steadily in the with codeine or paracetamol, respectively (Lam
developed world (Saadeh 2012). More recently, et al. 2012). Finally, using a sparse sampling
opioid consumption in the general population – study design to assess transfer of tramadol and
including women of childbearing age – also raised O-desmethyl tramadol into transitional breast
steadily (DeVane 2015). This means that the clinical milk, the relative infant dose of 2–3% remained
experience with maternal opioids is still relatively very limited. Based on these observations, the
limited with emerging data on (side) effects with authors concluded that short-term maternal use
codeine, oxycodone, methadone, and tramadol dur- of tramadol is compatible with breastfeeding
ing breastfeeding (Rowe et al. 2013; Berlin and van (Salman et al. 2011).
den Anker 2013; Koren et al. 2006). The same It remains somewhat difficult to convert the
phenomenon also explains the dramatic increase in available observations in the literature to clinical
the incidence of neonatal abstinence syndrome guidelines for pediatricians, but we tried to pro-
(cf infra). Referring to Fig. 1, oral absorption of vide some guidance (Van den Anker 2012;
opioids in neonates should be anticipated, while Allegaert and van den Anker 2015; DeVane
the extent of exposure through mother’s milk will 2015). Firstly – besides tramadol – it seems rea-
depend on maternal ingestion (dose) and metabo- sonable to anticipate that sedation may occur fol-
lism. Neonatal drug elimination relates to the neo- lowing maternal exposure to codeine, oxycodone,
nate’s metabolic or renal elimination, but will be methadone, or morphine. Secondly, and clinical
relatively limited (Allegaert et al. 2013). These cir- quite useful, there is a high concordance between
cumstances have the potential to result in side effects maternal and neonatal somnolence. When the
in individual infants. A pivotal case report in 2006 mother exhibits somnolence, the baby should be
of Koren et al. on codeine-related poisoning in an examined. This is likely due to the impact of
infant due to breastfeeding following maternal genetic polymorphisms and dose on the individ-
intake of codeine reinitiated the clinical interest ual maternal–infant-related effects and side
and research on maternal–infant opioid pharmaco- effects of these drugs. Severe somnolence only
kinetics and dynamics and its covariates (Koren emerges after 4 days of continued drug exposure
et al. 2006). A pharmacogenetic link with maternal and subsequent drug accumulation. When the
ultrafast metabolizer status for cytochrome p450 human milk volume increases, exposure (mg/l x
(CYP) 2D6 was documented. This genetic status volume) increases and is prolonged, making sub-
results in higher and faster conversion of codeine sequent accumulation in the infant more likely. As
to morphine (Koren et al. 2006). More recently, the a result of the above premises, maternal opioid
same researchers also described that a combination exposure for more than 72 h after delivery war-
of maternal genetic polymorphisms (i.c. CYP 2D6 rants specific clinical evaluation, with emphasis
and P-glycoprotein polymorphisms) predicted 87% on signs of sedation in both the mother and the
of the maternal and infant central nervous system newborn (Van den Anker 2012; Salman
depression cases with a sensitivity of 80% and et al. 2011; Rivers et al. 2012).
a specificity of 87% in a cohort of 111 breastfeeding There are two additional comments to be made.
mother–infant dyads (Sistonen et al. 2012). Firstly (Fig. 1), this rationale does not fully apply
Unfortunately, this observation is not limited to to newborns already exposed prenatally to opi-
codeine only. oids, but these aspects will be discussed in the
684 K. Allegaert et al.
section on neonatal abstinence syndrome. Sec- while taking antiepileptic drugs (AEDs) remains
ondly, the route of administration of opioids obvi- of some concern. This concern is also reflected in
ously matters (systemic, e.g., oral, intravenous, or the fact that the rates of breastfeeding of women
transcutaneous, or locoregional, e.g., spinal, epi- on AEDs are lower when compared to women not
dural). Because of the much lower doses used and on AEDs living in the same region or country
the lower plasma concentrations, the subsequent (Veiby et al. 2015). Moreover, women using either
drug exposure through human milk will be much AED poly-therapy (75%) or lamotrigine
lower. (undergoes glucuronidation, so poorer clearance
capacity in early neonatal life) had even lower
breastfeeding initiation rates (70%), when com-
43.4.2 Benzodiazepines pared to either the reference group (not on AEDs,
92%) or to women on AED monotherapy (80%),
Benzodiazepines (e.g., diazepam, lorazepam, with a subsequent similar decline in breastfeeding
midazolam) are commonly administered as anxi- rates with time (at 3 months, AED poly 67%,
olytics. These compounds and some of their lamotrigine 60%, reference group 86%, AED
metabolites can be retrieved in human milk, but mono 70%). Obviously, many factors affect the
the amounts remain very low and subsequent decision to initiate and maintain breastfeeding.
exposure remains very limited (Cole and Hailey Besides socioeconomic and social factors, emo-
1975; Nitsun et al. 2006). In 24 h of human milk tional status or self-esteem but also disease-
collection after a single dose, only 0.005% of the related aspects (e.g., need for day/night routine,
maternal midazolam dose was retrieved. Taking seizure control) likely affect the individual deci-
the subsequent oral bioavailability (50–60%) into sion of women (Veiby et al. 2015; Meador
account, it is very reasonable to assume that the et al. 2014).
exposure will be very low when administered
after delivery. In contrast, plasma diazepam and 43.4.3.1 Compound-Specific Risk
its active metabolite (desmethyldiazepam) could Assessment
be measured up to 7–10 days of postnatal age in Phenytoin, carbamazepine, and valproate are gen-
neonatal plasma samples after administration to erally considered to be safe AEDs during
the mother before or during delivery (Cole and breastfeeding (Veiby et al. 2015). Phenytoin and
Hailey 1975). We once again refer to Fig. 1 to valproate have a high and carbamazepine a mod-
explain this. Following administration during erate high plasma protein binding. Consequently,
delivery, the fetus and newborn will have already the M/P ratios are quite low (phenytoin, 0.1–0.6;
a relevant concentration of benzodiazepines in the carbamazepine, 0.2–0.7; valproate, 0.01–0.3).
blood (Fig. 1, level a instead of level b), and the Some suggest checking liver enzymes and throm-
neonatal clearance capacity for these compounds bocytes in the nursing infant exposed to valproate
is limited (De Wildt et al. 2002). and liver enzymes in infants exposed to carbamaz-
epine (Veiby et al. 2015).
Lamotrigine, oxcarbazepine, levetiracetam,
43.4.3 Antiepileptic Drugs topiramate, gabapentin, pregabalin, vigabatrin,
and tiagabine are classified as moderately safe
Continuation of antiepileptic treatment during AEDs. As mentioned earlier, lamotrigine (M/P
pregnancy and the postpartum period is extremely ratio 0.4–0.67) is cleared by glucuronidation and
important, since poor epileptic control has been is moderately plasma protein bound (55%). We
associated with adverse maternal and fetal out- suggest monitoring the infant for clinical signs
comes. Monitoring of maternal drug levels is and consider checking serum levels when the
often advised since pharmacokinetics may infant displays poor suckling. We hereby have
change. However, the safety of breastfeeding to take into account that the free lamotrigine
43 Safety of Medications During Pregnancy and Breastfeeding: Infants of Drug-Addicted Mothers 685
fraction in neonatal serum will be higher when neurodevelopmental outcome (e.g., gross motor
compared to maternal plasma (lower binding skills, fine motor skills, social skills). These
capacity) (Veiby et al. 2015). Oxcarbazepine neurodevelopmental observations further add to
(M/P ratio 0.5) has the same route of metabolic the available data on the impact of fetal exposure
elimination (glucuronidation), but clinical expe- on the incidence of congenital malformations
rience with this compound is much more limited. (Meador et al. 2014). AEDs such as valproate
The M/P ratio of levetiracetam is much higher (9.3%, RR 5.1 to lamotrigine) and phenobarbital
(M/P ratio 0.8–1.6), but clearance is through (4.2%, RR 2.9) are associated with a higher risk of
primary renal elimination, and there is a relevant major malformations than newer AEDs such as
amount of clinical experience with this com- lamotrigine (2%) and levetiracetam, (2.4%), while
pound to treat neonatal seizures (Pressler and topiramate (3%, RR 2.2) was associated with an
Mangum 2013). For all the other compounds increased risk of cleft lip compared with that of a
mentioned, there are only a limited number of reference population (Veiby et al. 2013).
clinical reports. As reported by the Neurodevelopmental
Finally, benzodiazepines, phenobarbital and Effects of Antiepileptic Drugs (NEAD) group,
primidone, ethosuximide, zonisamide, or felbamate, fetal valproate exposure is associated with a sig-
are classified as potential hazardous. Aspects on nificantly higher risk of impaired cognitive func-
benzodiazepines have been discussed earlier (3.2). tion at 3 years (mean IQ 92, mean IQ difference of
For phenobarbital and its prodrug primidone, accu- 6–9 when compared to carbamazepine,
mulation may occur because of the very long elim- lamotrigine, or phenytoin, 258 cases of AED
ination half-life of phenobarbital in neonates exposure) with a clear dose–effect relation for
(Marsot et al. 2014). Again, clinical observation valproate (Meador et al. 2009). Similarly,
and – in the presence of symptoms – drug monitor- Veiby et al. (Marsot et al. 2014) confirmed the
ing seem a very reasonable choice. Ethosuximide impact of fetal AED exposure on psychomotor
has a high M/P ratio, and the relative infant dose development. At age 6 years, infants of mothers
(32–113%) and subsequent levels in neonates are using antiepileptic drugs (n = 223) had a higher
quite high (24–75%) when compared to maternal risk of impaired fine motor skills compared with
levels. Since ethosuximide is commonly part of the reference group (11.5–4.8%, OR 2.1). The
poly-AED therapy, careful monitoring is maternal treatment with multiple antiepileptic
recommended. Zonisamide also results in signifi- drugs was associated with adverse outcome for
cant exposure (M/P ratio 0.8) and has a long elim- fine motor skills (25.0–4.8%, OR 4.3) and social
ination half-life in neonates. There are no data on skills (22.5–10.2%, OR 2.6).
felbamate, but this drug may induce hepatic failure Building on these background characteristics,
or aplastic anemia (Veiby et al. 2015). the same study also documented that
breastfeeding in infants of women using AEDs
43.4.3.2 Impact of Prenatal and was associated with improved neurodevelopment
Breastfeeding-Mediated outcome at ages 6 and 18 months, compared with
Exposure of Antiepileptic Drugs those with either no breastfeeding or
(AED) on Neurodevelopmental breastfeeding for less than 6 months (Meador
Outcome et al. 2014). At 36 months, fetal AED exposure
Similar to the breastfeeding rates, the assessment was associated with adverse development, regard-
of neurodevelopmental impact of AED exposure less of breastfeeding. Children of women with
through breastfeeding is also hampered by several epilepsy but without AED during pregnancy had
covariates (Meador et al. 2014). Firstly, postnatal normal development at 6 months. Based on these
exposure generally follows intrauterine exposure. observations, it is fair to encourage women with
Secondly, the impact of fetal exposure to AEDs epilepsy to breastfeed their infants, irrespective of
during pregnancy also affects subsequent antiepileptic drug treatment and taking the
686 K. Allegaert et al.
abovementioned suggestions on clinical monitor- 43.5.1 Opioid-Related Neonatal
ing into account (Meador et al. 2014). Abstinence Syndrome
The incidence of opioid-related neonatal abstinence
43.5 Neonatal Withdrawal syndrome (NAS) has increased significantly in the
Syndromes last decade, colinear with the increased medical use
of prescription opioids in adults (DeVane 2015).
Neonatal withdrawal or neonatal abstinence syn- The impact on the trends of NAS incidence through-
drome (NAS) is a withdrawal syndrome in neo- out the Western world has been illustrated in Fig. 2
nates due to acute cessation of the exposure to (Turner et al. 2015; Dow et al. 2012; Patrick
either illicit or prescribed drugs. Similar to toler- et al. 2012, 2015; O’Donnell et al. 2009; Creanga
ance or dependence, withdrawal may occur as a et al. 2012). This means that NAS is no longer
result of repeated or chronic administration of “restricted” to illicit drug users but also has become
drugs, but also after short-term high-dose use, a frequent complication following medical prescrip-
e.g., during neonatal stay. Consequently, NAS tion of opioids (DeVane 2015). The clinical picture
can appear both following discontinuation of of neonatal abstinence syndrome mimics to a large
drugs taken by the pregnant mother and following extent the syndrome of opioid withdrawal in adults
discontinuation of drugs administered intention- (“cold turkey”) and includes both neurological
ally to the newborn. The most commonly (e.g., agitation, crying, sleep disturbance, feeding
involved compounds are opioids, selective sero- difficulties, but also seizures) and extra-neurological
tonin reuptake inhibitors (SSRIs), benzodiaze- symptoms (e.g., diarrhea, vomiting, perianal exco-
pines, as well as cannabis or nicotine. riations, sneezing, sweating, hyperthermia). The
x/1000
.
6.
5.
4.0
3.
2.0
1.0
0.0
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
year
Fig. 2 The impact on the trends of NAS incidence and 2012 (Turner et al. 2015; Dow et al. 2012; Patrick
throughout the Western world is illustrated by the trends et al. 2012, 2015; O’Donnell et al. 2009; Creanga
in the annual incidence (1/1000) of neonatal abstinence et al. 2012)
syndrome in different cohorts as published between 1992
43 Safety of Medications During Pregnancy and Breastfeeding: Infants of Drug-Addicted Mothers 687
clinical presentation of NAS varies with the opioid The Finnegan score (modified version,
(elimination half-life short or prolonged, heroin 21 items, 0–37 points, Table 1) is universally
vs. methadone) used, co-drugs, maternal drug used to quantify the severity of withdrawal symp-
history, placental transfer, neonatal elimination toms (Hudak et al. 2012). The score hereby
capacity, but also pharmacogenetics (e.g., drug reflects the central nervous system driven as well
metabolism, transporters, receptor polymorphisms) as autonomic, intestinal, and respiratory signs
(Wachman et al. 2013). (Zimmermann-Baer et al. 2010). To document a
threshold for suspected NAS, Zimmermann-Baer
et al. documented the Finnegan score in 102 neo-
Table 1 Items and calculation of the modified Finnegan nates (>34 weeks gestational age), up to the age of
score (DeVane 2015; Hudak et al. 2012)
5–6 weeks. The 95th percentile increased from 5.5
Central nervous system symptom-related items on day 1 to 7 on day 2, and at 5–6 weeks, the 95th
High-pitched cry Present 2
percentile was 8 during daytime and 6 at nighttime
>2 h 3
(Zimmermann-Baer et al. 2010). Based on these
Sleeps less than 3 h after feeding 1
observations, the authors suggest that values above
2 h after feeding 2
8 should raise suspicion of withdrawal. When phar-
1 h after feeding 3
When disturbed Mild tremors 1
macological treatment of opiate withdrawal in neo-
Marked tremors 2 nates is deemed necessary, opiates (morphine,
When undisturbed Mild tremors 3 methadone, preferably by oral route) are the first
Marked tremors 4 choice, with subsequent slow weaning, although
Increased muscle 2 there is extensive variability in weaning and dis-
tone charge practices (Hudak et al. 2012). In the event of
Excoriation of the 1 non-opioid neonatal withdrawal, phenobarbital is
skin the first choice. More recently, clonidine (5 μg/kg
Myoclonic jerks 3
per day, divided in 8 doses) has been suggested as a
during sleep
Generalized 5
novel treatment modality (Bada et al. 2015). Sim-
convulsions ilarly, buprenorphine by sublingual route may also
Autonomous/vegetative symptom-related items become a new treatment modality (Ng et al. 2015).
Sweating/ 1 Besides pharmacological interventions, we
perspiring strongly recommend to consider the impact of
Body temperature 37.5–38 C 1 other interventions like swaddling, traditional
>38 C 2 supportive interventions, but also breastfeeding
Frequent yawning 1 (MacMullen et al. 2014). Although there are no
Mottling 1 prospective randomized controlled trials, there is
Nasal stuffiness 2
evidence in support of breastfeeding in women
Sneezing 1
who have used methadone in pregnancy (grade C),
Gastrointestinal and respiratory system symptom-related
items since this reduces the incidence (NNT 5–6) and
Frantic suckling 1 severity of NAS (grade C), without inducing clin-
Poor feeding 2 ically important sedation (grade C) (Lefevere and
Regurgitation 2 Allegaert 2015). Optimal NAS treatment remains
Projectile vomiting 3 undetermined and practices vary between and
Stools Loose 2 within hospitals. Prolonged length of stay for
Watery 3 NAS cases may result in patient harm and impaired
Tachypnea >60/min 1 maternal–infant attachment, besides significant
>60/min þ 2 costs. The development of an educational program
retractions and a standard treatment protocol for NAS has
688 K. Allegaert et al.
been the most effective interventions to reduce this 43.5.2 Antidepressants/SSRI-Related
length of stay for NAS newborns (Asti et al. 2015). Withdrawal Syndromes
Some key messages on neonatal abstinence syn-
drome for the practitioner are summarized in Selective serotonin reuptake inhibitors (SSRIs,
Table 2 (DeVane 2015; Turner et al. 2015; Dow e.g., citalopram, paroxetine, fluvoxamine) or
et al. 2012; Patrick et al. 2012, 2015; O’Donnell serotonin–norepinephrine reuptake inhibitors
et al. 2009; Creanga et al. 2012; Wachman (SNRIs, e.g., venlafaxine, duloxetine) are
et al. 2013; Hudak et al. 2012; Zimmermann-Baer commonly used during pregnancy and/or
et al. 2010; Bada et al. 2015; Ng et al. 2015; breastfeeding, since depression is a highly preva-
MacMullen et al. 2014; Lefevere and Allegaert lent disease in the peripartum period. This inci-
2015; Asti et al. 2015; Siu and Robinson 2014). dence is estimated to be as high as 1 in 8 women
(Verreault et al. 2014). During pregnancy, antide-
pressants cross the placenta, but a relevant (i.e.,
Table 2 Key messages on neonatal abstinence syndrome:
essentials for the practitioner (DeVane 2015; Turner robust and frequent) association with congenital
et al. 2015; Dow et al. 2012; Patrick et al. 2012, 2015; malformations is absent and likely limited to the
O’Donnell et al. 2009; Creanga et al. 2012; Wachman association between lithium and cardiopathy
et al. 2013; Hudak et al. 2012; Zimmermann-Baer
(RR fivefold to tenfold, but overall risk 1–5%
et al. 2010; Bada et al. 2015; Ng et al. 2015; MacMullen
et al. 2014; Lefevere and Allegaert 2015; Asti et al. 2015; instead of 0.5–1%), most specific for Ebstein’s
Siu and Robinson 2014) anomaly. Fetal exposure may result in a neonatal
The incidence of neonatal abstinence syndrome (NAS) clinical syndrome similar to a withdrawal syn-
varies extensively (fivefold to tenfold) between units, but drome (poor neonatal adaptation, 30%). SSRIs
there is an overall relevant increase in the incidence of have also been associated with respiratory dis-
NAS
tress, persistent pulmonary hypertension (PPHN,
Besides recreational use, this increase in NAS also
reflects a significant increase in the medical prescription
absolute risk <1%), and hypoglycemia. However,
of opioids when evaluating the risk/benefit ratio of SSRI
Fetal exposure does not necessary result in neonatal administration in pregnancy, the risk associated
abstinence syndrome. For heroin and methadone, its with treatment discontinuation (e.g., relapse of
incidence is about 60–80 % psychiatric problems, preterm delivery, postpar-
The timing of appearance of NAS symptoms in part tum depression) appears to outweigh the risks of
depends on the clearance characteristics of the opioid
(heroin <24–48 h versus methadone 48–72 h) involved. therapy continuation. Moreover, maternal depres-
The longer the elimination half-life, the later the sion may negatively affect the child’s develop-
symptoms appear ment, emphasizing the importance of prevention
Treatment should be protocol driven, based on by appropriate treatment during pregnancy with
assessment (Finnegan) and followed by
the least minimal effective dose (Ornoy and Koren
non-pharmacological as well as pharmacological
interventions. Treatment should also cover the 2014).
subsequent tapering of these drugs Recently, Reefhuis et al. applied a Bayesian
Neonatal seizures are the most life-threatening analysis to combine different datasets to explore
complication of NAS. Furthermore, treatment aims to associations between birth defects and specific
reduce the distress (Finnegan score, excessive crying),
preserve weight gain, and improve oral feeding
SSRIs. None of the earlier reported malformations
Breastfeeding has a proven positive effect on the associated with sertraline were confirmed, and
incidence and the extent of neonatal abstinence syndrome nine previously reported associations between
(NNT = 5–6) maternal SSRI use and birth defects were rejected
Opioid withdrawal should be treated with opioids, but (Reefhuis et al. 2015). In contrast, paroxetine
practices on the preferred compound (methadone, (anencephaly OR 3.2; atrial septum defect
morphine) vary
OR 1.8; right ventricular outflow tract obstruction
Although these concepts can also be applied to
withdrawal syndromes resulting from other drugs (e.g., OR 2.4; gastroschisis OR 2.5; omphalocele 3.5)
antidepressants, sedatives), the available evidence and and fluoxetine (right ventricular outflow tract
guidance are more limited OR 2; craniosynostosis OR 1.9) have been
43 Safety of Medications During Pregnancy and Breastfeeding: Infants of Drug-Addicted Mothers 689
associated with malformations (Reefhuis aminoglycosides, propofol), (iii) not excreted into
et al. 2015). It his hereby important to stress the human milk (e.g., insulin, heparin), and finally
fact that these are associations, not necessary (iv) a drug considered safe during pregnancy,
reflecting causality. Secondly, the OR values since fetal exposure is generally longer and more
observed only result in a very limited increase in extensive. The Pregnancy and Lactation Labeling
the absolute risks. Final Rule should also provide the tool to generate
and collect more reliable information on maternal
drug use during breastfeeding. Aspects of opioids,
43.6 Conclusions benzodiazepines, and antiepileptics used during
fetal or through breastfeeding were discussed
In general, drugs are not thoroughly evaluated for first to illustrate the concepts of pregnancy-related
use during pregnancy and/or during breastfeeding. clinical pharmacology, followed by a focused dis-
Simple extrapolation from data in adults is hazard- cussion on neonatal abstinence syndrome.
ous, since pregnancy itself affects pharmacokinet-
ics (PK, concentration–time profile) with a
subsequent extensive interindividual variability in 43.7 Summary
drug response (PD, concentration–effect profile).
Despite the limited available knowledge, women Any decision on maternal pharmacotherapy
need pharmacotherapy for different medical rele- should be balanced, comparing maternal and
vant conditions during pregnancy as well as in the fetal/neonatal outcome to withholding any treat-
postpartum period, either or not pregnancy related. ment. This is because there is a relevant body of
However, any decision on pharmacotherapy should evidence that uncontrolled maternal conditions
always be balanced, comparing maternal and fetal/ also affect fetal outcome. The same holds true
neonatal outcome to the absence of any maternal for breastfeeding.
treatment. This is because there is also a relevant Drugs are not thoroughly evaluated for use
body of evidence showing that uncontrolled or during pregnancy or breastfeeding. Knowledge
suboptimal controlled maternal conditions in them- on safety of drugs exposure during fetal and neo-
selves also affect fetal well-being and outcome. The natal (breastfeeding) life is limited. Pregnancy
same rationale holds true for breastfeeding. Com- category classifications for drugs are currently
pound or class-specific information on its use dur- used, but have their limitations. Pregnancy expo-
ing pregnancy, the postpartum period, and sure registries to build knowledge have been
breastfeeding is evolving. This means that updated, implemented in the recently revised version of
reliable information should be easy accessible for the FDA labeling guidelines (Pregnancy and Lac-
caregivers and suggestions on websites have been tation Labeling Final Rule).
provided. Suggestive indicators of “likely safe during
Pregnancy category classifications are one breastfeeding” are (i) drugs commonly administered
approach, but classifications vary somewhat to infants, (ii) drugs that are not absorbed following
between different authorities, and these categories oral administration, (iii) not excreted into human
do not include risks related to drugs or their milk, and finally (iv) drug considered safe during
metabolites via breast milk. The concept of preg- pregnancy, since fetal exposure is generally longer
nancy exposure registries to build knowledge has and more extensive. Aspects of opioids, benzodiaz-
been integrated in the recently revised version of epines, and antiepileptics used during fetal life or via
the FDA labeling medication guidelines during breastfeeding have been discussed to illustrate the
pregnancy and lactation. In the clinical setting, concepts of pregnancy-related clinical pharmacol-
suggestive indicators of “likely safe during ogy, followed by a focused discussion on neonatal
breastfeeding” are (i) a drug commonly adminis- abstinence syndromes. We hereby aim to provide
tered to infants (e.g., antibiotics), (ii) a drug that is the practicing clinician with some guidance and
not absorbed following oral administration (e.g., sources of information.
690 K. Allegaert et al.
Acknowledgments Karel Allegaert is supported by the Genung V (2013) Psychopharmacology column: a review
Fund for Scientific Research, Flanders (fundamental clin- of psychotropic medication lactation risks for infants
ical investigatorship 1800214 N), and the research activi- during breastfeeding. J Child Adolesc Psychiatr Nurs
ties are further facilitated by the agency for innovation by 26:214–219
Science and Technology in Flanders (IWT) through the Hendrickson RG, McKeown NJ (2012) Is maternal opioid
SAFEPEDRUG project (IWT/SBO 130033). John van use hazardous to breast-fed infants? Clin Toxicol 50:1–14
den Anker is supported by NIH (K24DA027992, http://www.fda.gov/Drugs/DevelopmentApprovalProcess/
R01HD048689, U54HD071601) and the European Com- DevelopmentResources/Labeling/ucm093307.html.
mission (TINN [223614], TINN2 [260908]. NEUROSIS Accessed 8 July 2015
[223060]). Hudak ML, Tan RC, Committee on Drugs, Committee on
Fetus and Newborn, American Academy of Pediatrics
(2012) Neonatal drug withdrawal. Pediatrics 129:
e540–e560
References Ito S, Blajchman A, Stephenson M, Eliopoloulos C,
Koren G (1993) Prospective follow up of adverse reac-
Allegaert K, van den Anker JN (2015) Maternal tions in breast-fed infants exposed to maternal medica-
analgosedation and breastfeeding: guidance for the tion. Am J Obstet Gynecol 168:1393–1399
pediatrician. JPNIM 4, e04117 Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ
Allegaert K, Langhendries JP, van den Anker JN (2013) (2006) Pharmacogenetics of morphine poisoning in a
Educational paper: do we need neonatal clinical phar- breastfed neonate of a codeine-prescribed mother. Lan-
macologists? Eur J Pediatr 172(4):429–435 cet 368:704
Amant F, Han SN, Gziri MM et al (2015) Management of Lam J, Kelly L, Ciszkowski C et al (2012) Central nervous
cancer in pregnancy. Best Pract Res Clin Obstet system depression of neonates breastfed by mothers
Gynaecol 29:741–753 receiving oxycodone for postpartum analgesia.
Anderson PO, Pochop SL, Manoquerra AS (2003) J Pediatr 160:33.e2–37.e2
Adverse drug reactions in breastfed infants: less than Lefevere J, Allegaert K (2015) Question: is breastfeeding
imagined. Clin Pediatr (Phila) 42:325–340 useful in the management of neonatal abstinence syn-
Asti L, Magers JS, Keels E et al (2015) A quality improve- drome? Arch Dis Child 100:414–415
ment project to reduce length of stay for neonatal absti- MacMullen NJ, Dulski LA, Blobaum P (2014) Evidence-
nence syndrome. Pediatrics 135:e1494–e1500 based interventions for neonatal abstinence syndrome.
Bada HS, Sithisam T, Gibson J et al (2015) Morphine Pediatr Nurs 40:165–172
versus clonidine for neonatal abstinence syndrome. Marsot A, Brevaut-Malaty V, Vialet R (2014) Pharmacoki-
Pediatrics 135:e383–e391 netics and absolute bioavailability of phenobarbital in
Berlin CM Jr, van den Anker JN (2013) Safety during neonates and young infants, a population pharmacoki-
breastfeeding: drugs, foods, environmental chemicals, netic modelling approach. Fundam Clin Pharmacol 28:
and maternal infections. Semin Fetal Neonatal Med 465–471
18:13–18 Meador KJ, Baker GA, Browning N et al (2009) Cognitive
Briggs GG, Polifka JE, Wisner KL et al (2015) Should function at 3 years of age after fetal exposure to
pregnant women be included in phase IV clinical drug antiepileptic drugs. N Engl J Med 360:1597–1605
trials? Am J Obstet Gynecol 213:810–815 Meador KJ, Baker GA, Browning N et al (2014)
Cole AP, Hailey DM (1975) Diazepam and active metab- Breastfeeding in children of women taking
olite in breast milk and their transfer to the neonate. antiepileptic drugs. Cognitive outcomes at age
Arch Dis Child 50:741–742 6 years. JAMA Pediatr 168:729–736
Creanga AA, Sabel JC, Ko JY et al (2012) Maternal drug Ng CM, Dombrowsky E, Lin H et al (2015) Population
use and its effect on neonates: a population-based study pharmacokinetic model of sublingual buprenorphine in
in Washington State. Obstet Gynecol 119:924–933 neonatal abstinence syndrome. Pharmacotherapy 35(7):
De Wildt SN, Kearns GL, Hop WC et al (2002) Pharma- 670–680
cokinetics and metabolism of oral midazolam in pre- Nitsun M, Szokol JW, Saleh HJ et al (2006) Pharmacoki-
term infants. Br J Clin Pharmacol 53:390–392 netics of midazolam, propofol, and fentanyl transfer to
DeVane CL (2015) An epidemic of opioid prescriptions. human breast milk. Clin Pharmacol Ther 79:549–557
Pharmacotherapy 35:241–242 O’Donnell M, Nassar N, Leonard H et al (2009) Increasing
Dow K, Ordean A, Murphy-Oikonen J et al (2012) Neonatal prevalence of neonatal withdrawal syndrome: popula-
abstinence syndrome clinical practice guidelines for tion study of maternal factors and child protection
Ontario. J Popul Ther Clin Pharmacol 19:e488–e506 involvement. Pediatrics 123:e614–e621
Feghali MN, Mattison DR (2011) Clinical therapeutics in Ornoy A, Koren G (2014) Selective serotonin reuptake
pregnancy. J Biomed Biotechnol 2011:783528 inhibitors in human pregnancy: on the way to resolving
Gadot Y, Koren G (2015) The use of antidepressants in the controversy. Semin Fetal Neonatal Med 19:188–194
pregnancy: focus on maternal risks. J Obstet Gynaecol Patrick SW, Schumacher RE, Benneyworth BD et al (2012)
Can 37:56–63 Neonatal abstinence syndrome and associated health
43 Safety of Medications During Pregnancy and Breastfeeding: Infants of Drug-Addicted Mothers 691
care expenditures: United States, 2000–2009. JAMA novel combination of maternal genetic markers. Clin
307:1934–1940 Pharmacol Ther 91:692–699
Patrick SW, Davis MM, Lehman CU, Cooper WO (2015) Siu A, Robinson CA (2014) Neonatal abstinence syn-
Increasing incidence and geographic distribution of drome: essentials for the practitioner. J Pediatr
neonatal abstinence syndrome: United States 2009 to Pharmacol Ther 19:147–155
2012. J Perinatol 35:650–655 Thomas SH, Yates LM (2012) Prescribing without evi-
Pavek P, Ceckova M, Staud F (2009) Variation of drug dence – pregnancy. Br J Clin Pharmacol 74:691–697
kinetics in pregnancy. Curr Drug Metab 10:520–529 Turner SD, Gomes T, Camacho X et al (2015) Neonatal
Pressler RM, Mangum B (2013) Newly emerging therapies opioid withdrawal and antenatal opioid prescribing.
for neonatal seizures. Semin Fetal Neonatal Med CAMJ Open 13:E55–E61
18:216–223 Van den Anker JN (2012) Is it safe to use opioids for
Ramoz LL, Patel-Shori NM (2014) Recent changes in obstetric pain while breastfeeding? J Pediatr 160:4–6
pregnancy and lactation labeling: retirement of risk Veiby G, Engelsen BA, Gilhus NE (2013) Early child
categories. Pharmacotherapy 34:389–395 development and exposure to antiepileptic drugs pre-
Reefhuis J, Devine O, Friedman JM et al (2015) Specific natally and through breastfeeding: a prospective cohort
SSRIs and birth defects bayesian analysis to interpret study on children of women with epilepsy. JAMA
new data in the context of previous reports. BMJ 351: Neurol 70:1367–1374
h3190 Veiby G, Bjork M, Engelsen BA, Gilhus NE (2015) Epi-
Rivers CM, Olsen D, Nelson LS (2012) Breastfeeding and lepsy and recommendations for breastfeeding. Seizure
oxycodone. J Pediatr 161:174 28:57–65
Rowe H, Baker T, Hale TW (2013) Maternal medication, Verreault N, Da Costa D, Marchand A et al (2014) Rates
drug use, and breastfeeding. Pediatr Clin North Am and risk factors associated with depressive symptoms
60:275–294 during pregnancy and with postpartum onset. J
Saadeh RJ (2012) The Baby-Friendly Hospital Initiative Psychosom Obstet Gynaecol 35:84–91
20 years on: facts, progress, and the way forward. Wachman EM, Hayes MJ, Brown MS et al (2013) Asso-
J Hum Lact 28:272–275 ciation of OPRM1 and COMT single-nucleotide poly-
Sachs HC, Committee on Drugs (2013) The transfer of morphisms with hospital length of stay and treatment
drugs and therapeutics into human breast milk: an of neonatal abstinence syndrome. JAMA 309:
update on selected topics. Pediatrics 132:e796–e809 1821–1827
Salman S, Sy SK, Ilett KF, Page-Sharp M, Paech MJ Zaijcek A, Giacoia GP (2007) Obstetric clinical pharmacol-
(2011) Population pharmacokinetic modeling of ogy: coming of age. Clin Pharmacol Ther 81:481–482
tramadol and its O-desmethyl metabolite in plasma Zimmermann-Baer U, Nötzi U, Rentsch K, Bucher HU
and breast milk. Eur J Clin Pharmacol 67:899–908 (2010) Finnegan neonatal abstinence scoring system:
Sistonen J, Madadi P, Ros CJ et al (2012) Prediction of normal values for first 3 days and weeks 5–6 in
codeine toxicity in infants and their mothers using a non-addicted infants. Addiction 105:524–528
Developmental Pharmacology
and Therapeutics in Neonatal 44
Medicine
Karel Allegaert, Janko Samardzic, Milica Bajcetic, and
John N. van den Anker
Contents
44.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
44.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695
44.2.1 Knowledge on Neonatal Pharmacotherapy Is Lagging Behind . . . . . . . . . . . . . . . 695
44.2.2 Aiming at a Moving Target: Neonatal Physiology Affects Neonatal
Pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
44.3 Developmental Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
44.3.1 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
44.3.2 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
44.3.3 Drug Elimination: Drug Metabolism and Primary Renal Clearance . . . . . . . . . 699
44.4 Developmental Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700
44.5 Therapeutic Drug Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700
44.5.1 Limited Predictability: Is There a Poor Correlation Between Dose and
Concentration? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
44.5.2 Is There a Quantitative Relationship Between
Concentration and Effect? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
K. Allegaert (*) M. Bajcetic
Neonatal Intensive Care Unit, University Hospitals Institute of Pharmacology, Clinical Pharmacology and
Leuven, Leuven, Belgium Toxicology, Medical Faculty, University of Belgrade,
Belgrade, Serbia
Department of Development and Regeneration, KU
Leuven, Leuven, Belgium Clinical Pharmacology Unit, University Children’s
Hospital, Belgrade, Serbia
Intensive Care and Department of Pediatric Surgery,
e-mail: [email protected]
Erasmus MC – Sophia Children’s Hospital, Rotterdam,
The Netherlands J. N. van den Anker
e-mail: [email protected]; Division of Pediatric Clinical Pharmacology, Children’s
[email protected] National Health System, Washington, DC, USA
J. Samardzic Departments of Pediatrics, Integrative Systems Biology,
Department of Paediatric Pharmacology, Pharmacology and Physiology, George Washington
University Children’s Hospital Basel, Basel, University, School of Medicine and Health Sciences,
Switzerland Washington, DC, USA
Institute of Pharmacology, Clinical Pharmacology and Intensive Care and Department of Pediatric Surgery,
Toxicology, Medical Faculty, University of Belgrade, Erasmus MC – Sophia Children’s Hospital, Rotterdam,
Belgrade, Serbia The Netherlands
e-mail: [email protected] e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 693
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_193
694 K. Allegaert et al.
44.5.3 Is There a Narrow Therapeutic Index: Concentration and (Side) Effects? . . . 701
44.5.4 Significant Consequences of Therapeutic Failure Should Be Considered . . . . 702
44.5.5 Therapeutic Drug Monitoring Will Not Replace Common Clinical Sense . . . 702
44.6 Neonatal Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
44.7 Adverse Drug Reactions in Neonates: Assessment Needs a Tailored
Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 704
44.8 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706
Abstract estimate of the relationship between a drug
Knowledge about the safe and effective use of concentration at a specific site and time.
medicines in neonates has increased substantially • Pharmacodynamics estimates the relationship
but resulted in few label changes. Despite the between a drug concentration and (side) effects
extent of these drug exposures, newborns remain (“what the drug does to the body”).
the last therapeutic orphans. Drugs, initially • A specific issue in neonates is the unantici-
developed for use in adults, are reshaped and pated higher absorption of drugs administered
tailored to specific neonatal indications. How- transdermally due to proportionally higher
ever, neonatal pharmacotherapy not only mirrors body surface area and increased skin
adult pharmacotherapy but should be driven by permeability.
their own specific needs. This is because both • Differences in the distribution of a drug are
pharmacokinetics (absorption, distribution, influenced by body composition, systemic
metabolism, elimination, concentration-time) and regional blood flow, plasma protein bind-
and pharmacodynamics (concentration-effect) ing, as well as the variable permeability of
display extensive maturation in early infancy, membranes associated with disease states.
reflecting maturational physiology. We describe • The primary organ for drug metabolism is the
and illustrate the relevance of these maturational liver, but other organs (kidneys, intestines,
changes. We subsequently focus on specific lungs, skin, brain) can also display drug metab-
aspects related to therapeutic drug monitoring, olizing capacity.
the need for population tailored neonatal formu- • Differences in neonatal physiology can also
lations (including dose flexibility and excipients), affect pharmacodynamics and may result in
and the difficulties related to the recognition of differences in drug potency, efficacy, or
adverse drug reactions in neonates (how to rec- toxicity.
ognize a signal in the noise). • Therapeutic drug monitoring may help to
avoid side effects, but any measurement
needs to be integrated into the clinical setting
44.1 Salient Points of the individual patient.
• For some drug classes, clinical monitoring
• Critically ill newborns receive between 15 and (e.g., body temperature, blood pressure, anal-
20 (intravenous) drugs per day, most of them gesia, sedation) is superior to drug monitoring
either unlicensed or off-label. that is driven by a therapeutic approach.
• Clinical pharmacology aims to predict drug- • Neonates require tailored drug product devel-
specific (side) effects based on pharmacokinet- opment that utilizes both low and flexible dos-
ics and pharmacodynamics. ing to maintain dose accuracy.
• Pharmacokinetics (absorption, distribution, • Neonatal pharmacotherapy is a powerful tool
and elimination, through either metabolism to improve outcome, but there is an obvious
or primary renal elimination) provides an and urgent need to improve our practices
44 Developmental Pharmacology and Therapeutics in Neonatal Medicine 695
through tailored adverse drug reaction preven- adults, extrapolating from indications initially val-
tion and management. idated in adult medicine and based on the patho-
• Pharmacovigilance to improve adverse drug physiology proper to the adult patient (Fanos and
reaction prevention and management needs to Yurdakök 2010; Kearns et al. 2003; Allegaert and
be adapted to the requirements and character- van den Anker 2014a).
istics of neonates and infants. Critically ill newborns receive between 15 and
20 (intravenous) drugs per day, most of them either
unlicensed or off-label. Off-label drugs are defined
44.2 Introduction as being prescribed in a different manner to label
recommendations in terms of age group, dose,
44.2.1 Knowledge on Neonatal frequency, formulation, administration route, indi-
Pharmacotherapy Is cation, or contraindication for use in neonates
Lagging Behind (Dessi et al. 2010; Kieran et al. 2014; Laforgia
et al. 2014; Carvalho et al. 2012; Di Paolo
Drug therapy is a very powerful tool to improve et al. 2006; Riou et al. 2015). Figure 1 depicts
the medical outcome of neonates. Yet, caregivers the extent of the problem (at least 50% of the
still commonly prescribe drug formulations and drugs administered, but up to >90% in extreme
dosing regimens that initially were developed for preterm neonates), resulting in the fact that almost
unlicensed and off label drug exposure in neonates (% of drugs)
100
90
80
70
60
50
40
30
20
Estonia, Brazil, Italy, South Ireland, Italy, Switzerland, France, 2015
2011 2012 2013 2013 Cagliari 2010 2006
all cases term 32-36 weeks 28-31 weeks < 28 weeks
Fig. 1 Overview of recent publications on the extent of et al. 2010; Kieran et al. 2014; Laforgia et al. 2014;
unlicensed and off-label drug exposure in neonates in Carvalho et al. 2012; Di Paolo et al. 2006; Riou
different regions of Europe and beyond. This practice is et al. 2015; Lass et al. 2011)
even more present in the most immature neonates (Dessi
696 K. Allegaert et al.
all NICU patients are exposed to off-label drugs. 44.2.2 Aiming at a Moving Target:
Figure 1 hereby also shows that this is an interna- Neonatal Physiology Affects
tional problem that persists (Dessi et al. 2010; Kie- Neonatal Pharmacotherapy
ran et al. 2014; Laforgia et al. 2014; Carvalho
et al. 2012; Di Paolo et al. 2006; Riou Human growth and development consists of a
et al. 2015). In a survey, it was documented that sequence of physiologic events that link somatic
the top 10 of medications most commonly pre- growth with maturation since weight gain coexists
scribed in the NICU were ampicillin, gentamicin, but is not similar to maturation. Across pediatric
ferrous sulfate, multivitamins, cefotaxime, caf- life, organ size and function change as does body
feine citrate, furosemide, vancomycin, surfactant, composition, (patho)physiology, and ultimately
and metoclopramide (Clark et al. 2006). Interest- cellular function. When we consider these phys-
ingly, drug prescription patterns differ in patient iological changes and the subsequent variability
populations with raised mortality and higher dis- in physiological characteristics, we should be
ease severity (Carvalho et al. 2012; Clark aware that maturational changes in physiology
et al. 2006). Over time, significant changes in are most prominent in early infancy (Kearns
drug utilization patterns occur. To illustrate this, et al. 2003; Allegaert and van den Anker 2014a;
drug utilization patterns (1997–1998 to Smits et al. 2012a). If we focus on weight changes
2001–2004) in a single NICU documented an to further illustrate this, there is an initial decrease
increased utilization of antibiotics, central nervous (6–12%) in birth weight, with a subsequent
system, endocrinology, cardiovascular, and gastro- increase of 50% in the first 6 weeks of postnatal
intestinal drugs. Some individual drug changes life. Moreover, weight doubles in the first 3–4
include an increased use of vancomycin, cefepime, months to result in a threefold higher weight at
and caffeine, whereas a decreased use of morphine the end of infancy. Consequently, total energy
was seen (Du et al. 2006). requirements change dramatically as the sum of
Despite the extent of these drug exposures, energy expenditure and energy deposition for
newborns remain the last therapeutic orphans growth (Kearns et al. 2003; Allegaert and van
(Stiers and Ward 2014; Laughon et al. 2014). den Anker 2014a; Smits et al. 2012a). These
The federal US legislation and similar maturational physiological trends are further
European initiatives have resulted in a relevant affected by either treatment modalities (e.g.,
increase in pharmacological studies in children, whole body cooling, extracorporeal membrane
with a subsequent significant increase in label oxygenation (ECMO), or pharmacotherapy)
changes. Unfortunately, only a few included used or pathophysiological processes or
drug label changes for neonates. To further comorbidities (e.g., perinatal asphyxia, cardiopa-
illustrate this: there were 406 pediatric label thy, sepsis, renal failure, patent ductus arteriosus)
changes (Food and Drug Administration, involved. All these changes, both maturational
1997–2010), but only 23 drugs resulted in (e.g., age, weight) and pathophysiological, result
11 labeled indications (e.g., linezolid, in extensive variability within the first months of
rocuronium, remifentanil, sevoflurane, stavu- postnatal life. This results in the fact that neonatal
dine, nevirapine) for neonates. The absence of pharmacotherapy is as diverse as the neonates
label change was most commonly because of taken care of in our units (Kearns et al. 2003;
unproven efficacy, despite the fact that these Allegaert and van den Anker 2014a; Smits
compounds (e.g., acetaminophen, caspofungin, et al. 2012a).
valganciclovir) are relevant for neonates (Stiers The aim of administering a given compound is
and Ward 2014; Laughon et al. 2014). This may to reach effective treatment for a specific disease
largely reflect the difficulties to proof efficacy while avoiding disproportional side effects. Clin-
(e.g., heterogeneity in patients, variability in ical pharmacology aims to predict drug-specific
outcome variables, uncertainty on biomarkers) (side) effects based on pharmacokinetics and
in neonates. pharmacodynamics. Pharmacokinetics (PK,
44 Developmental Pharmacology and Therapeutics in Neonatal Medicine 697
Table 1 Examples of the developmental changes in neonatal pharmacokinetics and the clinical implications
Neonatal physiology
Physiological compared to children and
system adults Pharmacokinetic implications Clinical implications
Gastrointestinal Reduced and irregular Slower absorption of the drug Possible sustained action after
tract peristalsis followed by slow (e.g., delayed Tmax) oral administration of the drug
gastric emptying, in part
driven by the feeding regimen
(breast milk vs. formula)
Increased gastric pH (>4) in Faster absorption of acid- The possibility of altered
relation to infants labile and reduced absorption bioavailability
of weak-acid drugs
Muscle tissue Reduction in muscle Poor perfusion limits the Avoid intramuscular
perfusion, decreased muscle absorption, unpredictable administration of drugs
contractility pharmacokinetics
Skin Thinner stratum corneum, Increased rate and extent of Increased bioavailability and
increased skin perfusion, absorption of the drug through potential toxicity of drugs
increased water content, and the skin applied topically
higher body surface area-to- The need for a reduced
weight ratio amount of the drug applied to
the skin
Body Lower proportion of adipose Increased volume of Consider to adjust the
composition tissue (10%), decreased distribution for water-soluble loading/maintenance dosing
muscle mass, increased drugs and a reduced volume (mg/kg) to achieve
amount of total body water for drugs which are bound to therapeutic plasma
related to the body weight muscles and adipose tissue concentrations of the drug
(80%), an increased
proportion of the extracellular
(45%) compared to the
intracellular fluid
compartment
Plasma protein Reduced concentrations of Increased plasma For drugs with high binding
binding albumin and α-1 acid concentration of unbound affinity for proteins (e.g.,
glycoprotein, with a decreased drug, with an increased >70%), please consider an
drug protein-binding affinity volume of distribution and the alternative, or maintain the
possibility of occurrence of plasma drug concentrations to
toxic effects the lower limit of the
recommended therapeutic
range, interaction with, e.g.,
indirect bilirubin
Drug Immature isoforms of Isoenzyme-specific, reduced To increase dosing interval of
metabolism cytochrome P450 and phase II hepatic drug metabolism, with the drug and/or reduce the
enzymes with isoenzyme- increase in half-life maintenance dose
specific maturation
Renal drug Decreased level of glomerular Accumulation of drugs and/or To increase dosing interval of
excretion filtration rate and active the active metabolites that are the drug and/or reduce the
tubular secretion/absorption secreted via the kidneys with a maintenance dose
decrease in plasma clearance
absorption, distribution, and elimination, through The potential impact of developmental phar-
either metabolism or primary renal elimination, macokinetics on neonatal pharmacotherapy is
ADME) hereby estimate the relationship between illustrated in Table 1. Pharmacodynamics
a drug concentration at a specific site (e.g., (PD) estimates the relationship between a drug
plasma, cerebrospinal fluid) and time (“what the concentration and (side) effects (“what the drug
body does to the drug”). does to the body”). We will first discuss aspects of
698 K. Allegaert et al.
developmental pharmacokinetics and pharmaco- 44.3.2 Distribution
dynamics in neonates. This will provide the ratio-
nale for a focused neonatal pharmacotherapy and The differences in distribution of the drug are
product development, as illustrated by the tailored influenced by body composition, systemic and
use of therapeutic drug monitoring (4), specific regional blood flow, plasma protein binding, as
issues on formulations (5), and pharmacov- well as permeability of membranes, associated
igilance (6) in neonates. with disease states (Kearns et al. 2003; Allegaert
and van den Anker 2014a; Smits et al. 2012a). The
body composition in early infancy changes con-
44.3 Developmental tinuously and rapidly, resulting in an
Pharmacokinetics age-dependent proportion of total body water
and fat. The total body water content is markedly
44.3.1 Absorption higher in neonates (80–90% of the body weight)
compared to the end of infancy (60–65%) or
Drug absorption is affected by age, formulation, adults (55–60%). To further illustrate this, hydro-
dose, or route of administration as well as by food philic drugs like aminoglycosides have a larger
and other drugs that interact with the active com- volume of distribution in neonates that can be
pound (Kearns et al. 2003; Allegaert and van den explained by a larger extracellular volume com-
Anker 2014a; Smits et al. 2012a; Choonara 1994). partment (40–45% of the body weight) compared
For example, in neonates intragastric pH is ele- to 25–30% at the end of infancy and to 20% in
vated (>4). This may increase the bioavailability adults (Kearns et al. 2003; Allegaert and van den
of acid-labile compounds (penicillin G) and Anker 2014a; Smits et al. 2012a). Thus, the peak
decrease the bioavailability of weak acids (pheno- plasma concentration of aminoglycosides will not
barbital) when given orally (Huang and High only be delayed but also blunted compared to
1953). Additionally, gastric emptying in neonates older children or adults. Protein-binding capacity
is delayed, which means that also duodenal is another covariate of the distribution volume.
absorption of drugs (e.g., paracetamol) is slower The amount and type of circulating plasma pro-
in neonates. Gastric emptying in part also depends teins does not only influence drug disposition but
on the nutrition with a faster emptying for breast also drug action, since only the unbound drug can
milk or extensive hydrolysate formulations be distributed throughout the body and have a
(Staelens et al. 2008). There is only limited pharmacological effect (Roberts et al. 2013). Clin-
knowledge on the ontogeny of intestinal trans- ical implications of alterations in drug protein
porters and its covariates, but some data suggest binding are most relevant for drugs which are
that this is at least in part driven by the intestinal highly protein bound and have a narrow therapeu-
microflora (Mooij et al. 2012). Characteristics that tic index (Roberts et al. 2013). To illustrate this,
affect variability in absorption, resulting in differences in protein-binding characteristics and
unpredictable pharmacokinetics of drugs admin- their covariates within neonates as well as com-
istered intramuscularly, include decreased muscle pared to other populations have recently been
mass, decreased contractility, and reduced overall described for cefazolin (Smits et al. 2012b)
muscular perfusion (Kearns et al. 2003). A spe- and differences in protein binding explain the
cific issue in neonates is the unanticipated higher higher clearance of micafungin in neonates
absorption of drugs administered transdermally (Yanni et al. 2011). Specifically in neonates,
due to proportionally higher body surface area unconjugated bilirubin, and free fatty acid con-
and a more permeable skin. These differences centrations will also display relevant competition
are even more pronounced in premature neonates for albumin-binding places (Kearns et al. 2003;
(Kearns et al. 2003; Choonara 1994). Smits et al. 2012b).
44 Developmental Pharmacology and Therapeutics in Neonatal Medicine 699
44.3.3 Drug Elimination: Drug 1A4, CYP3A7) is expressed at their highest
Metabolism and Primary level in fetal life and subsequent decrease and
Renal Clearance disappear over the first 2 years of life. The sec-
ond group contains enzymes (e.g., CYP2C19,
To eliminate a given compound from the body CYP3A5, SULT1A1) that display a modest
through bodily fluids such a urine or bile, either increase after birth and become more active
drug metabolism, primary renal elimination clear- after neonatal life or infancy. Finally, the last
ance, or both are involved. Both processes display group (e.g., CYP2D6, CYP3A4, CYP2C9,
ontogeny, i.e., age-driven maturation (Hines CYP1A2) already has moderate ontogeny in
2013; de Wildt 2011). However, the maturation the second half of pregnancy, with a subsequent
pattern of the individual hepatic or renal clearance more pronounced increase in phenotypic activ-
processes differs to a large extent. This means that ity during early life (Kearns et al. 2003; Hines
integration of all ontogeny-related knowledge of 2013; de Wildt 2011).
the different elimination routes is important to Most drugs or their metabolites are excreted
understand compound-specific, phenotypic from the body by the kidney. Again, renal elimi-
in vivo observations in neonates (Hines 2013; de nation capacity is influenced by physiological
Wildt 2011; Allegaert et al. 2014). changes depending on age, e.g., the glomerular
The primary organ for drug metabolism is the filtration rate (GFR) in full term neonates is 35%
liver, but also other organs (kidneys, intestines, of the adult values (Smits et al. 2012a; Schreuder
lungs, skin, brain) can display drug metabolizing et al. 2014). Term neonates have a rapid increase
capacity. In general, drug metabolism is low in in GFR during the first 2 weeks of life and reach
neonates and phenotypic activity of drug metabo- adult values by the end of the first year of life.
lizing enzymes is considered as a main contributor Premature infants have similar maturational
to the PK differences between neonates, children, trends, but with a slower initial GFR rise because
and adults. Variation in phenotypic metabolic clear- nephrogenesis is not completed before near term
ance is based on constitutional, environmental, and age, at about 34–35 weeks of gestation. Both
genetic factors (Kearns et al. 2003; Hines 2013; de active tubular secretion and reabsorption are also
Wildt 2011; Allegaert et al. 2014). In early infancy, immature at birth (20–30% of adult reference
this is mainly a reflection of the ontogeny, but other values) only to reach adult values in the second
covariates may also become relevant. However, this part of infancy or beyond (Smits et al. 2012a;
does not exclude extensive interindividual variabil- Schreuder et al. 2014).
ity within the neonatal population (Kearns In clinical care, a more integrated approach is
et al. 2003; Allegaert and van den Anker 2014a). needed when considering these different elimina-
Drug metabolizing enzymes are crucial in drug tion processes: there is no isolated neonatal liver
biotransformation and metabolic elimination. or neonatal kidney, but only newborns in need for
Consequently, drug metabolizing isoenzyme- improved pharmacotherapy. The maturational
specific ontogeny will affect neonatal drug clear- pattern of the individual renal or hepatic elimina-
ance. Profound maturational changes in drug tion processes may be different. This necessitates
metabolizing enzyme activity occur during devel- the integration of the ontogeny-related knowledge
opment. These changes have impact on drug of the different elimination routes (metabolic
clearance, drug effect, and the risk of adverse vs. elimination clearance) involved to predict
events in the neonate. The available evidence compound-specific, concentration-time profiles
suggests that the individual hepatic drug metabo- in neonates: accumulation of a given metabolite
lizing isoenzymes can be categorized into one of may be due to less effective (renal) elimination
three classes based on developmental trajecto- capacity compared to hepatic metabolic clearance
ries. A first group of enzymes (e.g., SULT1A3/ (Allegaert et al. 2014).
700 K. Allegaert et al.
44.4 Developmental especially on PD in the neonatal period and the
Pharmacodynamics subsequent clinical implications, is needed.
Differences in neonatal physiology can also affect
PD and may result in differences in drug potency, 44.5 Therapeutic Drug Monitoring
efficacy, or toxicity. However, most of the vari-
ability observed relates to differences in PK and Therapeutic drug monitoring (TDM) aims to inte-
maturational PD can only be considered once the grate drug measurement as an adjunct to clinical
PK aspects have been taken into account. decision-making, with the aim to improve thera-
Age-related developmental changes in the func- peutic responses and/or decrease adverse events.
tionality and expression of receptors and differ- In essence, it is common practice to collect plasma
ences in disease status may alter the samples at predefined time points and decrease the
pharmacological response to drugs (Mulla 2010; toxicity or efficacy by application of pharmacoki-
Stephenson 2005). For example, inotropic agents netics and pharmacodynamics (Van den Anker
in neonatal myocardium act in a more limited 2014; Young 2012).
fashion than those of the child or adult. This is One of the issues that really matter in the clin-
due to a lower ratio of active myofilaments to ical decision process is the relevance of “steady
noncontractile elements, greater stiffness of the state.” Especially in the absence of the use of a
ventricle, underdeveloped cardiac sympathetic loading dose, it takes time before the equilibrium
nerves, and higher cardiac output per unit surface is reached after a drug was started. This is illus-
area (Bajcetic et al. 2014). Furthermore, immatu- trated in Fig. 2, based on the estimated
rity can result in an altered risk of drug toxicity, concentration-time profile for a newborn, treated
even a decreased risk (McIntyre and Choonara twice daily with 10 mg/kg vancomycin intrave-
2004). To illustrate this, neonates appear to be nously. Figure 2 nicely shows that accumulation
less susceptible to renal toxicity induced by takes time, resulting in different trough concen-
aminoglycosides compared to children and adults. trations when sampled before the 3rd, 5th, or 7th
A reduced intracellular accumulation of these administration (arrows a, b, and c) because it takes
compounds in the tubular epithelial cells of the time to reach steady state.
renal cortex seems to be the underlying mecha- Current observations suggest that the greatest
nism of this PD characteristic. More research, benefit of TDM within the neonatal population
Fig. 2 The estimated
concentration-time profile
for a newborn, treated twice 20
daily with 10 mg/kg
vancomycin intravenously.
Accumulation takes time,
resulting in different trough
concentrations when
sampled just before the 3rd,
5th, or 7th administration mg/I 10
(arrows a, b, and c)
c
b
time (hours)
44 Developmental Pharmacology and Therapeutics in Neonatal Medicine 701
Table 2 The general rules to assess the usefulness of of aminoglycoside clearance is less than 65%
therapeutic drug monitoring when these covariates are considered (De Cock
It is reasonable to assume a quantitative relationship et al. 2012). Taking this indicator of appropriate-
between the concentration (e.g., plasma) and a clinical ness into account, TDM in early neonatal life may
(side)effect
be indicated. The same holds true for, e.g., vanco-
There is only a poor correlation between the dose
administered and the concentration reached (limited mycin and for phenobarbital (Van den Anker
predictability) 2014; Young 2012).
The pharmacokinetics are known (a TDM result can be
used to adapt the treatment)
The analytical technique is sufficiently specific, precise, 44.5.2 Is There a Quantitative
and accurate in the specific population considered (e.g.,
neonatal plasma)
Relationship Between
The therapeutic index of the given compound is narrow. Concentration and Effect?
There are significant consequences associated with either
overexposure (e.g., toxicity) or underexposure (e.g., For a relevant number of drug classes, clinical
therapeutic failure) monitoring (e.g., body temperature, blood pres-
sure, analgesia, sedation) is superior to any
very likely is mainly in targeted or special sub- TDM-driven approach. Bedside up or down titra-
populations: those with severely decompensated tion can be driven by the pharmacodynamic out-
renal function, those at the extremes of age, those come variables aimed for. Obviously, the
using immunosuppressive, specific antineoplas- introduction of more sophisticated tools (e.g.,
tic, or anticonvulsant drugs, and those with antic- aEEG vs. clinical seizures in neonates) may fur-
ipated drug-drug interactions. The general clinical ther support such clinical monitoring or may fur-
rules before TDM is considered to be useful are ther improve the concentration (TDM)/effect
provided in Table 2. We aim to discuss how these relation and clinical titration (Young 2012). In
clinical rules apply to neonates, followed by some contrast, it is much more difficult to evaluate the
additional comments on how to integrate TDM concentration-effect relation for antibiotics. Epi-
with other clinical characteristics (Van den Anker demiologic data on incidence of infections in neo-
2014; Young 2012). nates, the immaturity of the immune system, and
the occult clinical symptoms of infection explain
the frequent (over)use of antibiotics, including
44.5.1 Limited Predictability: Is There aminoglycosides or vancomycin in neonates
a Poor Correlation Between (Young 2012; De Cock et al. 2012; Van den
Dose and Concentration? Anker 2011). Infectious diseases or septicemia
are frequent causes of morbidity and mortality in
The interindividual variability of drug disposition preterm and term neonates.
in neonates is – in general – pronounced: despite
their small size, there is extensive variability
in clearance and concentration-time profiles 44.5.3 Is There a Narrow Therapeutic
(Allegaert and van den Anker 2014a). To illustrate Index: Concentration and (Side)
this, aminoglycosides are almost exclusively Effects?
eliminated by the renal route. Birth weight, post-
natal age, but also co-medication (ibuprofen, Besides effects, a drug may also cause side
indomethacin) and peripartal asphyxia are the effects. Such side effects may relate to idiosyn-
most relevant covariates of clearance, presumably crasy in individual cases (e.g., genetic predispo-
because it predicts the time course of development sition, allergy, or pseudo-allergy). TDM may be
of the glomerular filtration rate. However, helpful to avoid such side effects, similar to the
interindividual variability in aminoglycoside use of the oxygen saturation monitor to avoid
clearance is high. In early life, the predictability hyperoxia, or the measurement of thyroid
702 K. Allegaert et al.
function (e.g., amiodarone), liver enzymes (e.g., creatinine) or the drug itself (e.g., vancomycin
valproate), or renal function (e.g., ibuprofen). measurements) may differ. Finally, we should
The extended interval dosing approach for not forget that pharmacotherapy in newborn
aminoglycosides has resulted in higher peak infants remains shooting at a moving target.
and lower trough levels in neonates (Smits Using the indicators of appropriateness for TDM
et al. 2012a; Schreuder et al. 2014; De Cock (Table 2), we conclude that neonates are in a
et al. 2012). This practice is supported by data rapidly evolving pharmacokinetic state. In addi-
on reduced nephrotoxicity in children and adults, tion to these maturational processes, most drug
but there is only indirect evidence for this pharmacokinetic studies in neonates show wide
approach in neonates (Rao et al. 2011). Raised interindividual variability despite similar ages.
phenobarbital levels are associated with Taking this into account, and despite the relative
oversedation and miosis, and raised diphantoine lack of robust outcome data, TDM is a necessary
levels may cause arrhythmia (Young 2012; tool in the neonatal intensive care unit, when
Boylan et al. 2013). combined with the clinician input of a dedicated
pharmacist or pharmacologist (Van den Anker
2014; Young 2012).
44.5.4 Significant Consequences of
Therapeutic Failure Should Be
Considered 44.6 Neonatal Formulations
Morbidity and mortality in extreme preterm neo- The key characteristic of neonatal pharmacother-
nates is extensive, relevant, and common. Con- apy is its extensive variability, related to matura-
sequently, in the clinical setting, it is difficult to tional and non-maturational covariates. This
disentangle therapeutic failure due to immaturity, means that the neonatal community needs to
comorbidity, or inappropriate choice of antibi- have access to drug formulations tailored to the
otics (e.g., resistant pathogen), compared to characteristics of neonates (Turner 2011). How-
“just” insufficient dosing. Similar, prolonged ever, this does not mean that the basics of drug
low concentrations of antibiotics may also formulation should be neglected such as data on
induce bacterial resistance or fungal colonization product stability, palatability, or compatibility
(Van den Anker 2014; Young 2012). Although (Tuleu and Breitkreutz 2013). At present, neo-
clinicians may feel confident to use international nates are still commonly treated with drugs that
“reference” handbooks for drug dosing, we have not been designed, developed, nor evalu-
would like to stress that there is extensive and ated for use in them. As a consequence, this
unexplained variability in dosing regimens exposes neonates to the likely risks related to
between these textbooks (De Cock et al. 2012; suboptimal (too low, too high, or too variable)
Van den Anker 2011). dosing and side effects from potentially toxic
ingredients, including excipients (Turner 2011;
Tuleu and Breitkreutz 2013; Fabiano et al. 2011;
44.5.5 Therapeutic Drug Monitoring Turner et al. 2014). We have illustrated the
Will Not Replace Common impact of dosing accuracy for two different
Clinical Sense amikacin vials (50 or 250 mg/ml) in comparing
the extent of variability. The introduction of a
Even if TDM is implemented, any measurement pediatric amikacin vial resulted in a reduction in
needs to be integrated in the clinical setting of the clearance variability, reflecting improved dosing
individual patient. Some relevant issues relate to, precision (Allegaert et al. 2006). The issue of
e.g., the time of sampling: is the patient already at highly concentrated formulations is further illus-
steady state or not yet? Moreover, the specific trated in Table 3. This table is based on currently
methods used to measure either biomarkers (e.g., available vials in the Leuven NICU and reflects
44 Developmental Pharmacology and Therapeutics in Neonatal Medicine 703
Table 3 Illustrations of some highly concentrated formu- et al. 2011; Turner et al. 2013). In addition to the
lations for intravenous use, compared to the doses applied active compounds, drug formulations also com-
in neonates. As a consequence, consecutive dilution, dos-
ing inaccuracy, or tenfold errors are more likely to occur monly contain excipients such as, e.g., cosolvents,
preservatives, sweeteners, or colorants. Examples
Midazolam 15 mg/3 ml 0.05–0.1 mg/kg
of excipients are lactose, aspartame, xylitol, pro-
Paracetamol/ 500 mg/50 ml 10 mg/kg
acetaminophen pylene glycol, polyethylene glycol, benzyl alcohol,
Propofol 200 mg/20 ml 1–3 mg/kg ethanol, sorbitol, or mannitol. Historical observa-
Phenobarbital 200 mg/1 ml 5 mg/kg tions but also more recent case series repeatedly
Fentanyl 100 μgr/2 ml 1–3 μgr/kg confronted clinicians with unanticipated, but some-
Insulin 300 E/3 ml 0.1–1 E/kg/h times predictable, severe side effects of neonatal
Enoxaparin 40 mg/0.4 ml 1 mg/kg drug formulations merely because of its excipients,
Ranitidine 50 mg/2 ml 0.5–1 mg/kg e.g., benzyl alcohol, propylene glycol, or ethanol
Dopamine 50 mg/1.25 ml 4–16 μg/kg/min (Fabiano et al. 2011; Turner et al. 2013, 2014).
Heparin 5,000 IU/ml 10–30 IU/kg/h The use of potentially toxic excipients in med-
icines given to neonates is not rare, as they are
present in many commonly used drug products.
the necessity of sequential dilution and subse- At least, recent observational studies confirmed
quent reduced dosing precision (Nunn the almost uniform exposure to relevant excipi-
et al. 2013). In essence, neonates are in need of ents (e.g., propylene glycol, ethanol, benzyl alco-
tailored drug product development that considers hol) in neonates (Fabiano et al. 2011; Turner
both low and flexible dosing to maintain dose et al. 2013, 2014). The available knowledge on
accuracy. the safety or toxicity of excipients is limited and
At present, marketed formulations commonly difficult to retrieve, but there are initiatives (e.g.,
do not meet yet the specific requirements for neo- Safety and Toxicity of Excipients for Pediatrics
nates (formulation, dose), and it is unlikely that [STEP] database initiative) to improve the present
commercially manufactured, ready-to-administer situation (Salunke et al. 2013). In addition,
neonatal preparations will be available in the near population-focused studies on aspects of clinical
future for all compounds prescribed. As a conse- pharmacology of excipients in neonates are
quence, compounding (“extemporaneous prepa- conducted. The propylene glycol research project
ration”) practices will remain common practice and the European Study for Neonatal Excipient
in the near future for neonatal therapeutics Exposure (ESNEE) initiative illustrate at least the
(Nunn et al. 2013). Until tailored formulations feasibility to collect such information (methyl-
will make it to the market, compounding practices and propyl-parabens, propylene glycol) (Salunke
for drug formulations in neonates should be eval- et al. 2013; De Cock et al. 2013; Mulla
uated to guarantee correct dosing and product et al. 2015).
stability and safety and to support pharmacists in In order to improve formulations for neonates
their clinical practice. To illustrate the need to and young children, the World Health Organization
validate such compounding practices, we refer to has launched a global campaign: “Make medicines
the results of an evaluation of a pediatric oral child size” (WHO, UNICEF). Furthermore,
formulation with a low amount of hydrochloro- the European Paediatric Formulation Initiative
thiazide, also considered to be suited for use in (EuPFI) was founded with the aim of raising aware-
neonates: only one of five hydrochlorothiazide ness of pediatric formulation issues (European
suspensions guaranteed the correct dosing and Union Pediatric Formulations Initiative). Besides
stability after 3 weeks of storage in predefined, knowledge gathering on excipients (Salunke
optimal condition (Santovena et al. 2012). et al. 2013), novel formulations for neonates were
During the development of such formulations developed, like fast-dissolving drug formulations,
tailored for neonates, there is also a need for including orodispersible minitablets (ODMT) and
more guidance on excipient exposure (Fabiano oral thin (buccal wafers) and multiparticulate
704 K. Allegaert et al.
dosage forms that facilitate the administration of the underlying pathogenesis, since this should
low doses (Tuleu and Breitkreutz 2013). facilitate secondary prevention (cfr lower).
Specific new formulations for neonates are Neonatal pharmacotherapy is a powerful
orodispersible minitablets (ODMTs). Such tablets tool to improve outcome, but there is an obvi-
disintegrate immediately upon contact with water ous and urgent need to improve our practices
or saliva. This permits convenient oral adminis- through tailored adverse drug reaction (ADR)
tration, as well as preparation of drug solutions prevention and management. Besides the lack
immediately before administration. While of labeling (e.g., eminence-based practices),
minitablets retain some potential to stick to the inappropriate formulations (e.g., highly con-
esophagus, this risk is completely eliminated with centrated, excipients), (poly)pharmacy (e.g.,
ODMTs because of their rapid disintegration upon maturational drug-drug interactions), immature
contact with water or saliva (Stoltenberg and organ function (how to discriminate between
Breitkreutz 2011). At present, an ODMT formu- normal maturational function and toxicity, e.
lation of enalapril as well as hydrochlorothiazide g., renal), and multiple illnesses further
is evaluated (Stoltenberg and Breitkreutz 2011; increase the risks for ADRs in neonates.
FP7 LENA). Pharmacovigilance to improve ADR preven-
tion and management needs to be adapted to
the needs and characteristics of neonates and
infants. Such a strategy should be based on
44.7 Adverse Drug Reactions prevention through drug prescription and
in Neonates: Assessment administration error prevention (e.g., formula-
Needs a Tailored Approach tion, bedside manipulation, access) strategies,
detection through laboratory or clinical outlier
Because of the common practice to prescribe data signaling (e.g., reference laboratory
unlicensed and off-label drugs in neonates, a values, overall high morbidity), and subsequent
reasonable and relevant description for an assessment (Allegaert and van den Anker
adverse drug reaction (ADR) may be “the 2014b; Castro-Pastrana and Carleton 2011;
unintended, but harmful effect resulting from Lazou et al. 2013; Choonara 2013).
the administration of medication(s) intended Assessment is of utmost importance. This is
for diagnostic or therapeutic reasons because – once a signal has been detected – dif-
(irrespective of the dose).” Such a definition ferentiation of “true” ADRs from confounding
also covers medication errors (e.g., wrong events associated with immaturity, organ dysfunc-
dose, wrong route, or wrong patient) (Allegaert tion, or underlying diseases remains difficult.
and van den Anker 2014b; Fabiano et al. 2012; Because of these confounding events, commonly
Ligi et al. 2008). Obviously, the field of adverse applied ADR algorithm scoring systems do not
drug reactions and medication errors also has a sufficiently reliably document causality in neo-
link with the growing and broader field of nates (Rieder 2012). Moreover, none of these
research on iatrogenesis, i.e., any adverse con- algorithms have been validated in infants.
dition occurring as a result of a diagnostic pro- Because of this and using a stepwise approach, a
cedure or treatment (Kugelman et al. 2008). tailored algorithm was developed and subse-
History indeed repeatedly provided evidence quently validated. This new algorithm is based
that newborns and infants are more prone to on 13 questions and turned out to be more reliable
specific adverse reactions to drugs, although when compared to the classic Naranjo algorithm
some of these adverse reactions may have been (Du et al. 2012). Finally, improved understanding
anticipated based on the available knowledge on of the developmental toxicology (Table 4)
developmental pharmacology and toxicology. involved should further facilitate the avoidance
Table 4 provides some well-known illustrations of reoccurrence and the development of tailored
on neonatal adverse drug reactions, including guidelines (Dabliz and Levine 2012).
44 Developmental Pharmacology and Therapeutics in Neonatal Medicine 705
Table 4 Illustrative serious adverse drug reactions in neonates, with underlying pathogenesis to facilitate secondary
prevention
Compound/
formulation Clinical syndrome Developmental pharmacology/toxicology
Sulfisoxazole “Kernicterus” Highly albumin-bound antibiotic, competitive with endogenous
compounds, including bilirubin. This results in higher free bilirubin
concentrations and subsequent kernicterus. Similar effects can be
anticipated for other high protein-bound compounds, e.g., ceftriaxone
Chloramphenicol “Gray baby Impaired glucuronidation, capacity, results in chloramphenicol
syndrome” accumulation and subsequent mitochondrial dysfunction, circulatory
collapse, and death. Similar effects can be anticipated for other
glucuronidation dependent drug metabolism compounds, e.g.,
propofol
Lopinavir/ritonavir “Alcohol Kaletra syrup contains both ethanol and propylene glycol. Impaired
syrup accumulation” metabolic clearance results in accumulation, and subsequent
hyperosmolality, lactic acidosis, renal toxicity, central nervous system
impairment, cardiac arrhythmia, hemolysis, and collapse. Explained
by ethanol/propylene glycol competition for hepatic metabolic
elimination
Ceftriaxone + calcium “Cardiovascular Simultaneous administration of calcium-containing infusions and
collapse” ceftriaxone results in intravascular precipitate, as observed during
autopsy. May be similar for other “mixtures” with calcium-containing
formulations
Topical iodide “Hypothyroidism” More pronounced skin permeability and higher body surface area
application result in a more effective absorption of iodine with subsequent
suppression of thyroid function. Similar for other topical compounds,
e.g., steroids or hexachlorophene
and improved understanding. To convert the cur-
44.8 Conclusions
rent situation into better neonatal pharmacother-
apy, collaborative efforts between clinical
Pharmacotherapy is a potential powerful tool to
researchers, sponsors, patient representatives, reg-
improve outcome in neonates, but there is still a
ulatory authorities, and society are needed. Clini-
huge lack of appropriate labeling of drugs used in
cians should be encouraged to consult and to
the neonatal period. The knowledge on pharma-
assess the available evidence and to contribute to
cotherapy in infants is lagging behind, with often
more robust knowledge through collaborative net-
only poor and limited evidence in support of dos-
works that facilitate clinical research by covering
ing regimens: “the last therapeutic orphan.”
aspects related to dosing, efficacy, safety, and
Aspects to improve neonatal pharmacotherapy
formulations.
were discussed and these aspects interrelate with
each other (Fig. 3).
Acknowledgments Karel Allegaert is supported by the
Neonatal pharmacology displays extensive Fund for Scientific Research, Flanders (fundamental clin-
variability because of rapidly evolving physiol- ical investigatorship 1800214 N), and the research activi-
ogy: variability is the essence of neonatal phar- ties are further facilitated by the agency for innovation by
macology. Related to this, the use of therapeutic Science and Technology in Flanders (IWT) through the
SAFEPEDRUG project (IWT/SBO 130033). Janko
drug monitoring (TDM) and the need for formu- Samardzic is supported by ERAWEB II scholarship for
lations tailored to the characteristics of newborns postdoctoral program at the KU Leuven, Belgium
were discussed. Finally, pharmacovigilance also (2014–2015). Milica Bajcetic is supported by the Ministry
of Education, Science and Technological Development of
needs to be tailored to the characteristics of this
the Republic of Serbia (project No 173014) and the
population and relates to preventive strategies, European Commission (LENA, 602295). John van den
signal detection, as well as assessment of causality Anker is supported by NIH (K24DA027992,
706 K. Allegaert et al.
Fig. 3 Improvements in
neonatal pharmacotherapy
will be driven by improved
tal
knowledge on neona etics safe
developmental a c o k in ty
pharm odynamics adve
rse d
pharmacokinetics and m a c
phar reac ru
pharmacodynamics, tions g
tailored drug development,
individualized therapeutic
drug monitoring, and more
effective recognition of
adverse drug events to neonatal
improve drug safety pharmacotherapy
neonatal
formulations therapeutic drug
monitoring
R01HD048689, U54HD071601) and the European Com- Choonara I (2013) Educational paper: aspects of clinical
mission (TINN [223614], TINN2 [260908], NEUROSIS pharmacology in children – pharmacovigilance and
[223060]). safety. Eur J Pediatr 172:577–580
Clark RH, Bloom BT, Spitzer AR, Gerstmann DR (2006)
Reported medication use in the neonatal intensive care
unit: data from a large national data set. Pediatrics
References 117:1979–1987
Dabliz R, Levine S (2012) Medication safety in neonates.
Allegaert K, van den Anker JN (2014a) Clinical pharma- Am J Perinatol 29:49–56
cology in neonates: small size, huge variability. Neo- De Cock R, Allegaert K, Schreuder MF et al (2012) Mat-
natology 105:344–349 uration of the glomerular filtration rate in neonates, as
Allegaert K, van den Anker JN (2014b) Adverse drug reflected by amikacin clearance. Clin Pharmacokinet
reactions in neonates and infants: a population tailored 51:105–117
approach is needed. Br J Clin Pharmacol. https://doi. De Cock RF, Knibbe CA, Kulo A et al (2013) Developmen-
org/10.1111/bcp.12430 tal pharmacokinetics of propylene glycol in preterm and
Allegaert K, Anderson BJ, Vrancken M et al (2006) Impact term neonates. Br J Clin Pharmacol 75:162–171
of a paediatric vial on the magnitude of systematic de Wildt SN (2011) Profound changes in drug metabolism
medication errors in preterm neonates: amikacin as an enzymes and possible effects on drug therapy in neo-
example. Paediatr Perinat Drug Ther 7:59–63 nates and children. Expert Opin Drug Metab Toxicol
Allegaert K, van de Velde M, van den Anker J (2014) Neo- 7:935–948
natal clinical pharmacology. Paediatr Anaesth 24:30–38 Dessi A, Salemi C, Fanos V, Cuzzolin L (2010) Drug treat-
Bajcetic M, Uzelac TV, Jovanovic I (2014) Heart failure ments in a neonatal setting: focus on the off-label use in
pharmacotherapy: differences between adult and pae- the first month of life. Pharm World Sci 32:120–124
diatric patients. Curr Med Chem 21:3108–3120 Di Paolo ER, Stoetter H, Cotting J et al (2006) Unlicensed
Boylan GB, Stevenson NJ, Vanhatalo S (2013) Monitoring and off-label drug use in a Swiss paediatric university
neonatal seizures. Semin Fetal Neonatal Med hospital. Swiss Med Wkly 136:218–222
18:202–208 Du W, Warrier I, Tutag Lehr V et al (2006) Changing
Carvalho CG, Ribeiro MR, Bonilha MM et al (2012) Use patterns of drug utilization in a neonatal intensive care
of off-label and unlicensed drugs in the neonatal inten- population. Am J Perinatol 23:279–285
sive care unit and its association with severity scores. J Du W, Lehr VT, Leih-Lai M et al (2012) An algorithm to
Pediatr (Rio J) 88:465–470 detect adverse drug reactions in the neonatal intensive
Castro-Pastrana LI, Carleton BC (2011) Improving pediat- care unit: a new approach. J Clin Pharmacol 53:87–95
ric drug safety: need for more efficient clinical transla- European Union Pediatric Formulations Initiative. http://
tion of pharmacovigilance knowledge. J Popul Ther www.eupfi.org/. Accessed 19 May 2015
Clin Pharmacol 18:e76–e88 Fabiano V, Mameli C, Zuccotti GV (2011) Paediatric phar-
Choonara I (1994) Percutaneous drug absorption and macology: remember the excipients. Pharmacol Res
administration. Arch Dis Child 71:F73–F74 63:362–365
44 Developmental Pharmacology and Therapeutics in Neonatal Medicine 707
Fabiano V, Mameli C, Zuccotti GV (2012) Adverse drug Riou S, Plaisant F, Maucort Boulch D et al (2015)
reactions in newborns, infants and toddlers: pediatric Unlicensed and off-label drug use: a prospective study
pharmacovigilance between present and future. Expert in French NICU. Acta Paediatr 104:e228–e231
Opin Drug Saf 11:95–105 Roberts JA, Pea F, Lipman J (2013) The clinical relevance
Fanos V, Yurdakök M (2010) Personalized neonatal med- of plasma protein binding changes. Clin Pharmacokinet
icine. J Matern Fetal Neonatal Med 23(Suppl 3):4–6 52:1–8
FP7 LENA. http://www.lena-med.eu/. Accessed 19 May Salunke S, Brandys B, Giacoia G et al (2013) The STEP
2015 (Safety and Toxicity of Excipients for Paediatrics) data-
Hines RN (2013) Developmental expression of drug base: part 2 – the pilot version. Int J Pharm 457:310–322
metabolizing enzymes: impact on disposition in neo- Santovena A, Hernandez-Paiz Z, Farina JB (2012) Design
nates and young children. Int J Pharm 452:3–7 of a pediatric oral formulation with a low proportion of
Huang NN, High RH (1953) Infants and children of vari- hydrochlorothiazide. Int J Pharm 433:360–364
ous age groups. J Pediatr 42:657–658 Schreuder MF, Bueters RR, Allegaert K (2014) The inter-
Kearns GL, Abdel-Rahman SM, Alander SW et al (2003) play between drugs and the kidney in premature neo-
Developmental pharmacology – drug disposition, nates. Pediatr Nephrol 29:2083–2091
action, and therapy in infants and children. N Engl J Smits A, Kulo A, de Hoon JN et al (2012a) Pharmacokinetics
Med 349:1157–1167 of drugs in neonates: pattern recognition beyond com-
Kieran EA, O’Callaghan N, O’Donnell CP (2014) pound specific observations. Curr Pharm Des 18:
Unlicensed and off-label drug use in an Irish neonatal 3119–3146
intensive care unit: a prospective cohort study. Acta Smits A, Kulo A, Verbesselt R et al (2012b) Cefazolin
Paediatr 103:e139–e142 plasma protein binding and its covariates in neonates.
Kugelman A, Inbar-Sanado E, Shinwell ES et al (2008) Eur J Clin Microbiol Infect Dis 31:3359–3365
Iatrogenesis in neonatal intensive care units: observa- Staelens S, van den Driessche M, Barclay D et al (2008)
tional and interventional, prospective, multicenter Gastric emptying in healthy newborns fed an intact
study. Pediatrics 122:550–555 protein formula, a partially and an extensively
Laforgia N, Nuccio MM, Schettini F et al (2014) Off-label hydrolysed formula. Clin Nutr 27:264–268
and unlicensed drug use among neonatal intensive care Stephenson T (2005) How children’s responses to drugs
units in Southern Italy. Pediatr Int 56:57–59 differ from adults. Br J Clin Pharmacol 59:670–673
Lass J, K€a€ar R, Jõgi K et al (2011) Drug utilisation pattern Stiers JL, Ward RM (2014) Newborns, one of the last thera-
and off-label use of medicines in Estonian neonatal peutic orphans to be adopted. JAMA Pediatr 168:106–108
units. Eur J Clin Pharmacol 67:1263–1271 Stoltenberg I, Breitkreutz J (2011) Oral disintegrating
Laughon MM, Avant D, Tripathi N et al (2014) Drug mini-tablets (ODMTs) – an novel solid oral dosage
labeling and exposure in neonates. JAMA Pediatr form for paediatric use. Eur J Pharm Biopharm
168:130–136 78:462–469
Lazou K, Farini M, Koutkias V et al (2013) Adverse drug Tuleu C, Breitkreutz J (2013) Educational paper:
event prevention in neonatal care: a rule-based formulation-related issues in pediatric clinical pharma-
approach. Stud Health Technol Inform 186:170–174 cology. Eur J Pediatr 172:717–720
Ligi I, Arnaud F, Jouve E et al (2008) Iatrogenic events in Turner MA (2011) Neonatal drug development. Early Hum
admitted neonates: a prospective cohort study. Lancet Dev 87:763–768
371:404–410 Turner MA, Duncan J, Shah U et al (2013) European study
McIntyre J, Choonara I (2004) Drug toxicity in the neo- of neonatal exposure to excipients: an update. Int J
nate. Biol Neonate 86:218–221 Pharm 457:357–358
Mooij MG, de Koning BA, Huijsman ML, de Wildt SN Turner MA, Duncan JC, Shah U et al (2014) Risk assess-
(2012) Ontogeny of oral absorption processes in chil- ment of neonatal excipient exposure: lessons from food
dren. Expert Opin Drug Metab Toxicol 8:1293–1303 safety and other areas. Adv Drug Deliv Rev 73:89–101
Mulla H (2010) Understanding developmental pharmaco- Van den Anker JN (2011) Getting the dose of vancomycin
dynamics: importance for drug development and clin- right in the neonate. Int J Clin Pharmacol Ther 49:247–249
ical practice. Paediatr Drugs 12:223–233 Van den Anker J (2014) The impact of therapeutic drug
Mulla H, Yakkundi S, McElnay J et al (2015) An observational monitoring in neonatal clinical pharmacology. Clin
study of blood concentrations and kinetics of methyl- and Biochem 47:704–705
propyl-parabens in neonates. Pharm Res 32:1084–1093 WHO, UNICEF. Make medicines child size. http://www.
Nunn A, Craig JV, Shah UU et al (2013) Estimating the who.int/childmedicines/media/backgrounder/BG2/en/
requirement for manipulation of medicines to provide index.html. Accessed 19 May 2015
accurate doses for children. Eur J Hosp Pharm 20:3–7 Yanni SB, Smith PB, Benjamin DK Jr et al (2011) Higher
Rao SC, Srinivasjois R, Hagan R, Ahmed M (2011) One clearance of micafungin in neonates compared with
dose per day compared to multiple doses per day of adults: role of age-dependent micafungin serum bind-
gentamicin for treatment of suspected or proven sepsis ing. Biopharm Drug Dispos 32:222–232
in neonates. Cochrane Database Syst Rev 9:CD005091 Young TE (2012) Therapeutic drug monitoring – the
Rieder M (2012) New ways to detect adverse drug reac- appropriate use of drug level measurement in the care
tions in pediatrics. Pediatr Clin N Am 59:1071–1092 of the neonate. Clin Perinatol 39:25–31
Infants of Smoking Mothers
45
Roberto Paludetto, Letizia Capasso, and Francesco Raimondi
Contents
45.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 710
45.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 710
45.3 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 710
45.4 Pharmacology of Tobacco Smoke and Its Detection in Biological
Specimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711
45.5 Smoke, the Pregnancy, and the Fetus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711
45.6 Neonatal Consequences of Smoke Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712
45.7 Behavioral Aspects of the Offspring of the
Smoking Mother . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713
45.8 Smoke and SIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714
45.9 Reducing Damage from Prenatal Smoke Exposure or ETS . . . . . . . . . . . . . . . 714
45.10 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714
Abstract compounds whose effects have not been fully
Maternal smoking during pregnancy repre- studied, most of its detrimental effects are pre-
sents a serious health hazard for the fetus and sumed to be mediated by nicotine. Cotinine, a
the neonate; its consequences may persist well nicotine metabolite, is used as a biomarker of
into later life. Environmental tobacco smoke is tobacco exposure, and it has allowed an objec-
also a threat to pre- and postnatal life. Although tive measure of smoke-related adverse events
tobacco smoke contains thousands of spanning from preterm birth, intrauterine
growth retardation, and low birth weight to
congenital malformations. Deficient cardiovas-
R. Paludetto · L. Capasso (*) · F. Raimondi cular and respiratory functions have also been
Division of Neonatology, Department of Translational linked to intrauterine and neonatal exposure to
Medical Sciences, Università “Federico II” di Napoli, tobacco smoke such as an increased risk of
Naples, Italy
e-mail: [email protected]; [email protected];
metabolic syndrome in adulthood. Nicotine’s
[email protected] complex interaction with fetal and neonatal
# Springer International Publishing AG, part of Springer Nature 2018 709
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_194
710 R. Paludetto et al.
neurotransmitters induces behavioral alterations evidence to give the reader a practical approach
in the newborn period and may help to explain to the infant of the smoking mother.
the higher incidence of SIDS and ADHD
described in offspring of smoking mothers.
45.3 Epidemiology
45.1 Salient Points International authorities are monitoring the smoking
habits and their consequences and consider tobacco
• Smoking during pregnancy is still very com- as a “legalized health hazard” on a planetary scale.
mon in developed countries. In 2007, the WHO classified 18.2% of European
• Environmental tobacco smoke is a health haz- adult females as smokers (World Health Organiza-
ard for pregnant women and their fetuses. tion 2007). Figures vary among individual countries
• Recent studies use tobacco smoke biomarkers but have remained substantially stable since the
to document its adverse effects on the fetus and previous report in 2002. Separate data for smoking
the neonate. during pregnancy are not available on this scale and
• In utero tobacco smoke exposure has been have to be deduced from epidemiological surveys.
linked to an increased risk of some types of Reports from Sweden and the USA, respectively,
congenital malformations (i.e., orofacial clefts, estimate a prevalence of 13% and 10.4% of women
congenital heart disease). smoking during their pregnancy, but more recent
• Tobacco smoke exposure is associated with work from the UK sets this figure as high as 36%
adverse pregnancy outcome, preterm birth, low (Ward et al. 2007). Whatever the data at delivery, the
birth weight, and intrauterine growth retardation. percentage of women who smoke around the time of
• Early tobacco smoke exposure carries a higher conception is higher as most women who stop
risk of respiratory infections, poorer cardiovas- smoking achieve this goal very early in their gesta-
cular and respiratory function, and an increased tion (Chamberlain et al. 2013). However, since
risk of metabolic syndrome later in life. many will attempt to quit smoking throughout their
• Children of smoking mothers have a higher pregnancy, it is mandatory that they receive constant
incidence of behavioral problems, ADHD, support and encouragement from healthcare profes-
and SIDS. sionals. This should be continued after delivery,
since many women who quitted smoking during
pregnancy will resume this habit shortly after giving
45.2 Introduction birth. Moreover, Cnattingius et al. have demon-
strated that a previous adverse pregnancy outcome
The knowledge of adverse effects of tobacco prod- has only a modest influence on smoking habits in
ucts on adult health conditions has long been the successive gestation (Cnattingius et al. 2006).
established. Scientists and clinicians are now Besides direct smoking, a pregnant woman and
unraveling the multifaceted relation between her fetus can be exposed to environmental tobacco
tobacco smoke and human development starting smoke (ETS). While the detrimental effects of this
from the intrauterine and possibly periconceptional condition will be discussed below, it is difficult to
periods. Evidence now relates maternal smoke to gather good quality data on its prevalence. In
deranged organogenesis, decreased organ function, 2007, Ward et al. reported in the UK that as
poorer neurodevelopmental performance, and, many as 13% of infants were born to nonsmoking
recently, epigenetic changes that predispose to mothers who had had significant exposure to ETS
metabolic syndrome in adulthood. However, find- (Ward et al. 2007). Maternal smoking during
ings are not always unequivocal, mainly because pregnancy and ETS may have additive adverse
of methodological problems. In the next para- effects on infantile health.
graphs, we will critically address some of the Recently, a national study on all registered births
current issues, focusing on available clinical in England between 1995 and 2011 demonstrated
45 Infants of Smoking Mothers 711
that national legislation in 2007 to introduce smoke- may be invasive (i.e., plasma), and depends on
free workplaces was associated with an immediate cotinine half-life (except for hair) but often reveals
decrease in stillbirths (7.8%), low birth weight a greater exposure to tobacco smoke than maternal
infants (3.9%), and neonatal mortality (7.6%). The self-reports. In the study by Puig et al., infantile
authors estimated that in the first 4 years following exposure to ETS was significantly higher when
smoke-free legislation, 991 stillbirths, 5.470 cases assessed by infant urinary cotinine compared to
of low birth weight, and 430 neonatal deaths were parental self-reports (Puig et al. 2008). Similarly,
prevented (Been et al. 2015). Such results should 64.3% of pregnant women who claimed to be non-
encourage smoke-free legislation for all countries, smokers and not exposed to ETS had plasma cotin-
especially for low- and middle-income countries ine levels above the limit of detection (de Chazeron
where most of the burden of early life morbidity et al. 2007). Despite the proven value of this bio-
and mortality occurs. marker, much of the research published to date still
relies on self -reports.
45.4 Pharmacology of Tobacco
Smoke and Its Detection 45.5 Smoke, the Pregnancy,
in Biological Specimens and the Fetus
Tobacco smoke has thousands of compounds, Nicotine is a powerful vasoconstrictor that signif-
many of which might have effects on infant’s icantly reduces maternal blood supply to the fetus.
health and have not been yet investigated. The latter is further impaired by placental alter-
Carbon monoxide rapidly binds to both mater- ations and high carboxyhemoglobin levels. These
nal and fetal hemoglobin with carboxyhemoglobin effects combined may explain why smoking dur-
levels that eventually become higher in the fetus ing pregnancy has been associated with perinatal
than in the mother because the fetus has a higher death, spontaneous abortion, stillbirth, abruptio
hemoglobin affinity for carbon monoxide and a placentae, placenta previa, fetal growth restric-
longer elimination half-life than the mother. This tion, preterm birth, and low birth weight.
leads to a potentially profound impairment of oxy- The developmental origin of health and disease
gen delivery to the tissues that can be aggravated is a rapidly expanding research field. Molecular
by other smoke-derived chemicals (thiocyanates mechanisms such as DNA methylation may inter-
and other cyanides) also binding hemoglobin. vene during fetal life under the influence of envi-
Nicotine is the chemical that is primarily respon- ronmental stressors. This is an attractive model to
sible of tobacco addiction and organ toxicity. In the explain the long-term effects of prenatal exposure
brain, nicotine binds to nicotinic acetylcholine to tobacco smoke.
receptors eliciting the release of many neurotrans- From the analysis of umbilical cord blood of
mitters. Nicotine can also act peripherally stimulat- 418 pregnant women, prenatal exposure to ciga-
ing the release of epinephrine, ultimately increasing rette smoke can cause increased methylation of the
heart and respiratory rate and causing vasoconstric- insulin-like growth factor II (IGF2) gene, which is
tion. It also suppresses insulin release possibly associated with low birth weight, predominantly in
affecting glucose blood levels and appetite. Nico- male infants. IGF2 plays an important role in
tine passes into breast milk with concentrations that regulating growth (Pirini et al. 2015). Also, mater-
are in linear correlation with its levels in maternal nal smoking during pregnancy has been linked
serum (Pellegrini et al. 2007). with DNA methylation change of the AHRR
Cotinine, the major nicotine metabolite, is cur- gene, involved in pleiotropic responses to environ-
rently used to assess objectively an infant’s expo- mental contaminants and with the methylation of
sure to tobacco smoke both before and after birth. genes involved in the pathway for the detoxifica-
Cotinine may be detected in plasma, urine, saliva, tion of xenobiotics of tobacco smoke such as
hair, and meconium. This sampling is expensive, CYP1A1. The differential methylation of such
712 R. Paludetto et al.
genes persists also during adolescence; these find- incidence of cleft lip and palate in infants of
ings support a role for epigenetics as a mediator of smoking mothers (Lie et al. 2008). This piece of
long-term effects of smoking exposure in utero data has been recently confirmed by a biomarker-
such as increased risk of diabetes type 2, hyperten- based study. Women with a serum cotinine above
sion, and obesity (Novakovic et al. 2014). 2 ng/ml are 2.4 times more likely to deliver a child
In a cohort study on 7,098 pregnant women, an affected by an orofacial cleft (Shaw et al. 2009).
association with low birth weight was particularly Congenital heart defects have also been
strong for active smoking during late pregnancy, associated to prenatal smoke exposure. A large
while quitting smoking early in the gestation was questionnaire-based, case-control study
associated with a higher birth weight than continu- conducted by Malik et al. has concluded that
ing to smoke. In a cohort study on 927,424 births women who smoked around the periconceptional
between 2006 and 2012, the risk for fetal growth period were more likely to give birth to neonates
restriction below the tenth percentile increases with septal and right-sided obstructive defects
about 1.2-fold for cessation of smoking after the (Malik et al. 2008). The association of congenital
first trimester and about 1.7-fold for cessation after heart defects with prenatal smoke exposure is
the second trimester; women smoking throughout stronger with increasing number of daily ciga-
pregnancy have a 2.3-fold risk for fetal growth rettes and among the offspring of mothers over
restriction after accounting for the influence of the age of 35 years (Sullivan et al. 2015).
race, low socioeconomic status, and medical An impaired development of the fetal femur
comorbidities. Smoking only during the preconcep- and/or of its vasculature has been claimed to
tion period did not significantly increase fetal explain the increased risk of Legg-Calvè-Perthes
growth restriction risk (Blatt et al. 2015). disease in offspring of mothers who smoked during
A slight, nonsignificant trend to a beneficial effect pregnancy versus matched controls (Bahmanyar
on birth weight has been described for reducing the et al. 2008). More research is required to reevaluate
number of cigarettes without quitting completely this topic using biomarkers as an objective measure
(Jaddoe et al. 2008). Each additional pack smoked of the infant’s smoke exposure.
during pregnancy is associated with a 2.8 g reduction Besides organogenesis, neonatal organ func-
in neonatal body mass composition (0.7 g decrease tion is impaired by direct maternal smoking dur-
for fatty mass and 2.1 g for free-fatty mass) in a dose- ing pregnancy or by ETS.
dependent manner (Harrod et al. 2014). Pulmonary mechanics studies in infants with
Length and head circumference are also prenatal exposure to tobacco smoke have shown
affected though probably to a lesser degree. an alteration in expiratory flow, a reduction in
Tobacco-related effects on fetal growth are gener- respiratory compliance, and an increase in airway
ally reversible during the first few years of life resistance (Hanharan et al. 1992)
(Kannellopoulos et al. 2007). Children with intra- Prenatal smoke exposure has a long-lasting
uterine smoke exposure show a faster increase in effect on expiratory flow rates as a significant
height and ponderal index from birth to the age of reduction has been reported by Cunningham
2 years than controls, after which no difference et al. in 8–12-year-old children (Cunningham
can be documented (Harrod et al. 2012). et al. 1994). The respiratory function deficit was
larger for black children than for white and for
boys than for girls (Cunningham et al. 1995). The
45.6 Neonatal Consequences severity of wheezing may be further influenced by
of Smoke Exposure beta-2 adrenergic receptor variants in a complex
gene-environment interaction (Wang et al. 2008).
The multifaceted damage of smoking during preg- Offspring of nonsmoking mothers exposed to
nancy on neonatal health starts with an increased ETS during pregnancy has an increased risk of
rate of congenital malformations. Many asthma in childhood too (Simons et al. 2014). In
questionnaire-based studies reported a greater vitro and animal experiments recently showed
45 Infants of Smoking Mothers 713
that maternal smoking during pregnancy and lac- type 2 diabetes in offspring as a result of both
tation impairs metabolism and structural integrity impaired pancreatic β-cell (mass and function)
of the lung in the offspring by means of epigenetic and reduced peripheral insulin sensitivity (Bruin
changes (Maritz and Harding 2011). et al. 2010). Recently, newborns of smoking
Children of mothers who smoked during preg- mothers during pregnancy have been shown to
nancy have a higher risk of respiratory tract infec- have decreased IGF1 levels and borderline low
tions both in the neonatal period and in the first fetal β-cell function compared with newborns of
year of life. The same holds true, to a milder nonsmoking mothers (Fang et al. 2015). Larger
degree, for ETS which could directly damage the studies are required to confirm the hypothesis that
respiratory epithelial lining and also suppress the early life metabolic alterations in fetus may pre-
innate immune system (Kum-Nji et al. 2006). dispose to metabolic syndrome in adulthood.
A large, questionnaire-based cohort study has After birth, breastfeeding is an important
evaluated the effects of maternal smoking in preg- source of exposure to tobacco compounds as nic-
nancy on the cardiovascular function of the neo- otine passes into breast milk. The deleterious
nate (Geerts et al. 2007). Infants of smoking effect of nicotine in breast milk depends on
mothers had a 5.4 mmHg higher systolic pressure the amount of cigarettes smoked and on the
than offspring of nonsmoking mothers, but no time frame between cigarette smoked and
significant association was found with diastolic breastfeeding. Smoking mothers are less likely
pressure or heart rate. ETS alone (i.e., infants of to breastfeed because of smoke interference with
nonsmoking mothers but with smoke exposure in milk production and the mother’s feeling of inad-
the household) did not modify blood pressure or equate milk production; moreover, infantile colic
heart rate compared to controls. and crying are exacerbated by tobacco smoking
There is concern that smoking exposure in and increase the likelihood of the use of formula
utero may play a role in increased risk of obesity (Banderali et al. 2015).
later in childhood. Children of mothers who
smoked during pregnancy had higher risk of obe-
sity at a mean age of 9 years (Oken et al. 2008; 45.7 Behavioral Aspects
Banderali et al. 2015). Another study correlated of the Offspring of the Smoking
maternal smoking with higher total fat mass at Mother
the same age (Banderali et al. 2015; Leary
et al. 2006). Exposure to prenatal smoking was The profound impact of nicotine on neural cells
significantly associated with reduced neonatal fat anticipates a possible effect on neonatal behavior.
mass and fat-free mass at birth. In contrast, at Questionnaire-based research results, however,
5 months exposed offspring to prenatal smoking have not been entirely clear. Most studies exam-
had greater fat-free mass and sum of skin folds. ined tobacco in the context of other factors such as
Therefore, smoking exposure in utero is signifi- illicit substance abuse or obstetric complications
cantly associated with rapid postnatal growth, (Fried and O’Connell 1987). Our group has
which may increase the risk of metabolic diseases conducted a prospective analysis of neonatal
(Harrod et al. 2014). Nicotine-induced intrauter- behavior, assessed by the Brazelton Neonatal
ine starvation may directly alter the hypothalamic Behavioral Assessment Scale, monitoring the
control on energy intake and expenditure infant’s urine cotinine and administering a struc-
predisposing to later obesity and to modification tured questionnaire to the parents (Mansi
of brain and peripheral autonomic pathways et al. 2002). Newborns of mothers who smoked
(Oken et al. 2008; Banderali et al. 2015). during pregnancy had a higher urinary cotinine
Maternal smoking during pregnancy has been excretion. They were more irritable and less inter-
associated with elevated risk of type 2 diabetes active with the environment. The same was true,
among offspring in adulthood. In an animal study, although to a lesser extent, for offspring of
maternal nicotine exposure in utero may cause nonsmoking mothers but smoking fathers, used as
714 R. Paludetto et al.
a proxy of ETS. Using a different evaluation tool, the mean duration of apneic episodes with
Stroud et al. came to similar conclusions (Stroud desaturation (Blanchard et al. 2010).
et al. 2009). Neonates of smoking mothers had an These observations may provide the link
increased arousal and excitability throughout the between tobacco smoke, a defective cardiorespi-
first month of life, well past nicotine half-life. This ratory control, and SIDS.
has to be taken into account in the prevention of
early disruption of maternal-infant bonding.
The adverse effects of prenatal smoke exposure 45.9 Reducing Damage from
on behavior extend far beyond the neonatal period. Prenatal Smoke Exposure
Schmitz et al. have documented an odds ratio of or ETS
3.44 for an increase of the inattentive form of atten-
tion deficit hyperactivity disorder (ADHD), and It is intuitive that enforcing regulations on banning
some studies show a higher rate of smokers among smoke from public places and taxing tobacco prod-
adolescents affected by ADHD as they self- ucts should reduce smoking rates and ETS. More
medicated to alleviate cognitive or attentive disor- focused programs are in place in many developed
ders (Schmitz et al. 2006). A prospective longitudi- countries where smoking cessation services are
nal study by Hook et al. has linked prenatal smoke available before or during the gestation offering
exposure to externalizing problems and aggression behavioral support. The safety and efficacy of nic-
leading to a higher incidence of delinquent behavior otine replacement therapy in pregnant women is
both in males and females (Hook et al. 2006). debated (Coleman 2008; Pauly and Slotkin 2008).
More recently, maternal snuff use in pregnancy
(a source of nicotine containing low levels of nitro-
45.8 Smoke and SIDS samines and no combustion products) has been
associated with the same increased risk of oral clefts
After the recognition that sleeping supine is asso- as tobacco smoking (Gunnerbeck et al. 2014).
ciated with a decreased incidence of sudden
infant death syndrome, maternal smoking has
become the main preventable risk factor for 45.10 Conclusions
SIDS. There is evidence that infants of smokers
are less arousable both in REM and in non-REM Perinatal health professionals need to increase
phase of sleep (Chang et al. 2003) and have their awareness about the detrimental effects of
deficient hypoxic awakening response (Franco smoking during pregnancy and lactation. Further
et al. 1999). Work in lambs exposed in utero to research conducted with reliable biomarkers of
nicotine shows delayed arousal and reduced ven- smoke exposure will improve the quality of our
tilatory and heart rate responses to hypoxia. information both on direct maternal smoke and on
Infants who died of SIDS had increased apopto- its role as an environmental pollutant. This infor-
sis in their brain stem nuclei compared to babies mation is needed if measurable interventions have
who had suddenly died for another diagnosis; to be aimed toward success.
cigarette smoke exposure was especially associ-
ated with increased apoptosis in the dorsal motor
nucleus of the vagus and the arcuate nucleus References
(Machaalani and Waters 2008). Blanchard
et al. demonstrated in preterm neonates that Bahmanyar S, Montgomery SM, Weiss RJ et al (2008)
intrauterine smoking exposure has a negative Maternal smoking during pregnancy, other prenatal
and perinatal factors and the risk of Legg-Calvè-Perthes
impact on peripheral chemoreceptor tonic activ-
disease. Pediatrics 122:e459–e464
ity and increases the time spent in apnea (both Banderali G, Martelli A, Landi M et al (2015) Short and
with and without blood oxygen desaturation) and long term health effects of parental tobacco smoking
45 Infants of Smoking Mothers 715
during pregnancy and lactation: a descriptive review. J Harrod CS, Reynolds RM, Chasan-Taber L et al (2012)
Transl Med 13:327 Maternal smoking during pregnancy and offspring tra-
Been JV, Mackay DF, Millett C et al (2015) Impact of jectories of height and adiposity: comparing maternal
smoke-free legislation on perinatal and infant mortality: and paternal associations. Int J Epidemiol 41:722–732
a national quasi-experimental study. Sci Rep 5:13020 Harrod CS, Reynolds RM, Chasan-Taber L et al (2014)
Blanchard ES, Chardon K, Leke´ A (2010) In utero expo- Quantity and timing of maternal prenatal smoking on
sure to smoking and peripheral chemoreceptor function neonatal body composition: the healthy start study. J
in preterm neonates. Pediatrics 125(3):e592–e599 Pediatr 165:707–712
Blatt K, Moore E, Chen A et al (2015) Association of Hook B, Cederblad M, Berg R (2006) Prenatal and post-
reported trimester-specific smoking cessation with fetal natal maternal smoking as risk factors for preschool
growth restriction. Obstet Gynecol 125(6):1452–1459 children’s mental health. Acta Paediatr 95:671–677
Bruin JE, Gerstein HC, Holloway AC (2010) Long-term Jaddoe VWV, Troe EJWM, Hofman A et al (2008) Active
consequences of fetal and neonatal nicotine exposure: a and passive maternal smoking during pregnancy and
critical review. Toxicol Sci 116(2):364–374 the risks of low birthweight and preterm birth: the
Chang AB, Wilson SJ, Masters IB et al (2003) Altered generation R study. Paediatr Perinat Epidemiol
arousal response in infants exposed to cigarette 22:162–171
smoke. Arch Dis Child 88:30–33 Kannellopoulos TA, Varvarigou AA, Karatza AA
Chamberlain C, O’Mara-Eves A, Oliver S et al (2013) et al (2007) Course of growth during the first 6 years
Psychosocial interventions for supporting women to in children exposed in utero to tobacco smoke. Eur J
stop smoking in pregnancy. Cochrane Database Syst Pediatr 166:685–692
Rev 10:CD001055 Kum-Nji P, Meloy L, Herrod HG (2006) Environmental
Cnattingius S, Akre O, Lambe M et al (2006) Will adverse tobacco smoke exposure: prevalence and mechanisms
pregnancy outcome influence the risk of continued of causation of infections in children. Pediatrics
smoking in the next pregnancy? Am J Obstet Gynecol 117:1745–1753
195:1680–1686 Leary SD, Smith GD, Rogers IS et al (2006) Smoking
Coleman T (2008) Reducing harm from tobacco smoke during pregnancy and offspring fat and lean mass in
exposure during pregnancy. Birth Defects Res childhood. Obesity 14:2284–2293
84:73–79 Lie RT, Wilcox AJ, Taylor J et al (2008) Maternal smoking
Cunningham J, Dockery DW, Speizer FE (1994) Maternal and oral clefts: the role of detoxification pathway
smoking during pregnancy as a predictor of lung func- genes. Epidemiology 19:606–615
tion in children. Am J Epidemiol 139:1139–1152 Machaalani R, Waters KA (2008) Neuronal cell death in
Cunningham J, Dockery DW, Speizer FE (1995) Racial the sudden infant death syndrome brainstem and asso-
differences between maternal smoking during preg- ciation with risk factors. Brain 131:218–228
nancy and lung function in children. Am J Respir Crit Malik S, Cleves MA, Honein MA et al (2008) Maternal
Care Med 152:565–569 smoking and congenital heart defects. Pediatrics 121:
de Chazeron I, Llorca PM, Ughetto S et al (2007) Occult e810–e815
exposure to environmental tobacco smoke exposure. Mansi G, Raimondi F, Pichini S et al (2002) Neonatal
Tob Control 16:64–65 urinary cotinine correlates with behavioural alterations
Fang F, Luo Z-C, Dejemli A et al (2015) Maternal smoking in newborns prenatally exposed to tobacco smoke.
and metabolic health biomarkers in newborns. PLoS Pediatr Res 61:257–261
One 10(11):e0143660 Maritz GS, Harding R (2011) Life-long programming
Franco P, Grosswasser J, Hassid S (1999) Prenatal expo- implications of exposure to tobacco smoking and nic-
sure to cigarette smoking is associated with a decrease otine before and soon after birth: evidence for altered
in arousal in infants. J Pediatr 135:34–38 lung development. Int J Environ Res Public Health
Fried PA, O’Connell CM (1987) A comparison of the 8:875–898
effects of prenatal exposure to tobacco, alcohol, canna- Novakovic B, Ryan J, Pereira N et al (2014) Postnatal
bis and caffeine on birth size and subsequent growth. stability, tissue, and timing specific effects of AHRR
Neurotoxicol Teratol 9:79–85 methylation change in response to maternal smoking in
Geerts CC, Grobbee DE, van der Ent CK et al (2007) pregnancy. Epigenetics 9(3):377–386
Tobacco smoke exposure of pregnant mothers and Oken E, Levitan EB, Gillman MW (2008) Maternal
blood pressure in their newborns. Hypertension smoking during pregnancy and child overweight: sys-
50:572–578 tematic review and meta analysis. Int J Obes
Gunnerbeck A, Edstedt Bonamy AK, Wikstrom AK 32:201–210
et al (2014) Maternal snuff use and smoking and the Pauly JR, Slotkin TA (2008) Maternal tobacco smoking,
risk of oral cleft malformations – a population-based nicotine replacement and behavioural development.
cohort study. PLoS ONE 9(1):e84715 Acta Paediatr 97:1331–1337
Hanharan JP, Tager IB, Segal MR et al (1992) The effect of Pellegrini M, Marchei E, Rossi S et al (2007) Liquid
maternal smoking during pregnancy on early infant chromatography/electrospray ionization tandem
lung function. Am Rev Respir Dis 145:1129–1135 mass spectrometry assay for determination of
716 R. Paludetto et al.
nicotine and metabolites, caffeine and arecoline in breast associated with childhood asthma development. J
milk. Rapid Commun Mass Spectrom 21:2693–2703 Allergy Clin Immunol Pract 2(2):201–207
Pirini F, Guida E, Lawson F, Mancinelli A, Guerrero- Stroud LR, Paster RL, Papandonatos GD et al (2009)
Preston R (2015) Nuclear and mitochondrial DNA Maternal smoking during pregnancy and newborn
alterations in newborns with prenatal exposure to cig- neurobehavior: effects at 10 to 27 days. J Pediatr
arette smoke. Int J Environ Res Public Health 154:10–16
12:1135–1155 Sullivan PM, Dervan LA, Reiger S et al (2015) Risk of
Puig C, Garcia-Algar O, Monleon T et al (2008) A longi- congenital heart defects in the offspring of smoking
tudinal study of environmental tobacco smoke expo- mothers: a population based study. J Pediatr 166
sure in children: parental self reports versus age (4):978–984
dependent biomarkers. BMC Public Health 8:47–55 Wang C, Salam MT, Islam T et al (2008) Effects of in utero
Schmitz M, Demarolin D, Laufer Silva T et al (2006) and childhood tobacco smoke exposure and beta-2
Smoking during pregnancy and attention-deficit/ adrenergic receptor genotype on childhood asthma
hyperactivity disorder, predominantly inattentive type: and wheezing. Pediatrics 122:e107–e114
a case-control study. J Am Acad Child Adolesc Psy- Ward C, Lewis S, Coleman T (2007) Prevalence of mater-
chiatry 45:1338–1345 nal smoking and environmental tobacco smoke expo-
Shaw GM, Carmichael SM, Vollset SE et al (2009) sure during pregnancy and impact on birth weight:
Mid-pregnancy cotinine and risks of orofacial clefts retrospective study using Millennium Cohort. BMC
and neural tube defects. J Pediatr 154:17–19 Public Health 7:81
Simons E, To T, Moineddin R et al (2014) Maternal World Health Organization (2007) The tobacco atlas www.
second-hand smoke exposure in pregnancy is who.int/tobacco/statistics/tobacco_atlas/en/
Infants of Diabetic Mothers
46
Erin A. Osterholm, Jane E. Barthell, and Michael K. Georgieff
Contents
46.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 718
46.2 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 718
46.3 The Pedersen Hypothesis and Diabetic
Fetopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 718
46.4 Risks of Maternal Glucose Intolerance During the Periconceptional
Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 719
46.5 Risks of Maternal Glucose Intolerance During the Fetal Period . . . . . . . . . 720
46.5.1 Growth Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 720
46.5.2 Disorders of Glucose Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 720
46.5.3 Reduced Fetal Oxygenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 721
46.5.4 Disorders of Fetal Iron Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 721
46.5.5 Acute and Subacute Nonstructural Cardiac Abnormalities . . . . . . . . . . . . . . . . . . . 721
46.6 Risks of Maternal Glucose Intolerance During Pregnancy on the
Neonate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 721
46.6.1 Growth Disorders and Breastfeeding Considerations . . . . . . . . . . . . . . . . . . . . . . . . . 721
46.6.2 Neonatal Hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723
46.6.3 Neonatal Hypocalcemia and Hypomagnesemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723
46.6.4 Neonatal Polycythemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 724
46.6.5 Neonatal Iron Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 724
46.6.6 Pulmonary and Cardiac Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 725
46.6.7 Hyperbilirubinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 725
46.6.8 Neuropathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 725
E. A. Osterholm · M. K. Georgieff (*)
Division of Neonatology, Department of Pediatrics Center
for Neurobehavioral Development, University of
Minnesota, Minneapolis, MN, USA
e-mail: [email protected]
J. E. Barthell
Children’s Hospitals and Clinics of Minnesota,
Minneapolis, MN, USA
# Springer International Publishing AG, part of Springer Nature 2018 717
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_195
718 E. A. Osterholm et al.
46.7 Long-Term Health Sequelae in IDMs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 726
46.7.1 Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 726
46.7.2 Neurodevelopment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 726
46.8 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 727
46.9 Disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 727
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 727
Abstract of neonatal body habitus, glucose, calcium and
Ten per cent of all pregnancies are complicated magnesium metabolism, hematologic status,
by gestational diabetes mellitus or pre- cardiorespiratory function, bilirubin metabo-
conceptional diabetes and, given the increased lism, and neurologic functioning.
prevalence of obesity, this percentage is
expected to rise over the next few years.
While advances in maternal and neonatal med-
ical care continue to improve the outcomes 46.2 Overview
for infants born to mothers with glucose
intolerance during pregnancy, the risks for While advances in maternal and neonatal medical
spontaneous abortion, stillbirth, congenital care continue to improve the outcomes for infants
malformations, and perinatal mortality still born to mothers with glucose intolerance during
exist. Pregnancies of mothers with diabetes pregnancy, the risks for spontaneous abortion,
are given increased surveillance, as the multi- stillbirth, congenital malformations, and perinatal
faceted metabolic changes that occur in the mortality and morbidity still exist. Abnormal
mother affect fetal growth, glucose and iron maternal glycemic control caused by gestational
metabolism, cardiac anatomy and function, diabetes mellitus or pregestational diabetes
transition to extrauterine life, placing the infant mellitus complicate up to 10% of pregnancies,
at risk for periconceptional, fetal, neonatal, and and as the significantly overweight pediatric pop-
long-term morbidities. This chapter gives a ulation develops into their child-bearing years,
perspective on the risks of glucose intolerance this number is likely to rise (Nold and Georgieff
during pregnancies, neonatal complications, 2004). Pregnancies of mothers with diabetes are
and long-term health sequelae of infants of given increased surveillance, as the multifaceted
diabetic mothers. metabolic changes that occur in the mother can
place the infant at risk for periconceptional, fetal,
neonatal, and long-term morbidities (Nold and
Georgieff 2004; Widness 1989). Fortunately,
appropriate periconceptional and prenatal care
46.1 Salient Points
can improve the risks of perinatal complications
by close monitoring of maternal glycemic control.
• Appropriate periconceptional and perinatal
care can improve the risks for spontaneous
abortion, stillbirth, congenital malformations,
and perinatal mortality and morbidity. 46.3 The Pedersen Hypothesis
• Maternal hyperglycemia affects fetal growth, and Diabetic Fetopathy
glucose metabolism, iron metabolism, cardiac
anatomy and function, and transition to extra- In general, maternal glycemic control remains
uterine life. the primary factor that determines the potential
• Maternal hyperglycemia leads to multiple issues complications in the conceptus and the neonate.
in the neonatal period including abnormalities Some sequelae, such as failure of implantation,
46 Infants of Diabetic Mothers 719
Fig. 1 The fetal and neonatal events attributable to maternal diabetes mellitus (Reproduced from (Nold and Georgieff
2004), with permission)
miscarriage, and congenital malformations, are a conception and early gestation and the incidence
function of pre- and periconceptional maternal of congenital anomalies has been recognized in
glucose control. Other sequelae, such as several epidemiological studies, with a significant
macrosomia, neonatal hypoglycemia, and fetal/ decrease in congenital malformations reported in
neonatal iron deficiency, result from worsening mothers with strict metabolic regulation during
glycemic control in the last few weeks prior to the periconceptional period (Fuhrmann et al.
delivery (Georgieff 2006; Herranz et al. 2007). 1983; Georgieff 1995). Anomalies of the heart,
Fetal hyperglycemia, hyperinsulinemia, or the musculoskeletal system, and genitourinary system
combination of the two leads to the pathologic have been seen at a twofold to threefold higher
conditions seen in the late gestation fetus and incidence in infants of insulin-dependent diabetic
neonate (Fig. 1). mothers compared to the normal population
(Kalhan and Parimi 2006). The frequency of con-
genital anomalies has not been found to increase
46.4 Risks of Maternal Glucose in offspring of gestationally diabetic mothers
Intolerance During (Savona-Ventura and Gatt 2004).
the Periconceptional Period The mechanisms by which these anomalies
occur remain under investigation. Maternal
Up to 40 known congenital malformations associ- hyperglycemia, the major teratogenic factor, may
ated with maternal diabetes have been noted be involved in hyperglycemia-induced apoptosis
(Correa et al. 2008). Indeed, a strong association that is associated with oxidative stress, lipid per-
between maternal glycemic control at the time of oxidation, and decreased antioxidant defense
720 E. A. Osterholm et al.
capacity in the embryos (Rajdl et al. 2005; Zhao environment of hyperinsulinemia, a key anabolic
and Reece 2005). In studies of mouse embryos hormone, coupled with hyperglycemia, a key
from diabetic mice, hyperglycemia appears to dis- anabolic fuel. The combination produces a large
turb cellular pathways specific for cardiac and increase in fetal fat stores and some mild increase
neural tube development (Gao and Gao 2007; in protein content (Nold and Georgieff 2004).
Kumar et al. 2007; Morgan et al. 2008). A three- Hepatomegaly, splenomegaly, and cardiomegaly
to fivefold increase in major malformations in resulting from septal hypertrophy are often seen
infants as well as a fivefold increase in pregnancy in the context of a macrosomic infant, while the
loss rate in mothers with HbA1c levels (>7%) head circumference is usually not increased. A
early in pregnancy has been demonstrated significantly increased fetal abdominal area
(Galindo et al. 2006). Latest recommendations growth rate in the third trimester has been asso-
include maintaining an HbA1c less than 5% in ciated with high maternal HbA1c levels early in
the first trimester of pregnancy and below 6% in pregnancy (Wong et al. 2006) and has been used
the third trimester in healthy pregnant women to effectively reduce rates of macrosomia
with type 1 diabetes mellitus (Radder and van (Schaefer-Graf and Kleinwechter 2006). The
Roosmalen 2005). The American College of risk of shoulder dystocia, perhaps the most
Obstetricians and Gynecologists have feared birth complication, is greater for an infant
recommended that all women be offered routine of any weight born to a mother with diabetes or
screening ultrasound during pregnancy most com- gestational glucose intolerance versus a
monly between 18 and 20 weeks gestation, normoglycemic mother (Langer et al. 1991).
although the ability to identify congenital anoma- Accordingly, it has been recommended that elec-
lies with adequate sensitivity remains controver- tive cesarean be strongly considered for mothers
sial (Abuhamad AZ for the ACOG Practice with diabetes carrying a macrosomic fetus with
Committee 2009). The index of suspicion when fetal weight estimates greater than or equal to
evaluating a newborn infant of a diabetic mother 4,500 g (American College of Obstetricians and
(IDM) should clearly be very high. Gynecologists 2014).
In contrast to the pathophysiology leading to
the macrosomic infant, mothers with advanced
46.5 Risks of Maternal Glucose diabetic vascular disease are at risk of having
Intolerance During the Fetal fetuses with significant growth deceleration,
Period defined as birth weight less than the fifth percen-
tile for gestational age.
Maternal hyperglycemia has effects on fetal
growth, glucose metabolism, oxygenation, iron
metabolism, cardiac anatomy and function, and 46.5.2 Disorders of Glucose
transition to extrauterine life. Metabolism
Glucose intolerance coupled with resistance to or
46.5.1 Growth Disorders absence of insulin characterizes maternal diabetes
during pregnancy. Although glucose crosses the
Neonatal macrosomia is the classic presentation placenta to the fetus, insulin that is either maternal
of an IDM and results from biochemical changes in origin or exogenously delivered does not reach
along the maternal hyperglycemia – fetal the fetus. Therefore, fetal hyperglycemia leads to
hyperinsulinemia pathway (Gomella et al. 2004; pancreatic islet cell stimulation and subsequent
Nold and Georgieff 2004). Early in the second fetal insulin production. Additionally, hypoglyce-
half of pregnancy, the pancreatic islet cells mic episodes may result from sudden reductions
mature, and insulin production escalates in in maternal glucose in fetuses with islet cell
response to hyperglycemia creating an hyperplasia.
46 Infants of Diabetic Mothers 721
Both hyper- and hypoglycemia have been infancy and beyond (DeBoer et al. 2005; Deinard
identified as possible mechanisms for the et al. 1986; Riggins et al. 2009; Schmidt et al. 2004;
increased fetal mortality rate seen in pregnancies Siddappa et al. 2004). Decreased fetal hepatic iron
complicated by diabetes (Lucas 2001). stores, as indexed by abnormally low cord serum
ferritin concentrations, occur in 65% of live-born
IDMs (Georgieff et al. 1990).
46.5.3 Reduced Fetal Oxygenation
Abnormalities in fetal oxygenation during dia- 46.5.5 Acute and Subacute
betic pregnancies were discovered in the 1980s Nonstructural Cardiac
and account for the high rate of polycythemia in Abnormalities
offspring of poorly controlled diabetic mothers
(Nold and Georgieff 2004). Fetal cardiac septal hypertrophy and cardiomegaly
The fetal hypoxia is a consequence of an as a result of glycogen loading from chronic hyper-
elevated fetal basal metabolic rate stimulated by glycemia and hyperinsulinemia are specific phe-
chronic hyperglycemia and hyperinsulinemia. With notype findings associated with pregnancies
increases in rate of substrate uptake and oxidation, complicated by maternal diabetes. Despite good
the fetal environment becomes hypoxic, since the maternal metabolic control, serial evaluations of
higher oxygen demand cannot be met by increased cardiac growth demonstrated cardiac hypertrophy
oxygen transfer by the placenta (human or ovine). in late gestation (34–40 weeks) in fetuses of dia-
Several studies have demonstrated the attempt of the betic mothers (Weber et al. 1991) making
fetus to increase oxygen-carrying capacity in the cardiomegaly a possible contribution to the
face of hypoxemia including elevated erythropoietin increased risk of fetal death in these pregnancies
concentrations and fetal polycythemia (Bard and (Russell et al. 2008).
Prosmanne 1987; Georgieff et al. 1989, 1990;
Green et al. 1992; Stonestreet et al. 1989; Widness
et al. 1981). Fetal hypoxia constitutes a risk to the 46.6 Risks of Maternal Glucose
developing brain as does the potential for Intolerance During Pregnancy
hyperviscosity and resultant fetal stroke. on the Neonate
The abnormal metabolic milieu of hyperglycemia
46.5.4 Disorders of Fetal Iron and hyperinsulinemia during fetal life leads to
Metabolism multiple issues in the neonatal period, including
abnormalities of neonatal body habitus, glucose,
Chronic fetal hypoxemia and the subsequent com- calcium and magnesium metabolism, hemato-
pensatory erythropoiesis coupled with the larger logic status, cardiorespiratory function, bilirubin
blood volume of the macrosomic fetus place a metabolism, and neurologic functioning
large demand on fetal iron metabolism particu- (Table 1).
larly in light of limitations on maternal-fetal iron
transport to support this large demand.
IDMs are at greater risk for iron deficiency of 46.6.1 Growth Disorders
multiple organs due to the inability of the placenta and Breastfeeding
to upregulate iron transport sufficiently and subse- Considerations
quent iron prioritization and redistribution (DeBoer
et al. 2005; Deinard et al. 1986; Georgieff et al. Newborn macrosomia has been predicted by poor
1997; Petry et al. 1992, 1994; Riggins et al. 2009; maternal glycemic control, particularly in the last
Schmidt et al. 2004; Siddappa et al. 2004). These few weeks of gestation. Occurring in 15–45% of
deficiencies can affect neurodevelopment into diabetic pregnancies, macrosomia has been
722 E. A. Osterholm et al.
Table 1 Risk, assessment and management of neonatal metabolic complications in infants of diabetic mothers
Condition Assessment Action value Management
Hypoglycemia Serum glucose <40 mg/dL (<2.2 mmol/L) Early feedings; IV 10% dextrose solution
first 24 h; <50 mg/dL 2 mL/kg body weight; repeat serum
(<2.8 mmol/L) after 72 h glucose in ½ h
Hypocalcemia Serum ionized <3.5 mg/dL Calcium gluconate or calcium chloride if
calcium symptomatic; treat hypomagnesemia
prior to calcium treatment
Hypomagnesemia Serum <1.5 mg/dL Magnesium sulfate
magnesium
Polycythemia Hemoglobin >20–23 g/dL Partial exchange transfusion with target
hematocrit of 55%
Hematocrit >65–70% Partial exchange transfusion with target
(measured hematocrit of 55%
centrally)
Iron deficiency Serum ferritin <40 mcg/L Follow-up hemoglobin and ferritin at
6 months
Hyperbilirubinemia Serum indirect Dependent on age and infant Phototherapy, early feedings, hydration,
(unconjugated) size rarely exchange transfusion
bilirubin
generally defined as birth weight above the 90th metabolism with lipoproteins including long-chain
percentile for gestational age or greater than polyunsaturated fatty acids essential for develop-
4,000 g (Moore 1999). ment being lower in the IDMs (Herrera and Desoye
Macrosomia at birth serves as a marker for 2015). Infants at risk for metabolic instability in the
identifying infants at risk for neonatal morbidities, newborn period have been better identified by body
including hypoglycemia, hyperbilirubinemia, and proportion measurements, such as the mid-arm-cir-
neonatal acidosis (Moore 1999). Complete anthro- cumference-to-head-circumference ratio or body
pometric measurements, including weight, length, composition analysis via air displacement plethys-
and head circumference, should be assessed and mography (Georgieff et al. 1988).
plotted on population-specific appropriate growth Although there have been positive effects
curves for each infant soon after birth. noted on maternal metabolism in diabetic women
Appropriate for gestational age IDMs have been who breastfeed, there have been concerning
found to have significantly greater fat mass, percent reports of negative long-term effects for breastfed
of weight that was fat, and triceps, subscapular, offspring of diabetic mothers. Hyperglycemia dur-
abdominal, flank, and thigh skinfold measurements ing pregnancy has been associated with altered
than infants of nondiabetic women (Catalano et al. breast milk immune factors with decreased glyco-
2003). Subsequently, macrosomic IDMs generally sylation of secretory immunoglobulin A and
have higher weight than length and head circumfer- increased glycosylation of lactoferrin suggesting
ence percentiles. Fetal hyperinsulinism due to ges- that glucose dysregulation in pregnancy may have
tational diabetes mellitus (GDM) promotes the lasting consequences on the protective immune
excess accretion of adipose tissue, but there are functions of breast milk (Smilowitz et al. 2013).
additional metabolic alterations in these infants Breast milk from obese mothers has been shown to
that contribute to increased fat mass. Maternal alter- have an increased pro-inflammatory fatty acid
ations in blood leptin, retinol-binding protein 4, and profile (increased omega-6 to omega-3 ratio) and
adiponectin concentrations have been associated decreased concentrations of fatty acids including
with increased overall fatty acid placental transfer docosahexaenoic acid, eicosapentaenoic acid,
resulting in higher neonatal fat mass and birth docosapentaenoic acid, and lutein that have been
weight (Herrera and Ortega-Senovilla 2014). shown to have a critical role in neurodevelopment
There also appear to be alterations in lipid (Panagos et al. 2016).
46 Infants of Diabetic Mothers 723
GDM has been associated with delayed Maternal history, with attention to glycemic
lactogenesis in up to one third of women, especially control, and fetal anthropometric measurements
in those who required insulin treatment, were obese, and proportion studies can help to identify infants
or with suboptimal inhospital breastfeeding (Matias at highest risk (Georgieff et al. 1988).
et al. 2014). This delay in breast milk production Early initiation of feedings is highly
had a detrimental effect on both breastfeeding initi- recommended, as those infants who are asymp-
ation and duration in women with GDM. tomatic, normoglycemic, and able to tolerate feed-
ings do not need intravenous dextrose therapy.
46.6.2 Neonatal Hypoglycemia
46.6.3 Neonatal Hypocalcemia
Significant hypoglycemia, defined as a blood glu- and Hypomagnesemia
cose level less than 45 mg/dL (2.5 mmol/L), has
been seen in up to 50% of IDMs following birth, Neonatal hypocalcemia and hypomagnesemia are
with macrosomic or growth-restricted IDMs more two frequently encountered metabolic distur-
likely to have hypoglycemia than IDMs of appro- bances that occur in up to 50% of IDMs during
priate size for gestational age (Gomella et al. 2004; the first 3 days of life and are related to lack of
Nold and Georgieff 2004). The abrupt discontin- maternal glycemic control (Kalhan and Parimi
uation of maternally derived glucose combined 2006). A physiological nadir of serum calcium
with neonatal hyperinsulinemia leads to hypogly- has been seen in healthy term infants by 24–48 h
cemia in the macrosomic infants. Normally, this of age during the transition from fetal to neonatal
interruption in glucose delivery is followed by a parathyroid and calcitonin regulation (Jain et al.
decrease in neonatal plasma glucose between 2008). The nadir may be exaggerated to the point
30 and 90 min followed by spontaneous recovery of hypocalcemia, generally accepted as an ionized
in most infants (Kalhan and Parimi 2006). Hypo- calcium level less than 3.5 mg/dL (Gomella et al.
glycemia seen in infants with growth restriction 2004). Ionized calcium measurements, when
due to diabetic vascular disease is more likely due available, are preferable to total serum calcium
to decreased hepatic glycogen stores and may not measurements. Hypocalcemia in the IDM may
appear until 6–12 h after delivery (Gomella et al. be caused by an inadequate neonatal parathyroid
2004). Hypoglycemia can persist and therefore response to the abrupt interruption of maternally
requires intervention consisting of a constant derived calcium as well as continual high levels of
intravenous dextrose infusion. calcitonin and possibly disturbances in vitamin D
Controversy exists concerning the threshold of metabolism (Kalhan and Parimi 2006).
what constitutes hypoglycemia, as little outcome Recent studies correlate maternal vitamin D
data is available for symptomatic or asymptomatic levels in a significant negative relationship with
hypoglycemia. A common recommendation is HbA1c, supporting a potential role for this vita-
that IDMs be screened at 1/2, 1, 1.5, 2, 4, 8, 12, min in promoting glycemic control. Fetal cord
24, 36, and 48 h of age (Gomella et al. 2004) and blood vitamin D levels were directly correlated
be treated to maintain a glucose between 45 and with those of the mother, with significantly lower
60 mg/dL (2.5 mmol/L and 3.3 mmol/L) levels seen in obese versus normal weight women
(Schwartz 1997). (Bennett et al. 2014). Decreased bone density has
Although most infants with hypoglycemia are been found in large for gestational age (LGA)
asymptomatic, typical symptoms can include jitter- newborns among IDMs potentially related to vita-
iness, sweating, tachypnea or apnea, seizures, agi- min D status and reduced fetal movements sec-
tation, and respiratory distress. Newborn IDMs, ondary to macrosomia (Schushan-Eisen et al.
especially those who are macrosomic or growth 2015).
restricted, should be monitored closely with regu- Neonatal hypomagnesemia is related to mater-
larly scheduled serum glucose measurements. nal hypomagnesemia and severity of maternal
724 E. A. Osterholm et al.
diabetes (Gomella et al. 2004). A serum magne- intolerance or necrotizing enterocolitis may indi-
sium level less than 1.5 mg/dL is considered path- cate intestinal sludging. Finally, pulmonary vas-
ologic (Gomella et al. 2004) and may complicate cular bed sludging may present as persistent
the treatment of hypocalcemia. pulmonary hypertension with worsening respira-
Similar to hypoglycemia, neonatal hypocalce- tory distress syndrome.
mia and hypomagnesemia may present with Assessment including an initial hematocrit and
symptoms such as jitteriness, sweating, platelet count should be obtained soon after birth.
tachypnea, irritability, and seizures. They present Because of the physiologic diuresis that occurs in
later than hypoglycemia with nadirs seen at all newborns, an increasing hematocrit over the
24–72 h following birth (Nold and Georgieff first 3 days of life is not uncommon. This phe-
2004). Because of this similarity of symptoms, nomenon, however, may prolong the risk for
the jittery IDMs should have serum glucose, cal- microvascular sludging in the polycythemic
cium, and magnesium levels measured. Symp- IDM, emphasizing the importance of appropriate
tomatic hypocalcemic IDMs can be treated with monitoring and hydration. Sludging and thrombo-
calcium chloride or calcium gluconate preferably sis of the microvasculature of any of the afore-
via a central venous catheter to reduce the chance mentioned organ systems may first be indicated
of peripheral vein damage from the medication. by a declining platelet count. Asymptomatic
Hypomagnesemia needs to be corrected in order infants with hematocrit values from 65% to 70%
to enable normalization of calcium homeostasis. ought to be hydrated with intravenous fluids at a
rate of at least 100 mL/kg/day, and the hematocrit
should be followed daily for the first 3 days. If the
46.6.4 Neonatal Polycythemia infant becomes symptomatic or the hematocrit
continues to increase despite appropriate therapy,
Polycythemia is present in 20–30% of IDMs, a partial volume exchange transfusion should be
particularly if the mother’s glucose control was completed. An immediate partial exchange trans-
suboptimal. The definition of polycythemia is a fusion is indicated in any IDM who is symptom-
central venous hemoglobin concentration greater atic from blood hyperviscosity or those with a
than 20 g/dL or hematocrit greater than 65% central hematocrit greater than 70% (Nold and
(Nold and Georgieff 2004). Blood hyperviscosity Georgieff 2004).
at levels higher than these leads to morbidities
including vascular sludging, ischemia, and infarc-
tion of vital organ systems (Moore 1999). 46.6.5 Neonatal Iron Deficiency
The cerebral microcirculation is one area at
risk for hyperviscous blood sludging, resulting Abnormalities of iron metabolism, including a
in neurologic irritability, jitteriness, and a high- risk of reduced brain iron concentrations at birth,
pitched cry. Cerebral venous sinus thrombosis have been demonstrated in 65% of IDMs and 95%
must be considered in these infants, and even of macrosomic IDMs (Amarnath et al. 1989;
though neuroimaging studies may not detect Chockalingam et al. 1987; Georgieff et al. 1990).
pathology, symptomatic, polycythemic IDMs Of note, IDMs with the highest hematocrits at
should be treated with partial exchange transfu- birth tend to also have the lowest ferritin concen-
sion to reduce blood viscosity and the predisposi- trations, suggesting that the available fetal iron
tion to further clot formation (Nold and Georgieff has been shunted into the expanded red cell mass
2004). and away from storage and non-hematologic tis-
Symptoms of vascular sludging in the renal, sue pools, including the brain. Iron deficiency
intestinal, and pulmonary systems may or may not presents a risk to the developing brain including
be explicit. Hypertension, thrombocytopenia, effects on myelination (Connor and Menzies
hematuria, and abdominal mass are all possible 1996), brain energy metabolism (de Ungria et al.
signs of renal vein thrombosis. Feeding 2000), and brain monoamine neurotransmitter
46 Infants of Diabetic Mothers 725
metabolism (Beard 2003). Newborn IDMs have 46.6.7 Hyperbilirubinemia
altered cognitive processing compared to healthy,
term infants (de Regnier et al. 2000). Treatment Indirect hyperbilirubinemia is a common finding
with supplemental iron (beyond normal recom- in IDMs as they have an increased red cell mass,
mendations) in the immediate newborn period ineffective erythropoiesis, and relative immaturity
has not been assessed with respect to improving of hepatic bilirubin conjugation and excretion
the neurodevelopmental outcome and is currently (Nold and Georgieff 2004). A 30% greater source
not recommended since the tissue deficiency is of bilirubin is produced by the increased cell
thought to be due to a redistribution of iron into mass, and conjugation and excretion by the rela-
red cells rather than a total body iron deficiency. tively immature glucuronosyltransferase enzyme
system create elevated serum unconjugated bili-
rubin levels. Bilirubin levels should be assessed
46.6.6 Pulmonary and Cardiac Status within the first 24 h of life and then followed until
a peak has been reached. Phototherapy with
Respiratory distress syndrome (RDS) and tran- appropriate hydration monitoring is the mainstay
sient tachypnea of the newborn (retained fetal of treatment, but some infants will require
lung fluid) are more commonly seen in IDMs exchange transfusion, using the same criteria as
than age-matched controls (Nold and Georgieff in hyperbilirubinemic infants born to mothers
2004). Fetal hyperinsulinemia may inhibit the without diabetes.
normal maturational effect of cortisol on the lung
leading to a decreased production of dipalmitoyl
lecithin (Moore 1999). While the infant of a 46.6.8 Neuropathology
nondiabetic mother reaches pulmonary maturity
at a mean of 34–35 weeks gestation, the IDM is Central nervous system dysfunction can be seen
not considered to be past the risk of pulmonary immediately in the newborn period as well as
immaturity until 38.5 weeks gestational age manifested by neurodevelopmental and behavioral
(Moore 1999). Additionally, persistent pulmonary abnormalities not recognized until later infancy or
hypertension secondary to polycythemia- childhood. The IDM is at risk for multiple mor-
associated vascular sludging may complicate bidities that can result in neurologic injury and
RDS as both polycythemia and RDS are associ- symptoms. Polycythemia with vascular sludging,
ated with fetal hyperinsulinemia. glucose and electrolyte abnormalities, birth
Cardiopulmonary adaptation (e.g., transition) trauma, and perinatal asphyxia due to macrosomia
in IDMs has been shown to be significantly dif- all pose possible etiologies for neurologic symp-
ferent than infants born to nondiabetic mothers. toms such as seizures, jitteriness, lethargy, tone
The classic findings of interventricular septal abnormalities, and movement disorders. Different
hypertrophy caused by glycogen loading of the neurologic symptoms typically present at specific
septum and cardiomyopathy have been seen in up time periods based on the etiology. Perinatal
to 30% of IDMs (Moore 1999). Hypertrophic depression, birth trauma, and hypoglycemia all
subaortic stenosis physiology has been observed generally present with symptomatology within
with severe septal hypertrophy rendering those the first 24 h of life. Alternatively, symptoms due
infants in left ventricular outflow obstructive to hypocalcemia or hypomagnesemia typically
heart failure. In such a situation, inotropes and present between 24 and 72 h following birth, as
hypovolemia worsened the condition, whereas this is the time period at which nadir levels are
beta-blockers and volume helped to alleviate the expected to be reached.
obstruction. Cardiomyopathy has usually been Initial hypotonia followed by increased tone,
seen in conjunction with septal hypertrophy, jitteriness, and seizures are signs and symptoms of
although it may appear exclusively (Nold and brain injury secondary to perinatal asphyxia. The
Georgieff 2004). risk for seizures due to birth asphyxia generally
726 E. A. Osterholm et al.
peaks 24 h following birth. Glucose, electrolyte, of obesity, hypertension, and dyslipidemia (Boney
or hematologic abnormalities must be identified et al. 2005; Fahrenkrog et al. 2004; Plagemann
and corrected prior to starting anticonvulsant 2005; Touger et al. 2005; Vohr and Boney 2008).
therapy. A longitudinal study focusing on growth of Pima
Brachial plexus nerve injuries secondary to Indian children showed significantly different pat-
neck stretching during delivery are more com- terns of growth of offspring of diabetic mothers
monly seen in the macrosomic IDM than appro- compared to offspring of nondiabetic mothers. Off-
priately grown for gestational age infants. Erb’s spring of diabetic mothers showed significant
palsy (roots C5–C7), Klumpke’s paralysis (roots “catch-down” growth during their first 1.5 years
C–C8), diaphragmatic nerve paralysis (roots of life but by age 7 had greatly exceeded the weight
C3–C5), and recurrent laryngeal nerve damage of offspring of nondiabetic mothers (Touger et al.
(roots T1–T2) have all been reported. 2005). Another longitudinal study identified a
In humans, event-related potential (ERP) stud- trend toward a higher incidence of insulin resis-
ies have indicated that while healthy, term infants tance (defined as a fasting glucose/insulin ratio of
born to nondiabetic mothers discriminate their <7) in 11-year-old children who were large for
own mother’s voice from a stranger’s voice, gestational age at birth compared to those who
iron-deficient IDMs do not show evidence of dis- were appropriate despite no difference in obesity.
crimination, suggesting abnormal cognitive The authors also demonstrated by multivariate
processing (de Regnier et al. 2007; Siddappa logistic regression that childhood obesity and the
et al. 2004). Research in the newborn rat has combination of large for gestational age status and
demonstrated that maternal diabetes disrupts the maternal gestational diabetes were associated with
regulation of both insulin receptors and insulin- insulin resistance (Boney et al. 2005). A review of
like growth factor-1 receptors in the developing studies examining the consequent development of
hippocampus. These hippocampal changes may metabolic syndrome in mothers with gestational
be associated with cognitive and memory impair- diabetes and their offspring showed that metabolic
ment seen in IDMs (Hami et al. 2015). syndrome in children with increasing age is related
to maternal gestational diabetes, maternal glycemia
in the third trimester, maternal obesity, neonatal
46.7 Long-Term Health Sequelae macrosomia, and childhood obesity (Vohr and
in IDMs Boney 2008). Studies evaluating lipid status in
euglycemic offspring of diabetic parents have
Periconceptional, fetal, and neonatal events all con- shown decreased high-density lipoprotein levels
tribute to the long-term health issues of IDMs. The with significant association between parental dia-
future risks for development include metabolic betes status and dyslipidemia (Carlton Johnnny
syndrome and iron status abnormalities in conjunc- and Anuratha 2016).
tion with neurodevelopmental problems.
46.7.2 Neurodevelopment
46.7.1 Metabolic Syndrome
Because of the multiple morbidities for which
In light of the obesity epidemic, concerns have IDMs are at increased risk, the long-term motor
been raised about the long-term health risks of and cognitive developmental trajectories of these
IDMs given their fetal exposure to an abnormal children have been studied in comparison to
metabolic milieu and macrosomic neonatal body infants born to normoglycemic mothers. Acute
habitus. Several studies have focused on the initial perinatal events as well as abnormal intrauterine
growth and ultimate likelihood of IDMs to go on to environmental affects have contributed to the
develop metabolic syndrome, characterized by long-term risks to brain development. Both new-
increased insulin resistance often seen in the setting born studies and longitudinal research have
46 Infants of Diabetic Mothers 727
demonstrated significant neurodevelopmental dif- stressed the importance of long-term evaluation of
ferences between these groups of offspring. brain development in IDMs.
For infants that experience seizures in the new-
born period, the etiology of the seizures is critical
for determining prognosis. Seizures caused by
46.8 Summary
metabolic abnormalities such as hypoglycemia
or hypocalcemia have a 10–50% risk of later
Advances in medical care of pregnant women with
developmental delays. In contrast, infants who
diabetes have led to improved outcomes for
have seizures due to hypoxic-ischemic encepha-
mothers and their offspring. Despite this trend,
lopathy carry an 80% risk for developmental
the rising obesity epidemic has the potential to
problems (Volpe 2001). Transient hypoglycemia
alter the course of progress. Metabolic syndrome
in the presence of large for gestational age infants
characterized by insulin resistance and type II dia-
born to normoglycemic mothers has been shown
betes mellitus will likely continue to rise over the
to have no harmful impact on psychomotor devel-
ensuing decade making glycemic control a more
opment at 4 years (Brand et al. 2005). Symptom-
universal issue. Health-care providers who care for
atic, severe hypoglycemia (blood glucose
pregnant women ought to stress the possible impli-
<35 mg/dL or <2 mmol/L), however, has been
cations of poor glucose control, including fetal
shown to be associated with neurodevelopmental
hypoxia and iron deficiency, that can affect long-
abnormalities and white matter injury identified
term neurodevelopmental trajectories of their
on MRI (Burns et al. 2008). MRI has been
infants. Women who first present with insulin resis-
recommended for routine evaluation of a newborn
tance in pregnancy, particularly those who are
infant with symptomatic hypoglycemia to eluci-
overweight or obese, need to be followed for the
date any cerebral injury (Inder 2008).
possibility of developing type II diabetes later in
Specific areas of neurodevelopment of offspring
life. Additionally, health-care providers of infants
born to diabetic mothers have been shown to cor-
and children ought to be aware of the possible
relate with the degree of maternal glycemic control
sequelae for offspring of diabetic mothers both in
(Nelson et al. 2003; Ornoy 2005; Riggins et al.
the neonatal period as well as long term. Atypical
2009; Rizzo et al. 1997). Problems with attention
neurodevelopment and the propensity for a meta-
span and motor functions appear to be present even
bolic derangement are two arenas that warrant fur-
in well-controlled mothers. Gross cognitive ability
ther research and attention as these infants are
has appeared to be maintained unless pregnancies
followed throughout childhood.
are associated with significant maternal nephropa-
thy or hypertension or with neonatal iron defi-
ciency (Riggins et al. 2009) in which case the
effects negatively correlate with the level of mater- 46.9 Disclosure
nal glycemic control (Ornoy 2005; Riggins et al.
2009). Another longitudinal study that followed This work was sponsored in part by grants to
IDMs until 11 years of age showed that poorly MKG from the National Institutes of Health
controlled antepartum maternal glucose and lipid (HD-29421; NS-34458; HD-54490; and RR-
metabolism correlated with poorer child perfor- 00400-39).
mance on standard measures of neuropsychologi-
cal functioning (Rizzo et al. 1997). Research in
obese mothers with GDM actually demonstrated References
a temporary mild acceleration in cognitive devel-
opment in early infancy at 6 months of age; how- Abuhamad AZ for the ACOG Practice Committee (2009)
Ultrasonography in pregnancy. Obstet Gynecol
ever, by 18 months of age, there was a rapid
113:451–461, PMID: 19155920
deceleration of scores particularly in the language Amarnath UM, Ophoven JJ, Mills MM (1989) The rela-
domain (Torres-Espinola et al. 2015). This work tionship between decreased iron stores, serum iron and
728 E. A. Osterholm et al.
neonatal hypoglycemia in large-for-date newborn activity in selected regions of neonatal rat brain. Pediatr
infants. Acta Paediatr Scand 78:538–543 Res 48:169–176, CrossRef
American College of Obstetricians and Gynecologists DeBoer T, Wewerka S, Bauer PJ (2005) Explicit memory
(2014) Safe prevention of the primary cesarean deliv- performance in infants of diabetic mothers at 1 year of
ery. Obstet Gynecol 123:693–711 age. Dev Med Child Neurol 47:525–531
Bard H, Prosmanne J (1987) Relative rates of fetal hemo- Deinard AS, List A, Lindgren B et al (1986) Cognitive
globin and adult hemoglobin synthesis in cord blood of deficits in iron-deficient and iron-deficient anemic chil-
infants of insulin-dependent diabetic mothers. Pediat- dren. J Pediatr 108(5 Part 1):681–689
rics 75:1143–1147 Fahrenkrog S, Harder T, Stolaczyk E et al (2004) Cross-
Beard J (2003) Neonatal iron deficiency results in irrevers- fostering to diabetic rat dams affects early development
ible changes in dopamine function in rats. J Nutr of mediobasal hypothalamic nuclei regulating food
133:1174–1179 intake, body weight, and metabolism. J Nutr
Bennett SE, McPeake J, McCance DR, Manderson JG, 134:648–654
Johnston P, McGalliard R, McGinty A (2014) Maternal Fuhrmann K, Reiher H, Semmler K et al (1983) Prevention
vitamin D status in Type 1 diabetic pregnancy: impact of congenital malformations in infants of insulin-
on neonatal vitamin D status and association with dependent diabetic mothers. Diabetes Care 6:219–223
maternal glycaemic control. Pregnancy Hypertens Galindo A, Burguillo AG, Azriel S, Fuente Pde L (2006)
4:235–236, PMID: 26104623 Outcome of fetuses in women with pregestational dia-
Boney CM, Verma A, Tucker R, Vohr BR (2005) betes mellitus. J Perinat Med 34:323–331
Metabolic syndrome in childhood: association with Gao Q, Gao YM (2007) Hyperglycemic condition disturbs
birth weight, maternal obesity, and gestational diabe- the proliferation and cell death of neural progenitors in
tes mellitus. Pediatrics 115:e290–e296 mouse embryonic spinal cord. Int J Dev Neurosci
Brand PL, Molenaar NL, Kaaijk C, Wierenga WS (2005) 25:349–357
Neurodevelopmental outcome of hypoglycaemia in Georgieff MK (1995) Therapy of infants of diabetic
healthy, large for gestational age, term newborns. mothers. In: Burg FD, Ingelfinger JR, Wald ER, Polin
Arch Dis Child 90:78–81 RA (eds) Current pediatric therapy, 15th edn. WB
Burns CM, Rutherford MA, Boardman JP, Cowan FM Saunders, Philadelphia, pp 793–803
(2008) Patterns of cerebral injury and neurodeve- Georgieff MK (2006) The effect of maternal diabetes dur-
lopmental outcomes after symptomatic neonatal hypo- ing pregnancy on the neurodevelopment of offspring.
glycemia. Pediatrics 122:65–74 Minn Med 89:44–47
Carlton Johnnny J, Anuratha N (2016) Study of lipid status Georgieff MK, Sasanow SR, Chockalingam UM, Pereira
in the euglycemic offsrpin of diabetic parents with sex, GR (1988) A comparison of the mid-arm circumfer-
age matched controls among South India population. ence/head circumference ratio and ponderal index for
Diabetes Metab Syndr 16 pii: S1871 – 4021. PMID: the evaluation of newborn infants after abnormal intra-
27012159 uterine growth. Acta Paediatr Scand 77:214–219
Catalano PM, Thomas A, Huston-Presley L, Amini SB Georgieff MK, Widness JA, Mills MM, Stonestreet BS
(2003) Increased fetal adiposity: a very sensitive (1989) The effect of prolonged intrauterine
marker of abnormal in utero development. Am J Obstet hyperinsulinemia on iron utilization in fetal sheep.
Gynecol 189:1698–1704 Pediatr Res 26:467–469
Chockalingam UM, Murphy E, Ophoven JC et al (1987) Georgieff MK, Landon MB, Mills MM et al (1990) Abnor-
Cord transferrin and ferritin values in newborn infants mal iron distribution in infants of diabetic mothers:
at risk for prenatal uteroplacental insufficiency and spectrum and maternal antecedents. J Pediatr
chronic hypoxia. J Pediatr 111:283–286 117:455–461
Connor JR, Menzies SL (1996) Relationship of iron to Georgieff MK, Petry CD, Mills MM (1997) Increased
oligodendrocytes and myelination. Glia 17:89–93, N-glycosylation and reduced transferrin binding capac-
CrossRef ity of transferrin receptor isolated from placentas of
Correa A, Gilboa SM, Besser LM et al (2008) Diabetes diabetic mothers. Placenta 18:563–568
mellitus and birth defects. Am J Obstet Gynecol 199 Gomella TL, Cunningham MD, Eyal FG, Zenk KE (2004)
(237):e1–e9 Neonatology: management, procedures, on-call prob-
de Regnier RA, Nelson CA, Thomas KM et al (2000) lems, diseases, and drugs, 5th edn. McGraw-Hill,
Neurophysiologic evaluation of auditory recognition New York, pp 418–433
memory in healthy newborn infants and infants Green DW, Khoury J, Mimouni F (1992) Neonatal hemat-
of diabetic mothers. J Pediatr 137:777–784, CrossRef ocrit and maternal glycemic control in insulin-
de Regnier RA, Long JD, Georgieff MK, Nelson CA dependent diabetic mothers. J Pediatr 12:302–305
(2007) Using event-related potentials to study perinatal Hami J, Shojae F, Vafaee-Nezhad S, Lotfi N,
nutrition and brain development in infants of diabetic Kheradmand H, Haghir H (2015) Some of the experi-
mothers. Dev Neuropsychol 31:379–396, CrossRef mental and clinical aspects of the effects of the maternal
de Ungria M, Rao R, Wobken JD et al (2000) Perinatal iron diabetes on the developing hippocampus. World J Dia-
deficiency decreases cytochrome c oxidase (cytox) betes 15:412–422, PMID: 25897352
46 Infants of Diabetic Mothers 729
Herranz L, Pallardo LF, Hillman N et al (2007) Maternal Petry CD, Eaton MA, Wobken JA et al (1992) Liver, heart,
third trimester hyperglycaemic excursions predict and brain iron deficiency in newborn infants of diabetic
large-for-gestationalage infants in type 1 diabetic preg- mothers. J Pediatr 121:109–114
nancy. Diabetes Res Clin Pract 75:42–46 Petry CD, Wobken JD, McKay H et al (1994) Placental
Herrera E, Desoye G (2015) Maternal and fetal lipid transferrin receptor in diabetic pregnancies with
metabolism under normal and gestational diabetic con- increased fetal iron demand. Am J Physiol 267:
ditions. Horm Mol Biol Clin Invest 23:1868–1883, E507–E514
PMID: 26351960 Plagemann A (2005) Perinatal programming and functional
Herrera E, Ortega-Senovilla H (2014) Lipid metabolism teratogenesis: impact on body weight regulation and
during pregnancy and its implications for fetal obesity. Physiol Behav 86:661–668
growth. Curr Pharm Biotechnol 15:24–31, PMID: Radder JK, van Roosmalen J (2005) HbA1c in healthy,
247201597 pregnant women. Neth J Med 63:256–259
Inder T (2008) How low can I go? The impact of hypogly- Rajdl D, Racek J, Steinerová A et al (2005) Markers
cemia on the immature brain. Pediatrics 122:440–441 of oxidative stress in diabetic mothers and their
Jain A, Agarwal R, Sankar MJ (2008) Hypocalcemia in the infants during delivery. Physiol Res 54:429–436
newborn. Indian J Pediatr 75:165–169 Riggins T, Miller NC, Bauer PJ et al (2009) Conse-
Kalhan SC, Parimi PS (2006) Diabetes in pregnancy: the quences of low neonatal iron status due to maternal
infant of a diabetic mother. In: Martin RJ, Fanaroff AA, diabetes mellitus on explicit memory performance
Walsh MC (eds) Neonatal-perinatal medicine, 8th edn. in childhood. Dev Neuropsychol 34:762–779
Elsevier Mosby, Philadelphia, pp 1473–1478 Rizzo TA, Metzger BE, Dooley SL, Cho NH (1997) Early
Kumar SD, Dheen ST, Tay SS (2007) Maternal diabetes malnutrition and child neurobehavioral development:
induces congenital heart defects in mice by altering the insights from the study of children of diabetic mothers.
expression of genes involved in cardiovascular devel- Child Dev 68:26–38
opment. Cardiovasc Diabetol 30:34, CrossRef Russell NE, Holloway P, Quinn S et al (2008) Cardiomy-
Langer O, Berkus MD, Huff RW, Samueloff A (1991) opathy and cardiomegaly in stillborn infants of diabetic
Shoulder dystocia: should the fetus weighing greater mothers. Pediatr Dev Pathol 11:10–14
than or equal to 4000 grams be delivered by cesarean Savona-Ventura C, Gatt M (2004) Embryonal risks in
section? Am J Obstet Gynecol 165(4 Pt 1):831–837 gestational diabetes mellitus. Early Hum Dev 79:59–63
Lucas MJ (2001) Medical complications of pregnancy: Schaefer-Graf UM, Kleinwechter H (2006) Diagnosis and
diabetes complicating pregnancy. Obstet Gynecol new approaches in the therapy of gestational diabetes
Clin N Am 28:513–536 mellitus. Curr Diabetes Rev 2:343–352
Matias SL, Dewey KG, Quesenberry CP, Gunderson EP Schmidt AT, Waldow KJ, Salinas JA, Georgieff MK (2004)
(2014) Maternal prepregnancy obesity and insulin The long-term behavioral effects of fetal/neonatal iron
treatment during pregnancy are independently associ- deficiency on a hippocampally dependent learning task
ated with delayed lactogenesis in women with recent in the rat. Pediatr Res 55:279A
gestational diabetes mellitus. Am J Clin Nutr Schushan-Eisen I, Cohen M, Leibovitch L, Maayan-
99:115–121, PMID: 24196401 Metzger A, Strauss T (2015) Bone density among
Moore TR (1999) Diabetes in pregnancy. In: Creasy RK, infants of gestational diabetic mothers and macrosomic
Resnik R (eds) Maternal-fetal medicine. WB Saunders, neonates. Matern Child Health J 19:578–582, PMID:
Philadelphia, pp 964–995 25138627
Morgan SC, Relaix F, Sandell LL, Loeken MR (2008) Schwartz RP (1997) Neonatal hypoglycemia: how low is
Oxidative stress during diabetic pregnancy disrupts too low? J Pediatr 131:171–173
cardiac neural crest migration and causes outflow tract Siddappa AM, Georgieff MK, Wewerka S et al (2004) Iron
defects. Birth Defects Res A Clin Mol Teratol deficiency alters auditory recognition memory in new-
82:453–463 born infants of diabetic mothers. Pediatr Res
Nelson CA, Wewerka SS, Borscheid AJ et al (2003) Elec- 55:1034–1041
trophysiologic evidence of impaired cross-modal rec- Smilowitz JT, Totten SM, Huang J, Grapov D, Durham HA,
ognition memory in 8-month-old infants of diabetic Lammi-Keefe CJ, Lebrilla C, German JB (2013)
mothers. J Pediatr 142:575–582 Human milk secretory immunoglobulin a and
Nold JL, Georgieff MK (2004) Infants of diabetic mothers. lactoferrin N-glycans are altered in women with gesta-
Pediatr Clin N Am 51:619–637, CrossRef tional diabetes mellitus. J Nutr 143:1906–1912, PMID
Ornoy A (2005) Growth and neurodevelopmental outcome 24047700
of children born to mothers with pregestational and Stonestreet BS, Goldenstein M, Oh W, Widness JA (1989)
gestational diabetes. Pediatr Endocrinol Rev 3:104–113 Effect of prolonged hyperinsulinemia on erythropoiesis
Panagos PG, Vishwanathan R, Penfield-Cyr A, Matthan in fetal sheep. Am J Physiol 257:R1199–R1204
NR, Shivappa N, Wirth MD, Herbert JR, Sen S (2016) Torres-Espinola FJ, Berglund SK, Garcia-Valdes LM, Segura
Breastmilk from obese mothers has pro-inflamatory MT, Jerez A, Campos D, Moreno-Torres R, Rueda R,
properties and decreased neuroprotective factors. Catena A, Perez-Garcia M, Campoy C, PREOBE Team
J Perinatol 36:284–290, PMID: 26741571 (2015) Maternal obesity, overweight, and gestational
730 E. A. Osterholm et al.
diabetes affect the offspring neurodevelopment at 6 and Widness JA (1989) Fetal risks and neonatal complications
18 months of age- a follow up from the PREOBE cohort. of diabetes mellitus and metabolic and endocrine disor-
PLoS One 10:e0133010, PMID: 26208217 ders. In: Brody SA, Ueland K (eds) Endocrine disorders
Touger L, Looker HC, Krakoff J et al (2005) Early growth in pregnancy. Appleton-Lang, Norwalk, pp 273–297
in offspring of diabetic mothers. Diabetes Care Widness JA, Susa JB, Garcia JF et al (1981) Increased
28:585–589 erythropoiesis and elevated erythropoietin in infants
Vohr BR, Boney CM (2008) Gestational diabetes: the born to diabetic mothers and in hyperinsulinemic
forerunner for the development of maternal and child- rhesus fetuses. J Clin Invest 67:637–642
hood obesity and metabolic syndrome? J Matern Fetal Wong SF, Lee-Tannock A, Amaraddio D et al (2006) Fetal
Neonatal Med 21:149–157 growth patterns in fetuses of women with
Volpe JJ (2001) Neonatal seizures. In: Volpe JJ pregestational diabetes mellitus. Ultrasound Obstet
(ed) Neurology of the newborn, 4th edn. WB Saunders, Gynecol 28:934–938
Philadelphia, pp 178–216 Zhao Z, Reece EA (2005) Experimental mechanisms of
Weber HS, Copel JA, Reece EA et al (1991) Cardiac diabetic embryopathy and strategies for developing
growth in fetuses of diabetic mothers with good meta- therapeutic interventions. J Soc Gynecol Investig
bolic control. J Pediatr 118:103–107 12:549–557
Part V
Respiratory System
Neonatal Lung Development
and Pulmonary Malformations 47
Corrado Moretti and Paola Papoff
Contents
47.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734
47.2 Fetal Stage of Lung Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734
47.2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734
47.2.2 Embryonic Phase (3rd-7th Week) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735
47.2.3 Pseudoglandular Phase (6th–17th Week) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735
47.2.4 Canalicular Phase (16th–26th Week) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 736
47.2.5 Saccular Phase (25th–38th Week) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737
47.3 Postnatal Lung Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737
47.3.1 Alveolar Phase and Development of the
Pulmonary Vasculature (36th Week
of Gestation to 24 Months After Birth) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737
47.4 Physical Determinants of Lung Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . 738
47.5 Pulmonary Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 740
47.5.1 Intrapulmonary Cystic Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 740
47.5.2 Congenital Cystic Adenomatoid Malformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742
47.5.3 Bronchopulmonary Sequestration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 743
47.5.4 Congenital Lung Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 744
47.5.5 Congenital Lobar Emphysema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 744
47.5.6 Pulmonary Agenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 745
47.5.7 Pulmonary Hypoplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 747
47.5.8 Oligohydramnios Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 750
47.5.9 Pulmonary Lymphangiectasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751
47.5.10 Chylothorax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753
47.5.11 Misalignment of Pulmonary Veins with Alveolar
Capillary Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 754
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 755
C. Moretti (*)
Università degli Studi di Roma “La Sapienza”, Rome, Italy
e-mail: [email protected]
P. Papoff
Pediatric Intensive Care Unit, Sapienza University of
Rome, Rome, Italy
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 733
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_196
734 C. Moretti and P. Papoff
Abstract • Treatment is usually supportive care; surgery is
There are five stages of lung development: reserved for selected cases.
embryonal, pseudoglandular, canalicular, • Maternal betamethasone is a therapeutic option
saccular, and alveolar. Structural develop- for fetuses with large microcystic congenital
ment of the lung may be altered by a number lung lesions at risk of hydrops.
of prenatal conditions. The principal pulmo-
nary malformations include intrapulmonary
cystic malformations (i.e., congenital
47.2 Fetal Stage of Lung
cystic adenomatoid malformation, broncho-
Development
pulmonary sequestration, congenital lobar
47.2.1 Introduction
emphysema, and bronchogenic cysts), pul-
monary agenesia, pulmonary hypoplasia,
In the early weeks of gestation, the human lung
congenital pulmonary lymphangiectasia,
originates as a ventral endodermal pouch from the
and alveolar capillary dysplasia. Congenital
primitive foregut; it thereafter continues to grow
pulmonary malformations are often diag-
through to adulthood until it reaches an exchange
nosed by prenatal ultrasound; however,
surface area of around 70–100 m2; the air-blood
some will present either in the neonatal
barrier is some 0.2 μm thick, 1/50 of the thickness
period or during childhood. Symptoms
of a sheet of tissue paper.
vary according to the degree of lung involve-
From the structural standpoint, the lung is
ment. Initial management of pulmonary
made up of one part that serves to convey gas
malformations is supportive care, whereas
extending from the trachea to the terminal bron-
surgical repair is indicated for selected
chioles, characterized by a series of 23 branchings
cases. Prognosis is good for most pulmonary
of the respiratory tree, and of an alveolar zone
malformations except for severe pulmonary
where gas is exchanged, where the acinus is the
hypoplasia and alveolar capillary dysplasia.
functional unit. The acinus comprises the respi-
ratory bronchioles, often with alveoli on the
walls, the alveolar ducts, and the alveoli them-
47.1 Salient Points selves, which are characterized by a hexagonal
structure (Fig. 1). The surface area of this
• There are five stages of lung development:
embryonal, pseudoglandular, canalicular, sac-
cular, and alveolar.
• The principal pulmonary malformations include
intrapulmonary cystic malformations, which
encompass congenital cystic adenomatoid mal-
formation, bronchopulmonary sequestration,
congenital lobar emphysema, and bronchogenic
cysts; pulmonary agenesia; pulmonary hypopla-
sia; congenital pulmonary lymphangiectasia;
and misalignment of pulmonary veins.
• Most pulmonary malformations are often diag-
nosed by prenatal ultrasound.
• All patients with prenatally detected congenital
cystic malformations require postnatal evalua- Fig. 1 The electron micrograph shows some alveoli (A)
with a dense capillary network (C) between their walls.
tion, preferably by CT scan.
The capillaries stem from a branch of the pulmonary artery
• Symptoms vary according to the extension of (PA). Reproduced from (Abrams et al. 2004), with
lung lesion. permission
47 Neonatal Lung Development and Pulmonary Malformations 735
structure is vast and maintains a constant relation- talk.” This process is controlled through a multi-
ship with body mass during postnatal growth tude of molecular factors that include transcrip-
(about 1 m2/kg). tional regulators, growth factors, morphogens,
The development of the human lung begins and extracellular matrix molecules, all of which
when the lung bud appears in the embryo and must be carefully controlled in both space and
ends in early childhood after relatively stable time to form a properly functioning lung. If
and progressive growth. Even though birth is an some of these developmental factors do not func-
event that implies dramatic changes in the func- tion at the right time and/or place, then lung
tions of this organ, it should not be considered as defects may occur.
a precise point of transition from one stage of Toward the end of the sixth week of gestation,
development to another. Nevertheless, since this the main airways are complete, including the seg-
is an important event, the artifact of dividing lung mental and subsegmental bronchi (Fig. 2e).
development into a prenatal and postnatal stage is Developmental anomalies occurring in these
justified, also to emphasize that at the end of first weeks of gestation may lead to many congen-
gestation, this organ has not yet reached maturity. ital malformations such as pulmonary agenesia,
Indeed, at the time of writing, we cannot define laryngeal or tracheal stenosis or atresia, tracheoe-
exactly when the lung reaches maturity (Burri sophageal fistula, tracheomalacia or
1997). Prenatal development of the respiratory bronchomalacia, bronchial malformations, and
system is in turn conventionally divided into ectopic lobes (Table 1).
five periods (Langston et al. 1984); actually, a
precise watershed between these periods does
not exist, but their identification can however 47.2.3 Pseudoglandular Phase
simplify the understanding of the morphogenesis (6th–17th Week)
of the lung.
During the pseudoglandular period, the airways
continue to divide until they form terminal bron-
47.2.2 Embryonic Phase (3rd-7th chioles; by the end of this period, the bronchial
Week) branching process is complete, and the airways
will continue to grow in proportion with the
The lung bud appears on the 26th day of gestation increase in pulmonary volume. Since the newly
and is formed from relatively undifferentiated epi- formed epithelial tubules are surrounded by a
thelial cells that expand into the surrounding considerable amount of mesenchyme, they make
embryonic connective tissue or mesenchyme the lung look like a gland, hence the name of this
(Fig. 2a, b). The bud begins to grow in length phase (Fig. 3a, b). The proximal airways are cov-
and to branch until, toward the fifth week, it ered by an epithelium that gradually becomes
forms five small saccular structures, two on the thinner toward the periphery, where the cells
left and three on the right, which are the begin- take on a cuboidal shape.
nings of the future secondary bronchi and of the During this period the blood vessels
future lobes of the mature lung (Fig. 2c, d). develop in parallel to the airways so that, by
The developing airways will undergo further the end of this phase, their hierarchical struc-
branching and are accompanied by the pulmonary ture is already comparable to that of the adult
arteries that derive from the sixth aortic arches. (de Mello and Reid 1997). Also, the develop-
Interactions between the epithelial cells of ment of the nerves in these structures is
endodermic origin that form the respiratory tree already fairly complete.
and the mesenchymal tissue of mesodermal origin Alterations in the development of the lung
covering it are of basic importance for the during the pseudoglandular period may give
branching of the airways (Alescio and Cassini rise to many congenital malformations such as
1962); this process is often referred to as “cross pulmonary sequestration, cystic adenomatoid
736 C. Moretti and P. Papoff
a b Esophagus
Lung bud Trachea
Bronchial buds
Mesenchyme
c d
Right primary Left primary
bronchus bronchus
Tracheal bifurcation
Right upper lobe
Left upper lobe
Right middle lobe
Right lower lobe Left lower lobe
Fig. 2 Successive stages in the development of the bronchi and future lobes of the lungs: (a) and (b), four weeks; (c) and
(d) five weeks; (e), six weeks. Modified from (Alescio and Cassini 1962)
malformation, pulmonary cysts, and congenital hence the name, and by further development
pulmonary lymphangiectasia (Table 1). In the of the distal airways where the primitive acinar
early stages of this period, the pleuroperitoneal structures appear, each made up of a respiratory
cavity starts dividing into the peritoneal and the bronchiole, an alveolar duct, and rudimentary
pleural cavities due to the development of the alveoli or saccules (Hislop 1996). The develop-
diaphragm; when it does not divide correctly, the ment of the terminal airways and of the capil-
abdominal content in the chest becomes herniated lary network determines both the progressive
(diaphragmatic hernia). thinning of the mesenchyme lining and the
formation of the alveolar capillary membrane
(Fig. 3c, d). This phase is also characterized by
47.2.4 Canalicular Phase (16th–26th the differentiation from cuboidal type-II to
Week) squamous type-I cells in the distal epithelium.
Differentiation of these cell types is an impor-
The canalicular period is characterized by the tant step as the type-II cells will be required to
appearance of vascular canals (capillaries), produce and secrete surfactant and the type-I
47 Neonatal Lung Development and Pulmonary Malformations 737
Table 1 Stage of development of congenital pulmonary of the final number of alveoli, around 200–300
malformations million, happens during the alveolar phase,
Embryonic which begins toward the end of gestation and
Pulmonary agenesis ends during early infancy. The alveoli are
Tracheal or laryngeal agenesis or stenosis formed through the subdivision of the saccules
Tracheo- or bronchomalacia into subunits, thus considerably increasing the
Bronchial malformations exchange surface area. It must be pointed out
Ectopic lobes that, given the great difficulty in carrying out
Pseudoglandular
histological measurements and in standardizing
Cystic adenomatoid malformation
findings, there is still controversy over the
Pulmonary sequestration
beginning and the end of the alveolar phase
Lung cysts
and over the final number of alveoli.
Congenital pulmonary lymphangiectasia
Congenital diaphragmatic hernia
The formation of alveoli is to be considered as
Canalicular mainly a postnatal event since most form during
Pulmonary hypoplasia the first 24–36 months after birth with a subse-
Saccular/Alveolar quent slow increase in number up to around the
Pulmonary hypoplasia eighth year of life (Brody and Thurlbeck 1986).
Alveolar capillary dysplasia
47.3 Postnatal Lung Development
cells will form the thin cell layer to support
future gas exchange. 47.3.1 Alveolar Phase
In this period the presence of masses inside the and Development
chest and/or changes in the physical forces, essen- of the Pulmonary Vasculature
tial for lung development, produced by the pres- (36th Week of Gestation
ence of the pulmonary liquid and by the breathing to 24 Months After Birth)
movements of the fetus, may interfere with the
development of the respiratory system and give Crests, or secondary septa, grow out from the
rise to pulmonary hypoplasia. intersaccular walls, or primary septa (Fig. 4),
appearing as small ridges in the epithelium
(Burri 1986). Electron micrograph imaging
47.2.5 Saccular Phase (25th–38th shows the secondary septa to be formed by a
Week) thin layer of connective tissue flanked by capil-
laries on both sides and characterized by the
This phase is characterized by marked dilation presence of elastin at the tip. Elastin appears to
of the terminal airways and resultant formation have the function of supporting the outgrowth of
of saccules (Langston et al. 1984), with a con- the epithelium, and its presence is an essential
siderable increase in lung volume and in the prerequisite for the formation of the secondary
surface area for gas exchange together with a septa, which takes place only after its deposi-
further thinning of the alveolar capillary mem- tion. Also, the capillary network gradually
brane (Fig. 3e, f). In this way also, the microcir- develops until maturity: in the first few weeks
culation structure is modified because the after birth, the interstitial layer of the septa
capillary networks surrounding the saccules gradually thins, drawing the two capillary net-
gradually come closer to each other and, at the works closer until they finally merge. This
end of the process, the interstitial septa, or pri- transformation from a double to a single layer
mary septa, delimit a double network of capil- of the capillary network contained inside the
laries necessary for the subsequent formation of septa is the last stage of pulmonary development
the secondary septa (Burri 1997). The formation (Burri 1984).
738 C. Moretti and P. Papoff
Fig. 3 Drawing that illustrates the light microscopic overlying proliferating blood vessels thins to a squamous
appearance of human lung during the glandular (a,b), Type I morphology and that the most distal cells retain a
canalicular (c,d) and saccular (e,f) stages of in utero devel- cuboidal shape. At the saccular state (f), the septa are very
opment. Undifferentiated columnar cells of the early bron- thinned and the air spaces are lined by differentiated Type I
chi (b) rest upon a basal lamina, which has been and Type II cells. The low and high magnification draw-
emphasized. Mesenchymal cells and capillaries are present ings are shown at approximately the same magnification in
below the basal lamina. (d) shows that the epithelium each panel. Modified from (Asabe et al. 1994)
amniotic space. The fluid is rich in chloride and
47.4 Physical Determinants of Lung
low in bicarbonate and proteins. The rate of fluid
Development
production increases in fetal lambs from approx-
imately 5 mL/kg at midgestation to more than
Physical forces exerted on the lung during gesta-
20 mL/kg near term, with hourly rates increasing
tion are crucial to normal development. There are
from 2 to 5 mL/kg/h, respectively (Bland et al.
two main physical factors that aid lung develop-
1982). This increase mirrors the progressive
ment: lung fluid and fetal breathing movements
expansion of the contact surface between the alve-
(FBM).
olar epithelium and microcirculation, due to the
During fetal development the lung is a secre-
proliferation of pulmonary capillaries and to the
tory organ that exhibits breathing-like movements
growth of the terminal saccules.
without contributing to respiratory gas exchange.
The production of pulmonary fluid is essential
The lung fluid is produced by epithelial cells,
for the normal development of the respiratory
especially those in the distal airways, through
apparatus since it determines the form and volume
chloride secretion, and it flows to the upper airway
of its peripheral units; experimental evidence
where it is either swallowed or released into the
47 Neonatal Lung Development and Pulmonary Malformations 739
respiratory apparatus for postnatal life. Pulmonary
hypoplasia is a disorder that is frequently associ-
ated with oligohydramnios and experimentally it
can be determined in the uterus through bilateral
phrenectomy. These observations seem to confirm
the importance of fetal respiratory activity for the
development of the lung, which could undergo
alterations when this activity is prevented or
when there are obstacles (Porter 1999). The phys-
iological fluctuations of PaO2 and of PaCO2 do
not influence the respiratory activity of the fetus,
which stops if the PaO2 drops to a level of
16–18 mmHg. Hypoxia therefore has an
inhibiting effect on breathing movements, which
is not to be interpreted as a sign of neuronal
Fig. 4 Light micrograph of human lung. Air spaces are immaturity but rather as a response aimed at
subdivided into small alveoli (asterisks) by secondary
reducing the consumption of O2 by the fetus. In
septa (arrowheads) projecting from the primary one
fact, intrauterine respiratory activity demands up
to 15–30% of the total O2 available. By contrast,
shows that extended drainage of tracheal fluid the fetus responds to an increase in PaCO2 with a
causes pulmonary hypoplasia (PH). The amount corresponding increase in respiratory activity and
of pulmonary fluid that is present inside the respi- the opposite occurs in the case of hypocapnia.
ratory tree depends on the balance between pro- These observations suggest that the central che-
duction at the level of the alveolar epithelium and moreceptors are active in fetal life. Maternal
resistance to its outflow exerted by the upper ingestion of alcohol or sedatives has been shown
airway (Fewell and Johnson 1983); its volume at to decrease breathing movements, but drugs such
the end of gestation is around 20–30 mL/kg, a as caffeine increase them. Maternal smoking also
value that is comparable to that of the functional decreases fetal breathing movements through sev-
residual capacity (FRC) of a normal lung. eral mechanisms including decreased uterine
The other physical factor that is critical for nor- blood flow and hypoxia (Kotecha 2000).
mal lung development is FBM, periodic rhythmic The pressure inside the fetal respiratory system
contractions of the diaphragm that maintain ade- varies depending on the presence or absence of
quate fluid volume and lung distension. During breathing movements. During the periods in
pregnancy, the fetus spends most of its time, around which the fetus does not practice breathing, the
30–40% during the third quarter, performing pressure remains constant (Vilos and Liggins
breathing movements even though ventilation is 1982): if the amniotic pressure is considered to
exclusively a placental function (Dawes et al. be zero, the pressure inside the trachea is around
1970). Fetal breathing appears to be related to the 1–2 mmHg greater, while the intrapleural pressure
behavioral state of the fetus. As the fetus is about 0.7 mmHg lower. The positive pressure
approaches term, the incidence of these movements inside the respiratory tree is modulated mainly by
is considerably greater during active periods than the degree of resistance of the larynx. Similarly,
during periods of quiet activity (Mulder et al. 1994). the negative endopleural pressure is the product of
Observations of human fetuses with congenital the balance between elastic return of the lungs and
anomalies and of experimental animals show that of the thoracic cage. The resulting force between
the breathing movements of the fetus produce endotracheal positive pressure and endopleural
distension forces that stimulate cell multiplication negative pressure is a transpulmonary positive
(Liu et al. 1992) and are necessary to ensure an pressure of around 2.5 mmHg, a force that keeps
adequate development of the muscular and the lungs expanded hence stimulating their
740 C. Moretti and P. Papoff
growth. During the periods when the fetus per- lung development, despite some diversity in mor-
forms FBM, the glottis dilates and resistance phology. Fetal bronchial atresia or obstruction
decreases at the larynx, but the rhythmic contrac- probably plays a prominent role in their pathogen-
tions of the diaphragm attenuate the outflow of esis, perhaps inducing local abnormal pulmonary
fluid from the trachea and restrict the reduction of growth due to the obstructed outflow of fetal lung
pulmonary volume (Hooper and Harding 1995). fluid (Kunisaki et al. 2006), but it remains
unknown why this mechanism may lead to differ-
ent fetal chest masses.
47.5 Pulmonary Malformations The widespread use of antenatal ultrasound
with Doppler studies has also led to a better under-
Knowledge of the various phases of pulmonary standing of the development of some of these
development allows us to understand the patho- anomalies and to an improvement in their man-
physiology of the various congenital agement. Antenatal fast magnetic resonance
malformations of this organ, many of which, imaging is also an important adjunct to prenatal
thanks to the considerable development of prena- ultrasound in the evaluation of CTM: it may pro-
tal ultrasonography, may be diagnosed as early as vide further information on the nature of the lung
between the 18th and 20th weeks of gestation. anomaly, it may help to differentiate lung lesions
from extrathoracic abnormalities such as congen-
ital diaphragmatic hernia (CDH), and it may be
47.5.1 Intrapulmonary Cystic useful in planning pre- or postnatal surgery.
Malformations Large congenital malformations may compress
the ipsilateral lung or even the contralateral lung
Intrapulmonary cystic malformations comprise via mediastinal shift thus causing lung hypopla-
a spectrum of congenital malformations of sia. Compression of the esophagus may result in
the lower respiratory tract that have in common polyhydramnios; the resulting uterine distension
the fact that cysts may represent a prominent may induce premature labor. Impairment of car-
part of the anomaly (even if not always); these diac return due to the vena cava and to cardiac
include congenital cystic adenomatoid malfor- compression is responsible for fetal hydrops with
mation (CCAM), bronchopulmonary sequestra- ascites, pleural and pericardial effusions, and skin
tion (BPS), congenital lobar emphysemas and scalp edema.
(CLE), and bronchogenic cysts. CTM may change in size and/or appearance
Intrapulmonary cystic malformations have during pregnancy, but the growth pattern is rather
been increasingly detected at midgestation due to unpredictable. There is a wide spectrum of clinical
improvements in ultrasound technology and the severity, with a relationship between the size of
routine use of ultrasound as a screening test, but the malformation, concomitant lung hypoplasia,
those who interpret prenatal imaging should not and the occurrence of pulmonary hypertension in
attempt to make a histological diagnosis, which the newborn period. Most fetuses with CTM have
can be definitively supported only by the direct a good outcome, with majority of neonates being
examination of a tissue specimen. Actually, the asymptomatic at birth, and also an initially large
different postnatal diagnostic entities are difficult lesion does not necessarily correlate with a poor
to differentiate prenatally and there is confusion in prognosis (Adzick et al. 1998; Lacy et al. 1999).
terms of how these malformations should be Actually many lesions decrease in size over time
described; recently a new nomenclature using and some of them, defined as vanishing lesions,
the terms “congenital thoracic malformation” even disappear completely on serial prenatal ultra-
(CTM) and “congenital large hyperlucent lobe” sound scans toward the end of pregnancy (Adzick
have been proposed (Bush 2001). It has been et al. 1998; MacGillivray et al. 1993; Kunisaki
suggested that many, if not all, of these defects et al. 2015; Butterworth and Blair 2005; Calvert
may represent a continuum of anomalies of fetal et al. 2006; Borsellino et al. 2006). These lesions
47 Neonatal Lung Development and Pulmonary Malformations 741
are often undetectable on postnatal ultrasound and Recently it has been demonstrated that maternal
chest X-ray examination, except for some betamethasone therapy may induce regression of
extralobar lesions that may be identifiable, but in CTMs and reverse fetal hydrops. Several subse-
the vast majority of cases they can be detected by quent case series have confirmed that single and
computed tomography (CT) scans or magnetic multiple courses of steroid administration allow an
resonance imaging (MRI) (Blau et al. 2002; improved survival rate and decreased CVR (Baird
Kunisaki et al. 2015; van Leeuwen et al. 1999; et al. 2014; Peranteau et al. 2015). Steroids may act
Pumberger et al. 2003; Ierullo et al. 2005; at multiple levels, but the mechanism probably
Shanmugam et al. 2005). Therefore, all patients involves decreasing the production of lung fluid
with any prenatally detected lung malformation and increasing reabsorption within the CTM.
require mandatory postnatal evaluation by CT The postnatal clinical appearance of CTMs may
scan, that is, the gold standard to confirm the vary from immediate respiratory distress at birth to
presence or absence of a CTM. Due to the fact an incidental finding on a chest X-ray at any age. In
that many examples of hybrid lesions with fea- the neonatal period, a small number of patients
tures of CCAM and BPS have been described, it is with large lesions require surgery, which is the
also important in the postnatal period to seek an accepted standard of care for all symptomatic
anomalous blood supply in patients who have lesions. The treatment of the asymptomatic child
CTM, even if prenatally color flow Doppler stud- with CCAM is controversial because most of the
ies fail to identify a systemic arterial blood supply. lesions are microcystic and do not cause mediasti-
Most fetuses with a CTM will do well during nal shift postnatally. Most authors would recom-
pregnancy; however, if hydrops develops, the risk mend resection of CTMs because of complications
of fetal death is extremely high: up to 100% such as infections, hemorrhage, pneumothorax,
(Adzick et al. 1998; MacGillivray et al. 1993; sudden respiratory failure, and malignant transfor-
Wilson et al. 2006a). The CCAM volume ratio mation. The implication of operating on symptom-
(CVR), which measures the volume of the lung atic patients should not be underestimated (Baird
lesion divided by the head circumference, is a et al. 2014; Lakhoo 2009; Fitzgerald 2007; Stanton
widely accepted useful prognostic tool that allows and Davenport 2006). Moreover the outcome of
closer monitoring of fetuses at risk. Fetuses with early surgery is generally good, most of the infants
lung lesions with a CVR > 1.6 are at increased are extubated immediately after the procedure, the
risk of hydrops and require intervention and deliv- low complication rates are generally related to
ery at a high-risk center (Davenport et al. 2004; prolonged air leaks, and there is more time for
Baird et al. 2014). compensatory lung growth, which is thought to
In intrathoracic lesions with cystic parts, pre- explain the normal results of these children in
natal needle aspiration of the fluid has been pulmonary function tests (Baird et al. 2014). Fur-
performed but often leads to rapid thermore, conservative management of these
re-accumulation. Therefore, fetal surgery with lesions with repeated CT scans causes significant
the implantation of shunts between the cyst and radiation exposure. Successful expectant long-term
the amniotic space has successfully reduced the management has been reported particularly for
size of the lesion and improved hydrops fetalis; late-presenting asymptomatic or oligosymptomatic
however, this intervention may cause fetal death lobar emphysema (Ozcelik et al. 2003).
(Calvert et al. 2006; Salomon et al. 2003). CTMs can be removed surgically between
After 32 weeks of gestation, early delivery 3 and 6 months of age (Davenport et al. 2004;
should be considered in hydropic fetuses and, Calvert and Lakhoo 2007) either by open thora-
furthermore, when severe RDS is expected, the cotomy or, more recently, by using the minimally
ex-utero intrapartum therapy (EXIT) procedure invasive video-assisted thoracoscopy (VATS)
may be considered to allow interventions such as (Baird et al. 2014; Diamond et al. 2007; Shaw
drainage of large pleural effusions or even resec- et al. 2008). But, although VATS appears safe
tion of an affected lobe (Hedrick et al. 2005). and feasible and has clear cosmetic advantages,
742 C. Moretti and P. Papoff
this is based on its practice by experts and there is • Type 4: large air-filled cysts lined by flattened
currently insufficient evidence to endorse its epithelial cells (<10%).
widespread adoption outside institutions with
appropriate expertise and technical skills, which This classification can obviously only be
could cause excessively prolonged case durations applied to resected lung specimens and it is inap-
and related complications. propriate for describing fetal lung lesions. The
emerging consensus is that imaging findings
should simply describe without attempting to
47.5.2 Congenital Cystic Adenomatoid make a pathological diagnosis, as done by Adzick
Malformation in his classification (Adzick et al. 1985) in which
he simply differentiated prenatally detected cystic
CCAM is characterized by an adenomatoid pro- lesions into two types:
liferation of terminal bronchioles with the forma-
tion of solid, cystic, or mixed masses inside the • Macrocystic (single or multiple echogenic
pulmonary parenchyma without subsequent alve- cysts >5 mm)
olar differentiation (Hebra et al. 2000). This lesion • Microcystic (smaller echogenic cysts <5 mm)
is usually unilateral, without a right or left preva-
lence, and it affects a single lobe; vascularization
originates from the bronchial circulation, but in
47.5.2.3 Differential Diagnosis
hybrid cases it may depend on an anomalous
The chest radiograph and clinical symptoms of
systemic vessel.
CCAM may be easily confused with those of a
CDH: the insertion of a nasogastric tube and
47.5.2.1 Etiology and Pathogenesis
instilling a few mL of barium may help locate
The pathogenesis of CCAM is still unclear, but it
the stomach and hence facilitate differential diag-
is likely to be due to a failure of normal interaction
nosis (Fig. 5). Ultrasound and CT scans are also
between the mesenchymal tissue and epithelial
useful in determining the size of a normal lung
cells during early fetal life.
and the position of the diaphragm.
47.5.2.2 Clinical Aspects
47.5.2.4 Therapy and Treatments
The congenital cystic adenomatoid malformation
The risk of infections, associated with the
was originally classified by Stocker into three
risk of malignant degeneration of the
distinct histological subtypes and was subse-
quently expanded to five (Stocker 2002):
• Type 0: involvement of all lung lobes, incom-
patible with life (<2%).
• Type 1: single or multiple cysts, size >2 cm,
lined by pseudostratified columnar epithelium;
wall of fibromuscular and cartilaginous tissue
(60–70%).
• Type 2: single or multiple cysts (<2 cm)
lined by cuboidal or columnar epithelium
(15–20%).
• Type 3: predominantly solid lesions, with
small (<0.5 cm) cysts, lined by cuboidal epi-
thelium (5–10%). On the whole, this consti-
tutes a solid mass and is the form that has the Fig. 5 Left lower lobe CCAM with mediastinal shift to the
worst prognosis. contralateral side
47 Neonatal Lung Development and Pulmonary Malformations 743
adenomatoid tissue into rhabdomyosarcoma or located almost constantly on the left, may pre-
into bronchioloalveolar carcinoma or into sent as a subdiaphragmatic or retroperitoneal
other mesenchymal malignancies, a complica- mass, and is often associated with other congen-
tion described both in children and in adults ital malformations, in particular CDH. This mal-
(Lakhoo 2009; Stanton and Davenport 2006), formation has its own vascular supply that
is to be considered when deciding on surgery usually originates from the lower chest or
in an asymptomatic patient. Also, in asymp- upper abdominal aorta or one of its major
tomatic cases, a chest CT scan within 1 month branches, rather than from the pulmonary artery.
of birth is mandatory, even if a resolution is Usually the venous blood is normally drained
noted on prenatal scanning (Lakhoo 2009) and into the right atrium, but occasionally the venous
bearing in mind that a true resolution of these blood may also drain abnormally into the left
lesions is exceptional. atrium, the vena cava (the so-called scimitar
When needed, assisted ventilation in these syndrome for its characteristic chest radiograph
patients may determine a progressive distension appearance), or into the azygos system (Clem-
of the cysts with a life-threatening mediastinal ents 1999). The size of abnormal arteries and
shift: one-lung ventilation may be carried out in veins and consequently the blood flow through
order to achieve perioperative stabilization the malformation is considerable and may cause
(Fig. 5). High-frequency oscillatory ventilation heart failure and massive arteriovenous shunting
may also be successfully used in patients with (Cass et al. 1997). Recently many papers have
pulmonary hypertension (Rossi et al. 1998). described cystic lung lesions, defined as “hybrid
lesions,” with coexisting features of both CCAM
(the histological features are mostly Stocker
47.5.3 Bronchopulmonary type 2 lesions) and BPS, suggesting that they
Sequestration may represent the two ends of a broad spectrum
of disorders (Davenport et al. 2004; Rossi et al.
The term bronchopulmonary sequestration (BPS) 1998).
was introduced by Pryce in 1946, who took the Only a small percentage of children with
term from the Latin word sequestrate which intralobular sequestration have a symptomatology
means “to separate.” He used it to define a portion characterized by respiratory distress in the neona-
of the pulmonary tissue that does not work and is tal period. In most cases the malformation is
not linked to the bronchial tree. asymptomatic for a long time, and then it appears
later in life with localized recurrent pneumonias,
47.5.3.1 Etiology and Pathogenesis fever, and occasionally hemoptysis. By contrast,
The pathogenesis may be referred to an anomaly extralobular sequestration rarely presents respira-
in the development of the primitive lung bud tory symptoms and may also be found inciden-
with the formation of an ancillary structure that tally on routine chest radiography. BPSs have
has preserved the original arterial supply and rarely been linked with malignancy and most
that grows inside the pleural cavity in close con- likely these tumors develop in hybrid lesions
tact with the normal lung (intralobular seques- (Hekelaar et al. 2000).
tration), or it may remain separate and be
wrapped in its own visceral pleura (extralobular 47.5.3.3 Differential Diagnosis
sequestration). The initial detection of BPSs is currently
obtained by intrauterine sonography (Fig. 6)
47.5.3.2 Clinical Aspects and Doppler ultrasound is useful as it shows
Intralobular sequestration is the form most fre- the characteristic vascular abnormality. Postna-
quently found and is usually located in the tally, intralobular sequestration should be
paravertebral gutter in the posterior segment of suspected when the chest radiograph shows a
the left lower lobe. Extralobular sequestration is dense lesion on the posteromedial part of the
744 C. Moretti and P. Papoff
47.5.4.2 Clinical Aspects
Such lesions are found in the mediastinum in over
two-thirds of cases. They are usually located in the
right paratracheal or carinal regions, but can also
be found within the parenchyma of the lung. The
cysts contain a lining of respiratory epithelium
and have cartilage, smooth muscle, and glands in
the wall (Hebra et al. 2000). They are usually
unilocular, filled with fluid or mucus, and gener-
ally do not communicate with airways. The loca-
tion of the cyst is important in determining the
clinical presentation: a bronchogenic cyst may
Fig. 6 Pulmonary sequestration: midtrimester fetal sono- cause airway compression resulting in cough,
gram shows a triangular echogenic mass astride the left wheeze, dyspnea, or even respiratory distress,
diaphragm
and those located in the region of the carina may
determine lobar emphysema. Secondary infection
left or, less frequently, right lower zone of the of the cyst is also a very frequent complication and
lung. Multi-detector CT evaluation with intrave- may cause acute distension with exacerbation of
nous contrast for CT angiogram is useful in symptoms. In addition, peptic ulceration may
establishing the diagnosis: this study provides develop in cysts containing gastric mucosa
the best evaluation of the vascular anatomy of (Kirwan et al. 1973).
the lesion, of the appearance of the lesion itself,
of the diaphragm, and of the remainder of the 47.5.4.3 Differential Diagnosis
lung (Lee et al. 2004). Radiographic findings are variable and range
from a rounded mass to atelectasis or hyperin-
47.5.3.4 Therapy and Treatments flation of a lobe or an entire lung (Fig. 7). The
Surgery is recommended once the infant becomes diagnosis is usually established from the chest
symptomatic and should be undertaken only after X-ray, but the lesion must be differentiated
assessing the characteristics of the arterial supply from congenital lobar emphysema (CLE),
and of the venous drainage. acquired cysts complicating pulmonary intersti-
tial emphysema (PIE), and bronchopulmonary
dysplasia (BPD). Usually the latter two condi-
47.5.4 Congenital Lung Cysts tions can easily be differentiated through
patient history.
Congenital lung cysts are divided into broncho-
genic, alveolar, and combined forms. They may 47.5.4.4 Therapy and Treatments
lie outside the normal lung structure All congenital lung cysts require surgical resec-
(extrapulmonary) or within it (intrapulmonary). tion because they do not spontaneously regress,
The cysts tend to be limited to one lung and are and even those that are asymptomatic may cause
not associated with cystic disease elsewhere in the problems as a result of compression or infection
body. Bronchogenic cysts may vary notably in (Stanton and Davenport 2006).
size and are rare in the newborn period.
47.5.4.1 Etiology and Pathogenesis 47.5.5 Congenital Lobar Emphysema
Congenital lung cysts result from abnormal bud-
ding of the foregut; the position within the Congenital lobar emphysema (CLE), defined as a
branching pattern indicates when the cyst postnatal overdistension of one or more lobes of a
developed. histologically normal lung, is a rare cause of
47 Neonatal Lung Development and Pulmonary Malformations 745
Fig. 7 Left bronchogenic cyst. The arrow shows upper lobe emphysema
respiratory failure in the newborn, but in most the adjacent lobe collapsing down or up and medi-
patients the diagnosis is made before 6 months astinal shift to the contralateral side.
of life (Berlinger et al. 1987).
47.5.5.3 Differential Diagnosis
47.5.5.1 Etiology and Pathogenesis CLE can easily be confused with pneumothorax,
CLE may result from a malformation in the bron- but in the latter there are no bronchovascular
chial cartilage, with no or incomplete rings. It also markings in the radiolucent area (Stanton and
may result from extrinsic bronchial obstruction Davenport 2006). A CT scan is useful in the
caused by anomalous vessels or from intratho- differential diagnosis of a mediastinal mass.
racic masses such as bronchogenic cysts. The
etiology of the intrinsic bronchial obstruction is 47.5.5.4 Therapy and Treatments
thought to be a localized interruption of the blood The traditional treatment for most cases of CLE
supply to an already formed bronchus, resulting in with respiratory distress is lobectomy. Conserva-
bronchial infarction and luminal obstruction or tive treatment is possible in asymptomatic or
developmental abnormalities of the bronchial car- mildly symptomatic cases (Thakral et al. 2001).
tilage after completion of bronchial branching
(Kuhn and Kuhn 1992).
47.5.6 Pulmonary Agenesis
47.5.5.2 Clinical Aspects
The left upper lobe is most often involved (Fig. 8), Pulmonary agenesis may be classified morpholog-
followed by the right middle lobe; involvement of ically by the extent to which bronchopulmonary
the lower lobes is very rare. Dyspnea, tachypnea, tissue is absent (Hebra et al. 2000). Pulmonary
wheezing, tachycardia, and cyanosis are among agenesis is divided into (1) bilateral complete agen-
the most common presenting symptoms. Chest esis; (2) unilateral agenesis with (a) complete
radiograph, CT scan, ventilation scintigraphy, absence of the lung and bronchus and no vascular
and bronchoscopy are usually sufficient for diag- supply to the affected side (agenesis),
nosis. The chest radiograph will demonstrate (b) rudimentary bronchus with complete absence
marked hyperinflation of the affected lobe with of pulmonary parenchyma (aplasia), and
746 C. Moretti and P. Papoff
Fig. 9 Chest X-ray of a neonate with agenesis of the right
lung. Black arrows show the right lobar bronchi ending
blindly. Mediastinum shifts to the right side
47.5.6.1 Clinical Aspects
Unilateral pulmonary agenesis may present with
severe respiratory distress at birth or may be
asymptomatic. In this latter occurrence, recurrent
respiratory symptoms secondary to respiratory
tract infections may appear later in life. On aus-
cultation, mediastinal shift and hyperresonance of
the contralateral hemithorax side are usually pre-
Fig. 8 Congenital left upper lobar emphysema. The upper
arrows show retrosternal hernia. The lower arrow shows
sent. Asymmetry of the chest becomes more
the collapse of the lower lobe noticeable in the adult patient (Swischuck 2004).
With postnatal compensatory growth, the
remaining lung often herniates into the contralat-
(c) presence of variable amounts of the bronchial eral chest. Chest X-ray shows a mediastinal shift
tree, pulmonary parenchyma, and supporting vas- toward the affected side (Fig. 9), and skeletal
culature (hypoplasia); and (3) lobar agenesis. Pul- abnormalities may be present. Absent or incom-
monary agenesis is a very rare malformation and plete lung development may be associated with
the left lung is slightly more affected than the right abnormalities of the trachea, absence of one or
(Mardini and Nyhan 1985). Isolated agenesis of a both kidneys, cardiac defects (patent ductus
lobe or lobes is more common than total unilateral arteriosus, patent foramen ovale, ventricular
lung agenesis. This abnormality occurs more often defects, pulmonary veins entering the azygos
on the right than on the left, involving the upper vein), gastrointestinal malformations (atresia ani,
and middle lobes. esophageal atresia, short bowel), skeletal
47 Neonatal Lung Development and Pulmonary Malformations 747
anomalies (spina bifida, wedge-shaped vertebrae, 47.5.7.1 Etiology and Pathogenesis
hemivertebra, deformed ribs, absent left hand, Primary PH includes pulmonary agenesis (unilat-
absence of right radius, rudimentary atlas), eral) (Abrams et al. 2004) with or without associ-
deformed external ear, and many others. Differen- ated malformations and idiopathic PH (bilateral).
tial diagnosis should be made with lung atelecta- The causes of primary PH have not been identi-
sis, CDH, CCAM, and BPS (Gabarre et al. 2005). fied. Nakamura and colleagues (Nakamura et al.
The difficulty of diagnosis depends on the side of 1992) revealed five statistically significant risk
the absent lung, the apparent dextrocardia induced factors associated with secondary PH from a
by absence of the right lung being a striking large series of autopsy cases: (1) hydrops fetalis,
clinical finding. Bronchoscopy has been used to (2) renal anomalies, (3) CDH, (4) skeletal
establish the diagnosis of pulmonary agenesis. anomalies, and (5) oligohydramnios and
Typical findings include a bronchus narrowing polyhydramnios (Table 2).
and ending blindly. Pathologically, the hypoplastic lung shows a
low ratio of lung to body weight, low DNA con-
tent, or a decreased radial alveolar count
47.5.6.2 Prognosis (Askenazi and Perlman 1979). Epithelial differen-
About 50% of patients survive; the mortality rate tiation is delayed, and surfactant deficiency is
is higher with agenesis of the right lung than of the associated (Asabe et al. 1994). Both pulmonary
left lung. arterioles and bronchioles are decreased in size.
Arterial thickness is a common finding in periph-
eral pulmonary blood vessels (Barth and R€uschoff
47.5.7 Pulmonary Hypoplasia 1992).
Pulmonary hypoplasia (PH) is a common and 47.5.7.2 Clinical Aspects
serious problem in the perinatal period with a In patients with PH, the clinical profile and the
significant mortality rate. PH is defined as a time of presentation vary depending on the extent
defective or incomplete development of lung of hypoplasia and other anomalies. Severe respi-
tissue characterized by a reduction in the number ratory insufficiency resulting in a fatal outcome is
of lung cells, airways, and alveoli, resulting in a the presenting symptom in a vast majority of
lower organ size and weight. The pulmonary preterm infants with severe bilateral PH. In infants
vascular bed is reduced in size with a decreased with PH, the lung function is abnormal at birth
vessel count and increased pulmonary vascular with reduced tidal volume, increased respiratory
muscular development (Barth and R€uschoff rate, and reduced static lung compliance and func-
1992). PH encompasses a wide spectrum of ana- tional residual capacity. On autopsy, the gold stan-
tomic malformations ranging from total bron- dard to confirm PH is a lung to body weight ratio
chial and parenchymal agenesis to mild of less than 0.015 with reduced radial alveolar
pulmonary parenchymal hypoplasia. The lesions count or total DNA count (Burri 1986).
may be lobar, unilateral, or bilateral. Cases of The history of PH may include poor fetal
isolated lobar defects have only been rarely movement or amniotic fluid leakage and
reported. PH may be an isolated entity (primary oligohydramnios. In more mature neonates, mild
PH) or be secondary to lesions restricting lung to moderate hypoplasia or unilateral PH may be
growth (Abrams et al. 2004). Prolonged prema- asymptomatic or may present with respiratory
ture rupture of membranes (PPROM) at less than distress that requires mechanical ventilation.
25 weeks gestation, severe oligohydramnios Newborn infants with moderate to severe PH
(amniotic fluid index <4) for more than often present with persistent pulmonary hyperten-
2 weeks, and earlier delivery are known risk sion responding to inhaled nitric oxide (iNO)
factors for severe PH (de Waal and Kluckow (Uga et al. 2004) as a result of reduced vascular
2015). bed and secondary arterial muscular hypertrophy.
748 C. Moretti and P. Papoff
Table 2 Causes of secondary pulmonary hypoplasia should be caused by the associated renal defects
Small fetal thoracic volume (Potter 1946a). When the etiology of the PH is a
CDH neuromuscular disease, the patient may have
Eventration of the diaphragm myopathic facies, with a V-shaped mouth, muscle
Abdominal mass lesions weakness, and growth retardation.
Exomphalos A number of studies have described associated
Pleural effusions with fetal hydrops anomalies with PH including heart defects (e.g.,
Hydrothorax anomalous venous return to the right atrium or the
CAM inferior vena cava or scimitar syndrome, absence
Sequestration of the ipsilateral pulmonary artery), skeletal and
Malformations of the thorax (e.g., asphyxiating vertebral anomalies (metacarpal and radial anom-
thoracic dystrophy)
alies, failure of segmentation of thoracic or other
Achondroplasia
Thanatophoric dwarfism
vertebrae, rib abnormalities), abdominal defects
Osteogenesis imperfecta (diaphragm, abdominal wall defects), facial
Thoracic neuroblastomas abnormalities, and numerous lung and tracheo-
Prolonged oligohydramnios bronchial tree defects. There have been a number
Fetal renal agenesis of case reports of PH and tracheoesophageal fis-
Urinary tract obstruction tula and a number of reports of an association of
Bilateral renal dysplasia tracheal stenosis with pulmonary agenesis. Simi-
Bilateral cystic kidneys lar to patients with a more severe degree of PH,
Prolonged rupture of membranes neonates with isolated lobar hypoplasia may dem-
Early rupture of membranes onstrate other congenital malformations.
More severe oligohydramnios
(amniotic fluid index < 4)
47.5.7.3 Diagnostic Methods
Longer latent period before delivery
The diagnosis of PH can be made with certainty
Decreased fetal breathing
only at autopsy by measurement of total lung DNA
CNS lesions
content. Because of this, the incidence of PH is
Lesions of the spinal cord, brain stem
and phrenic nerve probably underestimated. The diagnosis should be
Neuromuscolar disease (e.g., myotonic suspected in the presence of perinatal factors sug-
dystrophy, spinal muscular atrophy) gestive of PH, unexpected respiratory distress, and
Arthrogryposis multiplex congenital specific findings at clinical examination.
Maternal depressant drugs Diagnosis of unilateral lobar PH requires a
Congenital heart disease with poor pulmonary blood high index of clinical suspicion and experience
flow
with reading neonatal and infant radiographs.
Tetralogy of Fallot
Characteristic findings on the chest radiograph
Hypoplastic right heart
are of a small bell-shaped chest with raised
Pulmonary artery hypoplasia
hemidiaphragms and clear lung fields, although
Scimitar syndrome causing a unilateral right-sided
pulmonary hypoplasia “clear lung fields” may be masked by radio-
graphic signs of respiratory distress in prema-
turely born infants. A radiographic diagnosis
Pneumothorax, spontaneous or associated with may be supported by clinical findings of an infant
mechanical ventilation, may occur (Knox and unresponsive to ventilatory support and exoge-
Barson 1986). Compression deformities due to nous surfactant therapy. Chest CT or MRI may
prolonged oligohydramnios, contractures, and be needed to better delineate the defect and to
arthrogryposis may be present when PH is asso- detect possible associated malformations (acces-
ciated with oligohydramnios. The Potter facies sory diaphragm, BPS adjacent to a small CDH).
(hypertelorism, epicanthus, retrognathia, Unilateral PH should be suspected in the presence
depressed nasal bridge, low-set ears) suggest PH of hyperlucency and smallness of one lung.
47 Neonatal Lung Development and Pulmonary Malformations 749
Hyperdistention of the contralateral lung can absence of amniotic fluid. A combination of clin-
be seen. ical, biometric, and Doppler parameters may be
The diagnosis of primary PH implies a lack of most predictive in identifying lethal PH. Although
any specific pathophysiologic process that could antenatal prediction may be useful in guiding
cause fetal lung compression. For the diagnosis of management and counseling parents, it should
secondary PH, abdominal masses, such as cystic be noted that a lethal outcome is also dependent
renal diseases and an enlarged bladder, must be on the postnatal management including intention
sought. Associated anomalies of the cardiovascu- to treat and level of neonatal care offered.
lar, gastrointestinal (e.g., tracheoesophageal fis-
tula, imperforate anus, communicating 47.5.7.4 Differential Diagnosis
bronchopulmonary foregut malformation), and The differential diagnosis of respiratory distress in
genitourinary system, as well as skeletal anoma- the newborn associated with marked opacification
lies of the vertebrae, thoracic cage, and upper of one side of the thorax on radiograph includes
limbs, may be found upon examination. atelectasis, CDH, CCAM, BPS, chylothorax, PH,
Echocardiography is fundamental to reveal bronchogenic cyst, and a chest tumor (e.g., neuro-
possible cardiac defects. Prenatal ultrasound blastoma, teratoma, fibrosarcoma). In a right-sided
(Gerards et al. 2008) and, more recently, fetal CDH, there may be opacification of the right
MRI constitute the methods of choice to investi- hemithorax if the liver is occupying that space. A
gate the fetal lung development throughout preg- left-sided CDH will have air-filled loops of bowel
nancy (Gorincour et al. 2005). in the chest except possibly in a chest radiograph
Basically, the MRI assessment of fetal lung taken shortly after birth or following bowel decom-
growth and maturation consists of three diagnos- pression. CCAM will usually appear as a cystic
tic elements. First, fetal MR volumetry is used to mass rather than a homogenous opacification.
identify restricted and insufficient lung growth. Obstruction of the bronchus with resultant
Second, the evaluation of signal intensities using opacification of the hemithorax may occur with a
different MR sequences provides information bronchogenic cyst or a vascular sling. Neonatal
about the maturation of the fetal lung. Third, the chest tumors are very rare and may present with a
high resolution and tissue contrast of MRI allows focal abnormality on chest X-ray.
us to examine the structure of the fetal lung and to In cases of bilateral PH with hyperlucent lungs,
offer a more detailed diagnosis of fetal pulmonary idiopathic PPHN should be considered in the dif-
pathologies (Kasprian et al. 2006). ferential diagnosis, whereas the presence of small
lungs may suggest spinal thoracic dysplasia or
Antenatal Prediction of Pulmonary neuromuscular diseases.
Hypoplasia
Three-dimensional ultrasound has been used to 47.5.7.5 Therapy and Treatments
identify PH in the high-risk fetuses. In a series of Treatment of PH is largely supportive, and prog-
35 fetuses (Pumberger et al. 2003), sensitivities of nosis will depend on the presence or absence of
85% and 92% for predicting PH were achieved the other anomalies. iNO administered to pre-
when the results were adjusted for gestational age, term infants with PPROM, oligohydramnios,
estimated fetal weight, and two-dimensional bio- and PH improves oxygenation, survival, or
metric measurements. As well as reduced lung other clinical outcomes (Shah and Kluckow
volume, these babies may also exhibit PPHN. 2011). Because of the surfactant deficiency,
Prediction of PPHN is difficult to assess before a significant number of infants with PH
birth. Despite this, reduced diastolic and systolic require surfactant replacement therapy and
velocities in the pulmonary arteries have been high-frequency oscillatory ventilation (HFOV)
demonstrated by Doppler examination of fetuses (Cacciari et al. 2001).
affected by PH (Wilson et al. 2006a), but mea- Conventional therapies may fail in these
surements can be technically difficult in the infants who then become candidates for ECMO
750 C. Moretti and P. Papoff
(Stevens et al. 2002). The eventual survival is 45 mmHg were predictive of poor outcome
limited by the underlying degree of PH. (Datin-Dorriere et al. 2008).
A high level of neonatal intensive care is likely
to be necessary, and delivery should take place,
where possible, in a tertiary neonatal center. Initial 47.5.8 Oligohydramnios Syndrome
aggressive management should be attempted even
if the infant shows signs of severe respiratory Bilateral PH commonly occurs in association with
failure compatible with PH. It is recognized that oligohydramnios caused by either renal disease in
a subset of infants suffers from isolated PPHN, the fetus or chronic leakage of amniotic fluid as a
who respond well to immediate ventilatory and consequence of PPROM. Infants subject to
pulmonary vasodilator therapy with relatively few oligohydramnios resulting from chronic leakage
long-term complications (Alescio and Cassini of amniotic fluid over many weeks may exhibit a
1962; Thakral et al. 2001). varying degree of PH. Oligohydramnios may act
The optimal ventilatory management of infants by compressing the fetal thorax or altering the
born following prolonged oligohydramnios and dynamics of lung fluid so that full expansion of
exhibiting signs of PH remains to be defined. the lungs cannot be maintained. The severity of
There is a theoretical advantage of HFOV among the PH is directly proportional to rupture of the
infants suffering from PH, as it provides the possi- membranes early in gestation, longer duration of
bility of optimal alveolar recruitment while reducing rupture, and the presence of the oligohydramnios
the risk of excessive barotrauma. The use of HFOV during the period of rupture.
in the context of PH following PPROM has been For the fetal lung to develop normally, the fetal
evaluated, and a positive effect has been proposed in airways must be filled with fluid (Copland and Post
addition to iNO (Shah and Kluckow 2011). 2004). Movement of chloride ions to the pulmo-
Preterm infants born following midtrimester nary lumen provides the main force for lung liquid
PPROM may also suffer from respiratory distress secretion with a net production rate of lung fluid of
syndrome, and “conventional” surfactant therapy about 4–5 mL/kg/h. The pressure in the fetal tra-
is indicated. Infants with severe PH, however, chea exceeds that in the amniotic fluid by about
may fail to show a positive response to surfactant 2 mmHg, thus amniotic fluid rarely enters the tra-
therapy alone. chea. Several factors affect the volume and com-
Due to the high incidence of neonatal infec- position of the amniotic fluid, including amount of
tion following prolonged oligohydramnios, fetal urine and chronic leakage of amniotic fluid
appropriate investigations should be undertaken, secondary to PPROM at 15–28 weeks’ gestation.
and treatment with broad-spectrum antibiotics is Possible mechanisms of abnormal lung growth
mandatory if an infection with an unknown path- following oligohydramnios include: reduced lung
ogen is suspected. fluid production (Blott et al. 1987) and consequent
reduced production of growth factors (e.g., vascu-
47.5.7.6 Prognosis lar endothelial growth factor, angiopoietins,
Long-term consequences of PH include: reduced endothelins and platelet-derived growth factor,
exercise tolerance, even in mild cases, scoliosis in fibroblast growth factor); reduced fetal breathing
adolescent years, recurrent respiratory infections, movements that are essential for lung growth;
and chronic pulmonary insufficiency. Right-sided inflammation and infection which have a detri-
hypoplasia has a worse prognosis than left-sided mental effect on pulmonary vascular develop-
hypoplasia, probably because of the loss of the ment, such as smooth muscle hypertrophy of the
bigger right lung mass and more severe mediasti- distal pulmonary arterioles and decreased produc-
nal shift and great vessel displacement (Fisher tion of endothelial nitric oxide synthase; and other
et al. 2008). vascular growth factors.
During the first 48 h of life, the best oxygena- Oligohydramnios can be associated with a
tion index above 13 and the best PaCO2 above spectrum of fetal positional and compression
47 Neonatal Lung Development and Pulmonary Malformations 751
abnormalities, such as pes equinovarus and a bell- studies suggest that approximately 0.5–1% of
shaped thorax. infants who are stillborn or die in the neonatal
The presence of PH in infants with bilateral period have congenital PL (Moerman et al. 1993).
renal agenesis was first recognized by Potter in
1946. It has since become apparent that a similar 47.5.9.1 Etiology and Pathogenesis
picture of the lethal PH is seen in conjunction with Noonan and colleagues classified congenital PL
bilaterally dysplastic kidneys with or without cyst into three pathophysiological groups (Noonan
formation and in infants with congenital obstruc- et al. 1970):
tive uropathy.
In the cases of renal agenesis, the reduction in • Type 1 – Generalized PL with thoracic and
lung volume and number of the alveoli is greater extrathoracic involvement
than in renal dysplasia, where these changes are • Type 2 – PL secondary to pulmonary venous
more variable in their severity (Potter 1946b). obstruction due to congenital heart disease
Despite attempts at in utero decompression • Type 3 – Primary pulmonary developmental
of the urinary system, fetal surgery in this dis- defect of the lung
ease remains controversial and has met limited
success. Clinically, two forms of PL have been recog-
nized: primary or congenital (types 1 and 3) and
47.5.8.1 Antenatal Management secondary (type 2), which occurs as a result of
of Oligohydramnios injury to the lymphatic vessels. The primary type
• Surveillance of infection by microbiological has a neonatal onset and is often fatal (Esther and
examination of the amniotic fluid. Barker 2004). It may be caused by a congenital
• Antibiotic therapy. defect in the primary development of the lung or
• Antenatal corticosteroids should be given to may represent the localized expression of more
women presenting with PPROM prior to generalized lymphatic involvement (nonimmune
32 weeks. hydrops).
• Tocolysis to delay delivery and allow for the The pulmonary lymphatic system is normally
administration of corticosteroids. well developed by the end of the 14th week of
• Normalizing amniotic fluid volume with gestation. Initially, large lymph channels are pre-
amnioinfusion. sent in the normal fetal lungs, which later undergo
• Promotion of fetal lung growth and develop- spontaneous regression. It is believed that failure
ment with tracheal occlusion (Keller et al. of these channels to undergo the normal regres-
2004). sion leads to congenital PL.
The secondary form results from impaired
lymphatic drainage and increased lymphatic pro-
47.5.9 Pulmonary Lymphangiectasia duction as a consequence of increased venous and
lymphatic hydrostatic pressure; it may also be due
Pulmonary lymphangiectasia (PL) is a rare develop- to cardiac lesions, which have been hypothesized
mental disorder involving the lung and is character- to interfere with the normal regression of the
ized by pulmonary subpleural, interlobar, lymphatic tissue elements after the 16th week of
perivascular, and peribronchial lymphatic dilatation. fetal life (Esther and Barker 2004). Hypoplastic
Reports of occurrence in siblings suggest a left heart syndrome, pulmonary vein atresia, con-
genetic inheritance in some families and possibly genital mitral stenosis, cor triatriatum, and tho-
an autosomal recessive mode of transmission (Ste- racic duct agenesis are the most likely causes of
venson et al. 2006); however, most cases occur secondary PL.
sporadically (Wilson et al. 2006b). Males are more Congenital PL may be associated with
frequently affected than females (ratio 2:1). The nonimmune hydrops fetalis and with congenital
incidence of PL is not clearly defined. Autopsy chylothorax (Cadichon 2008a).
752 C. Moretti and P. Papoff
47.5.9.2 Clinical Aspects lymphoscintigraphy (Sty et al. 1984), lung func-
Clinical diagnosis of congenital PL can be tionality tests (Barker et al. 2004), lung biopsy
strongly suspected in neonates who present (Bellini et al. 2006), bronchoscopy, and pleural
severe respiratory distress with or without gener- effusion examination (Bellini et al. 2006).
alized or localized lymphedema and with pleural Chest X-rays usually show hyperinflation with
effusion (especially if chylous) either monolateral interstitial markings. CT demonstrates diffuse
or bilateral although the disease affects both thickening of the interstitium, both of the
lungs. peribronchovascular interstitium and the septa sur-
In the postneonatal period, PL can occur any rounding the lobules. Coronal MRI T1 may show
time in childhood or even adult life. During both thickening of the interstitium, pleural fluid effu-
the neonatal and postneonatal period, PL may be sion, and atelectasia, if present. Axial MRI T2
associated with chylothorax, chylopericardium, usually shows high-signal material within the pul-
and chylous ascites (Dempsey et al. 2005). In monary interstitium, which is very often associated
older children it is frequently associated with with pleural effusion. Despite the greater dose of
recurrent cough, wheeze, increased respiratory radiation that is given during CT as compared to
effort with inspiratory crackle, and even conges- chest radiography, CT is preferable for the diagno-
tive heart failure (Smeltzer et al. 1986). sis of PL and, more generally, for the diagnosis of
Although most cases of PL are sporadic, con- pediatric interstitial lung disease. Lymphoscin-
genital PL has been described in autosomal dom- tigraphy is a mildly invasive technique that pro-
inant, recessive, and X-linked syndromes. The vides valuable morpho-functional information
occurrence of congenital PL in siblings and the regarding the lymphatic system (Sty et al. 1984).
association with a wide number of syndromes It highlights the accumulation of lymphatic fluid in
including patients with 46,XY/46,XX mosaicism, the interstitial tissue that causes swelling, which is
congenital ichthyosis, Noonan syndrome, Turner most evident in the limbs. In the few cases in which
syndrome, Fryns syndrome, Down syndrome, and lung function tests were performed, they showed
other syndromes suggest genetic predisposition various patterns including restrictive, obstructive,
(Esther and Barker 2004; Ozturk et al. 2000). and normal values. It is noteworthy that pulmonary
function tests were stable over time in the patients
47.5.9.3 Diagnostic Methods who obtained multiple values. Bronchoscopic
During the prenatal period, all causes leading to evaluation, while not specifically indicated in PL,
hydrops fetalis have to be taken into consideration. may be useful for ruling out other pulmonary
The diagnostic approach includes the following: pathologies. No tracheobronchial anatomical
complete family and obstetric history, laboratory abnormalities were reported in PL patients who
investigations including blood type, Rhesus factor were evaluated by bronchoscopy.
(Rh), antibody screening, TORCHES-CLAP titer Lung biopsy may be useful to demonstrate the
(Toxoplasma gondii, rubella virus, Cytomegalovi- presence of dilated lymphatic spaces in the
rus, herpes simplex virus, Enterovirus, syphilis, subpleural connective tissue, along the thickened
varicella-zoster virus, Lyme disease, AIDS interlobar septa, and around the bronchovascular
(acquired immune deficiency syndrome), parvovi- axes. Great care must be taken when interpreting
rus B19), metabolic studies, and hemoglobin (Hb) lung biopsies. In fact, the pathological findings in
electrophoresis (Stephenson et al. 1994). An instru- congenital PL patients may change a great deal
mental evaluation is needed to rule out various over time, especially in case of viral infection,
conditions possibly related to PL and to establish and, more generally, may range from initial recog-
whether PL is primary or secondary. nition of minimal evidence of lymphatic dilatation
Diagnostic methods that may be useful in eval- to proof of severe lymphangiectasia. In this case,
uating PL include conventional radiologic studies, the lymphatic vessels are characterized by a thin
echocardiography, high-resolution CT (Nobre wall, devoid of smooth muscle, and with slightly
et al. 2004) and MRI (Seed et al. 2009), dilated lumen, lined by flattened endothelial cells.
47 Neonatal Lung Development and Pulmonary Malformations 753
47.5.9.4 Differential Diagnosis many other plasma factors that must be replaced.
During the neonatal period, transient tachypnea of Nutrition plays a role in reducing lymphatic pro-
the newborn and interstitial pulmonary infection duction. Enteral nutrition with medium-chain tri-
are well known and are usually taken into consid- glycerides and a total parenteral nutrition have
eration in the differential diagnosis of respiratory been successfully employed. Octreotide has been
distress syndrome in the neonate. Rarer conditions used in PL to reduce lymph production. When the
must also be considered in the differential diag- chyle leakage persists, pleurodesis by instillation
nosis of chronic interstitial lung disease in infants of sclerosing agents or parietal pleurectomy
and include surfactant protein B deficiency, appears to be effective.
desquamative interstitial pneumonitis (familial
and nonfamilial forms), pulmonary alveolar 47.5.9.6 Prognosis
proteinosis, idiopathic pulmonary fibrosis, lym- Recent advances in neonatal intensive care have
phoid interstitial pneumonitis, cellular interstitial changed the previously nearly fatal outcome of PL
pneumonitis, and chronic pneumonitis of infancy at birth. However, contradictory data have been
(Esther and Barker 2004; Bellini et al. 2008). reported regarding the outcome and do not allow a
In older children or in adults, PL presents consistent prognosis to be established. The out-
with a milder course. Conditions that can come is more likely to be favorable if there are no
mimic interstitial lung disease in infants and associated defects. Respiratory problems can con-
children include neuroendocrine cell hyperpla- tinue over the first years of life and often require
sia of infancy, acute pulmonary hemorrhage of home supplemental oxygen and symptomatic
infancy, follicular bronchiolitis, pulmonary vas- treatment for recurrent cough and wheeze.
cular disorders (obstructive pulmonary venous
disease, i.e., total and partial anomalous pulmo-
nary venous return, pulmonary vein atresia or 47.5.10 Chylothorax
stenosis), hereditary hemorrhagic telangiectasia,
pulmonary hemangiomatosis, various systemic Chylothorax is an unusual entity in the neonate
diseases, and metabolic lipid storage disorders. that commonly is associated with respiratory
symptoms in the first day of life and may be
47.5.9.5 Therapy and Treatments expression of congenital PL. The incidence of
Delivery room management could be a challenge congenital chylothorax is about 1:10,000–15,000
in the presence of severe respiratory distress asso- pregnancies, with a male-female ratio of 2:1.
ciated with pleural effusion, and multiple proce- Chylothorax presenting at birth may be associated
dures might be required. Tracheal intubation and with cardiac anomalies, various syndromes, tho-
assisted ventilation are usually necessary. Infants racic ductal or venous thrombosis, birth trauma or
with persistent pulmonary hypertension and diffi- local compression of the thoracic duct, and con-
culties oxygenating should be ventilated with genital malformation of the lymphatic system
HFOV and could benefit from iNO administra- (lymphangiomatosis) (Moerman et al. 1993;
tion. Sterile thoracentesis or paracentesis should Mettauer et al. 2009; Ergaz et al. 2009).
be considered to reduce respiratory distress. Fluid Chylothorax has been described as a complication
replacement and inotropic support are often nec- of Down syndrome, in which there is presumably
essary. Patients with acute respiratory failure who a significant maldevelopment of the lymphatic
are refractory to maximal conservative treatment system. Other patients may have Turner or
might be considered candidates for ECMO. In Noonan syndrome. Infants may have cystic
patients with rapidly expanding pleural effusion hygroma malformations (Moerman et al. 1993;
that requires placing unilateral or bilateral chest Rocha et al. 2006). Acquired chylothorax results
tubes, the large amount of fluid (that is drained from damage to the thoracic duct. It has been
over days or weeks) leads to the loss of great reported as a surgical complication in the repair
quantities of albumin, immunoglobulin, and of congenital diaphragmatic hernia,
754 C. Moretti and P. Papoff
tracheoesophageal fistula, and a variety of con- cases the infant is managed with nothing by
genital heart disorder (e.g., patent ductus mouth, with nutritional support through a
arteriosus ligation). Acquired chylothorax may central line.
also be the consequence of drainage of pneumo- Octreotide, antiplasmin, and oral sildenafil have
thorax when the tube is inserted too far (Cadichon been used in CPL and chylothorax (Epaud et al.
2008b). In many cases, however, no underlying 2008; Malleske and Yoder 2015; Kalomenidis
cause for the chylothorax is found. Chylothorax is 2006).
more common on the right side: Chernick and A variety of approaches have been used with
Reed said that 53% of the cases were on the some success to treat the infant with persistent
right side, 35% on the left side, and 12% were chylothorax, including direct attempts at repair,
bilateral (Cadichon 2008b). Since chylothorax is thoracoscopic parietal pleural clipping (Clark
typically unilateral, there may be decreased breath et al. 2015), patching with fibrin glue, or obliter-
sounds over the side of the effusion and mediasti- ation of the pleural space with sclerosing agents
nal shift to the contralateral side. Bilateral (Rifai et al. 2003). Congenital chylothorax also
chylothoraces should be considered in the differ- has been managed successfully using a
ential diagnosis for any infant who cannot be pleuroperitoneal shunt (Podevin et al. 1999).
ventilated in the delivery room. The characteristic Finally some reports suggest that ligation of the
roentgenographic appearance is similar to that of a thoracic duct below the area of leakage is highly
large pleural effusion depressing the adjacent dia- effective; this procedure is well tolerated without
phragm and displacing the mediastinum. accumulation of fluid in the peripheral tissues or
The evaluation of the pleural effusion is essen- in the peritoneum (Andersen et al. 1984).
tial for the diagnosis of chylothorax. Chylothorax
is usually diagnosed in the presence of “milky”
pleural effusion with a triglyceride level 47.5.11 Misalignment of Pulmonary
>1.1 mmol/L and a cell count >1,000 cells/μL, Veins with Alveolar Capillary
with a predominance of lymphocytes (approxi- Dysplasia
mately 80%), according to the criteria drawn up
in previous reports (Bellini et al. 2006). However, Alveolar capillary dysplasia (ACD) is a rare dis-
this is an unreliable diagnostic test in malnour- order typically presenting at birth with severe
ished patients and in patients not receiving enteral hypoxemia, although an unusual late onset has
nutrition, including the fetus and occasionally the been reported as late as 7 months of age offering
neonate. Without enteral feeding, not enough chy- the possibility that long-term survivors with
lomicron (the main triglyceride carrier) is pro- milder forms of the disease may exist (Bishop
duced to raise chyle triglyceride levels. In these et al. 2011; Shankar et al. 2006). No gender pre-
patients, chylothorax may be diagnosed by dilection has been identified. While the cause is
detecting lymphocytes in the pleural fluid. unknown, there have been six cases reported in
Treatment of chylothorax may require repeated siblings, indicating that in some cases this may be
thoracenteses or even thoracostomy tube drainage a familial disorder with autosomal recessive
to prevent respiratory failure. The large amount of inheritance (Gutierrez et al. 2000). ACD is distin-
fluid that is drained over days and weeks leads to guished by immature lobular development and
the loss of great quantities of albumin, immuno- reduced capillary density, both of which indicate
globulin, and many other plasma factors that must premature growth arrest.
be replaced, in some cases even on a daily basis.
Once drainage is accomplished, these infants are 47.5.11.1 Etiology and Pathogenesis
placed on formulas containing medium-chain tri- Pathological features include reduction of alveolar
glycerides (MCTs) to reduce thoracic duct lymph capillaries, widened alveolar septa, and increased
flow. Oral intake of protein and water also stimu- muscularization of pulmonary arterioles (Melly
lates thoracic duct lymph flow, so in resistant et al. 2008). There is usually malpositioning
47 Neonatal Lung Development and Pulmonary Malformations 755
(“misalignment”) of pulmonary veins in the transplantation. However, successful transplanta-
bronchovascular bundle, but this is not required tion has not yet been reported. Donor availability
for the diagnosis. As a consequence blood entering continues to limit the utilization of lung transplan-
an individual lung unit can only drain via anoma- tation for neonatal diseases.
lous (“misaligned”) veins. The obstruction that is
created leads to the occlusive changes observed in
the pulmonary arterial circulation. A focal distribu-
tion of disease has been described, which makes it References
necessary to examine multiple lung sections if
Abrams ME, Ackerman VL, Engle WA (2004) Primary
ACD is suspected.
unilateral pulmonary hypoplasia: neonate through early
childhood – case report, radiographic diagnosis and
47.5.11.2 Clinical Aspects review of the literature. J Perinatol 24:667–670
Adzick NS, Harrison MR, Glick PL et al (1985) Fetal
Infants with ACD usually present with minimal or cystic adenomatoid malformation: prenatal diagnosis
no parenchymal lung disease. Profound hypoxemia and natural history. J Pediatr Surg 20:483–488
and severe metabolic acidosis consistent with severe Adzick NS, Harrison MR, Crombleholme TM et al (1998)
PPHN and right ventricular failure are nearly always Fetal lung lesions: management and outcome. Am J
Obstet Gynecol 179:884–889
present. However, infants with ACD do not respond Alescio T, Cassini A (1962) Induction in vitro of tracheal
or respond only transiently to therapies that are buds by pulmonary mesenchyme grafted on tracheal
usually effective in reversing pulmonary hyperten- epithelium. J Exp Zool 150:83–94
sion (iNO or ECMO) (Parker et al. 1997). Andersen EA, Hertel J, Pedersen SA et al (1984) Congenital
chylothorax: management by ligature of the thoracic
The diagnosis of ACD should be considered in duct. Scand J Thorac Cardiovasc Surg 18:193–194
infants who present with severe hypoxemia and Asabe K, Toki N, Hashimoto S et al (1994) An immunohis-
PPHN and who do not respond appropriately after tochemical study of the expression of surfactant
7–10 days of standard treatment as described apoprotein in the hypoplastic lung of rabbit fetuses
induced by oligohydramnios. Am J Pathol 145:631–639
below. The majority of patients with ACD Askenazi SS, Perlman M (1979) Pulmonary hypoplasia:
(approximately 75%) will have other associated lung weight and radial alveolar count as criteria of
anomalies of the cardiovascular, gastrointestinal, diagnosis. Arch Dis Child 54:614–618
urogenital, or musculoskeletal systems. The initial Baird R, Puligandla PS, Laberge JM (2014) Congenital
lung malformations: informing best practice. Semin
chest radiograph is usually normal. The diagnosis Pediatr Surg 23:270–277
can only be confirmed by lung biopsy or autopsy. Barker PM, Esther CR Jr, Fordham LA et al (2004) Pri-
FOXF1 mutation analysis may be useful to pro- mary pulmonary lymphangiectasia in infancy and
vide prenatal analysis for families at high risk childhood. Eur Respir J 24:413–419
Barth PJ, R€uschoff J (1992) Morphometric study on pul-
(Bishop et al. 2011). monary arterial thickness in pulmonary hypoplasia.
Pediatr Pathol 12:653–663
Bellini C, Boccardo F, Campisi C et al (2006) Congenital
47.5.11.3 Differential Diagnosis
pulmonary lymphangiectasia. Orphanet J Rare Dis 1:43
Conditions that must be considered in the differen- Bellini C, Boccardo F, Campisi C et al (2008) Lymphatic
tial diagnosis of ACD are idiopathic PPHN and dysplasias in newborns and children: the role of
surfactant protein B deficiency, sepsis, pneumonia, lymphoscintigraphy. J Pediatr 152:587–589
Berlinger NT, Porto DP, Thompson TR (1987) Infantile
PH, CDH, or cardiac lesions (Hugosson et al. 2005).
lobar emphysema. Ann Otol Rhinol Laryngol
96:106–111
Bishop NB, Stankiewicz P, Steinhorn RH (2011) Alveolar
47.5.11.4 Therapy and Treatments
capillary dysplasia. Am J Respir Crit Care Med
Standard therapies include mechanical ventila- 184:172–179
tion, high concentrations of inspired oxygen, and Bland RD, Hansen TN, Haberkern CM et al (1982) Lung
iNO and ECMO support. These therapies prolong fluid balance in lambs before and after birth. J Appl
Physiol 53:992–1004
life by days to weeks, but have not led to
Blau H, Barak A, Karmazyn B et al (2002) Postnatal
long-term survival (Tibballs and Chow 2002). management of resolving fetal lung lesions. Pediatrics
Theoretically, ACD could be treated by lung 109:105–108
756 C. Moretti and P. Papoff
Blott M, Greenough A, Nicolaides KH et al (1987) Fetal Copland I, Post M (2004) Lung development and fetal lung
breathing movements as predictor of favourable preg- growth. Paediatr Respir Rev 5:259–264
nancy outcome after oligohydramnios due to mem- Datin-Dorriere V, Walter-Nicolet E, Rousseau V et al
brane rupture in second trimester. Lancet 2:129–131 (2008) Experience in the management of eighty-two
Borsellino A, Zaccara A, Nahom A et al (2006) newborns with congenital diaphragmatic hernia treated
False–positive rate in prenatal diagnosis of surgical with high-frequency oscillatory ventilation and delayed
anomalies. J Pediatr Surg 41:826–829 surgery without the use of extracorporeal membrane
Brody JS, Thurlbeck WM (1986) Development, growth oxygenation. J Intensive Care Med 23:128–135
and aging of the lung. In: Fishman AP (ed) Handbook Davenport M, Warne SA, Cacciaguerra S et al (2004)
of physiology, the respiratory system. American Phys- Current outcome of antenatally diagnosed cystic lung
iological Society, Bethesda, pp 355–386 disease. J Pediatr Surg 39:549–556
Burri PH (1984) Fetal and postnatal development of the Dawes GS, Fox HE, Leduc BM et al (1970) Respiratory
lung. Annu Rev Physiol 46:617–628 movements and paradoxical sleep in the foetal lamb. J
Burri PH (1986) Development and growth of human lung. Physiol 210:47P–48P
In: Fishman AP (ed) Handbook of physiology, the de Mello DE, Reid L (1997) Arteries and veins. In: Crystal
respiratory system. American Physiological Society, RG et al (eds) The lung. Lippincott-Raven, Philadel-
Bethesda, pp 1–46 phia, pp 1117–1127
Burri PH (1997) Postnatal development and growth. In: de Waal K, Kluckow M (2015) Prolonged rupture of mem-
Crystal RG, West BG, Weibel ER, Barnes PG (eds) The branes and pulmonary hypoplasia in very preterm
lung. Lippincott- Raven, Philadelphia, pp 1013–1026 infants: pathophysiology and guided treatment. J
Bush A (2001) Congenital lung disease: a plea for clear Pediatr 166:1113–1120
thinking and clear nomenclature. Pediatr Pulmonol Dempsey EM, Sant’Anna GM, Williams RL et al (2005)
32:328–337 Congenital pulmonary lymphangiectasia presenting as
Butterworth SA, Blair GK (2005) Postnatal spontaneous nonimmune fetal hydrops and severe respiratory dis-
resolution of congenital cystic adenomatoid tress at birth: not uniformly fatal. Pediatr Pulmonol
malformations. J Pediatr Surg 40:832–834 40:270–274
Cacciari A, Ruggeri G, Mordenti M et al (2001) High- Diamond IR, Herrera P, Langer JC, Kim PC (2007)
frequency oscillatory ventilation versus conventional Thoracoscopic versus open resection of congenital
mechanical ventilation in congenital diaphragmatic lung lesions: a case-matched study. J Pediatr Surg
hernia. Eur J Pediatr Surg 11:3–7 42:1057–1061
Cadichon S (2008a) Congenital pulmonary Epaud R, Dubern B, Larroquet M et al (2008) Therapeutic
lymphangiectasia. In: Kumar P, Burton BK (eds) Con- strategies for idiopathic chylothorax. J Pediatr Surg
genital malformations. Mc Graw Hill Education, 43:461–465
New York, pp 165–169 Ergaz Z, Bar-Oz B, Yatsiv I, Arad I (2009) Congenital
Cadichon S (2008b) Congenital hydrothorax. In: Kumar P, chylothorax: clinical course and prognostic signifi-
Burton BK (eds) Congenital malformations. Mc Graw cance. Pediatr Pulmonol 44:806–811
Hill Education, New York, pp 159–164 Esther CR Jr, Barker PM (2004) Pulmonary
Calvert JK, Lakhoo K (2007) Antenatally suspected con- lymphangiectasia: diagnosis and clinical course.
genital cystic adenomatoid malformation of the lung: Pediatr Pulmonol 38:308–313
postnatal investigation and timing of surgery. J Pediatr Fewell JE, Johnson P (1983) Upper airway dynamics dur-
Surg 42:411–414 ing breathing and apnoea in fetal lambs. J Physiol
Calvert JK, Boyd PA, Chamberlain PC et al (2006) Out- 339:495–504
come of antenatally suspected congenital cystic Fisher JC, Jefferson RA, Arkovitz MS et al (2008)
adenomatoid malformation of the lung: 10 years expe- Redefining outcomes in right congenital diaphragmatic
rience 1991–2001. Arch Dis Child Fetal Neonatal Ed hernia. J Pediatr Surg 43:373–379
91:F26–F28 Fitzgerald DA (2007) Congenital cyst adenomatoid
Cass DL, Crombleholme TM, Howell LJ et al (1997) malformations: resect some and observe all? Paediatr
Cystic lung lesions with systemic arterial blood supply: Respir Rev 8:67–76
a hybrid of congenital cystic adenomatoid malforma- Gabarre JA, Izquierdo AG, Ponferrada MR et al (2005)
tion and bronchopulmonary sequestration. J Pediatr Isolated unilateral pulmonary agenesis: early prenatal
Surg 32:986–990 diagnosis and long-term follow-up. J Ultrasound Med
Clark ME, Woo RK, Johnson SM (2015) Thoracoscopic 24:865–868
pleural clipping for the management of congenital Gerards FA, Twisk JW, Fetter WP et al (2008) Predicting
chylothorax. Pediatr Surg Int 31:1133–1137 pulmonary hypoplasia with 2- or 3-dimensional ultra-
Clements BS (1999) Congenital malformations of the sonography in complicated pregnancies. Am J Obstet
lungs and airways. In: Taussig LM, Landau LI (eds) Gynecol 198:140–146
Pediatric respiratory medicine. Mosby, St. Louis, pp Gorincour G, Bouvenot J, Mourot MG et al (2005) Prenatal
1106–1136 prognosis of congenital diaphragmatic hernia using
47 Neonatal Lung Development and Pulmonary Malformations 757
magnetic resonance imaging measurement of fetal lung Kunisaki SM, Ehrenberg-Buchner S, Dillman JR et al
volume. Ultrasound Obstet Gynecol 26:738–744 (2015) Vanishing fetal lung malformations: prenatal
Gutierrez C, Rodriguez A, Palenzuela S et al (2000) Con- sonographic characteristics and postnatal outcomes. J
genital misalignment of pulmonary veins with alveolar Pediatr Surg 50:978–982
capillary dysplasia causing persistent neonatal pulmo- Lacy DE, Shaw NJ, Pilling DW, Walkinshaw S (1999)
nary hypertension: report of two affected siblings. Outcome of congenital lung abnormalities detected
Pediatr Dev Pathol 3:271–276 antenatally. Acta Paediatr 88:454–458
Hebra A, Othersen HB Jr, Tagge EP (2000) Lakhoo K (2009) Management of congenital cystic adeno-
Bronchopulmonary malformations. In: Ashcraft KW, matous malformations of the lung. Arch Dis Child Fetal
Murphy JP, Sharp RJ et al (eds) Pediatric surgery. Neonatal Ed 94:F73–F76
Saunders, Philadelphia, pp 273–286 Langston C, Kida K, Reed M, Thurlbeck WM (1984)
Hedrick HL, Flake AW, Crombleholme TM et al (2005) Human lung growth in late gestational and in the neo-
The ex utero intrapartum therapy procedure for high- nate. Am Rev Res Dis 129:607–613
risk fetal lung lesions. J Pediatr Surg 40:1038–1043 Lee EY, Siegel MJ, Sierra LM, Foglia RP (2004) Evalua-
Hekelaar N, van Uffelen R, van Vliet AC et al (2000) tion of angioarchitecture of pulmonary sequestration in
Primary lymphoepithelioma- like carcinoma within an pediatric patients using 3D MDCT angiography. AJR
intralobular pulmonary sequestration. Eur Respir J 183:183–188
16:1025–1027 Liu M, Skinner SJ, Xu J et al (1992) Stimulation of fetal rat
Hislop A (1996) Fetal and postnatal anatomical develop- lung cell proliferation in vitro by mechanical stretch.
ment. In: Greenough A, Roberton NRC, Milner AD Am J Physiol 263:L376–L383
(eds) Neonatal respiratory disorders. Arnold, London, MacGillivray TE, Harrison MR, Goldstein RB, Adzick NS
pp 3–12 (1993) Disappearing fetal lung lesions. J Pediatr Surg
Hooper SB, Harding R (1995) Fetal lung liquid: a major 28:1321–1325
determinant of the growth and functional development Malleske DT, Yoder BA (2015) Congenital chylothorax
of the fetal lung. Clin Exp Pharmacol Physiol treated with oral sildenafil: a case report and review of
22:235–247 the literature. J Perinatol 35:384–386
Hugosson CO, Salama HM, Al-Dayel F et al (2005) Pri- Mardini MK, Nyhan WL (1985) Agenesis of the lung:
mary alveolar capillary dysplasia (acinar dysplasia) and report of four patients with unusual anomalies. Chest
surfactant protein B deficiency: a clinical, radiological 87:522–527
and pathological study. Pediatr Radiol 35:311–316 Melly L, Sebire NJ, Malone M, Nicholson AG (2008)
Ierullo AM, Ganapathy R, Crowley S et al (2005) Neonatal Capillary apposition and density in the diagnosis of
outcome of antenatally diagnosed congenital cystic alveolar capillary dysplasia. Histopathology
adenomatoid malformations. Ultrasound Obstet 53:450–457
Gynecol 26:150–153 Mettauer N, Agrawal S, Pierce C et al (2009) Outcome of
Kalomenidis I (2006) Octreotide and chylothorax. Curr children with pulmonary lymphangiectasis. Pediatr
Opin Pulm Med 12:264–267 Pulmonol 44:351–357
Kasprian G, Balassy C, Brugger PC et al (2006) MRI of Moerman P, Vandenberghe K, Devlieger H et al (1993)
normal and pathological fetal lung development. Eur J Congenital pulmonary lymphangiectasis with
Radiol 57:261–270 chylothorax: a heterogeneous lymphatic vessel abnor-
Keller RL, Hawgood S, Neuhaus JM et al (2004) Infant mality. Am J Med Genet 47:54–58
pulmonary function in a randomized trial of fetal tra- Mulder EJ, Boersma M, Meeuse M et al (1994) Patterns of
cheal occlusion for severe congenital diaphragmatic breathing movements in the near-term human fetus:
hernia. Pediatr Res 56:818–825 relationship to behavioural states. Early Hum Dev
Kirwan WO, Walbaum PR, McCormack MM (1973) Cys- 36:127–135
tic intrathoracic derivatives of the foregut and their Nakamura Y, Harada K, Yamamoto I et al (1992) Human
complications. Thorax 28:424–428 pulmonary hypoplasia: statistical, morphological, mor-
Knox WF, Barson AJ (1986) Pulmonary hypoplasia in a phometric, and biochemical study. Arch Pathol Lab
regional perinatal unit. Early Hum Dev 14:33–42 Med 116:635–642
Kotecha S (2000) Lung growth for beginners. Paediatr Nobre LF, Muller NL, de Souza Junior AS et al (2004)
Respir Rev 1:308–313 Congenital pulmonary lymphangiectasia: CT and path-
Kuhn C, Kuhn JP (1992) Coexistence of bronchial atresia ologic findings. J Thorac Imaging 19:56–59
and bronchogenic cyst: diagnostic criteria and Noonan JA, Walters LR, Reeves JT (1970) Congenital
embryologic considerations. Pediatr Radiol pulmonary lymphangiectasis. Am J Dis Child
22:568–570 120:314–319
Kunisaki SM, Fauza DO, Nemes LP et al (2006) Bronchial Ozcelik U, Gocmen A, Kiper N et al (2003) Congenital
atresia: the hidden pathology within a spectrum of lobar emphysema: evaluation and long-term follow-up
prenatally diagnosed lung masses. J Pediatr Surg of thirty cases at a single center. Pediatr Pulmonol
41:61–65 35:384–391
758 C. Moretti and P. Papoff
Ozturk S, Cefle K, Palanduz S et al (2000) A case of Shaw JP, Dembitzer FR, Wisnivesky JP et al (2008) Video-
Noonan syndrome with pulmonary and abdominal assisted thoracoscopic lobectomy: state of the art and
lymphangiectasia. Int J Clin Pract 54:274–276 future directions. Ann Thorac Surg 85:S705–S709
Parker TA, Ivy DD, Kinsella JP et al (1997) Combined Smeltzer DM, Stickler GB, Fleming RE (1986) Primary
therapy with inhaled nitric oxide and intravenous pros- lymphatic dysplasia in children: chylothorax, chylous
tacyclin in an infant with alveolar-capillary dysplasia. ascites, and generalized lymphatic dysplasia. Eur J
Am J Respir Crit Care Med 155:743–746 Pediatr 145:286–292
Peranteau WH, Boelig MM, Khalek N et al (2015) Effect Stanton M, Davenport M (2006) Management of congen-
of single and multiple courses of maternal ital lung lesions. Early Hum Dev 82:289–295
betamethasone on prenatal congenital lung lesion Stephenson T, Zuccollo J, Mohajer M (1994) Diagnosis
growth and fetal survival. J Pediatr Surg 51:28–32 and management of non-immune hydrops in the
Podevin G, Levard G, Larroquet M et al (1999) newborn. Arch Dis Child Fetal Neonatal Ed
Pleuroperitoneal shunt in the management of 70:151–154
chylothorax caused by thoracic lymphatic dysplasia. J Stevens TP, Chess PR, McConnochie KM et al (2002)
Pediatr Surg 34:1420–1422 Survival in early- and late-term infants with congenital
Porter HJ (1999) Pulmonary hypoplasia. Arch Dis Child diaphragmatic hernia treated with extracorporeal mem-
Fetal Neonatal Ed 81:F81–F83 brane oxygenation. Pediatrics 110:590–596
Potter EL (1946a) Facial characteristics in infants with Stevenson DA, Pysher TJ, Ward RM et al (2006) Familial
bilateral renal agenesis. Am J Obstet Gynecol 51:885 congenital non-immune hydrops, chylothorax, and pul-
Potter EL (1946b) Bilateral renal agenesis. J Pediatr monary lymphangiectasia. Am J Med Genet A
29:68–76 140:368–372
Pumberger W, Hormann M, Deutinger J et al (2003) Lon- Stocker JT (2002) Congenital pulmonary airway malfor-
gitudinal observation of antenatally detected congenital mation – a new name for and an expanded classification
lung malformations (CLM): natural history, clinical of congenital adenomatoid malformation of the lung.
outcome and long-term follow-up. Eur J Cardiothorac Histopathology 41:424–431
Surg 24:703–711 Sty JR, Thomas JP Jr, Wolff MH et al (1984) Lymphoscin-
Rifai N, Sfeir R, Rakza T et al (2003) Successful manage- tigraphy. Pulmonary lymphangiectasia. Clin Nucl Med
ment of severe chylothorax with argon plasma fulgura- 9:716
tion and fibrin glue in a premature infant. Eur J Pediatr Swischuck LE (ed) (2004) Imaging of the newborn, infant,
Surg 13:324–326 and young child. Lippincott Williams & Wilkins,
Rocha G, Fernandes P, Rocha P et al (2006) Pleural effu- Philadelphia
sions in the neonate. Acta Paediatr 95:791–798 Thakral CL, Maji DC, Sajwani MJ (2001) Congenital lobar
Rossi R, Tjan TD, Hentschel R et al (1998) Successful emphysema: experience with 21 cases. Pediatr Surg Int
perioperative management of congenital cystic 17:88–91
adenomatoid malformation of the lung by high fre- Tibballs J, Chow CW (2002) Incidence of alveolar capil-
quency oscillatory ventilation – report of two cases. lary dysplasia in severe idiopathic persistent pulmonary
Klin Padiatr 210:94–96 hypertension of the newborn. J Paediatr Child Health
Salomon LJ, Audibert F, Dommergues M et al (2003) Fetal 38:397–400
thoracoamniotic shunting as the only treatment for Uga N, Ishii T, Kawase Y et al (2004) Nitric oxide inhala-
pulmonary sequestration with hydrops: favorable tion therapy in very low-birthweight infants with hypo-
long-term outcome without postnatal surgery. Ultra- plastic lung due to oligohydramnios. Pediatr Int
sound Obstet Gynecol 21:299–301 46:10–14
Seed M, Bradley T, Bourgeois J et al (2009) Antenatal MR van Leeuwen K, Teitelbaum DH, Hirschl RB et al (1999)
imaging of pulmonary lymphangiectasia secondary to Prenatal diagnosis of congenital cystic adenomatoid
hypoplastic left heart syndrome. Pediatr Radiol malformation and its postnatal presentation, surgical
39:747–749 indications, and natural history. J Pediatr Surg
Shah DM, Kluckow M (2011) Early functional echocar- 34:794–798
diogram and inhaled nitric oxide: usefulness in manag- Vilos GA, Liggins GC (1982) Intrathoracic pressures in
ing neonates born following extreme preterm fetal sheep. J Dev Physiol 4:247–256
premature rupture of membranes (PPROM). J Paediatr Wilson RD, Hedrick HL, Liechty KW et al (2006a) Cystic
Child Health 47:340–345 adenomatoid malformation of the lung: review of
Shankar V, Haque A, Johnson J, Pietsch J (2006) Late genetics, prenatal diagnosis, and in utero treatment.
presentation of alveolar capillary dysplasia in an infant. Am J Med Genet A 140:151–155
Pediatr Crit Care Med 7:177–179 Wilson RD, Pawel B, Bebbington M et al (2006b) Con-
Shanmugam G, MacArthur K, Pollock JC (2005) Congenital genital pulmonary lymphangiectasis sequence: a rare,
lung malformations–antenatal and postnatal evaluation heterogeneous, and lethal etiology for prenatal pleural
and management. Eur J Cardiothorac Surg 27:45–52 effusion. Prenat Diagn 26:1058–1061
Neonatal Pulmonary Physiology
of Term and Preterm Newborns 48
Corrado Moretti and Paola Papoff
Contents
48.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 760
48.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 760
48.3 Lung Mechanics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 760
48.4 Elastic Properties of the Lungs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 761
48.5 Airway Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 763
48.6 Alveolar Ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 765
48.7 Diffusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
48.8 Pulmonary Circulation and Ventilation/Perfusion Ratio . . . . . . . . . . . . . . . . 767
48.9 Transfer of O2 and CO2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
48.10 Causes of Hypoxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769
48.10.1 Hypoventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769
48.10.2 Abnormal Diffusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 770
48.10.3 Extrapulmonary Shunt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 770
48.10.4 Alterations in the Ventilation/Perfusion Ratio . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 771
48.10.5 Hypoxia Due to Anemia and Hypoperfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 772
48.11 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 772
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 772
Abstract for understanding the pathophysiology and
A knowledge of normal neonatal pulmonary optimizing the treatment of many respiratory
development and physiology is the cornerstone diseases of preterm and term infants. It forms
the groundwork not only for an individualized
treatment but also for increasing respiratory
C. Moretti (*) care technology, both important factors in
Università degli Studi di Roma “La Sapienza”, Rome, Italy improving pulmonary outcomes in these vul-
e-mail: [email protected] nerable patients. Pulmonary physiology and
P. Papoff (*) oxygen transport in the neonate are similar to
Intensive Care Unit, Sapienza University of Rome, older children; however, there are critical
Rome, Italy
# Springer International Publishing AG, part of Springer Nature 2018 759
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_197
760 C. Moretti and P. Papoff
differences that are important to take into con- The main steps in this process are:
sideration when treating the youngest age
group, and this chapter deals with the peculiar • Pulmonary ventilation, which consists in the
characteristics of neonatal respiratory mechan- rhythmic introduction of fresh gases into the
ics and the pathophysiology of the various alveolus; tidal volume (VT) is a term deriving
possible causes of hypoxia. from “tide” which offers an excellent represen-
tation of the flow and reflow of the gases.
• The diffusion of O2 and CO2 at the alveolus-
48.1 Salient Points capillary interface.
• Capillary perfusion, whereby O2 and CO2 are
• In premature infants the chest is subject to dis- transported into and out of the tissues.
tortion owing to the poor ossification of the ribs:
the inward distortion of the chest during inspi- Unlike the respiratory apparatus, the cardiocir-
ration compels the diaphragm to do more work culatory system is a closed-loop system with a
in order to maintain tidal volume constant. one-way flow.
• Compliance expresses the capacity of the lung
to be distended, and its reduction causes a drop
in tidal volume. 48.3 Lung Mechanics
• Severe neonatal respiratory diseases are charac-
terized by a right-left shunt through fetal chan- Alveolar ventilation is obtained through pulmo-
nels for the increase of pulmonary resistances. nary expansion, which in turn occurs through
• PaCO2 is not usually increased in the presence dilatation of the ribcage. At rest, the lungs and
of an extrapulmonary shunt because the hyp- ribcage are in a situation of equilibrium deter-
oxia and hypercapnia of non-oxygenated blood mined by the resultant of two contrasting forces:
cause an increase in alveolar ventilation; due to elastic inward recoil of the pulmonary paren-
the different shape of the dissociation curve of chyma and outward elastic traction of the ribcage.
CO2 and O2, hyperventilation is effective in The pulmonary volume that results from this equi-
reducing PaCO2 but totally ineffective in librium is defined as functional residual capacity
increasing PaO2. (FRC).
• The increase in PaCO2 represents a very The consequence of this interaction in opposite
important criterion for the diagnosis of directions is the presence of a negative pressure of
hypoventilation because, unlike hypoxia, this around 3, 5 cm H2O in the intrapleural space,
is virtually the sole cause of hypercapnia. which is a virtual cavity. During normal breathing
• Alterations in diffusion never involve CO2 most of the VT is ensured by the diaphragm, a
given the rapidity with which it diffuses. muscle supplied by the phrenic nerves, whose
• Alterations in the ventilation-perfusion ratio contraction causes an increase in the vertical
are responsible for most of the defects in the diameter of the ribcage; the increase in the
exchange of O2 in pulmonary diseases. anteroposterior diameter is due to the contraction
of the internal intercostal muscles whereby the
ribs rotate upwards along their axis.
48.2 Introduction Dilatation of the ribcage during inspiration
causes a reduction in intrapleural pressure, and
The transfer of O2 to the tissues and the removal of the lungs – hence the alveoli – undergo passive
CO2 are guaranteed by the simultaneous activity expansion (De Troyer 1997). The decrease in intra-
of the respiratory apparatus and of the cardiocir- alveolar pressure produces an airflow in the respi-
culatory system which ensures that O2 reaches the ratory system; the flow stops at the end of inspira-
tissues and that the CO2 produced by cell metab- tion when the alveolar pressure returns to a state of
olism is removed (Cumming et al. 1966). equilibrium with atmospheric pressure (Fig. 1).
48 Neonatal Pulmonary Physiology of Term and Preterm Newborns 761
muscles are not fully functional. The inward dis-
tortion of the chest during inspiration compels the
diaphragm to do more work: indeed, in order to
maintain the VT constant, the excursion of the
diaphragm must increase so as to offset the para-
doxical movement of the ribcage. This phenome-
non contributes to accelerating the respiratory
functional exhaustion to which low birth-weight
infants with respiratory distress are subject to.
The expiratory phase, by contrast, is usually a
passive phenomenon determined by the forces of
elastic recoil of distended tissues: the greater the
expansion of the lungs during inspiration, the
greater its elastic recoil. The intervention of expi-
ration muscles, the most important ones being the
muscles of the abdominal wall, occurs only in
some physiological situations such as coughing
and sneezing or in some pathological conditions.
48.4 Elastic Properties of the Lungs
Compliance (C) is a value that expresses the elas-
Fig. 1 Pressure, air flow, and volume signals of a respira- ticity of the lung or, rather, its capacity to be
tory cycle distended. It is defined by correlating the pressure
applied to the alveoli (P) to the ensuing volume
In newborns, chest stability is facilitated by a variations (V):
relatively horizontal position of the ribs so that
the intercostal muscles, which contract simulta- C ¼ V=P
neously with the diaphragm, can provide struc-
tural stiffness for the ribcage rather than Compliance is usually represented through pres-
expanding it during inspiration. Inspiration and sure/volume curves: the higher its value the
expiration are therefore ensured above all by the greater the variation of the amount of gas in the
activity of the diaphragm, which is less efficient in lung per unit pressure and the steeper the slope of
newborns compared to adults due both to its rather the curve (Fig. 2). A peculiar characteristic of lung
flat conformation that reduces its excursion and to pressure/volume curves is that inflation and defla-
its histological characteristics. In premature tion have different pressure curves, a phenomenon
infants, in particular, the proportion of diaphrag- that is called hysteresis.
matic slow-twitch muscle fibers that are resistant The factors determining the degree of elasticity
to oxidation and fatigue (Type I) is much smaller of the lung are the presence of elastic fibers in the
(10%) than the fast-twitch fibers which tire more parenchyma and the surface tension forces of the
easily (Type II); the proportion of Type I fibers liquid that wets the alveoli walls (Goerke and
increases progressively with age (about 25% in a Schurch 1997). Surface tension forces are gener-
term infant and 55% at eight months) (Keens et al. ated by the cohesion between the molecules mak-
1978). ing up the liquid: these forces are balanced in the
Moreover, the chest of a premature infant is liquid phase but not at the air-liquid interface; the
subject to distortion owing to the poor ossification result is that the molecules on the surface exercise
of the ribs and sternum and because the intercostal greater attraction towards the surrounding
762 C. Moretti and P. Papoff
molecules. The importance of the role of the sur- out that when the lungs are filled with saline
face tension forces can be demonstrated through a solution the hysteresis disappears.
simple experiment: by expanding an isolated lung The presence on the surface of the alveoli of a
with saline solution, and then with air, two differ- tensioactive factor or surfactant, consisting of var-
ent pressure/volume curves are obtained. In the ious phospholipids, has the function of reducing
first case the recoil forces are entirely due to the the superficial tension forces and of stabilizing the
elastic properties of the lung tissue because there size of the alveoli.
is no air-liquid interface. By contrast, when the According to Laplace’s law
lung is expanded with gas, the surface tension
forces require a greater pressure to obtain the Pressure ¼ 2 ðsurface tensionÞ=radius
same expansion; moreover, it must be pointed
the pressure required to maintain the alveoli
expanded increases proportionally to the decrease
in its radius: the consequence should be that the
smaller alveoli empty out into the larger ones, but
the action of the surfactant, i.e., decreasing surface
tension is more effective as the alveolus decreases
its size as a result of the greater concentration of
surfactant molecules. The intra-alveolar pressure
is thus uniformly maintained in the pulmonary
parenchyma, and the size of the alveolus is kept
stable.
The effects of the surfactant on lung mechanics
can be easily understood from the analysis of
Fig. 3, which shows two pressure/volume curves
obtained by inflating a lung affected by respira-
tory distress syndrome (RDS), before and after
treatment with surfactant.
Fig. 2 Pressure/volume diagram in a neonate with RDS The fundamental differences between the two
(dashed line) and in a normal neonate (solid line) curves are:
Fig. 3 Pressure-volume
relationships for the
inflation and deflation of
surfactant-deficient and
surfactant-treated preterm
rabbit lungs
48 Neonatal Pulmonary Physiology of Term and Preterm Newborns 763
• The opening pressure, i.e., the pressure at is a passive phenomenon. Conversely, the dissi-
which the alveoli begin to expand, is higher pation forces are the (flow-dependent) energies
before being treated with surfactant. required to overcome not only the friction of the
• Lung expansion at the same peak pressure gases against the airway walls but also the visco-
value is better after treatment with surfactant. elastic properties of the respiratory system deter-
• Before treatment with surfactant the lung does mined by the molecular movements in the tissues.
not have stability in the expiratory phase and The dissipation forces are also defined as resis-
has a tendency to collapse and to lose FRC. tance forces: the energy required to overcome
these forces is lost in the form of heat and hence
In summary, the surfactant has the following can no longer be used.
functions: In lung physiology the term airway resistance
(R) is used to define the ratio between the differ-
• It reduces the respiratory workload since the ence in pressure between the alveoli and the
lung is more prone to distension. mouth (ΔP) and the resulting flow (V): _
• It increases the FRC given the lesser tendency
of the lung to collapse. _
RðcmH2 O=L=sÞ ¼ ΔPðcmH2 OÞ=VðL=sÞ
• It has an anti-edema role since the increase in
surface tension facilitates the attraction of liq- In the respiratory system some 30–40% of the
uids from the capillaries into the alveoli. resistance occurs at the nose, in the oropharynx
• It stabilizes the sizes of the alveoli. and in the pharynx, while at the level of the
trachea and bronchial tree the structures that resist
A further factor that contributes to stabilizing most against the flow are the average sized bron-
the sizes of the alveoli is their mechanical chi and not the smaller sized airways.
interdependence: if an alveolus tends to collapse, The airways can indeed be schematized as a
the stress on the walls of the adjacent alveoli series of successive dichotomies (22 generations
increases and this helps it remain expanded. The or bronchial branching): at each branch division
alveoli support each other thus contrasting any the size of the segments slightly decrease in size,
tendency towards a reduction or increase in vol- but since the number of elements doubles, the
ume of any single alveolus. total cross section area increases with respect to
the previous level (Fig. 4). Thanks to this archi-
tecture the resistance of the peripheral airways is
48.5 Airway Resistance very mild even if the flow runs along ducts whose
size is truly very small.
The forces that have to be overcome in order to The factors that determine the degree of resis-
ventilate the air inside and outside the respiratory tance (R) of a duct include its length (l ), its radius
system are not only the forces of elastic recoil of (r), and type of flow, i.e., laminar or turbulent flow
the lungs and chest but also the airway resistance.
The forces required to ensure breathing, R ¼ l=r 4
whether the energy spent is stored and retrieved
thereafter, or whether it is lost by the system in the Turbulent flow, which occurs mainly at the points
form of heat, are defined conservative forces or of branching or when the airflow is high and the
dissipation forces. Conservative forces are the radius of the duct is large, generates a larger
(volume-dependent) pressures generated by the resistance compared to laminar flow. The pres-
elastic properties of the lungs and of the ribcage, sures in a laminar flow are proportional to the
forces that tend to cause these structures to return flow rate whereas in a turbulent flow they are
to their initial position after a deformation: the proportionate to the square of the flow; in these
energy spent on overcoming these forces during conditions the energy needed is obviously greater.
inspiration is recovered during expiration, which The progressive increase in total cross section area
764 C. Moretti and P. Papoff
Fig. 5 Dynamic compression of airways. On the left,
passive expiration: intrapleural pressure is 8 cm H2O,
pulmonary elastic recoil forces pressure is +10 cm H2O and
Fig. 4 Location of the main site of airway resistance. Note alveolar pressure is +2 cm H2O. On the right, forced
that the intermediate-sized bronchi contribute most of the expiration: intrapleural pressure is +25 cm H2O, pulmo-
resistance and that relatively little is located in the very nary elastic recoil forces pressure is +10 cm H2O and
small airways alveolar pressure is +35 cm H2O. The arrow indicates the
equal pressure point (EPP)
towards the periphery of the lung implies a pro- Making the intrapleural pressure positive
gressive reduction in the linear velocity (linear determines changes in transmural pressure
velocity = airflow/cross section area) of the air- whose effects are clearly seen in Fig. 5, which
flow, which is quite low and of the laminar type at represents the pressure values that come into
the level of the smaller airways, whereas in the play during normal expiration and forced expira-
trachea and in the larger branches it is essentially tion. During forced expiration the pressure inside
turbulent. the peripheral airways is greater than the
Lung volume is another important factor for the intrapleural pressure thanks to the pulmonary
resistance of the airways, above all of those with elastic recoil forces; in the larger airways by con-
little or no cartilage structure. Indeed the small trast, the pressure comes progressively closer to
airways distend and compress very easily, and the atmospheric pressure and is hence lower than
transmural pressure gradient of the walls of the intrapleural pressure. The point at which the pres-
small airways is important in defining their radius: sure inside and outside the airways is equal is
during deep inspiration the intrapleural negative defined as equal pressure point (EPP), situated in
pressure increases thus causing an increase in the normal individuals in the central airways within
transmural pressure gradient and hence an increase the first five branchings of the bronchial tree.
in their size. A further factor consists in increasing Downstream from this point the airways are com-
the elastic tension exercised by the pulmonary pressed and the compression increases with
parenchyma on the airways during volume expan- greater expiration effort, which will thus not be
sion in the inspiration phase. The resistance of the capable of increasing the flow velocity (dynamic
airways therefore is less during inspiration as com- flow limitation).
pared to expiration; in addition, during forced expi- The expiratory flow also decreases with the
ration, as occurs in the newborn when he cries, progressive reduction of the pulmonary volume
resistance is influenced by the dynamic compres- for the attenuation of the elastic recoil forces and
sion of the airways. for the smaller size of the airways; as expiration
48 Neonatal Pulmonary Physiology of Term and Preterm Newborns 765
proceeds, the EPP moves distally towards the slow renewal of air means that the variation in gas
inside of the lung. The flow-limiting mechanism concentration in the alveoli is only 3–4 mmHg for
is enhanced in some pathologic conditions char- each breathing cycle; relative constancy in gas
acterized by an increase in peripheral resistance concentration in arterial blood therefore depends
because the pressure drop is amplified inside the on the buffer action of the FRC.
airways, or in others marked by a pressure reduc- Let us now analyze the partial gas pressures in
tion of the elastic component as occurs in an ideal lung, considering that barometric pres-
emphysema. sure is around 760 mmHg: 20.9% of it is gener-
ated by O2 and 79% by nitrogen; as a
consequence, the PO2 in the air is 20.9% of
760, i.e., 159 mmHg. The air inspired is saturated
48.6 Alveolar Ventilation
with aqueous vapor in amounts proportionate to
body temperature; the value of the partial pressure
The amount of fresh air ventilated into the airways
of aqueous vapor at 37 C is 47 mmHg, which is
in one minute, or minute volume V_ E (V_ = volume/ to be subtracted from the relative value at total
time unit; the minute volume is measured with the pressure of unsaturated air. The PO2 of inspired air
amount of expired gas and it is indicated with V_ E ), is hence 20.9% of 760 – 47 mmHg, therefore
corresponds to the VT times the respiratory rate around 149 mmHg. The alveolar PO2 (PAO2) is
(RR): less than that of the inspired air because the alve-
olar air is continuously impoverished of O2 and
V_ E ¼ VT RR enriched with CO2 and its value is around
100 mmHg. The partial pressure values of O2
The VT, that is to say the inspiration and expira- and CO2 at the alveoli are determined by the
tion volume for each normal breathing cycle, balance between alveolar ventilation, consump-
measures about 6–8 mL/kg in the newborn and tion of O2, and production of CO2.
4–6 mL/kg in a preterm infant; about 30% of this Alveolar ventilation is regulated by the respi-
volume remains inside the airways without taking ratory centers in such a way as to maintain the
part in the exchange of gases with the blood value of the arterial PCO2 (PaCO2) around
(anatomic dead space) and is called the dead 40 mmHg and the value of the arterial PO2
space volume ( V_ D ). Alveolar ventilation ( V_ A ) is (PaO2) around 100 mmHg (Von Euler 1997).
the volume of fresh air that enters the respiratory The value of arterial PCO2, which is normally
zone every minute and is actually available for the identical to the alveolar PCO2 (PACO2), is
exchange of gases; the V_ A corresponds to: inversely proportionate to the degree of ventila-
tion and is hence used as an index of alveolar
ventilation; if alveolar ventilation is halved, the
V_ A ¼ V_ E V_ D PaCO2 doubles, if alveolar ventilation doubles,
the PaCO2 is halved (Fig. 6). Also the PaO2 var-
A reduction in the expansion of the lung, typical iations are proportionate to the degree of ventila-
of RDS, causes a drop in VT and hence in alveolar tion and inversely proportionate to the PaCO2, in
ventilation since the dead space remains that the total sum of the partial pressures of the
unchanged; this compels the newborn to increase gases at the alveoli is always 760 mmHg. Actu-
respiratory rate to keep the minute volume con- ally, the partial pressure of aqueous vapor does not
stant. In physiological conditions the amount of vary, and during ventilation the partial pressure of
air that remains inside the lung at the end of nitrogen varies slightly. However, the PaO2 is not
normal expiration, or FRC, is around 20–30 mL/ used as an index of ventilation because, unlike the
kg; therefore, for each breathing cycle, only a part PaCO2, its value varies also as a function of the
of the air in the alveoli (around 1/5–1/6) will be presence of an intra- or extrapulmonary shunt
replaced with new air from the atmosphere. This (Riley and Coumand 1951).
766 C. Moretti and P. Papoff
(Scheid and Piper 1997). O2 and CO2 move from
high partial pressure areas to others where the
partial pressure is low as a result of a process of
passive physical diffusion. The diffusion of the
gases across the alveolar wall is described by
Fick’s Law:
_
Vgas ¼ A K ðP1 P2 Þ=S
This law states that the volume of gas that diffuses
_
per unit of time ( Vgas) is proportional to the
surface area (A), to a diffusion constant (K) and
to the partial pressure difference (P1 – P2), and it is
inversely proportional to the thickness of the alve-
olar wall (S). The diffusion constant K is, in turn,
proportional to the solubility of the gas and
Fig. 6 Variations in analysis of blood gases related to inversely proportional to the square root of its
alveolar ventilation molecular weight. The CO2 has a molecular
weight that is not very different from that of the
The amount of work that respiratory muscles O2, but it has higher solubility, and so it diffuses
must do to maintain an optimal level of PaCO2 about 20 times more rapidly than the O2 through
depends on the type of ventilation. Each individ- the blood-gas barrier.
ual, depending on the elastic and resistance char- At the blood-gas barrier the flow pressure for
acteristics of his respiratory system, has an the O2 is around 60 mmHg (100 mmHg alveolar
optimal theoretical rate where a reduction in com- PO2; 40 mmHg PO2 capillary venous blood); the
pliance implies that it increases, whereas it is O2 crosses the membrane rapidly, and the PO2
reduced when resistance increases. In clinical increases just as rapidly in the blood. It must be
practice most patients with a pulmonary disorder pointed out that the blood PO2 reaches the values
use a ventilation mode that requires less respira- corresponding to the alveolar air just before the
tory work, and respiratory rate is often close to the red cells have completed half of their journey
optimal hypothetical one. Theoretically it is there- inside the lung capillaries, whose overall duration
fore possible to classify pulmonary diseases as is around 0.75 s; therefore there are huge possi-
restrictive or obstructive diseases on the basis of bilities for compensation.
high or reduced respiratory rate measurements, Moreover, thanks to the special form of the Hb
but the respiratory centers are regulated also by dissociation curve, a high partial pressure differ-
cortical influences and by mechanical or irritation ence persists between alveolar gas and blood also
stimuli coming from the respiratory system when the Hb is near total saturation. For instance,
that may gain the upper hand over the energy Hb is saturated at 94% with a PO2 of 70 mmHg,
advantage. when there is still a 30 mmHg gradient.
The time it takes the capillary CO2 to equili-
brate against the alveolar CO2 is more or less the
same as the time taken by the O2 in spite of the
48.7 Diffusion fact that the diffusion velocity of the CO2 is
20 times higher than that of the O2. In this case,
The next step after the cyclical renewal of alveolar however, we must consider that the partial pres-
air is the diffusion of O2 from the alveoli to the sure gradient between capillaries and alveoli is
blood, and of the CO2 in the opposite direction only 5 mmHg.
48 Neonatal Pulmonary Physiology of Term and Preterm Newborns 767
48.8 Pulmonary Circulation result is a V_ A =Q_ ratio of 0.8–1 as in the adult. This
and Ventilation/Perfusion Ratio means that each air volume that arrives at the
alveolar surface exchanges with an equal amount
The fetal pulmonary arterial muscle thickness of capillary perfusion blood. These values are
increases during the last quarter of pregnancy indicative, but they do give an idea of the order
blocking the perfusion of the lung circulation, of magnitude of these values.
which is rapidly developing. Of these two phe-
nomena, the latter is most prevalent and results in
a gradual reduction in pulmonary vascular resis- 48.9 Transfer of O2 and CO2
tances. The degree of development of pulmonary
circulation affects the clinical presentation of neo- In physiological conditions, O2 is transferred to
natal cardiorespiratory diseases where the alter- the tissues almost entirely in combination with the
ations in the ventilation/perfusion ratio are Hb of the red cells; only 3% is dissolved in the
determined by the capacity, or lack thereof, to aqueous phase of the plasma. It must be noted that
increase lung vascular resistances following stim- 1 g of Hb may bind to a maximum of 1.34 mL of
uli such as hypoxia and acidosis, with hemody- O2 and, since the normal concentration of Hb is
namic patterns ranging from extrapulmonary about 15 g/100 mL, it may bind 20 mL of O2 or, to
shunt to pulmonary overflow. use the generally accepted expression, 20 volumes
Let us look at the ventilation/perfusion ratio of O2 (Baumann 1987).
_ of a term newborn in physiological
( V_ A =Q) The amount of O2 that binds to Hb in the
conditions: their cardiac index (cardiac output erythrocytes is directly proportional to the PO2
referred to body surface) is approximately 3.5 in the plasma and is plotted graphically as a dis-
L/min/m2; since body surface is around 0.25 m2, sociation curve of hemoglobin (Fig. 7). The italics
the value of the output is 0.8–0.9 L/min. Consid- S shape of the Hb dissociation curve is due to the
ering a respiratory rate of around 45 breaths/min, functional interdependence or cooperative effect
alveolar ventilation is about 700–800 mL/min; the of its four hemes. As a result of this effect, while
Fig. 7 Hb dissociation
curve in a neonate (70%
HbF) and in an adult in
standard conditions (T=
37 C; pH 7.4)
768 C. Moretti and P. Papoff
the first heme combines slowly with O2, the sec- CO2 þ H2 O ! H2 CO3 ! Hþ þ HCO 3
ond, under the influence of the first that has
already been assigned, will combine more rapidly, CO2 combines with water to form carbonic acid,
and so on. Fetal Hb has a greater affinity for O2 which dissociates into hydrogen ions and bicar-
compared to that of the adult; its dissociation bonate ions; carbonic anhydrase, present in high
curve is shifted to the left and has a greater satu- concentrations in red cells, makes the reaction
ration at the same PaO2 (the position of the Hb faster. Some of the released Hþ ions bind to the
curve is defined by the P50, which is the PaO2 at hemoglobin according to the following reaction:
which the Hb is 50% saturated; the P50 of the HbF
is 19 mmHg, that of the HbA 26 mmHg). The shift Hþ þ HbO2 ! Hþ Hb þ O2
to the right of the curve, denoting a reduced affin-
ity of the Hb for O2, is caused by a reduction in The reduced form of Hb is less acidic than the
pH; this facilitates the transfer of O2 to the tissues oxygenated form and it more rapidly accepts the
(Bohr effect). hydrogen ions released by the dissociation reac-
The share of Hb bounded to O2 is expressed as tion of carbonic acid, thus allowing a greater
percentage saturation (SaO2%); this is equal to amount of carbon dioxide to be transported by
the O2 content in the blood (Cont. O2) divided venous blood in the form of bicarbonate ions
by the O2 transport capacity of the Hb (Cap. O2), (Haldane effect). This facilitates the uptake of
times 100: CO2 at tissue level and the inverse reaction facil-
itates its release into the lung capillaries where
SaO2 % ¼ Cont: O2 =Cap: O2 100 carbonic acid is converted into gas and removed
from alveolar ventilation.
It must be pointed out that hemoglobin saturation The acid–base status of the blood (pH) results
expresses only a percentage and not an amount or from the ratio between bicarbonate concentration
volume of O2. The special form of the Hb disso- and the CO2 in solution, and as long as this ratio is
ciation curve in its upper part means that satura- 20, the pH is stable at 7.4 (Jones 1997). (Normal
tion decreases only slightly with considerable arterial blood HCO3 concentration is 24 mmol/
drops in PO2; for the same reason, considerable L, and at 37 C about 0.03 CO2 mmol is dissolved
increases in alveolar PO2 do not cause a signifi- for every PCO2 mmHg in 1 L of plasma; conse-
cant increase in O2 content since maximum O2 quently the amount of CO2 in the blood is equal to
saturation cannot exceed 100%. The steepness of 0.03 PCO2. So in normal condition the
the lower part of the curve shows that the periph- HCO3/CO2 ratio is 24/0.03 40 = 20.)
eral tissues receive large amounts of O2 with The blood concentration of bicarbonate is deter-
small decreases in capillary PO2. In venous mined mainly by the kidneys and the PCO2 by the
blood, PO2 is around 40 mmHg, which corre- lungs. An increase in the latter reduces the pH
sponds to a 75% saturation; this means that dur- (respiratory acidosis) and the kidneys respond by
ing tissue perfusion only 25% of the total content eliminating a more acid urine, secreting H+ ions in
is used, in practice about 5 mL for every 100 mL the tubules as H2PO4 or NH+4, while the HCO3
of blood (Fig. 7). ions are reabsorbed. Kidney compensation, how-
The transport of CO2 in the blood is not as ever, is hardly ever accomplished. By contrast, a
complex as the transport of O2 (Klocke 1997). reduction in PCO2 determines an increase in pH
CO2 is found in the blood as a free gas in solution (respiratory alkalosis), and kidney compensation
(up to 10% since it is 20 times more soluble than occurs by eliminating a larger amount of bicarbon-
O2 in the plasma) or in a chemical combination ate. In the case of acidosis or metabolic alkalosis,
with hemoglobin and plasma protein in the form respiratory compensation mechanisms step in, i.e.,
of carbamino compounds (5–10%) and above all hyperventilation or hypoventilation, so as to main-
as bicarbonate ions (70–90%). The bicarbonate is tain the HCO3/CO2 ratio, and hence the pH, within
formed in the blood by the following reaction: physiological limits.
48 Neonatal Pulmonary Physiology of Term and Preterm Newborns 769
as respiratory quotient (RQ) and is expressed by
the following formula:
RQ ¼ CO2 eliminated=O2 uptake ¼ 0:8
48.10 Causes of Hypoxia
48.10.1 Hypoventilation
We have seen that the alveolar PO2 and hence the
arterial PO2 is determined by the equilibrium
Fig. 8 Portions of carbon dioxide dissociation curves between the speed of CO2 removal and O2 supply
when PO2 is 100 mmHg and 40 mmHg, respectively. by alveolar ventilation. If the ventilation is
Arrows represent the Haldane effect on the transport of
carbon dioxide
reduced, the alveolar PO2 drops and for the same
reason the PaCO2 rises, and it is the increase in
PaCO2 that represents a very important criterion
The dissociation curve of carbon dioxide for the diagnosis of hypoventilation because,
shows the relationship between PCO2 and the unlike hypoxia, this is virtually the sole cause for
total content CO2 in the blood (Fig. 8): at physio- hypercapnia. Hypoventilation is therefore charac-
logical levels of PCO2 the carbon dioxide content terized by an inadequate removal of CO2 com-
is around 50 mL or volumes per 100 mL, with an pared to its production and the relationship can be
oscillation of only 4 volumes per 100 between written as follows:
arterial blood and venous blood (48–52 mL). In
practice every 100 mL of blood that go through PaCO2 ¼ V_ CO2 =V_ A
the lungs release 4 mL of CO2.
In the normal range of the PCO2 values the where V_ CO2 is the production of CO2 and V_ A is
curve approximates a straight line without steep alveolar ventilation (V_ E V_ D ).
or flat portions; this means that an increase or The gradual reduction in ventilation progres-
slowdown in ventilation determines a propor- sively brings the alveolar gas values closer to the
tional decrease or increase in arterial CO2. Fur- venous blood values. Arterial PO2 can be easily
thermore, the lower the PO2, the greater the CO2 corrected by increasing the FiO2, since the larger
content for a given PCO2 (Haldane effect). amount of O2 that reaches the alveoli through each
The dissociation curve of CO2 is steeper than breath may offset the reduction in ventilation.
that of the O2; in other words, there is greater Conversely, hypercapnia can be corrected only
variation in gas content for partial pressure varia- by increasing respiration frequency and/or the
tions. Knowing the difference between the disso- VT and may require a certain amount of time
ciation curves of the Hb and CO2 is essential to because the CO2 is stored in large amounts in the
understand the pathophysiology of major ventila- form of bicarbonates.
tion alterations. We have seen how 100 mL of The causes that determine hypoventilation are
blood transport 5 mL of O2 from the lungs to the mostly non-pulmonary; among the most frequent
tissues, whereas the same amount of blood trans- causes in newborn we may mention:
ports some 4 mL of CO2 from the tissues to the
lungs. At resting conditions, therefore, for every • Apnea spells in premature infants
100 volumes of O2 assumed by the lungs only • Depression of the CNS due to anesthetics or
80 volumes of CO2 are eliminated, where the ratio drugs
between eliminated CO2 and O2 uptake is defined • Diseases of the CNS
770 C. Moretti and P. Papoff
• Diseases affecting the respiratory muscles
(paralysis of the diaphragm, weak respiratory
muscles in preterm infants, etc.)
• Obstruction of the upper airways (choanal atre-
sia, Pierre-Robin syndrome, laryngomalacia,
etc.)
• Obstruction or malpositioning of the tracheal
tube
Hypoventilation may also be a symptom of
functional exhaustion, and it may complicate pul-
monary diseases when a considerable increase in
work of breathing is required.
48.10.2 Abnormal Diffusion Fig. 9 Arterial PO2 variation with different inhaled O2
concentrations and different shunt percentage
Normal lungs present extensive compensation
possibilities to ensure O2 diffusion. It was
pointed out earlier that blood and alveolar PO2 ventilated pulmonary areas. The arterial PO2
and PCO2 are already in equilibrium even before drops when the desaturated blood mixes with the
the blood completes half of its journey along the oxygenated blood.
pulmonary capillaries. It is, however, possible Figure 9 shows the effect of the increase in
that in some pathological conditions, like pulmo- FiO2 at various levels of shunting: when the latter
nary edema or interstitial fibrosis, diffusion may exceeds 30%, the O2 is no longer capable of
be slowed down to such a rate as to make the redressing the hypoxemia, and this characteristic
equilibrium between PO2 of the alveolar gas and makes the difference between an extrapulmonary
that of the capillary blood incomplete. It is not shunt and the other causes of hypoxia. The mixing
clear, as yet, what the role of diffusion is in of arterial blood and shunt blood causes a consid-
determining hypoxia in these disorders, but it is erable drop in PaO2 because the dissociation
likely that most of the pathogenic mechanism is curve of the O2 is flat in its higher portion: it is
due to alterations in the ventilation/perfusion therefore possible to show up minor shunts by
ratio. However, hypoxia, secondary to a diffu- measuring the arterial PO2 during 100% O2 inha-
sion defect, may be rapidly redressed by admin- lation (hyperoxic test). By contrast, if hypoxemia
istering O2; the increase in alveolar PO2 helps is secondary to other causes (hypoventilation,
overcome the resistance to diffusion caused by limitations to diffusion, inhomogeneities in the
changes in the membrane. V_ A =Q_ ratio), during 100% O2 inhalation, the
Alterations in diffusion never involve CO2 PaO2 reaches levels that are virtually comparable
given the rapidity with which it diffuses; in such to those observed in normal individuals, albeit over
conditions, the PaCO2 is often slightly decreased longer time intervals. A healthy individual who
because of the hyperventilation caused by hypoxia. inhales 100% O2 has an ideal PaO2 of 673 mmHg
(760 mmHg – 47 mmHg H2O – 40 mmHg
CO2 = 673 mmHg).
48.10.3 Extrapulmonary Shunt The PaCO2 is not usually increased in the
presence of an extrapulmonary shunt because the
The term extrapulmonary shunt refers to the pas- hypoxia and hypercapnia of non-oxygenated
sage of blood from the right sections to the left blood cause an increase in alveolar ventilation;
sections of the heart without crossing the the latter is effective in reducing the PaCO2, but
48 Neonatal Pulmonary Physiology of Term and Preterm Newborns 771
totally ineffective in increasing the PaO2. As there is no gas exchange between blood and air,
described earlier, the reason is to be found in the but an equilibrium sets in between venous
shape of the two dissociation curves; the CO2 blood and the air in the nonventilated alveoli;
curve is virtually straight in the physiological inside the latter the partial pressures will be the
zone, with the result that an increase in ventilation same as those of venous blood (Fig. 10b). In
increases the elimination of CO2. By contrast, the this way an intrapulmonary shunt is caused
shape of the Hb dissociation curve, which is flat in because the blood that perfuses the
its upper portion, does not allow the increase in nonventilated zones is not oxygenated, nor is
ventilation to bring about an improvement in the the CO2 removed; the consequences are iden-
O2 contained in the blood. tical to those caused by an extrapulmonary
During neonatal age, several diseases are char- shunt.
acterized by a right-left shunt through fetal chan- In this case an efficient compensation mech-
nels for the increase of pulmonary resistances; in anism intervenes, hypoxic vasoconstriction,
this case oxygen therapy is a critical element in which involves the capillaries that perfuse the
solving pulmonary vasoconstriction and in reduc- areas where ventilation is reduced or totally
ing the shunt. absent; the local blood flow is diverted to the
ventilated alveoli, and the deleterious effects
on the exchange of gases is considerably
48.10.4 Alterations in the Ventilation/ reduced. It is interesting to point out that
Perfusion Ratio when this occlusion of the airways persists,
the alveoli end up collapsing because of the
Alterations in the ventilation-perfusion ratio diffusion of gas in the blood, and the formation
_ are undoubtedly responsible for most of
(V_ A =Q) of atelectasis due to reabsorption is more rapid
the defects in the exchange of O2 in pulmonary if the patient breathes O2 at high concentra-
diseases and rarely for CO2 defects (West and tions. Indeed, nitrogen has a low degree of
Wagner 1997). The reason hypercapnia rarely solubility, and its presence provides support
occurs with alterations of the V_ A =Q_ ratio is for the alveoli and delays their collapse in the
because of the high degree of efficiency of the case of obstruction of the airways. Oxygen
chemoreceptors that keeps the arterial CO2 con- dependence, which is typical of children with
stant by increasing ventilation. As shown ear- bronchopulmonary dysplasia (BPD), is almost
lier, the linear shape of the CO2 dissociation certainly due to the presence of multiple shunts
curve ensures this compensation. having a low V_ A =Q_ ratio.
Also in the healthy lung there are regional • V_ A =Q_ ¼ infinite. In practice the alveoli are
variations in the V_ A =Q_ ratio, but the overall effect ventilated but not perfused (dead space effect).
on the total gas exchange is negligible. The distri- Also in these conditions there is no blood-air
bution of ventilation in particular is regulated by exchange; and indeed, instead of having partial
tissue compliance and by the resistance of the pressures similar to those of venous blood, the
airways; differences in these factors in the pulmo- air in the alveoli has the same partial pressures
nary district cause a nonuniform distribution of as atmospheric air. In other words, O2 is not
ventilation. transferred to the blood and CO2 is not
Let us now look at the consequences of the two removed. This quota of ventilation remains
extreme variations of the V_ A =Q_ ratio, bearing in unused (physiological dead space) and
mind that in practice intermediate degrees of these increases the respiratory dead space thus caus-
alterations coexist: ing a reduction in alveolar ventilation
(Fig. 10c). It is not possible to describe the
gas composition of the blood coming from
• V_ A =Q_ ¼ 0. In practice the alveoli are not ven- these units because perfusion is totally absent,
tilated but perfused (shunt effect). In this case but clearly the PO2 and the PCO2 of the blood
772 C. Moretti and P. Papoff
Fig. 10 Effects of altering
the ventilation-perfusion
ratio on the PO2 and PCO2
in a lung unit
will always be closer to those of inspired air as mechanisms often coexist and contribute to deter-
the perfusion is progressively reduced. The mining respiratory failure.
units with a high V_ A =Q_ ratio add little O2 to The most typical example in neonatology is
the blood compared to the decrease caused by RDS, where the lack of surfactant and an alteration
the alveoli with a low V_ A =Q_ ratio, and the in pulmonary compliance cause the formation of
reason is always to be sought in the shape of atelectasis and the uneven distribution of ventila-
the Hb dissociation curve. tion; as a consequence the V_ A =Q_ ratio is altered.
The edema and the presence of exudates at the
alveoli may have a negative impact also on the
48.10.5 Hypoxia Due to Anemia
diffusion of O2. The resulting hypoxia, combined
and Hypoperfusion
with acidosis, further worsens the ratio due to the
increase in vascular resistance with the formation of
It is worth remembering that to ensure an adequate
shunts in the fetal channels and hypoperfusion of
O2 supply to the tissues, a normal Hb concentration
the pulmonary circulation. Finally, owing to the
is required and also the cardiac output must be
considerable increase in respiratory work, the
adequate. The efficacy of the latter may be deter-
patient may present with hypoventilation symptoms
mined indirectly by assessing skin color and skin
after an initial phase characterized by tachypnea.
temperature, peripheral pulses, gas-analysis values,
diuresis and directly by means of color-Doppler
echocardiography. And finally, it must be pointed
out that a reduction in Hb causes a decrease in the References
O2 content without any variation in the PaO2; an
anemic patient may therefore have a good PaO2 but Baumann R (1987) Blood oxygen transport. In: Farhi L,
a low O2 content. Tenney SM (eds) Handbook of physiology. The
respiratoty system. American Physiology Society,
Bethesda, pp 147–172
Cumming G, Crank J, Horsfield K et al (1966) Gaseous
48.11 Conclusions diffusion in the airways of the human lung. Respir
Physiol 1:58–74
De Troyer A (1997) The respiratory muscles. In: Crystal
After having schematically described the patho- RG, West JB, Bames PJ, Weibel ER (eds) The lung:
physiology of the possible causes of hypoxia, it is scientific foundations, 2nd edn. Lippincott-Raven
worthwhile underlining that in practice these Press, New York, pp 1203–1215
48 Neonatal Pulmonary Physiology of Term and Preterm Newborns 773
Goerke J, Schurch S (1997) Mechanical properties of the dioxide in gas and blood of lungs: theory. J Appl
alveolar surface. In: Crystal RG, West JB, Bames PJ, Physiol 4:77–101
Weibel ER (eds) The lung: scientific foundations, 2nd Scheid P, Piper J (1997) Diffusion. In: Crystal RG, West
edn. Lippincott-Raven Press, New York, pp 1169–1176 JB, Bames PJ, Weibel ER (eds) The lung: scientific
Guyton AC (1987) Trattato di fisiologia medica. Piccin, foundations, 2nd edn. Lippincott-Raven Press,
Padova, p 572 New York, pp 1592–1618
Jones NL (1997) Acid–base physiology. In: Crystal RG, Von Euler C (1997) Neural organization and rhythm gen-
West JB, Bames PJ, Weibel ER (eds) The lung: scien- eration. In: Crystal RG, West JB, Bames PJ, Weibel ER
tific foundations, 2nd edn. Lippincott-Raven Press, (eds) The lung: scientific foundations, 2nd edn.
New York, pp 1657–1671 Lippincott-Raven Press, New York, pp 1711–1724
Keens TG, Bryan AC, Levison H et al (1978) Develop- West JB (1985) Ventilation/blood flow and gas exchange,
mental pattern of muscle fiber types in human ventila- 4th edn. Blackwell, Oxford
tory muscles. J Appl Pysiol 44:909–913 West JB (2008a) Respiratory physiology: the essentials,
Klocke RA (1997) Carbon dioxide transport. In: Crystal 8th edn. Wolters Kluwer/Lippincott Williams & Wil-
RG, West JB, Bames PJ, Weibel ER (eds) The lung: kins, Baltimore
scientific foundations, 2nd edn. Lippincott-Raven West JB (2008b) Pulmonary pathophysiology. The essen-
Press, New York, pp 1633–1642 tials, 7th edn. Wolters Kluwer/Lippincott Williams &
Rider ED, Jobe AH, Ikegami M, Sun B (1992) Different Wilkins, Baltimore
ventilation strategies alter surfactant responses in pre- West JB, Wagner PD (1997) Ventilation-perfusion relation-
term rabbits. J Appl Physiol 73:2089–2096 ships. In: Crystal RG, West JB, Bames PJ, Weibel ER
Riley RL, Coumand A (1951) Analysis of factors (eds) The lung: scientific foundations, 2nd edn.
affecting partial pressures of oxygen and carbon Lippincott-Raven Press, New York, pp 1289–1305
Control of Breathing in Newborns
49
Ruben E. Alvaro and Henrique Rigatto
Contents
49.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 775
49.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 776
49.3 Breathing Pattern at Rest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 776
49.4 Periodic Breathing and Apnea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 778
49.5 Chemical Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 782
49.6 Upper Airways and Pulmonary Reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784
49.7 Respiratory Muscles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 786
49.8 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 786
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787
Abstract oxygenation during this type of breathing
Prematurity profoundly affects breathing, mak- pattern represents a unique clinical challenge.
ing it highly irregular, with frequent pauses or In this chapter, we review some of the con-
apneas. This respiratory instability is secondary cepts and the progress made in the area of
to the immature development of the respiratory control of breathing in the newborn. We also
network as well as the underdevelopment of the highlight major developments and critically
lungs and the resultant lung injury that occurs in analyze the scientific foundations of our
this population. The increased activity of the knowledge in this area.
peripheral chemoreceptors and the closeness of
eupneic and threshold PCO2 confer a great
vulnerability to respiratory stability in these
49.1 Salient Points
infants. Maintaining adequate ventilation and
• In very small preterm infants, significant bra-
dycardia and desaturation can occur with very
short apneic pauses. This is likely related to
R. E. Alvaro (*) · H. Rigatto
their inadequate end expiratory lung volumes
Department of Pediatrics, WR004 Women’s Hospital,
University of Manitoba, Winnipeg, MB, Canada due to unstable chest wall secondary to the
e-mail: [email protected] excessive chest wall compliance and to the
# Springer International Publishing AG, part of Springer Nature 2018 775
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_198
776 R. E. Alvaro and H. Rigatto
tonic inhibition of chest wall muscles during position (Davi et al. 1979; Kalapesi et al. 1981).
REM sleep. Third, babies are usually studied with a nosepiece
• Most short apneas in preterm infants are cen- because they are nose breathers; adults are usually
tral, whereas long apneas are mixed. Purely studied using a mouthpiece. These methodologi-
obstructive apneas are rare. Obstructive apneas cal differences have made comparison of breath-
are more commonly seen as part of a mixed ing in newborn with that in adult subjects difficult
apneic event. to interpret. There is currently a major need for
• Respiratory efforts against a closed airway studies to be done using similar methodology.
seem to prolong apnea and aggravate the oxy- Unless there is some consistency in the method-
gen desaturation and the decrease in heart rate ology, it is hard to define what is actually distinct
that are usually associated with apneas. or unique about the control of breathing in the
• The basic reason for the respiratory instability neonate. In recent years, we have experienced
observed in preterm infants appears to be the tremendous advances in the field of respiratory
major contribution of the peripheral chemore- control, and we are now witnessing the initial
ceptor drive to normal breathing and the close- discovery of several of the genes that control the
ness of eupneic and threshold PACO2. development and maturation of multiple neurally
• Periodic breathing and apnea are more frequent controlled respiratory functions.
in REM sleep than in quiet sleep. This is due to In this chapter, we review some of the concepts
decreases in diaphragmatic activity, the tone of and the progress made in the area of control of
the intercostal muscles, and the tone of the breathing in the newborn. We also highlight major
adductor muscles of the upper airway produc- developments and critically analyze the scientific
ing chest distortion, impairment of the braking foundations of our knowledge in this area.
mechanism during expiration, pulmonary col-
lapse, and apnea during REM sleep.
• In extremely preterm infants, periodic breath- 49.3 Breathing Pattern at Rest
ing can be associated with episodes of inter-
mittent hypoxia. Pre- and postnatal infection The neonate, and particularly the premature
together with the inflammation induced by infant, breathes irregularly. There is significant
mechanical ventilation and oxygen toxicity breath-to-breath variability and long stretches of
could alter the structure and function of the periodic breathing in which breathing and apnea
peripheral and central respiratory control sys- alternate (Kalapesi et al. 1981; Cross and Oppé
tem leading to chronic episodes of intermittent 1952; Waggener et al. 1984). Haldane’s statement
hypoxia. that “the surprising fact is not that we breathe
regularly, but that we do not breathe periodically
most of the time” applies more at this age than at
49.2 Introduction any other (Douglas and Haldane 1908-1909). The
resting breathing pattern of the neonate is not
There are at least three important considerations sleep state dependent, although sleep greatly mod-
regarding the study of the control of breathing ulates it (Rigatto et al. 1982a; Gabriel et al. 1976).
during the neonatal period. First, the neonates Sleep has traditionally been divided into quiet,
are noncooperative subjects. This means that we REM, transitional, and indeterminate states.
must study their respiratory control without their Twenty-nine percent (29%) of sleep time in neo-
being aware and try to compare the measurements nates is spent in quiet sleep, 33% in REM, 7% in
with those of the adult under similar conditions. transitional sleep, and 31% in indeterminate sleep.
This is difficult to do. Second, measurements in The proportion of quiet sleep increases with age,
the neonate are usually made, by necessity, in the while the amount of REM decreases with age. The
decubitus position, whereas those in the adult proportion of wakefulness decreases with decreas-
subject are usually made in the sitting or standing ing gestational age, and in very immature infants, it
49 Control of Breathing in Newborns 777
Fig. 1 Periodic breathing during quiet sleep in an intervals keeping a constant length. Note also the classic
8-day-old preterm infant born at 32 weeks. Note the regular trace alternant pattern on the electroencephalogram (EEG)
periodicity of breathing, with both apneic and breathing
becomes difficult to define wakefulness or arousal is that periodic breathing in quiet sleep is regular –
(Curzi-Dascalova and Challamel 2000; Lehtonen that is, the breathing and apneic intervals are of
and Martin 2004). We have shown that periodic similar duration – and very irregular in REM
breathing, a common breathing pattern in prema- sleep. The most well-defined periodic breathing
ture infants in which they alternate between breath- observable in small babies is in quiet sleep during
ing intervals and apneas lasting 5–10 s, occurs in trace alternant (Fig. 1). Therefore, there are two
the three states, wakefulness, REM, and quiet, but major differences between neonates and adults
its prevalence is increased in REM sleep (Rigatto regarding staging of sleep state. One difference
et al. 1982a). It is frequently stated in textbooks that relates to the patterns of breathing observed in
in quiet sleep, in analogy with criteria used for adult quiet and REM sleep states and the other to the
subjects, breathing is regular. Prechtl and we, how- presence of the trace alternant electroencephalo-
ever, have clearly shown that periodic breathing is gram (EEG) during quiet sleep in the neonate. As
common in quiet sleep (Kalapesi et al. 1981; this pattern subsides after 44 weeks’
Moriette et al. 1985; Prechtl 1974). The difference postconceptional age, it is not used in adults to
778 R. E. Alvaro and H. Rigatto
characterize quiet sleep. The overall minute venti- the length of the respiratory pause is not a very
lation is increased in REM sleep as compared with useful indicator of severity of the disruption in
quiet sleep, and this is due to a primary increase in breathing. For this reason, many centers, includ-
respiratory frequency with little change in tidal ing ours, have decided to rely on heart rate and
volume (Davi et al. 1979; Kalapesi et al. 1981; oxygen saturation as the primary indicators of
Rigatto et al. 1982a; Gaultier 1987). Increasing severity.
respiratory rate instead of tidal volume is more Apneic episodes in the neonate are classified
energy efficient to cope with higher ventilator according to the absence or presence of breathing
needs (Mortola 1983). There is a well-known efforts during the period of no airflow (Lee
inverse relationship between resting respiratory et al. 1987). Central apneas are those with no
rate and body size with smaller and younger infants flow and no observable breathing efforts. Obstruc-
having higher respiratory rates per unit body weight tive apneas are those with no flow despite breathing
than larger, older infants (Gagliardi and Rusconi efforts. Mixed apneas begin as central and end as
1997). Tidal volume remains essentially unchanged obstructive apnea. Breath-holding apneas are those
from birth to adulthood (about 6 ml/kg). Minute in which flow stops at mid-expiration, and the
ventilation, as expected, decreases with age as remaining expiration occurs just before breathing
respiratory frequency and metabolic demands starts again. A new method of classifying apneas,
decrease (Polgar and Weng 1979). based on a magnified cardiac-induced pulse
observed on the respiratory flow tracing, has been
recently described by us. This method is able to
49.4 Periodic Breathing and Apnea detect the presence and timing of airway obstruc-
tions with great precision. Using this method, it is
Periodic breathing, defined as pauses in respira- obvious that some apneas, previously classified as
tory movements that last for up to 20 s alternating central because of the absence of respiratory
with breathing, is common in preterm infants. efforts, are indeed obstructive (silent obstruction)
When the respiratory pause is longer than 20 s, it (Fig. 2; Lemke et al. 1996; Al-Sufayan et al. 2009).
is called apnea (Rigatto 1988). Although the dura- We have been using this method extensively in our
tion used to distinguish periodic breathing and experimental studies, but its use in routine clinical
apnea is arbitrary, it has proved useful and has care is not yet established.
been widely adopted. Periodic breathing is not as In preterm infants with underlying disease
harmful as apnea since the respiratory pause is followed longitudinally over a period of 3 months,
short and the decrease in heart rate is minor. In central apneas predominated and purely obstruc-
contrast, apnea is a more serious condition, the tive apneas were rare (Fig. 3; Lee et al. 1987).
respiratory pause being longer and frequently Obstructive apneas are more commonly noted as
associated with decreases in heart rate below part of a mixed apneic event. Most short apneas
80 beats/min (Rigatto 1988, 1986). In very small are central, whereas long apneas are mixed. The
preterm infants, significant bradycardia and mechanism of obstruction in mixed apneas is
desaturation can occur with very short apneic unknown, and it is not completely clear whether
pauses, likely related to their higher oxygen con- the obstructed respiratory efforts prolong the
sumption per unit weight and their relatively apnea or whether a longer initial central pause
smaller lung volumes and oxygen stores than the predisposes the airway to collapse at the end of
term infants and adult subjects. These inadequate the apnea. We found that airway closure, as mea-
end expiratory lung volumes are due to excessive sured by the absence of cardiac oscillations on the
chest wall compliance leading to distal airway respiratory flow tracing, was present in about 20%
closure (Poets 2010; Poets et al. 1997) and to the of central apneas and preceded 59% of the
tonic inhibition of chest wall muscles during REM obstructed respiratory efforts in mixed apneas.
sleep leading to unstable chest wall stability This airway closure during central apneas did
(Lopes et al. 1981a). In this instance, therefore, not limit the severity of oxygen desaturation or
49 Control of Breathing in Newborns 779
Central Apneas Mixed Apnea
Patent Airway Closed Airway
EKG
3
Flow
0
l•min-1
3
0.3
Amplified
Flow 0
l•min-1 0.3
Cardiac
Oscillations
Chest
Movement Obstructed
Respiratory Efforts
Abdominal
Movement
100
O2 Sat
% 90
Fig. 2 Representative tracing: examples of three types of Cardiac oscillations and respiratory effort signals are indi-
apneas diagnosed by absent (central apneas) or present cated. The flow channel shows baseline respiratory flow
obstructed respiratory efforts (mixed apnea). Central with minor amplification. The amplified flow represents a
apneas are further classified using the amplified cardiac tenfold amplification of the flow signal by the chart
airflow oscillation into those with open airway (oscillations recorder so that cardiac oscillation may be easily analyzed
present) and those with closed airway (oscillations absent). (Rigatto 1988)
the decrease in heart rate. We also found that Periodic breathing and apnea are clearly a con-
although the length of mixed apneas was longer sequence of a disturbance of the respiratory con-
than central apneas, the length of the initial central trol system, but the precise mechanisms are
component of the mixed apneas was significantly unclear. Investigators in this area tend to believe
shorter than the length of central apneas, that the negative feedback loop controlling
suggesting that respiratory efforts against a closed respiration is affected by multiple factors related
airway prolong apnea. These respiratory efforts primarily to anatomic and physiologic immaturity
against a closed airway also aggravated the oxy- that affect many levels of the respiratory
gen desaturation and the decrease in heart rate that control system including central and peripheral
are usually associated with apneas (Al-Sufayan chemoreceptors. For example, arborization of
et al. 2009). In preterm infants recovering from dendrites at 30 weeks’ gestation is meager, and
respiratory support, with some degree of residual neuroconduction and synaptic relay are
lung disease (bronchopulmonary dysplasia), the impaired (Purpura 1975). Delays in traffic of
prevalence of obstructive apneas appears to be neuromessages may then make the system oscil-
increased, comprising up to 48% of the apneas late. Unfortunately, we do not know how much
in some studies. There is no clear explanation for immaturity is needed for a given impairment
the obstruction, but it seems to be at the level of in neurophysiologic traffic. Oscillation in arterial
the larynx (Mathew et al. 1982). gas tensions, changes in circulation time,
780 R. E. Alvaro and H. Rigatto
Fig. 3 Frequency distribution of the various types of is greater in term than in preterm infants. Obstructive and
apneas in healthy preterm and term infants. Central apneas mixed types of apneas are rare (Gagliardi and Rusconi
are predominant. The frequency of breath-holding apneas 1997)
incoordination of the respiratory pump owing to a have shown that the periodic breathing cycles in
compliant chest wall, and changes in sleep state REM but not in quiet sleep were associated with
may all contribute to this instability of the respira- progressive decrease in minute ventilation and
tory control system (Rigatto 1988). Many inhibi- oxygenation likely related to the mechanical and
tory neurotransmitters and neuromodulators, chemoreceptor limitations known to be present in
including adenosine, prostaglandins, endorphins, this sleep state (Ali et al. 2006). We believe that
and GABA, have been also implicated in the path- periodic breathing, especially during REM sleep,
ogenesis of periodic breathing and apnea (Martin is a marker for apnea since apneas almost never
et al. 2004). occur abruptly in infants breathing regularly, but
There has been controversy in the literature on only in infants whose respiratory pattern is char-
whether periodic breathing and apnea are mecha- acterized by significant periodicity.
nistically different or whether long apneas are just Compared with infants who breathe continu-
a step further in the basic respiratory disturbance ously, neonates breathing periodically have lower
that induces the short apneas of periodic breath- arterial PO2 values, and their peripheral chemore-
ing. In a study carried out in our laboratory, we ceptors are more hyperactive as reflected by the
were able to show that (i) a prolonged apnea longer apneic period and more pronounced imme-
almost never occurred in the absence of preceding diate decrease in ventilation in response to inhala-
short apneas and (ii) the risk of a prolonged apnea tion of high oxygen mixtures (Rigatto 1986;
occurring increased significantly when the pre- Rigatto and Brady 1972a; Al-Matary et al. 2004).
ceding period contained an increased number of Thus, the basic reason for background instability
apneic episodes, increased duration of the longest appears to be the major contribution of the periph-
apneic interval, or increased duration of the apneic eral chemoreceptor drive to normal breathing at
time (Al-Saedi et al. 1997). More recently, we this age. Indeed, the arterial PO2 tension of these
49 Control of Breathing in Newborns 781
infants sits on the steep portion of the minute eupneic and apneic PACO2 during hypoxia was
ventilation-arterial PO2 regression curve for due to a disproportionate reduction in the eupneic
human adults. This means that small changes in PACO2 rather than a higher apneic threshold (Xie
baseline arterial PO2 produce large changes in et al. 2001). The low arterial PO2 in newborn
baseline ventilation. Hypoxia may be a contribut- infants may keep the eupneic PCO2 relatively
ing factor, because inhalation of a low-oxygen low, not by hyperventilation as in adult subjects
mixture easily induces periodic breathing and but by a decrease in metabolism which parallels
apnea in these infants. the decreased in arterial PO2.
We found that the average CO2 apneic thresh- The sleep state appears also to be a contribut-
old in preterm infants is only 1.5 Torr lower than ing factor, since periodic breathing and apnea are
the eupneic PCO2, whereas in adults the average more frequent in REM sleep than in quiet sleep.
is ~3.5 Torr lower (Khan et al. 2005). The close- The neonate sleeps almost uninterruptedly, con-
ness of eupneic and threshold PACO2 likely con- tinuously alternating between REM sleep and
fers a great vulnerability to respiratory stability in quiet sleep. This pattern increases instability in
these infants. It is not surprising, therefore, that the respiratory control system. Indeed, minor
brief startles, movements, or change in sleep state alterations during sleep, such as a startle or a
could allow eupneic PCO2 to dive below the sigh, produce apnea in these infants. The almost
PCO2 apneic threshold, inducing periodic breath- continuous change in baseline ventilation during
ing and apnea in these infants (Fig. 4). We believe sleep is what Haldane called “the hunting of the
that the key element responsible for this narrow respiratory centre.”
difference is the well-known hypoxemic status of Although sleep modulates breathing, it does
these infants. Xie et al. have recently shown in not cause apnea; apnea also occurs during wake-
adults that the time course of the occurrence of fulness. The high prevalence of apnea during
apnea after transient hyperpnea was consistent REM sleep may be related to muscle activity in
with a peripheral chemoreceptor mechanism. In this stage. During REM sleep, the tone of the
this study, hypoxia shortened the apnea latency intercostal muscles is abolished in conjunction
and narrowed the eupneic-apneic PACO2 thresh- with a decrease in diaphragmatic activity and in
old, while hyperoxia delayed the onset of apnea the tone of the adductor muscles of the upper
and widened the eupneic-apneic PACO2 threshold airway – a combination of factors likely to induce
(Xie et al. 2006). The same group had previously chest distortion, impairment of the braking mech-
shown that the smaller difference between anism during expiration, pulmonary collapse, and
Fig. 4 Diagrammatic
representation of the
Adult Subjects
relationship between the
CO2 apneic threshold and Actual PCO2
the baseline or actual PCO2 4 Torr
levels in neonates and Apneic threshold
adults. Because of the
proximity of these two Respiratory
levels in neonates, PCO2 is Flow
much more likely to dive
below the apneic threshold
than in the adult Neonates
Actual PCO2
1.5 Torr
Apneic threshold
Apneas
Respiratory
Flow
782 R. E. Alvaro and H. Rigatto
respiratory control system that could lead to
chronic episodes of intermittent hypoxia
(Hofstetter et al. 2008; Olsson et al. 2003;
Gresham et al. 2011; Balan et al. 2011). These
episodes of hypoxia and reoxygenation have the
potential to maintain the proinflammatory cascade
and produce multisystemic morbidity (Martin
et al. 2011). A recent study has shown that
among extremely preterm infants who survived
to 36 weeks postmenstrual age, prolonged hypox-
emic episodes during the first 2–3 months after
birth were associated with adverse 18-month out-
comes (Poets et al. 2015).
49.5 Chemical Regulation
Inhalation of carbon dioxide increases ventilation
during REM and quiet sleep in newborn infants.
Fig. 5 Diagrammatic changes in tidal volume, timing, and The response to steady-state inhalation of carbon
diaphragmatic EMG in non-rapid eye movement (REM) dioxide is the same in these two sleep states, but
(quiet) and REM (active) sleep. Note that total phasic the response during rebreathing of carbon dioxide
activity diminishes from non-REM to REM sleep. Also,
is less in REM than in quiet sleep (Davi
in both sleep states, it is shorter in esophageal (DE) than in
surface EMG (DS). Expiratory phase activity as a propor- et al. 1979; Rigatto et al. 1982a; Moriette
tion of total phasic activity decreases significantly from et al. 1985; Reed and Kellogg 1958; Fig. 6). We
non-REM to REM sleep (Al-Saedi et al. 1997) postulated that the differences in response with
these two techniques relate to the fact that using
apnea (Rigatto 1988; Rigatto et al. 1982b; Fig. 5). rebreathing, it is possible to measure the response
When chest distortion occurs, diaphragmatic in “phasic” REM only, whereas using the steady-
work increases by about 40%, adding to the state technique, the response always covers both
mechanical impairment. This observation is com- “phasic” and “tonic” REM sleep (Moriette
patible with the finding that the application of et al. 1985). As the carbon dioxide response in
continuous negative pressure around the chest “tonic” REM is the same as that during quiet
tends to abolish apnea (Thibeault et al. 1967). sleep, the results using the steady-state method
In extremely preterm infants (<28 weeks), tend to resemble those in quiet sleep (Phillipson
especially in those with residual lung disease, 1978; Phillipson et al. 1977).
this type of breathing pattern can be associated The pattern of breathing observed with inhala-
with episodes of intermittent hypoxia. These epi- tion of carbon dioxide varies with the percentage
sodes are observed in intubated and extubated of carbon dioxide inhaled. If the percentage of
patients and are a consequence of an immature inhaled carbon dioxide is low (<2%) during
respiratory control system superimposed to imma- steady-state inhalation, the response consists pri-
ture lungs (Dimaguila et al. 1997; Esquer marily of an increase in tidal volume (Kalapesi
et al. 2007; Di Fiore et al. 2013). Pre- and postna- et al. 1981). If the percentage of inhaled carbon
tal infection together with the inflammation dioxide is high (>2%), the response in both sleep
induced by mechanical ventilation and oxygen states consists of an increase in respiratory fre-
toxicity not only could cause abnormal cardiopul- quency and in tidal volume (Moriette et al. 1985;
monary development but may also alter the struc- Rigatto and Brady 1972a). Periodic breathing is
ture and function of the peripheral and central abolished with a small increase in inhaled carbon
49 Control of Breathing in Newborns 783
Fig. 6 The ventilatory response to CO2 rebreathing in neonates. Note that a preterm and b term infants showed a
decreased response to CO2 in phasic rapid eye movement sleep as compared with quiet sleep (Moriette et al. 1985)
dioxide of about 1–2% (Kalapesi et al. 1981; (Davi et al. 1979). The more sustained hyperven-
Rigatto and Brady 1972a). This response has tilation in these infants during quiet sleep reflects
been attributed to the increased central drive and the more autonomic control during this sleep state,
increased stores of carbon dioxide, with better the system being more responsive to chemical
buffering capacity for the oscillations in PaCO2. stimuli (Phillipson 1978; Phillipson et al. 1977).
Inhalation of low oxygen produces an imme- The immediate increase in ventilation reflects
diate increase in ventilation (1 min) followed by a peripheral chemoreceptor stimulation and is asso-
later decrease (5 min) (Waggener et al. 1984; ciated with an increase in frequency and in tidal
Rigatto and Brady 1972b; Brady and Ceruti volume. The late response is primarily manifested
1966; Brady et al. 1964). The response is by a decrease in frequency (Rigatto 1986; Rigatto
similar in wakefulness, REM, and quiet sleep, and Brady 1972b). The mechanism responsible
although hyperventilation seems slightly more for this response is still unclear and may vary
sustained during late hypoxia in quiet sleep according to species. In humans, it is likely related
784 R. E. Alvaro and H. Rigatto
to central release of inhibitory neuromodulators 49.6 Upper Airways and Pulmonary
(Easton et al. 1988). This late hypoxic ventilatory Reflexes
depression is likely mediated through several
complex mechanisms. In addition to hypoxic The laryngeal chemoreflexes (LCR) comprise a
hypometabolism (Mortola 1999), several group of reflexes triggered by the contact between
neuromodulators play a role in the hypoxic liquids and receptors of the laryngeal mucosa. The
ventilatory depression including adenosine receptors involved appear to be unmyelinated nerve
(Elnazir et al. 1996), γ-aminobutyric acid fibers located immediately beneath the laryngeal
(GABA) (Kneussl et al. 1986), serotonin (5-HT) mucosal epithelium (Lucier et al. 1979). Stimula-
(Di Pasquale et al. 1992), opioids (Xia and tion of the laryngeal mucosa, either chemically or
Haddad 1991), and platelet-derived growth factor mechanically, causes laryngospasm, swallowing,
(PDGF-β) receptors (Gozal et al. 2000). However, central or mixed apnea, oxygen desaturation, and
experiments in kittens and in newborn monkeys bradycardia (Thach 2001). This reflex-induced
suggest that the late decrease in ventilation may be apnea is mediated through superior laryngeal
a mechanical effect rather than a depression of the nerve afferents (Martin and Abu-Shaweesh 2005).
central respiratory neurons (LaFramboise Immature LCR, characterized by exaggerated
et al. 1983; LaFramboise and Woodrum 1985). inhibitory cardiorespiratory responses, are mainly
In these experiments, diaphragmatic activity and observed in preterm infants or in conditions where
frequency remained elevated during hypoxia, but upper airway inflammation is present (Lindgren
tidal volume decreased below control values dur- et al. 1992). Some authors have suggested that up
ing late hypoxia. These experiments were carried to 70% of apnea of prematurity and the apneas
out during quiet sleep. The peculiar response of associated with respiratory syncytial viral infection
the neonate to low inhaled oxygen is of great are related to LCR (Lindgren et al. 1992; Miller and
clinical significance. Infants who are borderline DiFiore 1995; Pickens et al. 1988). With matura-
hypoxic tend to breathe periodically or develop tion, the duration and severity of apneas secondary
apneic spells. Hypoxia can induce periodic to LCR reflexes decrease. This is in part related to
breathing in these infants, as shown previously decrease stimulation of the LCR due to improved
(Harned and Ferreiro 1973). The relief of these coordination of upper airway muscles and to the
apneic spells, which are frequently associated increase in the excitatory respiratory-related neu-
with bradycardias, can be obtained by increasing rons within the respiratory network that counterbal-
the inspired oxygen concentration (Rigatto 1986; ance the inhibitory afferent input from the LCR
Rigatto and Brady 1972a). (Gewolb et al. 2001; Kurth et al. 1989).
Administration of high concentrations of oxy- The patency of the pharyngeal airway is deter-
gen, on the other hand, produces an immediate mined by the interaction between anatomical and
decrease in ventilation followed by hyperventila- neural mechanisms. Impairments of either or both
tion, a response that is similar during wakefulness, mechanisms result in pharyngeal airway obstruc-
REM, and quiet sleep. These findings suggest a tion (Isono 2008; Kuna and Remmers 2000). The
lack of major differences in the activity of the anatomical forces include the mechanical proper-
peripheral chemoreceptors during these sleep ties of the pharynx and the transmural pressure.
states (Rigatto 1988; Aizad et al. 1984). The Neonates are characterized by a small maxilla and
immediate decrease in ventilation following the mandible compared with a relatively large cra-
administration of 100% oxygen is related to a nium. This anatomical imbalance improves in
decrease in frequency (apnea being common in the first year of life as the anatomical properties
preterm infants) and a decrease in tidal volume. of the pharynx progressively gain stability in
The late increase in ventilation with oxygen is favor of maintaining a patent airway (Isono
likely related to cerebral vasoconstriction with et al. 2000). Increase in soft tissue surrounding
increase Hþ concentration at the chemoreceptor the tube (macroglossia, obesity, hypertrophied
site (Davi et al. 1980). adenoid) and decrease in size of bony structure
49 Control of Breathing in Newborns 785
(micrognathia, midfacial hypoplasia) decrease air- and the mediated reflexes are also abolished dur-
way size. Neck extension and mandibular ing REM sleep (Fleming et al. 1978). Therefore,
advancement increase the mandible enclosure airway mechanisms responsible for clearing, such
size, favoring maintenance of pharyngeal airway as cough, are impaired during REM sleep. The
patency. Neck flexion and bite opening narrow the paradoxical reflex of the head is commonly
pharyngeal airway. Supine position increases the observed in the neonate in the form of a sigh
gravitational force on the soft tissue and (Bodani et al. 1984). Many attribute the high
encroaches the airway within the mandibular prevalence of sighs to the greater need for lung
enclosure by the tongue worsening pharyngeal recruitment at this age (Thach and Tauesch 1976).
airway patency (Isono 2008). Sighs are more frequent in REM than in quiet
These anatomical disadvantages make the neu- sleep and are also more frequent during periodic
ral mechanisms important to maintain patency of than regular breathing. During periodic breathing,
the neonatal airway. These neural mechanisms reg- a sigh usually appears during the first or second
ulate central drives to the pharyngeal and pump breath after apnea. When it occurs during regular
muscles and determine the size of the pharyngeal breathing, it tends to be followed by short apneas
airway by the balance between two antagonistic (Reed and Kellogg 1958). Efforts to discover the
forces: the pharyngeal muscle contraction that mechanisms triggering sighs have been fruitless.
stiffens and maintains airway patency and the con- Thach and Tauesch showed that asphyxia does not
traction of inspiratory pump muscles that narrows seem to be a stimulus (Thach and Tauesch 1976).
the pharyngeal airway by producing a negative Alvarez and colleagues, however, have observed
airway pressure (Remmers et al. 1978; Brouillette that airway occlusion in the presence of hypoxia
and Thach 1979). This negative pharyngeal pres- predisposes to sighs (Alvarez et al. 1993).
sure sensed by upper airway receptors is known for When studying the morphology of sighs in
reflexively increase pharyngeal muscle activity to infants and adult subjects, we have found that
stiffen airway (negative pressure reflex). Sleep the sighs in infants are relatively larger than
depresses pharyngeal muscle activity and that sup- those in adults and that while post-sigh ventilation
pression is greater during REM sleep (Sauerland is usually increased in adults, it is decreased in
and Harper 1976; Tangel et al. 1991). Wakefulness infants (Qurashi et al. 2005). Since the drive
improves neural responses. Neonates have a strong to breathe early in life is dependent on the
negative pressure reflex that compensates for the increased peripheral chemoreceptor activity, it is
relatively high collapsibility of the passive pharyn- conceivable that the sudden increase in arterial
geal airway. This reflex preferentially activates the PO2 with sighs could produce a rapid decline
upper airway muscles without activation of the in carotid body afferent discharge leading to
diaphragm (Cohen and Henderson-Smart 1989; hypoventilation and apnea. The other almost
Carlo et al. 1985). This negative pressure reflex instantaneous change that occurs with a sigh
diminishes later in life (Malhotra et al. 2000). includes a decrease in PCO2. Since the CO2
The inflation reflex of Hering-Breuer is much apneic threshold is much closer to the baseline
more active in the newborn period than in adult CO2 in neonates compared with adults, the
life (Cross et al. 1960; Olinsky et al. 1974). Small decline in CO2 below the threshold during a sigh
increases in lung volume cause apnea. This could trigger an apnea or initiate an epoch of
response is so powerful in the newborn that periodic breathing in infants with immature respi-
many have used this inflation to produce apnea ratory feedback loop (Khan et al. 2005; Bradley
and then study the mechanical properties of the 2002). These findings suggest that although the
respiratory system during the passive expiratory ability to sigh may be an important mechanism to
phase following apnea. The action of the stretch restore lung volume, sighs have the potential to
receptors is much influenced by sleep, being destabilize breathing and cause hypoventilation
abolished during REM sleep. The irritant recep- and apnea in infants at risk for inadequate control
tors are also poorly developed in preterm infants, of breathing (Henderson-Smart and Read 1979).
786 R. E. Alvaro and H. Rigatto
49.7 Respiratory Muscles (Harding et al. 1980). Sleep state profoundly
affects the muscular control of upper airway resis-
The activity of the respiratory muscles is much tance. Studies in fetal and neonatal lambs suggest
altered by sleep state. Tonic activity of most respi- that the abductor muscles of the larynx – the
ratory muscles is abolished during REM sleep posterior cricoarytenoid and cricothyroid – have
(Harding et al. 1977; Dawes et al. 1982; Lopes inspiratory activities in parallel with that of the
et al. 1981b; Luz et al. 1982). The disappearance diaphragm, during both quiet and REM sleep. On
of tone in the intercostal muscles has been the other hand, the adductor muscles of the larynx
suggested as a major factor responsible for the – the thyroarytenoid, lateral cricoarytenoid, and
increased chest distortion seen during REM intraarytenoid – have a phasic expiratory activity
sleep in infants with this condition. The lack of during quiet sleep. This activity is lost during
tone leads to chest wall collapse during inspira- REM sleep in the fetus and in the newborn lamb
tion, and caudal displacement of the diaphragm (Harding et al. 1977; Dawes et al. 1982). A reduc-
has to be twice as long to produce the same lung tion in adductor activity of the larynx, in conjunc-
volume displacement (Henderson-Smart and tion with decreased intercostal and decreased
Read 1979; Luz et al. 1982). Because of chest postinspiratory diaphragmatic activity during
wall collapse, functional residual capacity is REM sleep, may cause the decrease in lung vol-
decreased in these infants during REM sleep ume observed during this sleep state.
(Henderson-Smart and Read 1979). We have A recent study using electrical activity of the
found that distorted and nondistorted breaths pro- diaphragm (Edi) measured by electrodes within a
duce the same instantaneous ventilation as long as nasogastric tube positioned at the level of the dia-
they are of the same duration, although the work phragm has shown that Edi peak was higher while
of the diaphragm is 40% greater when distortion is the term neonates was awake than during sleep and
present (Luz et al. 1982). lower in the postprandial state than preprandial and
It has been shown that in newborns, in contrast feeding states (Stein et al. 2012). The same author,
to adults, expiration is actively terminated at sub- using the same technique in preterm infants, has
stantial flow rates. The role of this expiratory also shown that Edi peak and the tonic activity of
braking mechanism is to maintain lung volume the diaphragm do not change with postnatal matu-
above FRC. The newborn uses two mechanisms ration or with the level of noninvasive respiratory
to actively slow expiration. The first one is the support (Stein et al. 2013).
postinspiratory activity of the diaphragm (Kosch
et al. 1988). This activity controls, in part, the
duration of expiratory time and is also affected 49.8 Conclusions
by sleep (Remmers and Bartlett 1977; Remmers
et al. 1978). In neonates, this activity is more In summary, although the basic mechanisms
pronounced in the lateral than in the crural part involved in the control of breathing during neona-
of the diaphragm, longer in quiet than in REM tal life are similar to those investigated more
sleep, and more prolonged in preterm than in term extensively in adult subjects, there are some
infants (Reis et al. 1994). The length and variabil- unique aspects of this control affecting primarily
ity of this activity in preterm infants suggest that in the preterm infant. First, sleep seems to have a
because of their highly compliant chest wall, these very profound effect during this period of life.
infants use the postinspiratory diaphragmatic REM sleep increases the incidence of periodic
activity as a braking mechanism whose role in breathing and apnea, decreases de ventilatory
maintaining lung volume and controlling expira- response to CO2, enhances the late decrease in
tory time is much more important than in older ventilation with hypoxia, increases chest distor-
children and adult subjects. The second mecha- tion leading to muscle fatigue, inhibits pulmonary
nism that the newborn uses to slow expiration is reflexes, and decreases upper airway tone and
the laryngeal narrowing during expiration postinspiratory activity of the diaphragm leading
49 Control of Breathing in Newborns 787
to decrease lung volume during expiration. Sec- Bodani J et al (1984) The effect of periodic breathing and
ond, the highly compliant chest wall due to the sleep state on the incidence and “structure” of aug-
mented breaths in neonates. Pediatr Res 18:402A
lack of mineralization puts these newborn infants Bradley TD (2002) Crossing the threshold: implications
at a mechanical disadvantage which is worsened for central sleep apnea. Am J Respir Crit Care Med
by the inhibitory effects of REM sleep. These 165(9):1203–1204
shortcomings favor instability of the respiratory Brady JP, Ceruti E (1966) Chemoreceptor reflexes in the
new-born infant: effects of varying degrees of hypoxia
control system. Third, the low FRC of small on heart rate and ventilation in a warm environment. J
infants means low O2 stores with less buffering Physiol Lond 184:631
capacity and increase risk of atelectasis, leading to Brady JP et al (1964) Chemoreflexes in the newborn infant:
intrapulmonary right-to-left shunts and reduced effects of 100% oxygen on heart rate and ventilation. J
Physiol Lond 17:332
arterial O2 tension. This relatively hypoxic envi- Brouillette RT, Thach BT (1979) A neuromuscular mech-
ronment increases the activity of the peripheral anism maintaining extrathoracic airway patency. J Appl
chemoreceptors and narrows the difference Physiol 46:772–779
between baseline PCO2 and CO2 apneic threshold Carlo WA, Miller MJ, Martin RJ (1985) Differential
response of respiratory muscles to airway occlusion in
levels favoring the establishment of periodic infants. J Appl Physiol 59:847–852
breathing and apneas. Thus, neonates have some Cohen G, Henderson-Smart DJ (1989) Upper airway mus-
unique features of their respiratory control system cle activity during nasal occlusion in newborn babies. J
which may at times compromise their health. It is Appl Physiol 66:1328–1335
Cross KW, Oppé TE (1952) The effect of inhalation of high
the understanding of these features and their inti- and low concentrations of oxygen on the respiration of
mate physiologic mechanisms by physicians and the premature infant. J Physiol Lond 117:38
other healthcare workers that represents the best Cross KW et al (1960) The response of the new-born baby
promise for a good quality of medical care at the to inflation of the lungs. J Physiol 151:551
Curzi-Dascalova L, Challamel MJ (2000) Neurophysio-
time of birth. logical basis of sleep development. In: Loughlin GM,
Carroll JL, Marcus CL (eds) Sleep and breathing in
children. A developmental approach. Marcel Dekker,
New York, pp 3–37
Davi M et al (1979) Effect of sleep state on chest distortion
References and on the ventilatory response to CO2 in neonates.
Pediatr Res 13:982
Aizad T et al (1984) Effect of a single breath of 100% Davi M et al (1980) Effect of inhaling 100% O2 on venti-
oxygen on respiration in neonates during sleep. J Appl lation and acid-base balance in cerebrospinal fluid in
Physiol 57:1531 neonates. Biol Neonate 38:85
Ali I, Alallah J, Kwiatkowski K, et al (2006) Morphology Dawes GS et al (1982) Effects of hypercapnia on tracheal
of Periodic Breathing (PB) in Quiet (Q) and REM sleep pressure, diaphragm and intercostal electromyograms
and its role on the control of breathing in preterm in unanesthetized fetal lambs. J Physiol Lond 326:461
infants. Pediatr Res 59:2635.7 Di Fiore JM, Martin RJ, Gauda EB (2013) Apnea of
Al-Matary A, Kutbi I, Qurashi M et al (2004) Increased prematurity – perfect storm. Respir Physiol Neurobiol
peripheral chemoreceptor activity may be critical in 189(2):213–222
destabilizing breathing in neonates. Semin Perinatol Di Pasquale E, Morin D, Monteau R, Hilaire G (1992)
24(4):264–272 Serotonergic modulation of the respiratory rhythm gen-
Al-Saedi SA, Lemke RP, Haider AZ et al (1997) Prolonged erator at birth: an in vitro study in the rat. Neurosci Lett
apnea in the preterm infant is not a random event. Am J 143(1–2):91–95
Perinatol 14:195–200 Dimaguila MA, Di Fiore JM, Martin RJ, Miller MJ (1997)
Al-Sufayan F, Bamehrez M, Kwiatkowski K, Alvaro RE Characteristics of hypoxemic episodes in very low birth
(2009) The effects of airway closure in central apneas weight infants on ventilatory support. J Pediatr
and obstructed respiratory efforts in mixed apneas in 130:577–583
preterm infants. Pediatr Pulmonol 44(3):253–259 Douglas CG, Haldane JS (1908–1909) The causes of periodic
Alvarez JE et al (1993) Sighs and their relationship to or Cheyne-Stokes breathing. J Physiol (Lond) 38:401
apnea in the newborn infant. Biol Neonate 63:139 Easton PA, Slykerman LJ, Anthonisen NR (1988) Recov-
Balan KV, Kc P, Hoxha Z, Mayer CA, Wilson CG, Martin ery of the ventilatory response to hypoxia in normal
RJ (2011) Vagal afferents modulate cytokine-mediated adults. J Appl Physiol 64:521–528
respiratory control at the neonatal medulla oblongata. Elnazir B, Marshall JM, Kumar P (1996) Postnatal devel-
Respir Physiol Neurobiol 178(3):458–464 opment of the pattern of respiratory and cardiovascular
788 R. E. Alvaro and H. Rigatto
response to systemic hypoxia in the piglet: the roles of Isono S, Tanaka A, Ishikawa T et al (2000) Developmental
adenosine. J Physiol 492(Part 2):573–585 changes in collapsibility of the passive pharynx
Esquer C, Claure N, D’Ugard C, Wada Y, Bancalari E during infancy. Am J Respir Crit Care Med
(2007) Role of abdominal muscles activity on dura- 162:832–836
tion and severity of hypoxemia episodes in mechani- Kalapesi Z et al (1981) Effect of periodic or regular respi-
cally ventilated preterm infants. Neonatology 92: ratory pattern on the ventilatory response to low inhaled
182–186 CO2 in preterm infants during sleep. Am Rev Respir
Fleming PJ et al (1978) Functional immaturity of pulmo- Dis 123:8
nary irritant receptors and apnea in newborn preterm Khan A, Qurashi M, Kwiatkowski K et al (2005) Measure-
infants. Pediatrics 61:515 ment of the CO2 apneic threshold in newborn infants:
Gabriel M et al (1976) Apneic spells and sleep states in possible relevance for periodic breathing and apnea. J
preterm infants. Pediatrics 57:142 Appl Physiol 98:1171–1176
Gagliardi L, Rusconi F (1997) Respiratory rate and body Kneussl MP, Pappagianopoulos P, Hoop B, Kazemi H
mass in the first three years of life. The working party (1986) Effect of centrally administered gamma-
on respiratory rate. Arch Dis Child 76(2):151–154 aminobutyric acid on metabolic function. J Appl
Gaultier C (1987) Respiratory adaptation during sleep from Physiol 61(2):472–476
the neonatal period to adolescence. In: Guilleminault C Kosch PC, Hutchinson AA, Wozniak JA, Carlo WA
(ed) Sleep and its disorders in children. Raven, et al (1988) Posterior cricoarytenoid and diaphragm
New York, pp 67–98 activities during tidal breathing in neonates. J Appl
Gewolb IH, Vice FL, Schwietzer-Kenney EL, Taciak VL Physiol 64(5):1968–1978
et al (2001) Developmental patterns of rhythmic suck Kuna S, Remmers JE (2000) Anatomy and physiology of
and swallow in preterm infants. Dev Med Child Neurol upper airway obstruction. In: Kryger MH, Roth T,
43:22–27 Dement WC (eds) Principles and practice of sleep
Gozal D, Simakajornboon N, Czapla MA, Xue YD medicine, 3rd edn. WB Saunders, Philadelphia, pp
et al (2000) Brainstem activation of platelet-derived 840–858
growth factor-beta receptor modulates the late phase Kurth CD, Hutchison AA, Caton DC, Davenport PW
of the hypoxic ventilatory response. J Neurochem (1989) Maturational and anesthetic effects on
74(1):310–319 apneic thresholds in lambs. J Appl Physiol 67:
Gresham K, Boyer B, Mayer C, Foglyano R, Martin R, 643–647
Wilson CG (2011) Airway inflammation and LaFramboise WA, Woodrum DE (1985) Elevated dia-
central respiratory control: results from in vivo and phragm electromyogram during neonatal hypoxic ven-
in vitro neonatal rat. Respir Physiol Neurobiol tilatory depression. J Appl Physiol 59:1040
178:414–421 LaFramboise WA et al (1983) Pulmonary mechanics dur-
Harding R et al (1977) Laryngeal function during breathing ing the ventilatory response to hypoxemia in the new-
and swallowing in foetal and newborn lambs. J Physiol born monkey. J Appl Physiol: Respir Environ Exerc
Lond 272:14P Physiol 55:1008
Harding R, Johnson P, McClelland ME (1980) Respiratory Lee DSC et al (1987) A developmental study on types and
function of the larynx in developing sheep frequency distribution of short apneas (3 to 15 seconds)
and the influence of sleep state. Respir Physiol in term and preterm infants. Pediatr Res 22:344
40(2):165–167 Lehtonen L, Martin RJ (2004) Ontogeny of sleep and
Harned HS Jr, Ferreiro J (1973) Initiation of breathing by awake states in relation to breathing in preterm infants.
cold stimulation: effects of change in ambient temper- Semin Neonatol 3:229–238
ature on respiratory activity of the full-term fetal lamb. Lemke RP, Al-Saedi SA, Alvaro RE et al (1996) Use of
J Pediatr 83:663 a magnified cardiac airflow oscillation to classify
Henderson-Smart DJ, Read DJC (1979) Reduced lung neonatal apnea. Am J Respir Crit Care Med
volume during behavioral active sleep in the newborn. 154(5):1537–1542
J Appl Physiol 46:1081 Lindgren C, Jing L, Graham B, Grögaard J, Sundell H
Hofstetter AO, Legnevall L, Herlenius E, Katz-Salamon M (1992) Respiratory syncytial virus infection reinforces
(2008) Cardiorespiratory development in extremely reflex apnea in young lambs. Pediatr Res 31(4 Pt 1):
preterm infants: vulnerability to infection and persis- 381–385
tence of events beyond term-equivalent age. Acta Lopes J, Muller NL, Bryan MH, Bryan AC (1981a) Impor-
Paediatr 97:285–292 tance of inspiratory muscle tone in maintenance of FRC
Isono S (2008) Interaction between upper airway muscles in the newborn. J Appl Physiol 51:830–834
and structures during sleep. In: Marcus CL, Carroll JL, Lopes J et al (1981b) Importance of inspiratory muscle
Donnelly DF, Loughlin GM (eds) Sleep and breathing tone in maintenance of FRC in the newborn. J Appl
in children: developmental changes in breathing during Physiol: Respir Environ Exerc Physiol 51:830
sleep, 2nd edn. Informa Healthcare, New York, pp Lucier GE, Storey AT, Sessle BJ (1979) Effects of upper
131–156 respiratory tract stimuli on neonatal respiration: reflex
49 Control of Breathing in Newborns 789
and single neuron analyses in the kitten. Biol Neonate Poets CF, Roberts RS, Schmidt B et al (2015) Association
35:82–89 between intermittent hypoxemia or bradycardia and
Luz J et al (1982) Effect of chest and abdomen uncoupling late death or disability in extremely preterm infants.
on ventilation and work of breathing in the newborn JAMA 314(6):595–603
infant during sleep. Pediatr Res 16:297A Polgar G, Weng TR (1979) The functional development
Malhotra A, Pillar G, Fogel RB et al (2000) Genioglossal of the respiratory system from the period of
but no palatal muscle activity relates closely to pharyn- gestation to adulthood. Am Rev Respir Dis
geal pressure. Am J Respir Crit Care Med 120(3):625–695
162:1058–1062 Prechtl HRF (1974) The behavioural states of the newborn
Martin RJ, Abu-Shaweesh JM (2005) Control of breathing infant (a review). Brain Res 76:185
and neonatal apnea. Biol Neonate 87(4):288–295, Purpura DP (1975) Dendritic differentiation in human
Epub 2005 June 1 cerebral cortex: normal and aberrant development pat-
Martin RJ, Wilson CG, Abu-Shaweesh JM, Haxhiu MA terns. In: Kreutzberg GW (ed) Advances in neurology,
(2004) Role of inhibitory neurotransmitter interac- vol 9. Raven, New York, pp 91–116
tions in the pathogenesis of neonatal apnea: implica- Qurashi MJ, Khalil M, Kwiatkowski K, et al (2005) Mor-
tions for management. Semin Perinatol 28(4): phology of sighs and their role on the control of breath-
273–278 ing in preterm infants, term infants and adult subjects.
Martin RJ, Wang K, Köroğlu O, Di Fiore J, Kc P (2011) Neonatology 96(1):43–49. 2009
Intermittent hypoxic episodes in preterm infants: do Reed DJ, Kellogg RH (1958) Changes in respiratory
they matter? Neonatology 100:303–310 response to CO2 during natural sleep at sea level and
Mathew OP et al (1982) Pharyngeal airway obstruction in at altitude. J Appl Physiol 13:325
preterm infants during mixed and obstructive apnea. J Reis FJC, Cates DB, Vandriault LV et al (1994) Diaphrag-
Pediatr 100:964 matic activity and ventilation in preterm infants – the
Miller MJ, DiFiore JM (1995) A comparison of effects of sleep state. Biol Neonate 65:16–24
swallowing during apnea and periodic breathing in Remmers JE, Bartlett D Jr (1977) Reflex control of expi-
premature infants. Pediatr Res 37(6):796–799 ratory airflow and duration. J Appl Physiol: Respir
Moriette G et al (1985) The effect of rebreathing CO2 on Environ Exerc Physiol 42:80
ventilation and diaphragmatic electromyography in Remmers JE, deGroot WJ, Sauerland EK et al (1978) Path-
newborn infants. Respir Physiol 62:387 ogenesis of upper airway occlusion during sleep. J Appl
Mortola JP (1983) Some functional mechanical implica- Physiol 44:931–938
tions of the structural design of the respiratory system Rigatto H (1986) Disorders of the control of breathing. In:
in newborn mammals. Am Rev Respir Dis 128: US Dept. of Health and Human Services (ed) Pediatric
S69–S72 respiratory diseases. National Institutes of Health,
Mortola JP (1999) How newborn mammals cope with Bethesda, pp 20–25, Publication #86-2107
hypoxia. Respir Physiol 116(2–3):95–103 Rigatto H (1988) Control of breathing in the neonate and
Olinsky A et al (1974) Influence of lung inflation on the sudden infant death syndrome. In: Fishman AP
respiratory control in neonates. J Appl Physiol (ed) Pulmonary diseases and disorders, 2nd edn.
36:426 McGraw-Hill, New York, pp 1363–1372
Olsson A, Kayhan G, Lagercrantz H, Herlenius E (2003) Rigatto H, Brady JP (1972a) Periodic breathing and apnea in
IL-1 beta depresses respiration and anoxic survival via preterm infants. I: evidence for hypoventilation possibly
a prostaglandin-dependent pathway in neonatal rats. due to central respiratory depression. Pediatrics 50:202
Pediatr Res 54:326–331 Rigatto H, Brady JP (1972b) Periodic breathing and apnea
Phillipson EA (1978) Control of breathing during sleep. in preterm infants. II: hypoxia as a primary event.
Am Rev Respir Dis 118:909 Pediatrics 50:219
Phillipson EA et al (1977) Ventilatory and waking Rigatto H et al (1982a) Ventilatory response to 100% and
responses to CO2 in sleeping dogs. Am Rev Respir 15% O2 during wakefulness and sleep in preterm
Dis 115:251 infants. Early Hum Dev 7:1
Pickens DL, Schefft G, Thach BT (1988) Prolonged apnea Rigatto H, Reis F, Cates D, Horvath L (1982b) Effect of
associated with upper airway protective reflexes in sleep on phasic and “tonic” diaphragmatic EMG in
apnea of prematurity. Am Rev Respir Dis 137(1): preterm infants. Fed Proc 41:1103
113–118 Sauerland EK, Harper RM (1976) The human tongue dur-
Poets CF (2010) Apnea of prematurity: what can observa- ing sleep: electromyographic activity of the
tional studies tell us about pathophysiology? Sleep genioglossus muscle. Exp Neurol 51:160–170
Med 11:701–707 Stein HM, Wilmoth J, Burton J (2012) Electrical activity of
Poets CF, Rau GA, Neuber K, Gappa M, Seidenberg J the diaphragm in a small cohort of term neonates.
(1997) Determinants of lung volume in spontaneously Respir Care 57(9):1483–1487
breathing preterm infants. Am J Respir Crit Care Med Stein H, Hall R, Davis K, White DB (2013) Electrical
155:649–653 activity of the diaphragm (Edi) values and Edi catheter
790 R. E. Alvaro and H. Rigatto
placement in non-ventilated preterm neonates. J Waggener TB et al (1984) Apnea duration is related to
Perinatol 33(9):707–711 ventilatory oscillation characteristics in newborn
Tangel DJ et al (1991) Influence of sleep on tensor palatine infants. J Appl Physiol 57:536
EMG and upper airway resistance in normal men. J Xia Y, Haddad GG (1991) Ontogeny and distribution
Appl Physiol 70:2574–2581 of opioid receptors in the rat brainstem. Brain Res
Thach BT (2001) Maturation and transformation of reflexes 549(2):181–193
that protect the laryngeal airway from liquid aspiration Xie A, Skatrud JB, Dempsey JA (2001) Effect of hypoxia
from fetal to adult life. Am J Med 111:69S–77S on the hypopnoeic and apnoeic threshold for CO2 in
Thach BT, Tauesch HW (1976) Sighing in human newborn sleeping humans. J Physiol 535:269–278
infants: role of inflation-augmenting reflex. J Appl Xie A, Skatrud JB, Puleo DS et al (2006) Influence
Physiol 41:502 of arterial O2 on the susceptibility to posthyperven-
Thibeault DW et al (1967) Thoracic gas volume changes in tilation apnea during sleep. J Appl Physiol 100:
premature infants. Pediatrics 40:403 171–177
Meconium Aspiration Syndrome
50
Simone Pratesi and Carlo Dani
Contents
50.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791
50.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 792
50.3 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 792
50.4 Prevention Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794
50.5 Clinics and Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 798
Abstract newer and more efficient modalities of treat-
Meconium aspiration syndrome is a disease ment. On the other hand, concern exists about
characterized by a respiratory insufficiency of the long-term neurodevelopmental and pulmo-
variable severity, where lung injury probably nary outcome of survivors.
starts prenatally. The role of meconium in the
pathogenesis of the disease is still partly Abbreviations
unknown, while increasing evidence suggests ECMO Extracorporeal membrane
that chronic in utero insults may be responsible oxygenation
for starting lung damage as well as triggering HFOV High-frequency oscillatory
fetal distress and meconium passage into the ventilation
amniotic fluid. Survival rate has greatly iNO Inhaled nitric oxide
improved over the last three decades with MAS Meconium aspiration syndrome
MSAF Meconium-stained amniotic fluid
S. Pratesi
Neonatal Intensive Care Unit, Careggi University Hospital,
Florence, Italy
50.1 Salient Points
e-mail: simone.pratesi@unifi.it
• Approximately 13% of live-born infants are
C. Dani (*)
Neonatal Intensive Care Unit, Careggi University Hospital, born through meconium-stained amniotic
Florence, Italy fluid (MSAF), while meconium aspiration syn-
Università degli Studi di Firenze, Florence, Italy drome (MAS) occurs only in 2–6% of these
e-mail: cdani@unifi.it neonates.
# Springer International Publishing AG, part of Springer Nature 2018 791
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_199
792 S. Pratesi and C. Dani
• Most cases of meconium aspiration occur in Meconium is first noted to be present at 12 weeks
utero when fetal gasping is initiated before gestation in human fetus. It is the by-product of fetal
delivery. amniotic fluid, lanugo, skin cells, and vernix
• Inflammation plays a major role in the patho- caseosa swallowing; as well it contains cells derived
genesis of MAS. from the gastrointestinal tract. Meconium composi-
• Antepartum, intrapartum, and postpartum strat- tion also includes four different biliary acids (cholic,
egies are mandatory for prevention of MAS. chenodeoxycholic, deoxycholic, and lithocholic)
• Most infants born through MSAF require no and minerals of which copper, zinc, magnesium,
interventions; however, it is important to monitor calcium iron, and phosphorus are the most common.
these infants closely during the first 12 h of life. In addition, it contains plasmatic proteins such as
• The percentage of newborns requiring ECMO α1-antitripsin and phospholipase A2, free fatty
has decreased since the introduction of treat- acids, bilirubin, and enzymes. The passage of meco-
ment with inhaled nitric oxide (iNO) and high- nium from fetus into the amnion at early stage of
frequency oscillatory ventilation. gestation is prevented by the lack of intestinal peri-
stalsis due to low motilin levels, tonic contraction of
the anal sphincter, and a terminal cap of viscous
50.2 Introduction meconium. MSAF in advanced gestation may
therefore be a natural phenomenon that reflects a
The term meconium is derived from the Greek postterm fetus with a mature gastrointestinal tract in
word mekoni, which means poppy juice or which motilin levels have risen. On the other hand,
opium due to its tarry appearance or to Aristotle’s MSAF has been associated with perinatal condi-
belief that it induced sleep in the fetus. Meconium tions (such as intrauterine growth retardation, pre-
constitutes the first stool of a newborn infant. The eclampsia, eclampsia, maternal diabetes mellitus)
passage of meconium typically occurs within 48 h which can compromise the uteroplacental circula-
after birth; however, it can occur in utero. tion with resultant acute or chronic fetal hypoxia
The optimal care of an infant born through and acidosis, in the presence or absence of fetal
meconium-stained amniotic fluid (MSAF) should distress, producing relaxation of the anal sphincter,
involve obstetrician and pediatrician together. more easily to occur in term than preterm neonates.
Indeed, management of a baby at risk of meco-
nium aspiration syndrome (MAS) starts in the
delivery room or even earlier during intrauterine 50.3 Pathogenesis
life. MAS is defined as respiratory distress in an
infant born through MSAF whose symptoms can- The traditional belief was that meconium aspiration
not be otherwise explained; approximately 13% occurs immediately after birth. Several investigators
of live-born infants are born through MSAF, while have suggested, however, that most cases of meco-
MAS occurs only in 2–6% of these neonates nium aspiration occur in utero when fetal gasping is
(Cleary and Wiswell 1998). A retrospective review initiated before delivery. Thus, it is believed that
of the outcomes and treatment patterns in term MAS will sometimes occur despite appropriate air-
neonates admitted for intensive care during a way management at delivery. There is currently no
10-year period indicates an increasing likelihood way to distinguish between the infant who has devel-
of MAS with advancing gestational age (from oped MAS by intrauterine respiration or gasping and
1.1% at 37 weeks gestation to 24% at >42 weeks the infant who has developed MAS by inhalation of
gestation), a quite constant mortality rate of about meconium at the first breaths after delivery.
1,2% despite changes in care during the last But is MAS really caused by a direct injury of
decade, and a higher mortality risk for infants meconium on the lung? It is unclear why some
born smaller, outborn, and delivered by C-section, infants born through MSAF develop an aspiration
who had lower Apgar scores, pulmonary hyperten- syndrome whereas others do not. It is known
sion, and use of cefotaxime (Singh et al. 2009). that meconium presence under the vocal cords is
50 Meconium Aspiration Syndrome 793
associated with higher risk of MAS, but its absence possibility to prevent severe MAS, because proba-
does not mean the infant will not develop severe bly the only possible prevention could be during
respiratory failure. According to Ghidini and Spong, intrauterine life. Undoubtedly meconium in the
there are no correlations between the presence of lungs alters the pulmonary physiology, but it is not
meconium in the trachea and clinical symptoms, as clear how much of the lung injury seen in MAS
two thirds of babies with meconium in the trachea (inflammation, surfactant dysfunction, vasoconstric-
do not develop any respiratory syndrome and a half tion, airway hyperreactivity) has to be ascribed to a
of those with a respiratory syndrome did not have direct toxicity of meconium on lung tissues or par-
meconium in the lungs (Ghidini and Spong 2001). tially to other chronic or acute insults beginning
Thus, the correlation, so far considered obvious, before delivery or even how those injuries could
between the presence of meconium into the airways be partially a consequence of the start of therapy
and respiratory disease, would be not so obvious. It (oxygen, ventilatory support, etc.).
is suggested that other pathological events such as Mechanisms of injury in MAS are (1) meconium
intrauterine asphyxia could cause the syndrome, mechanical obstruction of airways of variable
while the presence of meconium into the amniotic degree, leading to zones of atelectasis with ventila-
fluid and the lungs only being an incidental finding tion/perfusion mismatch or zones of air trapping at
or a consequence of the stress insult to the fetus. high risk for air leaks; (2) pneumonitis, with an
Intrauterine asphyxia would lead to a remodeling of inflammatory response characterized by the pres-
the pulmonary vascular tree determining a thicken- ence of elevated cell count and pro-inflammatory
ing of the pulmonary vascular media and an abnor- cytokines (IL8, IL6, Il1β, TNF-α), that can adversely
mal vascular reactivity responsible for the persistent affect tissues and cause an increase in microvascular
pulmonary hypertension associated with persistent permeability leading to hemorrhagic pulmonary
hypoxemia frequently seen in newborn with severe edema and exudation of plasma proteins into the
MAS (Wiswell et al. 2000). Autopsy data from alveolar space leading to (3) inactivation of pulmo-
cases of MAS severe enough to result in neonatal nary surfactant through dilution and direct inhibition,
demise within 48 h of birth show that besides a damage of type II alveolar pneumocytes;
muscularization of the distal pulmonary arterioles and (4) vasoconstriction of pulmonary vessels
is present in close to 100% of cases. As de novo resulting in pulmonary hypertension and persistence
muscularization requires a minimum of 3–8 days to of fetal circulation that in vitro studies indicate not
develop, it may actually precede the aspiration of due to the direct vasoconstrictor effect of meconium
meconium (Thureen et al. 1997). Increasing evi- but possibly to the release of agonist humoral factors,
dence suggests that a chronic in utero insult may such as thromboxane or TNF-α, by lung paren-
be responsible for most cases of severe MAS as chyma capable of enhancing the pulmonary arterial
opposed to an acute peripartum event. Chronic constrictor potential (Tessler et al. 2008).
fetal hypoxia and acidosis may lead to fetal gasping Inflammation plays a major role in the pathogen-
and the subsequent in utero aspiration of meconium. esis of MAS, and pulmonary function improves
This is supported by autopsy findings of meconium concomitantly with resolution of inflammation.
in the alveoli of stillbirths or of infants who died Pro-inflammatory substances in meconium can
shortly after birth and never developed spontaneous induce lung inflammation in MAS directly via cyto-
respirations. In contrast to these severe cases, the kines and heme present in meconium and indirectly
vigorous infant who aspirates meconium-stained by inducing cytokine release from epithelial cells
fluid from the nasopharynx at birth usually develops and alveolar macrophages. IL-1b, IL-6, and IL-8
mild to moderate disease. The pathogenic events appear to be expressed at high levels in early post-
leading to mild MAS and severe MAS seem to be natal life of infants with MAS, making it highly
different, and events antedating labor (such as likely that these cytokines are already expressed in
chronic asphyxia or infection) are predominantly utero before birth supporting the hypothesis of peri-
responsible for the lung disease among infants with natal timing of meconium aspiration in most cases of
severe MAS. This is a crucial point as it concerns the MAS (Cayabyab et al. 2007).
794 S. Pratesi and C. Dani
50.4 Prevention Strategies as possible from the airway before the infant is able
to take a breath. However, the most recent interna-
As aforementioned, a reduction of the incidence of tional guidelines on neonatal resuscitation suggest
MAS over the past three decades has probably due the suction immediately after birth only if the air-
to a better prenatal care, leading to a reduction of way appears obstructed or if positive pressure ven-
postterm pregnancies, and a better fetal surveillance tilation is required to prevent the risk of induced
before and during labor of high-risk fetuses such as bradycardia. Routine intervention of intubation and
those with intrauterine growth retardation. Inter- suction for the nonvigorous newborn with
ventions of some efficacy to further decrease the meconium-stained amniotic fluid is not
incidence of MAS could probably be done only at a recommended, while it suggests of initiating the
prenatal or perinatal stage, removing causes of respiratory support as indicated for each individual
acute or above all chronic fetal asphyxia. infant (Wyckoff et al. 2015). This is in agreement
Antepartum, peripartum, and postpartum interven- with a recent randomized controlled trial which
tions to remove meconium from the newborn’s demonstrated that endotracheal suctioning of
airway in order to prevent its aspiration in the nonvigorous infants born through MSAF does not
presence of MSAF have been evaluated over the reduce the risk and complications of MAS com-
past three decades, including (1) amnioinfusion, pared to a no-suction strategy (Chettri et al. 2015).
(2) suctioning the infant before the first breath, Also the ACOG Committee on Obstetric Prac-
and (3) intubation and tracheal suctioning of the tice recently recommended that “infants with
infant immediately after delivery. Amnioinfusion MSAF should no longer receive intrapartum
has been proposed for interventions when monitor- suctioning” (ACOG Committee on Obstetric
ing detects variable fetal heart. Potential mecha- Practice 2007). On the other hand, some have
nisms through which amnioinfusion could act suggested an even more aggressive approach:
include mechanical cushioning of the umbilical endoscopic in utero suctioning of the fetus before
cord, which could correct or prevent recurrent delivery (Petrikovsky 2004). However, this pro-
umbilical compressions, and dilution of meconium cedure has yet to be tested and proven and there-
that could reduce its mechanical and inflammatory fore cannot be recommended.
effects in the pathogenesis of MAS. It would appear Current recommended delivery room manage-
that in settings where electronic fetal monitoring is ment of the meconium-stained newborn is that
routinely used, amnioinfusion confers no additional pressure positive ventilation should be initiated
benefit in terms of prevention of MAS, while in if the infant is not breathing or the heart rate is
settings without these capabilities, often in devel- less than 100/min after the initial steps are com-
oping countries, amnioinfusion has been protective pleted (Wyckoff et al. 2015). Thus, a skilled resus-
with improved neonatal outcomes, reduced MAS citation team should be present at all deliveries
(4% vs. 18%), and improved maternal outcomes that involve MSAF to perform neonatal resuscita-
(Xu et al. 2007). ACOG Committee on Obstetric tion as needed. Resuscitation should be initiated
Practice has recently recommended that “routine with air (21% oxygen at sea level), and supple-
prophylactic amnioinfusion for the dilution of mentary oxygen may be administered under
MSAF should be done only in the setting of addi- preductal oxygen saturation monitoring (Wyckoff
tional clinical trials. However, amnioinfusion et al. 2015).
remains a reasonable approach in the treatment of
repetitive variable decelerations, regardless of
amniotic fluid meconium status” (ACOG Commit- 50.5 Clinics and Therapy
tee Obstetric Practice 2006).
Intrapartum suctioning, combined with intuba- Most infants born through MSAF require no inter-
tion after delivery of a newborn from MSAF, has ventions; however, it is important to monitor these
been considered standard procedure for more than infants closely for signs of respiratory distress
25 years. The aim was to clear as much meconium able to develop within the first 12 h of life.
50 Meconium Aspiration Syndrome 795
A severely compromised neonate born with pulmonary interstitial emphysema, which fre-
MSAF should not be a priori labeled as a case of quently complicate MAS. Roentgenographic
MAS until other causes of neonatal compromise findings may include coarse irregular or nodular
have been excluded. Severe MAS should cease pulmonary densities, areas of diminished aera-
to be a diagnosis of inclusion (any respiratory tion or consolidation (atelectasis) alternating
distress in the context of MSAF with any radio- with areas of hyperinflation and generalized
logic finding), but rather become a diagnosis of hyperinflation (Fig. 1). The classic findings in
exclusion. Its diagnostic criteria should be strict MAS are described as diffuse, asymmetric
(i.e., the presence of meconium in the mouth or patchy infiltrates, but because of the diverse
trachea at delivery, early onset of respiratory mechanisms that cause disease, various radio-
distress, and chest X-ray evidence of “patchy” graphic findings may be present. Radiographic
areas of opacification or pulmonary air leak) and clearing is slow over a period of days or weeks if
limited to cases without infection or chronic classic radiographic findings of MAS are pre-
asphyxia. Infants at risk of MAS who show sent. A two-dimensional echocardiogram will
sign of respiratory distress (tachypnea, cyanosis, be performed to exclude a congenital heart defect
retractions, grunting, rales, and rhonchi at chest and to assess pulmonary hypertension, myocar-
auscultation, barrel-shaped chest) must be trans- dial contractility and cardiac output, intracardiac
ferred to the neonatal intensive care unit. An right to left shunts, and shunt through the ductus
infant developing a severe MAS will require a arteriosus. Usually in case of MAS, early blood
wide range of intensive therapies to be rapidly tests are characterized by hypoxemia, metabolic
available and aimed at increasing oxygenation acidosis, mild to severe hypercarbia, and no
while minimizing the barotraumas that may signs of infection (C-reactive protein negative,
lead to air leak syndromes: intubation and endo- no leukocytosis or leukopenia). This kind of
tracheal suction in the delivery room, mechanical biochemical pattern prevents the physiological
ventilation (conventional or high-frequency ven-
tilation) preferably already started in delivery
room (to avoid bag ventilation at higher risk of
determining air leaks), placement of a central
catheter in the umbilical vein, sedation with
continuous iv infusion of fentanyl and/or
midazolam, administration of endotracheal sur-
factant as bolus or lavage, inhaled nitric oxide
(iNO) if persistent pulmonary hypertension is
present, inotropic drugs and/or plasma transfu-
sion to treat hypotension, antibiotics prophylaxis
(as sepsis is often in the differential diagnosis),
anti-inflammatory drugs to reduce lung inflam-
mation, strict evaluation and management of
acidosis, electrolyte imbalance, and hypoglyce-
mia. Severe case of MAS may need for extracor-
poreal membrane oxygenation (ECMO), even
if the percentage of newborns requiring ECMO
has decreased since the introduction of treatment
of persistent pulmonary hypertension with
iNO. A chest X-ray will be performed to evaluate Fig. 1 Chest x ray of infant with meconium aspiration
syndrome. They can be appreciated coarse irregular or
if radiographic features are compatible with nodular pulmonary densities, asymmetric areas of dimin-
the diagnosis of MAS and to exclude the pres- ished aeration or consolidation (atelectasis) alternating
ence of pneumothorax, pneumomediastinum, or with areas of hyperinflation, and left pneumothorax
796 S. Pratesi and C. Dani
drop of pulmonary arterial resistance with parenchymal disease, at a phospholipid dose of at
increase in pulmonary blood flow, resulting in least 100 mg/kg, rapidly instilled into the trachea.
right-to-left shunts at atrial and ductus arteriosus Natural surfactant or a third-generation synthetic
level, thus maintaining and further reducing hyp- surfactant should be used and the dosage repeated
oxemia into a vicious cycle. Leukopenia may every 6 h until oxygenation has improved. Lung
present later as a consequence of the accumula- lavage with dilute surfactant has recently emerged
tion of polymorphonuclear leukocytes into the as an alternative to bolus therapy in MAS, which
lung tissues. has the advantage of removing surfactant inhibi-
Cleary and Wiswell have proposed criteria to tors (hemoglobin, plasma proteins) from the alve-
define MAS severity: (1) mild MAS is disease olar space in addition to augmenting surfactant
that requires less than 40% oxygen for less than phospholipid concentration. The ideal fluid vol-
48 h, (2) moderate MAS is disease that requires ume and technique for lavage in MAS are not yet
more than 40% oxygen for more than 48 h with clear; experimental data would suggest a total
no air leak, and (3) severe MAS is disease that lavage volume of 30 mL/kg (administered as two
requires assisted ventilation for more than 48 h 15 mL/kg aliquots) at a 5 mg/ml phospholipid
and is often associated with persistent pulmonary concentration (lower concentrations make surfac-
hypertension (Cleary and Wiswell 1998). Pneu- tant more sensitive to inactivation) as most effec-
mothorax is still a frequent complication of MAS tive in improving oxygenation and pulmonary
(8–20%), and it is an important indicator of a mechanics and in attenuating lung injury. Lesser
poorer prognosis. Approximately 40% of the total lavage volumes or smaller aliquot volumes
babies with MAS require mechanical ventilation, removed meconium less effectively, whereas a
about 1.4% of ECMO. ECMO use is decreased greater total lavage volume resulted in unaccept-
during the last decade, while high-frequency ably high deposition of aqueous fluid in the lung.
oscillatory ventilation (HFOV) and iNO have The advised procedure would be the following:
been used with increasing frequency (Singh (a) adequate stabilization of the newborn;
et al. 2009). However, no prospective, random- (b) sedation and muscle relaxation to minimize
ized, controlled trials have compared conven- bradycardia and maximize fluid recovery;
tional ventilation versus HFOV in MAS. (c) perform lavage in a rapid sequence, with instil-
Theoretically, high-frequency ventilators should lation and recovery of each lavage aliquot within
reduce air leak syndromes in MAS, but animal 60–80 s; (d) use open suction with the ventilator
and clinical models have yielded conflicting disconnected and manual vibratory chest squeez-
results. High-frequency ventilators may slow ing to collect as much fluid as possible; and
the progression of meconium down the tracheo- (e) ventilate with higher mean airway pressure
bronchial tree and allow more time for meco- (2–4 cm H2O more) than the pre-lavage one for
nium removal (Walsh and Fanaroff 2007). 30 min to re-recruit lung volume and clear
Inhibition of surfactant function in the alveolar retained lavage fluid. As large-volume lavage pro-
space is an important element of the pathophysi- cedure is inevitably associated with a fall in oxy-
ology of the disease, thus representing the ratio- genation during and for a short time after lavage, it
nale for administration of exogenous surfactant needs to be included in randomized controlled
preparations in MAS, initially as standard bolus trial of lavage therapy in ventilated infants with
therapy and, more recently, in association with severe MAS in order to assess the real benefits
therapeutic lung lavage. In infants with MAS, against the potential risk associated with the pro-
surfactant administration may reduce the severity cedure (Dargaville et al. 2008). Thus, this proce-
of respiratory illness and decrease the number of dure cannot be routinarily recommended,
infants with progressive respiratory failure requir- although a recent meta-analysis suggests that it
ing support with ECMO (El Shahed et al. 2014). may be beneficial by decreasing the risk of the
Bolus surfactant should be administered as early composite outcome of death or use of ECMO
as practicable to infants who exhibit significant (Hahn et al. 2013).
50 Meconium Aspiration Syndrome 797
MAS is frequently accompanied by persistent associated lung injury and to improve outcome
pulmonary hypertension. iNO causes selective pul- (Kugelman et al. 2005).
monary vasodilation by acting directly on the vas- Other potential therapeutic interventions for
cular smooth muscle. By dilating the blood vessels treating MAS have been indicated: synthetic sur-
in well-ventilated areas of lung, iNO decreases the factant, captopril, tezosentan, and pentoxifylline.
ventilation perfusion ratio mismatch and improves Some surfactants may be more resistant to inacti-
oxygenation in infants with persistent pulmonary vation by meconium (Herting et al. 2001); how-
hypertension. Proper administration of iNO ever, the search for new synthetic surfactant
requires adequate delivery to the alveoli; thus, it preparations that are highly resistant to inactiva-
may be less effective in patients with MAS, in part tion by meconium or other forms of toxic pneu-
because of the physical “barrier” to its diffusion monitis is ongoing.
across the alveolar membrane produced by the In MAS inflammation plays an important role
meconium. Pretreatment with surfactant seems to in the pathogenesis of lung injury. A number of
aid the delivery of iNO to alveoli, with a resultant anti-inflammatory agents have been investigated
increase in oxygenation (Rais-Bahrami et al. 1997). for their therapeutic values, such as corticoste-
Kinsella et al. showed that the combination of roids, pentoxifylline, and aminophylline. A
HFOVand iNO may be more successful than either Cochrane systematic review of available clinical
treatment alone in patients with MAS, likely trials concludes that there is insufficient evidence
because of improved lung inflation and better deliv- on the use of systemic steroids in the treatment of
ery of the drug (Kinsella et al. 1997). iNO appears MAS (Ward and Sinn 2003). In a recent random-
to improve outcome in hypoxemic term and near- ized controlled study, however, both intravenous
term infants by reducing the need for ECMO, but methylprednisolone and nebulized budecort were
has no apparent effect on mortality (Finer and able to suppress TNF-α level in the tracheal aspi-
Barrington 2006). rate of infants with MAS. Treated infants also had
Since the introduction of treatment of persis- a shorter hospital stay, shorter duration of oxygen
tent pulmonary hypertension with iNO, the need dependency, and earlier radiological clearance of
for ECMO has decreased. However, about 40% of the lung fields (Tripathi and Saili 2007). Local
infants with MAS treated with iNO fail to respond corticosteroid administration, both nebulized or
and require bypass. ECMO is still considered an intracheally administered (budesonide), could
important tool in treating the newborns with MAS result in same benefits with lower adverse effects
and intractable respiratory failure, with the highest than systemic corticosteroid. In fact, a recent ran-
survival rate for any neonatal condition suitable domized controlled trial demonstrated that nebu-
for ECMO (on the order of 93–100%). Despite the lization with budesonide of term infants with
evidence pointing to the efficacy of ECMO in MAS improves the respiratory distress with lesser
severe MAS, without causing excess pulmonary oxygen requirement and thus early discharge from
or neurological morbidity (because of prolonged NICU compared to the control group (Garg
hypoxia), some infants are still referred late for et al. 2016).
ECMO. Recent introduction of new therapies for In acute lung injury following meconium aspi-
respiratory failure in the newborn with MAS such ration, pulmonary hypertension is related to an
as iNO, surfactant, and HFOV may determine a increase of endothelin (ET)-1 levels. Recently
longer pre-ECMO course in infants not tezosentan, an intravenous dual ETA and ETB
responding to these therapies. A delay in ECMO receptor antagonist, has been shown to improve
initiation longer than 96 h results in a significant pulmonary gas exchange and hemodynamics by
increase in duration of ECMO and length of post- decreasing mean arterial pulmonary pressure and
ECMO ventilation, with also a significant increase pulmonary vascular resistance in experimental
in mortality in this group of infants. Thus, the meconium aspiration. Tezosentan thus seems to
need of ECMO in severe MAS should be act predominantly in the pulmonary vasculature,
predicted as early as possible to avoid ventilator- the site of turnover of ET-1, and its effect to be
798 S. Pratesi and C. Dani
enhanced by the combination with an inhalational Finer NN, Barrington KJ (2006) Nitric oxide for respira-
drug-like iloprost (Geiger et al. 2008). tory failure in infants born at or near term. Cochrane
Database Syst Rev 4, CD000399
Cell death by apoptosis in the lungs has been Garg N, Choudhary M, Sharma D, Dabi D, Choudhary JS,
demonstrated in MAS. Meconium-induced apo- Choudhary SK (2016) The role of early inhaled
ptosis is activated by a strong vasoconstrictor, budesonide therapy in meconium aspiration in term
angiotensin II, which is the product of conversion newborns: a randomized control study. J Matern Fetal
Neonatal Med 29(1):36–40
of angiotensin I by angiotensin-converting Geiger R, Kleinsasser A, Meier S et al (2008) Intravenous
enzyme (ACE) within the cell. Pretreatment with tezosentan improves gas exchange and hemodynamics
captopril, blocking the conversion of angiotensin in acute lung injury secondary to meconium aspiration.
I to the apoptotic-inducer angiotensin II, signifi- Intensive Care Med 34(2):368–376
Ghidini A, Spong CY (2001) Severe meconium aspiration
cantly inhibits meconium-induced lung apoptosis syndrome is not caused by aspiration of meconium. Am
and also reduces mortality of rabbit pups from J Obstet Gynecol 185:931–938
meconium. Captopril could represent another Hahn S, Choi HJ, Soll R, Dargaville PA (2013)
potential new therapeutic intervention for MAS Lung lavage for meconium aspiration syndrome in
newborn infants. Cochrane Database Syst Rev
(Zagariya et al. 2006). 4, CD003486
More efficient modalities of treatment have Herting E, Rauprich P, Stichtenoth G et al (2001) Resis-
greatly improved survival rate of MAS infants tance of different surfactant preparations to inactivation
over the last three decades, but the amount of by meconium. Pediatr Res 50:44–49
Kinsella JP, Truog WE, Walsh WF et al (1997) Random-
morbidity among survivors seems not changed, ized, multicenter trial of inhaled nitric oxide and high-
and growing concern exists on long-term poor frequency oscillatory ventilation in severe, persistent
neurodevelopmental and pulmonary sequelae of pulmonary hypertension of the newborn. J Pediatr
infants even asymptomatic at the time of dis- 131:55–62
Kugelman A, Gangitano E, Taschuk R et al (2005)
charge from the nursery. Extracorporeal membrane oxygenation in infants
with meconium aspiration syndrome: a decade of
experience with venovenous ECMO. J Pediatr Surg
40:1082–1089
References Petrikovsky B (2004) In utero meconium suctioning may
prevent meconium aspiration. Fetal Diagn Ther
ACOG Committee Obstetric Practice (2006) ACOG Com- 19:533e5
mittee Opinion Number 346, October 2006: Rais-Bahrami KRO, Seale WR, Short BL (1997) Effect of
amnioinfusion does not prevent meconium aspiration nitric oxide in meconium aspiration syndrome
syndrome. Obstet Gynecol 108:1053 after treatment with surfactant. Crit Care Med
ACOG Committee on Obstetric Practice (2007) ACOG 25(10):1744–1747
Committee Opinion No. 379: Management of delivery Singh BS, Clark RH, Powers RJ, Spitzer AR (2009) Meco-
of a newborn with meconium-stained amniotic fluid. nium aspiration syndrome remains a significant prob-
Obstet Gynecol 110(3):739 lem in the NICU: outcomes and treatment patterns in
Cayabyab RG, Kwong K, Jones C et al (2007) Lung inflam- term neonates admitted for intensive care during a
mation and pulmonary function in infants with meco- ten-year period. J Perinatol 29:1–7
nium aspiration syndrome. Pediatr Pulmonol 42:898–905 Tessler R, Pan J, Holmer Fiori H, Belik J (2008)
Chettri S, Adhisivam B, Bhat BV (2015) Endotracheal Human meconium has a pulmonary vascular and
suction for nonvigorous neonates born through meco- airway smooth muscle relaxant effect. Pediatr Res
nium stained amniotic fluid: a randomized controlled 64(1):24–28
trial. J Pediatr 166(5):1208–1213.e1 Thureen PJ, Hall DM, Hoffenberg A, Tyson RW (1997)
Cleary GM, Wiswell TE (1998) Meconium-stained amni- Fatal meconium aspiration in spite of appropriate peri-
otic fluid and the meconium aspiration syndrome: an natal airway management: pulmonary and placental
update. Pediatr Clin N Am 45:511–529 evidence of prenatal disease. Am J Obstet Gynecol
Dargaville PA, Copnell B, Tingay DG et al (2008) Refining 176:967–975
the method of therapeutic lung lavage in meconium Tripathi S, Saili A (2007) The effect of steroids on the
aspiration syndrome. Neonatology 94:160–163 clinical course and outcome of neonates with meco-
El Shahed AI, Dargaville P, Ohlsson A, Soll RF (2014) nium aspiration syndrome. J Trop Pediatr 53:8–12
Surfactant for meconium aspiration syndrome in term Walsh MC, Fanaroff JM (2007) Meconium stained fluid:
and late preterm infants. Cochrane Database Syst Rev approach to the mother and the baby. Clin Perinatol
12, CD002054 34:653–665
50 Meconium Aspiration Syndrome 799
Ward M, Sinn J (2003) Steroid therapy for meconium cardiopulmonary resuscitation and emergency cardio-
aspiration syndrome in newborn infants. Cochrane vascular care. Pediatrics 136(Suppl 2):S196–S218
Database Syst Rev;(4) CD003485 Xu H, Hofmeyr J, Roy C, Fraser WD (2007) Intrapartum
Wiswell TE, Gannon CM, Jacob J et al (2000) Delivery amnioinfusion for meconium-stained fluid: a system-
room management of apparently vigorous meconium- atic review of randomised controlled trials. BJOG
stained neonate: results of the multicenter, international 114:383–390
trial. Pediatrics 105:1–7 Zagariya A, Bhat R, Navale S et al (2006) Inhibition
Wyckoff MH, Aziz K, Escobedo MB, Kapadia VS of meconium-induced cytokine expression and cell
et al (2015) Part 13: neonatal resuscitation: 2015 Amer- apoptosis by pre-treatment with captopril. Pediatrics
ican Heart Association Guidelines update for 117(5):1722–1727
Molecular Structure of Surfactant:
Biochemical Aspects in Newborns 51
Tore Curstedt
Contents
51.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 801
51.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 802
51.3 Alveolar Surface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 802
51.4 Isolation of Pulmonary Surfactant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 803
51.5 Composition of Surfactant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 803
51.5.1 Phospholipid Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 803
51.5.2 Surfactant-Associated Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 804
51.6 Structure of Pulmonary Surfactant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805
51.7 Synthetic Surfactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 806
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 806
Abstract synthetic surfactants may replace or be an
The surfactant-lining alveolar surface is a pre- alternative to animal-derived preparations.
requisite for gas exchange in order to fulfill the
energy needs of the living organism. Surfactant
is composed of lipids, mainly phospholipids, 51.1 Salient Points
and four surfactant-associated proteins. It facil-
itates alveolar increase during inspiration and • Surfactant forms a thin layer lining the alveolar
prevents their collapse at end-expiration. Insuf- surface.
ficient amounts of surfactant in premature • It facilitates alveolar increase during inspira-
babies can be successfully treated with surfac- tion and prevents their collapse at the end of
tant preparations derived from animal lungs. expiration.
Preliminary studies show that in a near future • Surfactant consists of lipids, mainly phospho-
lipids and four specific surfactant-associated
proteins (SP)-A, -B, -C, and -D.
T. Curstedt (*)
• The phospholipids, especially dipalmitoyl-
Department of Molecular Medicine and Surgery,
Karolinska Institutet, Karolinska University Hospital, phosphatidylcholine, reduce surface tension
Stockholm, Sweden but need SP-B and SP-C for spreading the
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 801
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_200
802 T. Curstedt
surfactant film at the alveolar air-liquid inter- the alveolar area is 3–5 m2 at end-expiration and
face. The other two proteins, SP-A and SP-D, about 80 m2 in adults (Hislop et al. 1986;
are important in host defense. Parmigiani et al. 2005). Thus, the area is about
• Synthetic surfactants containing phospholipids 1 m2/kg body weight. The number of alveoli
and the two hydrophobic proteins SP-B and increases in a curvilinear fashion with up to
SP-C or their analogues seem to function very 150 million at birth, which is half to one third of
well and will probably replace or become an the number in adults.
alternative to surfactant preparations purified The alveoli are lined with a surface-active
from animal lungs in the near future. material, called surfactant. This material facili-
tates alveolar increase during inspiration and pre-
vents alveolar collapse at end-expiration. Thus,
51.2 Introduction pulmonary surfactant is essential for normal lung
function and must fulfill properties such as rapid
Oxygen is needed for energy production in the film formation through adsorption from the hypo-
living organism and is a prerequisite of life. This phase, low surface tension at end-expiration, and
oxygen, which is taken up from the air during effective replenishment of the surface film during
breathing, has to pass from the alveoli to the inspiration.
blood in order to be transported to different organs The surfactant lines the alveoli as a monolayer
where it can participate in the metabolic processes in combination with areas of multilayers (Schürch
in the body. The passage from the alveoli to blood et al. 1998). The amount of surfactant needed for
is crucial and is dependent on a barrier composed formation of a monolayer at end-expiration is
of the alveolar wall, basal laminae, and the endo- about 3 mg/m2, indicating that a newborn term
thelial cells. Exposure of a large alveolar surface infant needs 10 mg surfactant for the monolayer.
to the air is required to facilitate an appropriate gas However, during inspiration the alveolar area will
exchange in order to fulfill the energy needs of the increase and some of the surfactant is continu-
living organism. ously metabolized. Thus, there must be a surplus
of surfactant in the lungs and the pool in newborn
full-term animals has been calculated to be about
51.3 Alveolar Surface 100 mg/kg body weight (Jobe and Ikegami 1987).
The alveolar subphase beneath the surfactant film
The development of the alveoli starts in the has been shown in rat lungs to have an average
weeks before birth and the alveolar area increases thickness of about 0.2 μm (Bastacky et al. 1995).
roughly linear with body weight (Fig. 1). At birth If humans have a similar thickness, the total
Fig. 1 Correlation 12
between body weight and
total alveolar surface area. 10
The values are taken from
Alveolar suface (m2)
Hislop et al. (1986)
8
0
0 2 4 6 8
Body weight (kg)
51 Molecular Structure of Surfactant: Biochemical Aspects in Newborns 803
aqueous alveolar phase would be about 0.2 mL/ lipid but trace amounts of triglycerides and free
m2 alveolar surface area. This indicates that term fatty acids are also present. Other components
infants may have a mean alveolar surfactant con- such as complex carbohydrates and glycolipids
centration of about 500 mg/mL presuming that are also found in surfactant.
newborn term infants have about the same surfac-
tant pool size as animals.
51.5.1 Phospholipid Composition
51.4 Isolation of Pulmonary The phospholipids are mainly responsible for
Surfactant reducing the surface tension at the air-liquid
interface. Its composition is complex and at
The knowledge about the composition of pulmo- least 50 different phospholipids may be found
nary surfactant has usually been obtained from in surfactant (Berggren et al. 1985) and the
lung lavage. The lungs are lavaged using isotonic phospholipid composition is important for sur-
sodium chloride solution, followed by fractional factant activity (Calkovska et al. 2016). The
centrifugation of the lavage fluid. In the first cen- most common structure is a glycerol skeleton
trifugation, using 300–400 g for 10 min, cell debris with two ester-linked fatty acids and a phos-
is removed and the supernatant is then centrifuged phate group (Fig. 2). Different components,
at 10,000 g for 20 min. The pellets obtained contain for example, choline, ethanolamine, glycerol,
a highly surface-active material composed of lipid- serine, or inositol, are usually bound to
protein aggregates that are enriched in tubular mye- the phosphate group, thus making up the
lin and lamellar bodies. Lamellar bodies are stored different classes of phospholipids such as phos-
in type II epithelial cells and are secreted by exo- phatidylcholine, phosphatidylethanolamine,
cytosis into the alveolar lumen and converted to phosphatidylglycerol, phosphatidylserine, and
tubular myelin, which is the source for the surface- phosphatidylinositol. Depending on the fatty
active monolayer lining the alveolar surface. acid composition, each phospholipid class is com-
posed of many molecular species. About 80% of
the phospholipids consist of phosphatidylcholine
51.5 Composition of Surfactant with its surface-active disaturated species.
These disaturated species, containing 40–60% of
Pulmonary surfactant lining the alveolar surface is total phosphatidylcholines, are dominated by
a complex mixture of lipids and proteins. It is dipalmitoylphosphatidylcholine, a phosphatidyl-
composed of about 80–85% phospholipids, choline containing two palmitic acids. Although
8–10% neutral lipids, and 8–10% proteins phosphatidylcholines predominate among the
(Veldhuizen et al. 1998; Johansson and Curstedt phospholipids, phosphatidylglycerol is present in
1997) (Table 1). Cholesterol is the main neutral amounts up to 10% and smaller amounts of
Table 1 Composition of pulmonary surfactant H2C O fatty acid
Component %
Dipalmitoylphosphatidylcholine 30–40 fatty acid O CH
Other disaturated phosphatidylcholines 3–5
O
Unsaturated phosphatidylcholines 35–40
Phosphatidylglycerol 5–10 H 2C O P O X
Other phospholipids 5–10
Neutral lipids (mainly cholesterol) 5–10 O
Hydrophobic surfactant proteins (SP-B, SP-C) 1–4
Fig. 2 General structure of phospholipids. X: e.g. choline,
Hydrophilic surfactant proteins (SP-A, SP-D) 4–8
ethanolamine, glycerol, serine, inositol
804 T. Curstedt
phosphatidylethanolamine, phospatidylserine, and 51.5.2.1 Surfactant Proteins A and D
phosphatidylinositol are also present. SP-A and SP-D belong to a larger family of pro-
At the air-liquid interface lining the alveoli, the teins termed collectins containing both collage-
phospholipids are oriented in a monolayer with nous and lectin domains. The lectin domain
the hydrophilic head groups towards the aqueous mediates the calcium-dependent carbohydrate
phase and the hydrophobic acyl groups towards binding and is also called carbohydrate recogni-
the air (Pérez-Gil 2008). tion domain. The basic structural unit of collectins
A high concentration of phospholipids, mainly are trimers which are composed of three similar or
dipalmitoylphosphatidylcholine, at the interface identical polypeptides. These trimers then multi-
diminishes the number of water molecules merize, resulting in differently shaped multimeric
exposed to the air, resulting in a lower alveolar forms.
surface tension and less force required to open SP-A is the most abundant protein in surfac-
up the alveoli during inspiration. This saturated tant. Each monomer with a molecular mass of
phospholipid, in contrast to unsaturated species, about 30–36 kDa contains four structural domains
can be packed to a very high density at with a short N-terminal segment containing
the air-liquid interface and provides a large interchain disulfide bonds, a collagenous region,
reduction of surface tension during expiration, a hydrophobic neck region, and a carbohydrate
thus preventing the alveoli from collapse at recognition domain. Three monomers form a tri-
end-expiration. However, the melting point mer by association of the collagenous and neck
of dipalmitoylphosphatidylcholine bilayers is regions. Six trimers form the octadecameric mol-
41 C, which is above the physiological tempera- ecule, which is stabilized by disulfide linkages in
ture of the human body while that of unsaturated the N-terminal regions. This octadecameric mol-
species is much lower. Thus, the presence of sig- ecule forms a bouquet-like structure with an
nificant amounts of unsaturated phospholipids in apparent molecular mass of about 650 kDa. The
surfactant reduces the melting temperature of the protein is closely associated with the phospho-
monolayers to values lower than 37 C, which is lipids in the presence of calcium ions and together
important for the physiological properties of pul- with SP-B and phospholipids tubular myelin is
monary surfactant. Resent results indicate that formed.
cholesterol, which constitutes 5–10% of pulmo- SP-D is composed of monomeric subunits,
nary surfactant, may modulate the structure of each with a molecular mass of about 43 kDa.
surfactant membranes by decreasing the packing Each monomer possesses similar domains as that
and increasing the mobility of phospholipids in of SP-A. SP-D usually forms a cruciform
the monolayer. dodecamer assembled from four trimers with a
molecular mass of about 520 kDa. However,
SP-D can assemble into even higher-order multi-
51.5.2 Surfactant-Associated Proteins mers when dodecamers assemble into “fuzzy-
ball” structures. SP-D binds to phosphatidy-
Proteins represent less than 10% of the total mass linositol and a variety of glycolipids, which are
of pulmonary surfactant. Four different minor components of surfactant. However, only a
surfactant-associated proteins have been identi- small part of SP-D co-isolates with surfactant
fied. The two hydrophobic surfactant proteins, lipids.
SP-B and SP-C, increase the adsorption and SP-A and SP-D are synthesized and secreted
spreading of the surfactant film at the alveolar by alveolar type II cells and by Clara cells, but
air-liquid interface (Johansson and Curstedt SP-D especially is also expressed in other tissues
1997) and are crucial for obtaining a functional such as gastric and intestinal mucosa. Both pro-
surfactant. The two hydrophilic surfactant pro- teins interact with a variety of pathogens such as
teins, SP-A and SP-D, have a primary role in bacteria, viruses, and fungi and protect the lungs
host defense (Haagsman et al. 2008). from infection by aggregation of pathogens,
51 Molecular Structure of Surfactant: Biochemical Aspects in Newborns 805
stimulation of phagocytic activity, and modula- saposins by being a covalent dimer not soluble
tion of inflammatory response. SP-A does not in water. The dimeric structure of SP-B may
seem to have any effect on spreading of surfactant account for its ability to cross-link juxtaposed
phospholipids, but the protein enhances the resis- lipid membranes, thus catalyzing the transfer of
tance to inactivation of surfactant by proteins, for phospholipids from surfactant membranes into
example, albumin. It has also been shown that the interfacial surface-active film. The protein
SP-A deficient mice survive and breed normally, has a net positive charge, which may promote a
but they lack tubular myelin and have increased selective interaction with anionic phospholipids,
susceptibility for infections. especially phosphatidylglycerol, but clear evi-
dence about that is missing. SP-B is critical for
51.5.2.2 Surfactant Proteins B and C formation of lamellar bodies and is required for
The hydrophobic surfactant proteins SP-B and formation of tubular myelin.
SP-C are important for surfactant function. SP-B SP-C is a small very hydrophobic lipopeptide
is expressed in alveolar type II cells and Clara of 35 amino acid residues with two palmitoylated
cells, while SP-C is expressed only in type II cysteines in the N-terminal part (Johansson and
cells. The proteins are structurally different, but Curstedt 1997). It consists of a very regular and
they are both required for sustaining respiratory rigid α-helix covering more than 70% of the mol-
physiology by decreasing surface tension of the ecule and an unstructured N-terminal part. The
alveolar air-liquid interface and to prevent the α-helical segment adopts a transmembrane local-
alveoli from collapse at end-expiration. Mutations ization orientated near parallel to the phospholipid
in the SP-B gene have been shown to lead to lethal acyl groups. The length of the helix is in very
respiratory failure at birth (Wert et al. 2009). good agreement with the thickness of a fluid
However, these mutations also interact with dipalmitoylphosphatidylcholine bilayer. The pri-
SP-C processing by inhibiting the formation of mary translation product of human SP-C is a
mature SP-C from its proform. Also abnormalities proform of 197 amino acid residues. Mutations
in surfactant phospholipids have been observed in in the C-terminal part of the molecule, not involv-
SP-B-deficient infants. The pathophysiology of ing the mature SP-C, are seen in patients with
lung disease associated with mutations in the interstitial lung diseases. These mutations may
SP-C gene is incompletely understood. These result in a conversion of the proSP-C from the
mutations are usually linked to lung disease in native structure to b-sheets found in amyloid-like
older children and adults. Also heterozygotes fibrils (Johansson et al. 2006). These fibrils are
have a lack of mature SP-C leading to alveolar thought to be cell toxic and may give rise to organ
instability with atelectasis, inflammation, and malfunction and disease.
fibrosis.
SP-B has 79 amino acid residues with three
intramolecular disulfide bridges and one 51.6 Structure of Pulmonary
intermolecular disulfide bridge, thus forming a Surfactant
dimer. This dimer may interact with the surface
of lipid bilayers by means of four or five The surfactant components are synthesized in
amphipatic α-helices in each monomer. SP-B alveolar type II cells and secreted as lamellar
belongs to the saposin family of proteins, in bodies into the alveolar subphase. The lamellar
which all members interact with lipids (Johansson bodies are transformed into tubular myelin
and Curstedt 1997). However, in contrast to the whereupon the material adsorbs quickly to the
other members of the saposin family, SP-B is alveolar air-liquid interface forming a surface-
permanently associated to the membranes, which active film. The thin aqueous phase covering
is probably due to its high hydrophobicity. The the alveolar surface contains multiple membrane
three dimensional structure of SP-B has not been structures, including lamellar bodies, tubular
determined, but SP-B differs from the other myelin, and the surface-active film. The
806 T. Curstedt
air-liquid interface is necessary for respiratory A synthetic surfactant containing 0.2% SP-B
gas exchange, and the alveoli must be able to analogue and 1.5% SP-C analogue mixed with
open during inspiration without collapsing dur- dipalmitoylphosphatidylcholine:palmitoyloleoyl-
ing end-expiration. These criteria may be ful- phosphatidylglycerol 1:1 (w/w) has been evalu-
filled with a complex phospholipid mixture, ated in preterm lambs (Sato and Ikegami 2012;
which can be packed to a very high density at Seehase et al. 2012). The surfactant was as effec-
the air-liquid interface and have a melting point tive as Survanta under the study period of 5 h
below the physiological temperature of the (Sato and Ikegami 2012). Treatment with the syn-
human body. For spreading the phospholipids thetic surfactant in combination with albumin
during breathing, the hydrophobic proteins gave a significantly higher survival rate after
SP-B and SP-C are necessary. The interface 48 h of ventilation than treatment with Cursurf
should also be a defense against different patho- and albumin (Seehase et al. 2012). The first study
gens, and for this reason native surfactant con- in humans with this synthetic surfactant has now
tains the hydrophilic proteins SP-A and SP-D. been finished (Curstedt et al. 2015) and a phase II
study has started.
Thus, synthetic surfactants containing two pep-
51.7 Synthetic Surfactants tides combined with phospholipids seem to be
ideal to replace natural surfactants within a near
Preterm babies with respiratory distress syndrome future. These preparations can be produced in large
are successfully treated with exogenous surfac- quantities to a reasonable cost for the treatment of
tants purified from animal lungs (Halliday 2006). various lung diseases with inadequate surfactant
These preparations are expensive to produce and function or as carrier for different drugs.
supplies are limited, and there is a need for syn-
thetic preparations that can be produced in large
amounts to a reasonable cost.
References
Animal experiments with synthetic surfactants
based on a simple synthetic phospholipid mixture Almlén A, Stichtenoth G, Linderholm B, Haegerstrand-
and only one peptide have shown adequate tidal Björkman M, Robertson B, Johansson J, Curstedt T
volumes during inspiration, but the lungs have a (2008) Surfactant proteins B and C are both necessary
for alveolar stability at end expiration in premature
tendency to collapse at end-expiration (Johansson
rabbits with respiratory distress syndrome. J Appl
et al. 2003). Stabilization of the lungs at Physiol 104:1101–1108
end-expiration is facilitated especially if both Bastacky J, Lee CY, Goerke J et al (1995) Alveolar lining
SP-B and SP-C or their analogues are present in layer is thin and continuous: low-temperature scanning
electron microscopy of rat lung. J Appl Physiol
the surfactant preparation (Calkovska et al. 2016;
79:1615–1628
Almlén et al. 2008). Berggren P, Curstedt T, Grossmann G et al (1985) Physio-
Two synthetic preparations, containing phos- logical activity of pulmonary surfactant with low pro-
pholipids and one peptide, have been used in tein content: effect of enrichment with synthetic
phospholipids. Exp Lung Res 8:29–51
clinical trials. Patients with acute respiratory
Calkovska A, Linderholm B, Haegerstrand-Björkman M
distress syndrome have been treated with recom- et al (2016) Phospholipid composition in synthetic
binant SP-C surfactant (Venticute) (Spragg et al. surfactants is important for tidal volumes and alveolar
2003, 2011), but the results showed no clinical stability in surfactant-treated preterm newborn rabbits.
Neonatology 109:177–185
benefit (Spragg et al. 2011). Lucinactant
Curstedt T, Halliday HL, Speer CP (2015) A unique story
(Surfaxin), containing a simple lipid mixture in neonatal research: the development of a porcine
and sinapultide (KL4), was given as prophylac- surfactant. Neonatology 107:321–329
tic treatment to premature infants (Halliday Haagsman HP, Hogenkamp A, van Eijk M, Veldhuizen
EJA (2008) Surfactant collectins and innate immunity.
2006) and was approved by FDA in 2012 for
Neonatology 93:288–294
prevention of respiratory distress syndrome in Halliday HL (2006) Recent clinical trials of surfactant
preterm babies. treatment for neonates. Biol Neonate 89:323–329
51 Molecular Structure of Surfactant: Biochemical Aspects in Newborns 807
Hislop AA, Wigglesworth JS, Desai R (1986) Alveolar Sato A, Ikegami M (2012) SP-B and SP-C containing new
development in the human fetus and infant. Early synthetic surfactant for treatment of extremely imma-
Hum Dev 13:1–11 ture lamb lung. PLoS One 7(7), e39392
Jobe A, Ikegami M (1987) Surfactant for the treatment of Schürch S, Green FHY, Bachofen H (1998) Formation and
respiratory distress syndrome. Am Rev Respir Dis structure of surface films: captive bubble surfactometry.
136:1256–1275 Biochim Biophys Acta 1408:180–202
Johansson J, Curstedt T (1997) Molecular structures and Seehase M, Collins JJ, Kuypers E, Jellema RK,
interactions of pulmonary surfactant components. Eur J Ophelders DRMG, Ospina OL, Perez-Gil J, Bianco F,
Biochem 244:675–693 Garzia R, Razzetti R, Kramer BW (2012) New surfactant
Johansson J, Some M, Linderholm BM, Almlén A, with SP-B and C analogs gives survival benefit after
Curstedt T, Robertson B (2003) A synthetic surfactant inactivation in preterm lambs. PLoS One 7(10), e47631
based on a poly-Leu SP-C analog and phospholipids: Spragg RG, Lewis JF, Wurst W, Häfner D, Baughman RP,
effects on tidal volumes and lung gas volumes in ven- Wewers MD, Marsh JJ (2003) Treatment of acute respi-
tilated immature newborn rabbits. J Appl Physiol ratory distress syndrome with recombinant surfactant
95:2055–2063 protein C surfactant. Am J Respir Crit Care Med
Johansson H, Nordling K, Weaver TE, Johansson J (2006) 167:1562–1566
The Brichos domain-containing C-terminal part of Spragg RG, Taut FJH, Lewis JF, Schenk P, Ruppert C,
pro-surfactant protein C binds to an unfolded poly- Dean N, Krell K, Karabinis A, Günther A (2011)
val transmembrane segment. J Biol Chem 281: Recombinant surfactant protein C-based surfactant for
1032–1039 patients with severe direct lung injury. Am J Respir Crit
Parmigiani S, Solari E, Bevilacqua G (2005) Current con- Care Med 183:1055–1061
cepts on the pulmonary surfactant in infants. J Matern Veldhuizen R, Nag K, Orgeig S, Possmayer F (1998) The
Fetal Neonatal Med 18:369–380 role of lipids in pulmonary surfactant. Biochim
Pérez-Gil J (2008) Structure of pulmonary surfactant Biophys Acta 1408:90–108
membranes and films: the role of proteins and lipid- Wert SE, Whitsett JA, Nogee LM (2009) Genetic disorders
protein interactions. Biochim Biophys Acta 1778: of surfactant dysfunction. Pediatr Dev Pathol 12:
1676–1695 253–274
Surfactant Metabolism in Neonatal
Lung Diseases 52
Virgilio P. Carnielli and Paola E. Cogo
Contents
52.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 810
52.2 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 810
52.2.1 Surfactant Function and Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 810
52.3 Surfactant Synthesis, Secretion, and Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . 811
52.4 Surfactant Kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 812
52.5 Surfactant Pool Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 813
52.6 Effects of Surfactant Therapy on Surfactant Synthesis in Preterm
Infants with RDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 814
52.7 Effects of Prenatal Corticosteroids on Surfactant Synthesis in Preterm
Infants with RDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 814
52.8 Surfactant Status of Preterm Infants Recovering from RDS . . . . . . . . . . . . . 814
52.9 Neonatal Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 815
52.10 Meconium Aspiration Syndrome (MAS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 816
52.11 Congenital Diaphragmatic Hernia (CDH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 817
52.12 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 818
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 818
Abstract
Surfactant treatments have been the standard
of care for infants with respiratory distress
syndrome (RDS) since the early 1990s. The
V. P. Carnielli (*) development of surfactant is one of the great
Division of Neonatology, Salesi Hospital, success stories in neonatal care because the
Polytechnic University of Marche, Ancona, Italy
e-mail: [email protected]; [email protected]
therapy specifically treats surfactant deficiency
and changes the pathophysiology and outcome
P. E. Cogo
Division of Pediatrics, Department of Medicine, S. Maria
of RDS. However, deficiency or dysfunction of
della Misericordia University Hospital, University of pulmonary surfactant still persist in selected
Udine, Udine, Italy
# Springer International Publishing AG, part of Springer Nature 2018 809
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_201
810 V. P. Carnielli and P. E. Cogo
preterm and term infants and contribute to • The de novo synthesis rates and turnover rates
the pathogenesis of several respiratory diseases of surfactant disaturated phosphatidylcholine
in the newborn. After a short review of pulmo- (DSPC) in preterm infants with respiratory dis-
nary surfactant, including the role of surfactant tress syndrome (RDS) are very low.
in selected neonatal respiratory conditions, we • Patients recovering from RDS who required
describe a series of studies made by applying higher CPAP setting after extubation or
two recently developed methods to measure reintubation had lower amount of intra-
surfactant kinetics. In a first set of studies pulmonary surfactant that those who did well
which we call “endogenous studies” by using after extubation.
stable isotope-labelled intravenous surfactant • Term newborn infants with pneumonia have
precursors, we have shown the feasibility of greatly accelerated surfactant catabolism.
measuring surfactant synthesis and kinetics • Infants with uncomplicated congenital dia-
in infants using several metabolic precursors phragmatic hernia (CDH) and on conventional
including plasma glucose, plasma fatty acids, mechanical ventilation have normal surfactant
and body water. In a second set of studies, synthesis, but those requiring ECMO do not.
named “exogenous studies,” with the use of Information obtained from these studies in
stable isotope-labelled phosphadylcholine (PC) infants will help to better tailor exogenous
tracer given endotracheally, we could estimate surfactant treatment in neonatal lung diseases.
surfactant DSPC pool size and half-life. Major
finding of the surfactant kinetic studies in the
newborn infant can be summarized as follow: 52.2 Background
(a) the de novo synthesis rates and turnover rates
of surfactant disaturated phosphatidylcholine Avery and Mead (1959) showed in 1959 that
(DSPC) in preterm infants with respiratory dis- pulmonary surfactant deficiency is a major factor
tress syndrome (RDS) are very low, (b) in pre- in the pathophysiology of respiratory distress
term with RDS pool size is very small and half- syndrome (RDS). In 1980 Fujiwara et al. (1980)
life much longer in comparison with animal administered exogenous surfactant successfully to
studies, (c) patients recovering from RDS who preterm infants with RDS for the first time. This
required higher CPAP setting after extubation was followed by numerous clinical trials, which
or reintubation had lower amount of intra- demonstrated a marked reduction in death rates
pulmonary surfactant that those who did well and pneumothorax, and this is nowadays a stan-
after extubation, (d) term newborn infants with dard of care. Data, which suggest that a disturbed
pneumonia have greatly accelerated surfactant surfactant metabolism plays a role in several
catabolism, and (e) infants with uncomplicated other neonatal lung diseases, such as congenital
congenital diaphragmatic hernia (CDH) and on diaphragmatic hernia (CDH), meconium aspiration
conventional mechanical ventilation have nor- syndrome (MAS), pneumonia, and surfactant pro-
mal surfactant synthesis, but those requiring tein-B (SP-B) deficiency, are now accumulating.
ECMO do not. Information obtained from Surfactant therapy may have a therapeutic role in
these studies in infants will help to better tailor the management of these clinical conditions.
exogenous surfactant treatment in neonatal lung
diseases.
52.2.1 Surfactant Function and
Composition
52.1 Salient Points
Pulmonary surfactant decreases the surface ten-
• The kinetics of selected surfactant components sion at the air-liquid interface in the alveoli and
can be measured in humans and in the tiniest distal bronchioles, to promote lung expansion
preterm infants with stable isotope tracers. during inspiration and to prevent alveolar collapse
52 Surfactant Metabolism in Neonatal Lung Diseases 811
at end expiration. Surfactant also plays a pivotal regulates the phospholipid ordering in the mono-
role in pulmonary host defense (Phelps 2001). layer, enhances the reuptake of surfactant lipids in
Pulmonary surfactant consists in complex mixture vitro, and may have a role in surfactant catabo-
of lipids (90%) and proteins (10%), which lism. Mice that lack SP-C have normal surfactant
is strikingly comparable across various species and lung function and have no abnormalities in
including humans (Hunt et al. 1991). Of the SP-B processing (Glasser et al. 2001). However,
lipids, 80–90% are phospholipids, of which phos- the stability of surfactant at low lung volumes is
phatidylcholine (PC) is quantitatively the most decreased.
important, accounting for 70–80% of the total. Interestingly the alveolar pool of surfactant in
Other lipids include phosphatidylglycerol (PG), newborn infants with RDS does not differ much
phosphatidylethanolamine, phosphatidylinositol, from the alveolar pool of adults without respira-
phosphatidylserine, sphingomyelin, cholesterol, tory disease (Rebello et al. 1996). However, with-
triacylglycerols, and free fatty acids. Approx- out surfactant supplementation, newborns with
imately 60% of the PC contains two saturated RDS develop severe respiratory failure, possibly
fatty acids (DSPC) of which dipalmitoyl through a combination of mechanisms including
(16:0/16:0; DPPC) is the most abundant. DPPC altered surfactant composition, lung structural
is the principal surface tension-lowering compo- immaturity, and increased surfactant inactivation
nent of surfactant. (Jobe and Ikegami 1994).
Four surfactant proteins have been identified Limited information is available on the role of
so far (Haagsman and Diemel 2001). SP-A and -D surfactant proteins in newborn infants with respi-
are hydrophilic, and SP-B and -C are hydropho- ratory conditions.
bic. They are either exclusively lung associated or
predominately found in the lung. SP-A is the most
abundant surfactant protein and is essential for 52.3 Surfactant Synthesis, Secretion,
the formation of tubular myelin. It functions as a and Clearance
regulator of phospholipid insertion into the mono-
layer and modulates the uptake and secretion of Surfactant PC is synthesized from phospholipid
phospholipids by type II cells. However, mice that precursors (e.g., fatty acids, glycerol, choline, glu-
lack SP-A indeed have no tubular myelin but have cose) in the Golgi apparatus (Batenburg 1992). In
normal lung function and surfactant metabolism the fetal type II cell, intracellular glycogen stores
even during exercise (Korfhagen et al. 1996). appear to be a major source of the glycerol back-
Furthermore, together with SP-D, SP-A has an bone of PC, whereas in the adult lung glucose from
important role in lung defense (Crouch 1998). the circulation is a major substrate. Choline is
SP-A and -D bind pathogens and facilitate their mainly derived from the diet. The fatty acids of
clearance (Crouch 1998). The absence of SP-D surfactant phospholipids are synthesized de novo
results in increased surfactant lipid pools in the in the type II cell, or taken up from the blood, or
airspaces and emphysema in lungs of mice (Botas they are derived from recycling of alveolar surfac-
et al. 1998). SP-B plays a role in formation tant phospholipids (Batenburg 1992).
of tubular myelin, and together with SP-C, it Lamellar bodies are condensed, highly struc-
promotes rapid phospholipid insertion into the tured lipoprotein packages that serve as the intra-
air-liquid interface. SP-B also influences the cellular storage form of surfactant. Lamellar
molecular ordering of the phospholipid layer. bodies are secreted into the alveolar space by
Infants with a genetic absence of SP-B develop fusing of their limiting membrane with the plasma
lethal respiratory distress after birth, which can membrane. After secretion the lamellar bodies
only be treated by lung transplantation (Nogee et unravel to form loose membranous arrays and
al. 1993). Absence of SP-B causes a loss of lamel- lattice-like structures, the tubular myelin. At alve-
lar bodies, tubular myelin, and an incompletely olar surface expansion during inspiration, surfac-
processed SP-C (deMello et al. 1994). SP-C tant components insert from the hypophase
812 V. P. Carnielli and P. E. Cogo
(epithelial lining fluid (ELF)) into the monolayer. [1-13C]acetate to study surfactant kinetics, the
At expiration the alveolar surface reduces and same results were estimated (Cavicchioli et al.
the monolayer is compressed, thereby squeezing 2001; Bohlin et al. 2003). In term ventilated neo-
out some surfactant proteins, unsaturated PC, and nates without significant lung disease using infu-
other lipids. By this mechanism, the monolayer sion of [U-13C]glucose, [U-13C]palmitic acid or
comprises mainly DPPC, which is the most [1-13C]acetate as precursor, the first appearance
important surface-tension-lowering component of label in surfactant PC was after 9 h from the
during compression. start of the infusion and the maximal enrichment at
Alveolar surfactant can be cleared by different 44 h (Bohlin et al. 2003; Cogo et al. 2002;
pathways. Surfactant components can be reuti- Janssen 2003). As in animal studies, these results
lized through uptake by the type II cell, incorpo- of human stable isotope studies show slower sur-
ration into the lamellar bodies, and then direct re- factant kinetics in preterm infants compared to term
secretion (Jacobs et al. 1983). Another way is infants. The kind of precursor does not affect the
recycling of degraded surfactant components results. The fractional synthesis rate (FSR) of sur-
to synthesize new surfactant lipids or proteins. factant after infusion of labelled glucose is a mea-
Finally, surfactant can be removed from the sure of the percentage of surfactant that is
lung, either as intact molecules or as degraded synthesized from glucose per day. In premature
products (Wright and Dobbs 1991). The effi- infants who received a 24-h [U-13C]glucose infu-
ciency of recycling is age dependent and has sion, the FSR was calculated to be 4%/day (Bunt
been calculated to be 90% in young pigs (Martini et al. 1998; Merchak et al. 2002). Different values
et al. 1999), >90% in the newborn rabbit, and were found for different precursors: preterm infants
50% in adult rabbits (Jacobs et al. 1985). who received labelled palmitic acid and linoleic
acid had an FSR of 12 and 25%/day, respec-
tively (Cavicchioli et al. 2001). FSR in preterm and
52.4 Surfactant Kinetics term infants after infusion of labelled acetate was
2 and 15%/day, respectively (Merchak et al.
The time required for de novo PC synthesis, 2002). When term infants received labelled
secretion, and significant alveolar accumulation palmitic acid, the FSR was found to be 17%/
has been studied in animals using radioactively day (Cogo et al. 2002). After infusion with labelled
labelled substrates (Jobe et al. 1980). Compared glucose, term infants had a FSR of 8%/day
to adult animals, the time to reach peak specific (Janssen 2003). These data show a lower FSR in
activity is longer in term newborns (Jobe 1988). preterm infants compared to term infants.
Preterm ventilated lambs show a slow movement of The slow secretion and alveolar accumulation
surfactant PC from the synthesis sites to the alveo- of surfactant are balanced in the term and pre-
lus similar to term ventilated lambs (Jobe et al. term lungs by slow catabolism and clearance.
1983). Recently, stable isotope techniques were For example, the half-life of radiolabel surfactant
used to study surfactant metabolism in human phospholipids given endotracheally to term lambs
infants. Labelled precursors were infused intrave- is about 6 days (Glatz et al. 1982). However, in
nously and incorporation of label was measured by premature baboons using the same method, the
mass spectrometry in surfactant PC or DSPC iso- half-life is about 30 h (Seidner et al. 1998), which
lated from tracheal aspirates. In preterm infants may be due to more recycling in premature ani-
with RDS who received a 24-h intravenous infu- mals and to species difference. Half-lives calcu-
sion of the stable isotope [U-13C]glucose, the lated in animal studies differ depending on
palmitic acid of surfactant PC became labelled gestational age, postnatal age, the labelled sub-
approximately about 17 h and was maximally strate used, and the surfactant pool studied.
labelled after 75 h (Bunt et al. 1998; Merchak et Half-life measurements of disappearance of
al. 2002). By using other precursors such as labelled surfactant in human infants have been
[U-13C]palmitic acid, [U-13C]linoleic acid, and performed mainly in preterm infants with RDS.
52 Surfactant Metabolism in Neonatal Lung Diseases 813
Half-lives were longer when disappearance of label concentrations increase, reflecting accumulation
in surfactant was measured after the intravenous of alveolar surfactant. This increase is also
use of labelled precursors: the half-life of reflected in an increasing lecithin/sphingomyelin
13
C-labeled PC-palmitate measured in tracheal (L/S) ratio (Gluck et al. 1974). During and
aspirates of preterm infants with RDS after labelled shortly after birth, large amounts of surfactant
glucose infusion was 96 h (Bunt et al. 1998, are released into the alveolar space (Faridy and
2000a; Merchak et al. 2002). In preterm infants, Thliveris 1987). Since there is no depletion of the
the surfactant half-life after infusion of [U-13C] intracellular surfactant pool, this increase in alve-
palmitic acid, [U-13C]linoleic acid or [1-13C]ace- olar pool shortly after birth is accompanied by an
tate was 98, 47, and 106 h, respectively increase in de novo surfactant synthesis. How-
(Bohlin et al. 2003; Cogo et al. 1999). Using ever, incorporation studies, as mentioned above,
[U-13C]palmitic acid, [U-13C]glucose, or [1-13C] showed slow surfactant metabolism, which
acetate in term infants, the half-life was 43, means that it takes a long time before de novo
63, and 28 h, respectively (Bohlin et al. 2003; synthesized surfactant is detectable in the alveo-
Cogo et al. 2002; Janssen 2003). Thus, surfactant lar space. Increased lung tissue and alveolar sur-
half-life is different between preterm and term factant pools can only be explained by the rapid
infants, with a lower disappearance of label in the mobilization of surfactant from other pools
preterm infants reflecting slower surfactant kinet- (lamellar bodies, small vesicles) within type II
ics, especially in RDS. cells. The amount of lung tissue and alveolar
There are in the literature two studies on surfactant changes with age. Surfactant pools
critically ill term infants who were studied using are very high in the newborn period in all species
different metabolic precursors for surfactant meta- studied to date and decrease subsequently with
bolism (Bohlin et al. 2003; Cogo et al. 1999). lung maturity. In humans total amounts of DSPC
Cogo et al. after infusing labelled fatty acids in in alveolar washes at autopsy also decrease with
a group of critically ill infants with various diag- age (Rebello et al. 1996). In preterm infants with
noses showed marked patient differences in PC RDS, surfactant pool sizes in the alveolus are low
kinetics (Cogo et al. 1999). Bohlin et al. reported (2–10 mg/kg) (Jobe 1988). Total lung DSPC in
that term infants with primary respiratory failure the human adult, at autopsy, was 22 mg/kg and
had a surfactant metabolism similar to that pre- 2 mg/kg in alveolar wash (Rebello et al. 1996).
term infants with RDS, suggesting either delayed In infants surfactant pool size can be estimated in
maturity of the surfactant system or disruption vivo by measuring the dilution of a labelled sur-
from the underlying disease (Bohlin et al. 2003). factant component. Hallman et al. (1986) and
In summary, animal studies show a slower Griese et al. (1995) showed an apparent phospho-
surfactant turnover in newborns compared to lipid pool size of 16 mg/kg in human preterm
adults. In human studies using stable isotopes neonates with RDS, by using PG as label to
the surfactant PC metabolism is even slower measure surfactant pool size. Pool size measure-
in preterm infants with RDS compared to term ments in preterm infants with RDS using endo-
infants without lung disease. Moreover, term tracheally administered stable isotope (13C-
infants with respiratory failure have abnormal DPPC) in combination with a treatment dose of
surfactant metabolism which resembles that of surfactant (100 mg/kg) showed an endogenous
preterm infants with RDS. surfactant PC pool size (before treatment) rang-
ing from 1 to 15 mg/kg (Torresin et al. 2000),
while term infants without RDS have three times
52.5 Surfactant Pool Size or more that value (Cogo et al. 2003). As syn-
thetic rates of surfactant in preterm infants are
In most species studied, PC, and DSPC in partic- low, it is clear that pulmonary surfactant can
ular, increase in the last trimester of pregnancy only be rapidly increased by surfactant replace-
(Oulton et al. 1986). In amniotic fluid, surfactant ment therapy.
814 V. P. Carnielli and P. E. Cogo
52.6 Effects of Surfactant Therapy protein synthesis (Ballard 1989). In in vitro exper-
on Surfactant Synthesis in iments with lung slices and isolated type II cells,
Preterm Infants with RDS corticosteroids increase the incorporation of
radiolabel precursors into surfactant PC, reflecting
Although the administration of exogenous increased PC synthesis (Rooney et al. 1979; Post
surfactant has become the routine treatment of et al. 1986; Gonzales et al. 1990). Prenatal corti-
RDS in the preterm infant, there is very little costeroid treatment in preterm lambs rapidly
information regarding effects of exogenous sur- increases surfactant protein mRNAs and surfac-
factant on endogenous surfactant metabolism. tant proteins in lung tissue (Tan et al. 1999).
In healthy adult rabbits in vivo, administration In a study by Kessler et al. (1982) in premature
of surfactant to the left lung only resulted in baboons, a 72-h treatment with prenatal dexa-
increased incorporation of palmitic acid from methasone did not increase radioactive palmitate
plasma into surfactant PC in the left lung but incorporation in lung lipids, but it increased total
not in the right lung (Oetomo et al. 1990), lung phospholipids and alveolar lavage DPPC in
suggesting stimulation of endogenous synthesis. lung lavage fluid at birth. Bunt et al. (1999) used
In preterm ventilated lambs, surfactant treatment stable isotope labelled glucose in preterm baboons
stimulated [3H]palmitic acid incorporation into to measure the synthesis rate of surfactant PC
surfactant PC after correction for the increased from plasma glucose. The synthesis was doubled
surfactant pool (Ikegami et al. 1989). In 3-day- after a 48-h treatment with prenatal corticoste-
old rabbits, the administration of surfactant did roids. In preterm infants, it was also found that
not, however, influence the incorporation of two doses of prenatal corticosteroids doubled the
labelled precursor in the total lung surfactant endogenous surfactant synthesis from plasma
pool (Oguchi et al. 1985). In preterm infants [U-13C]glucose (Bunt et al. 2000b). In summary,
with RDS, the half-life of PG was independent prenatal corticosteroids enhance surfactant PC
of the dose of exogenous surfactant (60 vs. synthesis in vivo, but de novo synthesis rates
120 mg/kg) (Hallman et al. 1986). This indicates remain low, and alveolar pool sizes are not
that the absolute turnover had doubled after two increased within 48 h. In preterm animals with
doses of surfactant compared to one dose. More RDS, prenatal corticosteroids improve pulmonary
recent work with stable isotopes in infants shows compliance within 15 h (Ikegami et al. 1996)
that the incorporation of 13C from intravenous accompanied by stimulated structural develop-
[U-13C]glucose into alveolar surfactant PC pal- ment (Beck et al. 1981; Walther et al. 1991,
mitate increased after exogenous surfactant treat- 1998; Ikegami et al. 1987; Ballard and Ballard
ment (Bunt et al. 2000a). In summary, there is 1996; Pinkerton et al. 1997). Therefore, the path-
little information from animal and human studies ophysiology of the improved lung function after
on the effect of exogenous surfactant therapy on prenatal corticosteroids remains controversial.
surfactant metabolism.
52.8 Surfactant Status of Preterm
52.7 Effects of Prenatal Infants Recovering from RDS
Corticosteroids on Surfactant
Synthesis in Preterm Infants The common belief that after surfactant replace-
with RDS ment the exogenous surfactant is fully retained
by the lung of the preterm infants suffering from
In many in vitro studies, corticosteroids increase RDS has been recently challenged by Verlato et al.
the activity of the enzymes involved in surfactant (2008) who studied whether reduced amounts of
PC synthesis (Spragg and Li 2000; Rooney pulmonary surfactant contribute to postextubation
et al. 1979; Ballard 1989; Pope and Rooney respiratory failure in preterm infants who had
1987; Post et al. 1986) and increase surfactant RDS, needed mechanical ventilation and
52 Surfactant Metabolism in Neonatal Lung Diseases 815
exogenous surfactant replacement for treatment of of neonates who have been treated with rescue
moderate/severe respiratory distress syndrome, surfactant replacement for sepsis and pneumonia.
and could not be extubated before day 3 of These studies demonstrated improved gas
life. Verlato et al. studied 88 preterms by the exchange compared to no surfactant treatment
“exogenous” tracing approach. They adminis- (Herting et al. 2000; Finer 2004; Fetter et al.
tered endotracheally 13C-DPPC as tracer before 1995; Auten et al. 1991; Chinese Collaborative
extubation, for the estimation of surfactant DSPC Study Group for Neonatal Respiratory Distress
pool size and half-life. Patients were retro- 2005; Hintz et al. 2000). Verlato et al. (2003)
spectively divided into three groups: that is, (a) used the “exogenous” tracing approach with an
extubation failure if, after extubation, they needed endotracheal administration of 13C labelled DPPC
reintubation or high setting CPAP (6 or more cm to study surfactant kinetics in full-terms with
H2O of continuous positive airway pressure and a pneumonia, and in preterm infants with RDS. In
fraction of inspired oxygen greater than 0.4), (b) this small study, the authors found that amount of
extubation success if they did not meet the failure DSPC recovered from the tracheal aspirates was
criteria, and (c) not extubated if they needed ongo- not different among the study groups, whereas its
ing ventilation. Hence, 16, 23, and 24 neonates half-life was significantly shorter in full-terms
were categorized in the extubation failure, with pneumonia (19.3 7.3 h) than in preterm
extubation success, and not extubated groups, infants with RDS (28.7 15.9 h). Mean half-life
respectively. Mean DSPC pool size was smaller in of term control infants with normal lungs was
the extubation failure group than in the extubation 62 h. We recently studied a group of 28 term
success group (25 vs. 43 mg/kg), and it was 37 mg/ newborns, 13 with pneumonia, and 15 with no
kg in the not extubated group. Mean DSPC half-life lung disease (Finer 2004). We measured SP-B,
was 19, 24, and 28 h in the extubation failure, SP-A, disaturated-phosphatidylcholine (DSPC),
extubation success, and not extubated groups, and total phospholipids (PL) concentrations in
respectively. The authors concluded that marginal tracheal aspirates at intubation and close to extu-
surfactant deficiency may contribute to extubation bation. DSPC kinetics was also measured with
failures or need for high continuous positive airway stable isotope labelling. At baseline, SP-B,
pressure settings after xtubation and perhaps more expressed as % of PL, was significantly different
importantly they draw the attention on individual between the groups, being 3.5-fold higher in
differences in exogenous surfactant handling or on pneumonia than controls. SP-A was not different
individual differences in endogenous synthesis. between the groups. At extubation, SP-B and SP-
Interestingly a recent report in abstract form A concentrations had decreased significantly in
showed that the administration of exogenous sur- newborns with pneumonia, while there was no
factant (Infasurf 3 ml/kg) in infants below 28 weeks significant change in controls. DSPC t1/2 was
of gestation and beyond 7 days of age resulted in an significantly shorter in the pneumonia group
improvement in respiratory severity score (Merrill 11.8 versus 26.6 h confirming the early report of
et al. 2006). (Verlato et al. 2003; Herting et al. 2002). Interest-
ingly in term newborns with pneumonia, SP-B
increased relative to PL, and DSPC turned over
at a significantly faster rate.
52.9 Neonatal Pneumonia Conclusion: If it is apparent from one side
that large randomized controlled studies are nec-
Pneumonia in children and newborn infants essary to evaluate the effects of surfactant treat-
may be associated with surfactant dysfunction ment on morbidity and mortality, it may well be
and severe acute respiratory distress syndrome that the dose and time intervals of exogenous
(Herting et al. 2000, 2002; Finer 2004; Fetter surfactant therapy ought to be different in neonatal
et al. 1995; Rivera et al. 2004; Escande et al. pneumonia from the schemes currently used for
2004). There are studies involving a small number neonatal RDS.
816 V. P. Carnielli and P. E. Cogo
52.10 Meconium Aspiration in MAS. PC concentration in ELF in MAS was
Syndrome (MAS) 4 mg/ml (significantly lower than controls:
12.8 mg/ml). The half-life of endogenous surfac-
Aspiration of meconium into the lungs tant was 69 h (not different from controls).
directly inhibits surfactant function and induces With endotracheally administered 2H3-DPPC as
an inflammatory response in the lung with label, surfactant pool PC size was measured to
possible detrimental effects on type II cell func- be 50 mg/kg in neonates with MAS requiring
tion and thereby surfactant metabolism. Surfac- ECMO, which was not significantly different
tant function is inhibited by meconium in from controls or other ECMO infants with persis-
a concentration-dependent way (Moses et al. tent pulmonary hypertension of the newborn
1991; Sun et al. 1993). Meconium increases the (Janssen et al. 2003). Exogenous administration
minimum and maximum surface tensions and of surfactant in animal models of MAS improves
lowers the surface-spreading rate of surfactant lung function and morphology, especially when
(Moses et al. 1991; Sun et al. 1993; Bae et al. surfactant is given at a high dose (200 mg/kg)
1998). Studies of surfactant concentrations and (Sun et al. 1996). Several studies showed an
composition in MAS are scarce. Cleary et al. improvement in oxygenation after surfactant
(1997) found decreased SP-A and SP-B levels in therapy, although most infants required 2 or
the large aggregates of surfactant in a rat model of more doses of exogenous surfactant (Halliday et
MAS. However, phospholipid and DPPC levels al. 1996). In a randomized trial, three doses of
did not change significantly after meconium bovine surfactant (150 mg/kg) were administered
instillation in either lung tissue or bronchoalveolar to 20 infants with MAS. Infants treated with sur-
lavage fluid (BAL). Analyses of BAL fluid from factant had improved oxygenation, a reduction
eight ventilated infants with MAS revealed no in severity of pulmonary morbidity, a decrease
difference in phospholipid and SP-A content com- in ECMO requirement, and a decrease in hospi-
pared to control subjects (Dargaville et al. 2001). talization time compared to the control group
However, concentrations of nonsurfactant protein (n = 20) (Findlay et al. 1996). Lotze et al.
and albumin were more than three times those (1998) performed a trial in term infants with
found in normal lung. In MAS infants who severe respiratory distress who received 4 doses
required ECMO, surfactant phospholipids, PC, of bovine surfactant (100 mg/kg/dose) at 30 h
and SP-A in tracheal aspirates increased during after birth. Half of these infants had MAS.
the ECMO treatment (Lotze et al. 1990, 1993). They were unable to demonstrate a difference in
One study investigated the surfactant kinetics in oxygenation, pulmonary morbidity, or hospital-
the presence of meconium (Higgins et al. 1996). ization, although the need for ECMO in the sur-
This in vitro study in type II cells of adult rats factant-treated group was decreased. From these
showed that meconium in low concentrations studies, it seems that surfactant therapy in MAS is
(1%) increases the PC secretion by type II cells, most effective when given in the early phase of
but had no effect on surfactant PC synthesis. respiratory failure, and at a high dose. Lavage
Higher meconium concentrations were toxic to with surfactant could remove meconium, inflam-
cultured type II cells, though the effect of these matory cells, edema fluid, proteins, and other
higher concentrations on surfactant synthesis is debris from the lungs, leaving behind a layer of
not known. Janssen et al. studied surfactant functional exogenous surfactant (Cochrane et al.
metabolism in MAS infants on ECMO with the 1998). Animal studies showed a beneficial effect
“endogenous approach” using [U-13C]glucose as from surfactant lavage on pulmonary function and
a precursor for surfactant PC palmitate (Janssen radiographical and histological appearance. There
2003). The FSR in MAS infants was 3.3%/day are few reports of lavage therapy in human neo-
(compared to controls 8%/day, p = 0.058) and nates with MAS (Moller et al. 1999). However,
peak enrichment was significantly lower than in the patient groups were small and no control
controls ( p = 0.027), suggesting lower synthesis group was included. Recently, a multicenter,
52 Surfactant Metabolism in Neonatal Lung Diseases 817
randomized controlled trial comparing surfactant Cogo et al. has conducted a series of studies
lavage with standard treatment of MAS has been using the stable isotope technology to trace pulmo-
reported (Wiswell et al. 2002). A trend towards nary surfactant in newborn infants with CDH who
shorter duration of ventilation and improvement were treated with mechanical ventilation and did
in oxygenation were noted, but the differences not require ECMO. In the first study using the
were not statistically significant. “endogenous approach,” surfactant DSPC synthe-
In conclusion, surfactant inactivation seems to sis and metabolism were compared between CDH
play a more important role in the pathophysiology patients and control subjects. Secretion time was
of MAS than surfactant deficiency. In the sickest 8.3 5.5 and 8.5 2.5 h and peak time
MAS infants on ECMO, surfactant synthesis is 51.9 15.2 and 51 13 h in infants with CDH
disturbed. Surfactant therapy seems to be effective and in control subjects, respectively. FSR was not
in MAS and should probably be given at a high different for infants with CDH and control subjects
dose and at an early stage in the development of ( p = 0.4). It was concluded that surfactant DSPC
the disease. synthesis and kinetics were not significantly
deranged in infants with CDH compared with con-
trol subjects and speculated that other factors than
52.11 Congenital Diaphragmatic surfactant deficiency, such as lower surface area or
Hernia (CDH) increased DSPC catabolism, may have contribute
to surfactant pool alteration in CDH (Cogo et al.
Although CDH lungs are immature and show 2002). Cogo et al. (2003) also studied surfactant
morphologically some resemblance to lungs of DSPC half-life, turnover and apparent pool size in
preterm infants with RDS, it is still unclear CDH newborns with no ECMO by the “exogenous
whether a primary surfactant deficiency is present tracing approach.” In 13 CDH infants DSPC half-
in human CDH. Several animal models have life was shorter (24 vs. 53 h), turnover faster (0.6
been developed to study the pathogenesis of vs. 1.5 d 1), apparent pool size smaller (34 and
CDH. In bronchoalveolar lavage (BAL) fluid of 57 mg/kg body weight), DSPC amount from tra-
surgically created CDH lambs, the amounts of cheal aspirates lower (2.4 and 4.6 mg/mL) Epithe-
phospholipids, PC, SP-A, and SP-B are decreased lial Lining Fluid (ELF) than in controls. The data
compared to controls (Glick et al. 1992a; Wilcox from the “exogenous tracer” suggested that surfac-
et al. 1995). However, the amniotic L/S ratio is tant kinetics was grossly abnormal in mechanically
not different in CDH lambs compared to control ventilated CDH. This study could not ascertain
lambs (Wilcox et al. 1995). In vitro studies whether alterations of DSPC kinetics in CDH
in isolated type II cells of CDH lambs show infants were caused by a primary surfactant defi-
a decreased incorporation of choline into PC ciency or were secondary to oxygen therapy and
(Glick et al. 1992a), suggesting decreased surfactant ventilator support. In the third study of this series,
synthesis in CDH. Human studies show contradic- Cogo et al. (2004) developed a new approach to
tory results; the L/S ratios in amniotic fluid have measure DSPC net synthesis and kinetics by using
been reported to be either decreased or to be normal dual stable isotope tracer approach, i.e., combining
(Sullivan et al. 1994). SP-A and DSPC concentra- the “endogenous” and “exogenous” techniques in
tions in amniotic fluid were lower in fetuses with the same patient. All infants received simulta-
CDH who died or required extracorporeal mem- neously an intratracheal (carbon-13 DPPC) and an
brane oxygenation (ECMO) (Moya et al. 1995). intravenous (deuterated palmitic acid) stable iso-
Autopsy studies in CDH infants who died at birth tope tracer. DSPC net synthesis from plasma pal-
or within the first few days of life showed decreased mitate was nearly identical in infants with CDH and
SP-A in lung tissue (Minowa et al. 2000). No dif- control subjects (8.6 and 8.1 mg • kg 1 • d 1).
ference in L/S ratio, PC, and PG concentrations in DSPC apparent pool size was 36.7 7.5 and
BAL fluid from CDH infants was found compared 58.5 9.1 mg/kg, p = 0.07 and half-life was
to age-matched controls (Ijsselstijn et al. 1998). 26 and 50, p = 0.03 in infants with CDH and
818 V. P. Carnielli and P. E. Cogo
control subjects, respectively. Both DSPC turnover have a lower rate of synthesis of SP-B and less SP-
and percentage of catabolism/recycling signifi- B in tracheal aspirates. We speculate that in CDH
cantly correlated with duration of mechanical ven- infants, partial SP-B deficiency could contribute
tilation. In summary this study confirmed that to the severity of respiratory failure and its cor-
synthesis was not reduced in ventilator-dependent rection might represent a therapeutic goal (Cogo
CDH patients and that DSPC turnover was faster et al. 2013).
presumably reflecting an increased DSPC
catabolism/recycling, and the authors speculate
that increased catabolism may ultimately lead to a 52.12 Conclusions
secondary surfactant deficiency.
When patients with CDH were studied on We reviewed the role of surfactant on selected
ECMO by the “exogenous” tracer (Janssen et al. respiratory condition of the preterm and term
2003), surfactant PC pool size was comparable in newborn infants with emphasis on human studies
CDH infants and in term newborn with severe and more specifically on the recent studies based
respiratory failure who were not on ECMO on stable isotopes. These studies have produced
(73 vs. 69 mg/kg, respectively). In CDH infants novel information on surfactant kinetics in vivo in
on ECMO, Janssen (2003) measured FSR by infants who require endotracheal intubation. This
using [U-13C]glucose as a precursor and found it novel information is and will be proven to be very
to be lower than in controls (2.4 vs. 8%/day) with valuable to answer clinical questions concerning
a similar half-life of endogenous surfactant of pulmonary surfactant in humans.
65 h. It is unclear at present if these discrepan-
cies in pool sizes and synthesis were due to
ECMO or the severity of the patients studied.
There are only a few reports of surfactant treat- References
ment in human CDH infants (Bos et al. 1991;
Auten RL, Notter RH, Kendig JW, Davis JM, Shapiro DL
Glick et al. 1992b; Lotze et al. 1994). Bos et al.
(1991) Surfactant treatment of full-term newborns with
(1991) showed an improvement of oxygenation in respiratory failure. Pediatrics 87:101–107
3 of 5 infants with CDH after surfactant adminis- Avery ME, Mead J (1959) Surface properties in relation to
tration. When surfactant was given prophylacti- atelectasis and hyaline membrane disease. Am J Dis
Child 97:517–523
cally to high-risk neonates with CDH, all 3 infants
Bae CW, Takahashi A, Chida S, Sasaki M (1998)
survived (Glick et al. 1992b). Surfactant treatment Morphology and function of pulmonary surfactant
in 9 infants with CDH who required ECMO had inhibited by meconium. Pediatr Res 44:187–191
no beneficial effect on lung function, morbidity, or Ballard PL (1989) Hormonal regulation of pulmonary sur-
factant. Endocr Rev 10:165–181
survival (Lotze et al. 1994). Recent studies on
Ballard RA, Ballard PL (1996) Antenatal hormone therapy
surfactant supplementation in CDH (Van Meurs for improving the outcome of the preterm infant.
2004) show no benefit associated with surfactant J Perinatol 16:390–396
therapy for term infants with a prenatal diagnosis Batenburg JJ (1992) Surfactant phospholipids: synthesis
and storage. Am J Physiol 262:L367–L385
of isolated CDH and a lower survival rate in
Beck JC, Mitzner W, Johnson JW, Hutchins GM,
preterm infants with CDH (Lally et al. 2004). Foidart JM, London WT, Palmer AE, Scott R (1981)
Even today it is still not clear if there is a Betamethasone and the rhesus fetus: effect on lung
primary surfactant deficiency in CDH. We suggest morphometry and connective tissue. Pediatr Res
15:235–240
that there is inactivation of surfactant function due
Bohlin K, Merchak A, Spence K, Patterson BW, Hamvas A
to the intensive ventilation (Sakurai et al. 1999), (2003) Endogenous surfactant metabolism in newborn
which is often necessary in CDH infants, although infants with and without respiratory failure. Pediatr Res
a decreased surfactant synthesis due to severe 54:185–191
Bos AP, Tibboel D, Hazebroek FW, Molenaar JC,
hypoplasia of the lungs (especially in the more
Lachmann B, Gommers D (1991) Surfactant replace-
severe cases of CDH) cannot be excluded. ment therapy in high-risk congenital diaphragmatic
We have recently reported that infants with CDH hernia [letter]. Lancet 338:1279
52 Surfactant Metabolism in Neonatal Lung Diseases 819
Botas C, Poulain F, Akiyama J, Brown C, Allen L, Goerke (DSPC) turnover and pool size in newborn infants with
J, Clements J, Carlson E, Gillespie AM, Epstein C, congenital diaphragmatic hernia (CDH). Pediatr Res
Hawgood S (1998) Altered surfactant homeostasis 54:653–658
and alveolar type II cell morphology in mice lacking Cogo PE, Zimmermann LJ, Verlato G, Midrio P, Gucciardi
surfactant protein D. Proc Natl Acad Sci USA A, Ori C, Carnielli VP (2004) A dual stable isotope
95:11869–11874 tracer method for the measurement of surfactant
Bunt JE, Zimmermann LJ, Wattimena JL, van Beek RH, disaturated-phosphatidylcholine net synthesis in
Sauer PJ, Carnielli VP (1998) Endogenous surfactant infants with congenital diaphragmatic hernia. Pediatr
turnover in preterm infants measured with stable iso- Res 56:184–190
topes. Am J Respir Crit Care Med 157:810–814 Cogo PE, Simonato M, Danhaive O, Verlato G, Cobellis G,
Bunt JH, Carnielli VP, Seidner SR, Ikegami M, Savignoni F, Peca D, Baritussio A, Carnielli VP (2013)
Wattimena JLD, Sauer PJJ, Jobe AH, Zimmermann LJI Impaired surfactant protein B synthesis in infants
(1999) Metabolism of endogenous surfactant in prema- with congenital diaphragmatic hernia. Eur Respir
ture baboons and effect of prenatal corticosteroids. Am J 41:677–682
J Respir Crit Care Med 160:1481–1485 Crouch EC (1998) Collectins and pulmonary host defense.
Bunt JE, Carnielli VP, Janssen DJ, Wattimena JLD, Am J Respir Cell Mol Biol 19:177–201
Hop WC, Sauer PJJ, Zimmermann LJI (2000a) Treat- Dargaville PA, South M, McDougall PN (2001) Surfactant
ment with exogenous surfactant stimulates endogenous and surfactant inhibitors in meconium aspiration
surfactant synthesis in premature infants with respira- syndrome. J Pediatr 138:113–115
tory distress syndrome. Crit Care Med 28:3383–3388 deMello DE, Heyman S, Phelps DS, Hamvas A, Nogee L,
Bunt JE, Carnielli VP, Wattimena DJL, Hop WC, Sauer PJ, Cole S, Colten HR (1994) Ultrastructure of lung in
Zimmermann LJ (2000b) The effect in premature surfactant protein b deficiency. Am J Respir Cell Mol
infants of prenatal corticosteroids on endogenous sur- Biol 11:230–239
factant synthesis as measured with stable isotopes. Am Escande B, Kuhn P, Rivera S, Messer J (2004) Secondary
J Respir Crit Care Med 162:844–849 surfactant deficiencies. Arch Pediatr 11:1351–1359
Cavicchioli P, Zimmermann LJ, Cogo PE, Badon T, Faridy EE, Thliveris JA (1987) Rate of secretion of lung
Giordano G, Torresin M, Zacchello F, Carnielli VP surfactant before and after birth. Respir Physiol
(2001) Endogenous surfactant turnover in preterm 68:269–277
infants with respiratory distress syndrome studied Fetter WP, Baerts W, Bos AP, van Lingen RA (1995)
with stable isotope lipids. Am J Respir Crit Care Med Surfactant replacement therapy in neonates with respi-
163:55–60 ratory failure due to bacterial sepsis. Acta Paediatr
Chinese Collaborative Study Group for Neonatal Respira- 84:14–16
tory Distress (2005) Treatment of severe meconium Findlay RD, Taeusch HW, Walther FJ (1996) Surfactant
aspiration syndrome with porcine surfactant: a multi- replacement therapy for meconium aspiration syn-
centre, randomized, controlled trial. Acta Paediatr drome. Pediatrics 97:48–52
94:896–902 Finer NN (2004) Surfactant use for neonatal lung injury:
Cleary GM, Antunes MJ, Ciesielka DA, Higgins ST, beyond respiratory distress syndrome. Paediatr Respir
Spitzer AR, Chander A (1997) Exudative lung injury Rev 5(Suppl A):S289–S297
is associated with decreased levels of surfactant pro- Fujiwara T, Meata H, Chida S, Morita T, Watabe Y, Abe T
teins in a rat model of meconium aspiration. Pediatrics (1980) Artificial surfactant therapy in hyaline mem-
100:998–1003 brane disease. Lancet 1:55–59
Cochrane CG, Revak SD, Merritt TA, Schraufstatter IU, Glasser SW, Burhans MS, Korfhagen TR, Na CL, Sly PD,
Hoch RC, Henderson C, Andersson S, Takamori H, Ross GF, Ikegami M, Whitsett JA (2001) Altered sta-
Oades ZG (1998) Bronchoalveolar lavage with KL4- bility of pulmonary surfactant in SP-C-deficient mice.
surfactant in models of meconium aspiration syndrome. Proc Natl Acad Sci USA 98:6366–6371
Pediatr Res 44:705–715 Glatz T, Ikegami M, Jobe A (1982) Metabolism of exoge-
Cogo PE, Carnielli VP, Bunt JEH, Badon T, Giordano G, nously administered natural surfactant in the newborn
Zacchello F, Sauer PJJ, Zimmermann LJI (1999) lamb. Pediatr Res 16:711–715
Endogenous surfactant metabolism in critically ill Glick PL, Stannard VA, Leach CL, Rossman J, Hosada Y,
infants measured with stable isotopes labeled fatty Morin FC, Cooney DR, Allen JE, Holm B (1992a)
acids. Pediatr Res 45:242–246 Pathophysiology of congenital diaphragmatic hernia
Cogo PE, Zimmermann LJ, Rosso F, Tormena F, Gamba P, II: the fetal lamb CDH model is surfactant deficient.
Verlato G, Baritussio A, Carnielli VP (2002) Surfactant J Pediatr Surg 27:382–387; discussion 387–388
synthesis and kinetics in infants with congenital Glick PL, Leach CL, Besner GE, Egan EA, Morin FC,
diaphragmatic hernia. Am J Respir Crit Care Med Malanowska-Kantoch A, Robinson LK, Brody A,
166:154–158 Lele AS, McDonnell M et al (1992b) Pathophysiology
Cogo PE, Zimmermann LJ, Meneghini L, Mainini N, of congenital diaphragmatic hernia. III: exogenous sur-
Bordignon L, Suma V, Buffo M, Carnielli VP (2003) factant therapy for the high-risk neonate with CDH. J
Pulmonary surfactant disaturated-phosphatidylcholine Pediatr Surg 27:866–869
820 V. P. Carnielli and P. E. Cogo
Gluck L, Kulovich MV, Borer RC Jr, Keidel WN (1974) Ikegami M, Polk D, Jobe A (1996) Minimum interval
The interpretation and significance of the lecithin- from fetal betamethasone treatment to postnatal lung
sphingomyelin ratio in amniotic fluid. Am J Obstet responses in preterm lambs. Am J Obstet Gynecol
Gynecol 120:142–155 174:1408–1413
Gonzales LW, Ertsey R, Ballard PL, Froh D, Goerke J, Jacobs H, Jobe A, Ikegami M, Conaway D (1983) The
Gonzales J (1990) Glucocorticoid stimulation of fatty significance of reutilization of surfactant phosphatidyl-
acid synthesis in explants of human fetal lung. Biochim choline. J Biol Chem 258:4156–4165
Biophys Acta 1042:1–12 Jacobs HC, Ikegami M, Jobe AH, Berry DD, Jones S
Griese M, Dietrich P, Reinhardt D (1995) Pharmacokinet- (1985) Reutilization of surfactant phosphatidylcholine
ics of bovine surfactant in neonatal respiratory distress in adult rabbits. Biochim Biophys Acta 837:77–84
syndrome. Am J Respir Crit Care Med 152:1050–1054 Janssen DJMT (2003) Surfactant phosphatidylcholine
Haagsman HP, Diemel RV (2001) Surfactant-associated metabolism in severe neonatal lung disease studied
proteins: functions and structural variation. Comp with studied with stable isotopes. Erasmus MC.
Biochem Physiol A Mol Integr Physiol 129:91–108 Erasmus, Rotterdam
Halliday HL, Speer CP, Robertson B (1996) Treatment Janssen DJ, Tibboel D, Carnielli VP, van Emmen E,
of severe meconium aspiration syndrome with porcine Luijendijk IH, Darcos Wattimena JL, Zimmermann LJ
surfactant. Collaborative surfactant study group. Eur (2003) Surfactant phosphatidylcholine pool size in
J Pediatr 155:1047–1051 human neonates with congenital diaphragmatic hernia
Hallman M, Merritt TA, Pohjavuori M, Gluck L (1986) requiring ecmo. J Pediatr 142:247–252
Effect of surfactant substitution on lung effluent phos- Jobe A (1988) Metabolism of endogenous surfactant and
pholipids in respiratory distress syndrome: evaluation exogenous surfactant for replacement therapy. Semin
of surfactant phospholipid turnover, pool size, and the Perinatol 12:231–239
relationship to severity of respiratory failure. Pediatr Jobe A, Ikegami M (1994) Movement of fluid and particles
Res 20:1228–1235 between the airspaces and pulmonary interstitium
Herting E, Gefeller O, Land M, van Sonderen L, Harms K, protein permeability abnormalities in the preterm. In:
Robertson B (2000) Surfactant treatment of neonates Effros R, Chang H (eds) Fluid and solute transport in
with respiratory failure and group b streptococcal infec- the airspaces of the lungs (lung biology in health and
tion. Members of the collaborative european multicen- disease). Marcel Dekker, New York, pp 335–355
ter study group. Pediatrics 106:957–964; discussion Jobe A, Ikegami M, Sarton-Miller I, Barajas L (1980)
1135 Surfactant metabolism of newborn lamb lungs in
Herting E, Moller O, Schiffmann JH, Robertson B (2002) vivo. J Appl Physiol 49:1091–1098
Surfactant improves oxygenation in infants and chil- Jobe A, Ikegami M, Glatz T, Yoshida Y, Diakomanolis E,
dren with pneumonia and acute respiratory distress Padbury J (1983) Saturated phosphatidylcholine secre-
syndrome. Acta Paediatr 91(11):1174–1178 tion and the effect of natural surfactant on premature
Higgins ST, Wu AM, Sen N, Spitzer AR, Chander A and term lambs ventilated for 2 days. Exp Lung Res
(1996) Meconium increases surfactant secretion in iso- 4:259–267
lated rat alveolar type II cells. Pediatr Res 39:443–447 Kessler DL, Truog WE, Murphy JH, Palmer S,
Hintz SR, Suttner DM, Sheehan AM, Rhine WD, Standaert TA, Woodrum DE, Hodson WA (1982)
Van Meurs KP (2000) Decreased use of neonatal extra- Experimental hyaline membrane disease in the prema-
corporeal membrane oxygenation (ecmo): how new ture monkey: effects of antenatal dexamethasone. Am
treatment modalities have affected ecmo utilization. Rev Respir Dis 126:62–69
Pediatrics 106:1339–1343 Korfhagen TR, Bruno MD, Ross GF, Huelsman KM,
Hunt AN, Kelly FJ, Postle AD (1991) Developmental Ikegami M, Jobe AH, Wert SE, Stripp BR,
variation in whole human lung phosphatidylcholine Morris RE, Glasser SW, Bachurski CJ, Iwamoto HS,
molecular species: a comparison with guinea pig and Whitsett JA (1996) Altered surfactant function and
rat. Early Hum Dev 25:157–171 structure in SP-A gene targeted mice. Proc Natl Acad
Ijsselstijn I, Zimmermann LJ, Bunt JE, de Jongste JC, Sci USA 93:9594–9599
Tibboel D (1998) Prospective evaluation of surfactant Lally KP, Lally PA, Langham MR, Hirschl R, Moya FR,
composition in bronchoalveolar lavage fluid of Tibboel D, Van Meurs K (2004) Surfactant does not
infants with congenital diaphragmatic hernia and of improve survival rate in preterm infants with congenital
age-matched controls. Crit Care Med 26:573–580 diaphragmatic hernia. J Pediatr Surg 39:829–833
Ikegami M, Berry D, elKady T, Pettenazzo A, Seidner S, Lotze A, Whitsett JA, Kammerman LA, Ritter M,
Jobe A (1987) Corticosteroids and surfactant change Taylor GA, Short BL (1990) Surfactant protein a
lung function and protein leaks in the lungs of venti- concentrations in tracheal aspirate fluid from infants
lated premature rabbits. J Clin Invest 79:1371–1378 requiring extracorporeal membrane oxygenation.
Ikegami M, Jobe A, Yamada T, Priestly A, Ruffini L, Rider J Pediatr 116:435–440
E, Seidner S (1989) Surfactant metabolism in surfac- Lotze A, Knight GR, Martin GR, Bulas DI, Hull WM,
tant-treated preterm ventilated lambs. J Appl Physiol O’Donnell RM, Whitsett JA, Short BL (1993)
67:429–437 Improved pulmonary outcome after exogenous
52 Surfactant Metabolism in Neonatal Lung Diseases 821
surfactant therapy for respiratory failure in term infants lung during perinatal development. J Lipid Res
requiring extracorporeal membrane oxygenation. 27:602–612
J Pediatr 122:261–268 Phelps DS (2001) Surfactant regulation of host defense
Lotze A, Knight GR, Anderson KD, Hull WM, function in the lung: a question of balance. Pediatr
Whitsett JA, O’Donnell RM, Martin G, Bulas DI, Pathol Mol Med 20:269–292
Short BL (1994) Surfactant (beractant) therapy for Pinkerton KE, Willet KE, Peake JL, Sly PD, Jobe AH,
infants with congenital diaphragmatic hernia on ecmo: Ikegami M (1997) Prenatal glucocorticoid and T4
evidence of persistent surfactant deficiency. J Pediatr effects on lung morphology in preterm lambs. Am
Surg 29:407–412 J Respir Crit Care Med 156:624–630
Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Pope TS, Rooney SA (1987) Effects of glucocorticoid
Gunkel JH (1998) Multicenter study of surfactant and thyroid hormones on regulatory enzymes of
(beractant) use in the treatment of term infants with fatty acid synthesis and glycogen metabolism in
severe respiratory failure. Survanta in term infants developing fetal rat lung. Biochim Biophys Acta
study group. J Pediatr 132:40–47 918:141–148
Martini WZ, Chinkes DL, Barrow RE, Murphey ED, Post M, Barsoumian A, Smith BT (1986) The cellular
Wolfe RR (1999) Lung surfactant kinetics in conscious mechanism of glucocorticoid acceleration of fetal
pigs. Am J Physiol 277:E187–E195 lung maturation. Fibroblast-pneumonocyte factor stim-
Merchak A, Janssen DJ, Bohlin K, Patterson BW, ulates choline-phosphate cytidylyltransferase activity.
Zimmermann LJ, Carnielli VP, Hamvas A (2002) J Biol Chem 261:2179–2184
Endogenous pulmonary surfactant metabolism is Rebello CM, Jobe AH, Eisele JW, Ikegami M (1996)
not affected by mode of ventilation in premature Alveolar and tissue surfactant pool sizes in humans.
infants with respiratory distress syndrome. J Pediatr Am J Respir Crit Care Med 154:625–628
140:693–698 Rivera S, Gaugler C, Langlet C, Villega F, Astruc D,
Merrill J, Ballard P, Hibbs A, et al (2006) Booster Escande B, Kuhn P, Messer J (2004) Secondary surfac-
surfactant therapy beyond the first week of life tant deficiencies in extremely low birth weight prema-
in ventilated extremely low gestational age infants. E- ture infants. Arch Pediatr 11:1346–1350
PAS2006:59:26351. Available at www.abstracts2vie w. Rooney SA, Gobran LI, Marino PA, Maniscalco WM,
com/pasall/index.php. Accessed 14 May 2008 Gross I (1979) Effects of betamethasone on phospho-
Minowa H, Takahashi Y, Kawaguchi C, Sadou T, Konishi lipid content, composition and biosynthesis in the fetal
N, Nishikubo T, Yoshioka A (2000) Expression of rabbit lung. Biochim Biophys Acta 572:64–76
intrapulmonary surfactant apoprotein-A in autopsied Sakurai Y, Azarow K, Cutz E, Messineo A, Pearl R,
lungs: comparative study of cases with or without pul- Bohn D (1999) Pulmonary barotrauma in congenital
monary hypoplasia. Pediatr Res 48:674–678 diaphragmatic hernia: a clinicopathological correlation.
Moller JC, Kohl M, Reiss II, Diederich W, Nitsche EM, J Pediatr Surg 34:1813–1817
Gopel W, Gortner L (1999) Saline lavage with Seidner SR, Jobe AH, Coalson JJ, Ikegami M (1998)
substitution of bovine surfactant in term neonates with Abnormal surfactant metabolism and function in pre-
meconium aspiration syndrome (MAS) transferred for term ventilated baboons. Am J Respir Crit Care Med
extracorporeal membrane oxygenation (ECMO): 158:1982–1989
a pilot study. Crit Care 3:19–22 Spragg RG, Li J (2000) Effect of phosphocholine
Moses D, Holm BA, Spitale P, Liu MY, Enhorning G cytidylyltransferase overexpression on phosphatidyl-
(1991) Inhibition of pulmonary surfactant function by choline synthesis in alveolar type II cells and related
meconium. Am J Obstet Gynecol 164:477–481 cell lines. Am J Respir Cell Mol Biol 22:116–124
Moya FR, Thomas VL, Romaguera J, Mysore MR, Sullivan KM, Hawgood S, Flake AW, Harrison MR,
Maberry M, Bernard A, Freund M (1995) Fetal lung Adzick NS (1994) Amniotic fluid phospholipid analy-
maturation in congenital diaphragmatic hernia. Am sis in the fetus with congenital diaphragmatic hernia.
J Obstet Gynecol 173:1401–1405 J Pediatr Surg 29:1020–1023
Nogee LM, de Mello DE, Dehner LP, Colten HR (1993) Sun B, Curstedt T, Robertson B (1993) Surfactant
Brief report: deficiency of pulmonary surfactant protein inhibition in experimental meconium aspiration. Acta
B in congenital alveolar proteinosis. N Engl J Med Paediatr 82:182–189
328:406–410 Sun B, Curstedt T, Robertson B (1996) Exogenous
Oetomo SB, Lewis J, Ikegami M, Jobe AH (1990) Surfac- surfactant improves ventilation efficiency and alveolar
tant treatments alter endogenous surfactant metabolism expansion in rats with meconium aspiration. Am
in rabbit lungs. J Appl Physiol 68:1590–1596 J Respir Crit Care Med 154:764–770
Oguchi K, Ikegami M, Jacobs H, Jobe A (1985) Clearance Tan RC, Ikegami M, Jobe AH, Yao LY, Possmayer F,
of large amounts of natural surfactants and liposomes Ballard PL (1999) Developmental and glucocorticoid
of dipalmitoylphosphatidylcholine from the lungs of regulation of surfactant protein mRNAs in preterm
rabbits. Exp Lung Res 9:221–235 lambs. Am J Physiol 277:L1142–L1148
Oulton M, Fraser M, Dolphin M, Yoon R, Faulkner G Torresin M, Zimmermann LJ, Cogo PE, Cavicchioli P,
(1986) Quantification of surfactant pool sizes in rabbit Badon T, Giordano G, Zacchello F, Sauer PJ,
822 V. P. Carnielli and P. E. Cogo
Carnielli VP (2000) Exogenous surfactant kinetics in Walther FJ, Jobe AH, Ikegami M (1998) Repetitive prena-
infant respiratory distress syndrome: a novel method tal glucocorticoid therapy reduces oxidative stress in
with stable isotopes. Am J Respir Crit Care Med the lungs of preterm lambs. J Appl Physiol 85:273–278
161:1584–1589 Wilcox DT, Glick PL, Karamanoukian HL,
Van Meurs K (2004) Is surfactant therapy beneficial in the Azizkhan RG, Holm BA (1995) Pathophysiology of
treatment of the term newborn infant with congenital congenital diaphragmatic hernia. XII: amniotic fluid
diaphragmatic hernia? J Pediatr 145:312–316 lecithin/sphingomyelin ratio and phosphatidylglycerol
Verlato G, Cogo PE, Pesavento R, Gomirato S, Benettazzo concentrations do not predict surfactant status in
A, Gucciardi A, Grazzini M, Carnielli VP (2003) Sur- congenital diaphragmatic hernia. J Pediatr Surg
factant kinetics in newborn infants with pneumonia and 30:410–412
Respiratory Distress Syndrome. Ital J Pediatr 29: Wiswell TE, Knight GR, Finer NN, Donn SM, Desai H,
354–357 Walsh WF, Sekar KC, Bernstein G, Keszler M,
Verlato G, Cogo PE, Balzani M, Gucciardi A, Burattini I, Visser VE, Merritt TA, Mannino FL, Mastrioianni L,
De Benedictis F, Martiri G, Carnielli VP (2008) Marcy B, Revak SD, Tsai H, Cochrane CG (2002)
Surfactant status in preterm neonates recovering A multicenter, randomized, controlled trial comparing
from respiratory distress syndrome. Pediatrics surfaxin (lucinactant) lavage with standard care for
122:102–108 treatment of meconium aspiration syndrome. Pediatrics
Walther FJ, Ikegami M, Warburton D, Polk DH (1991) 109:1081–1087
Corticosteroids, thyrotropin-releasing hormone, and Wright JR, Dobbs LG (1991) Regulation of pulmonary
antioxidant enzymes in preterm lamb lungs. Pediatr surfactant secretion and clearance. Annu Rev Physiol
Res 30:518–521 53:395–414
Respiratory Distress Syndrome:
Predisposing Factors, 53
Pathophysiology, and Diagnosis
Mikko Hallman, Timo Saarela, and Luc J. I. Zimmermann
Contents
53.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 824
53.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 824
53.3 Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 825
53.3.1 Genetic Factors Influencing Susceptibility to RDS . . . . . . . . . . . . . . . . . . . . . . . . . . . 826
53.4 Symptoms and Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 827
53.4.1 Respiratory Course and Lung Function in RDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 827
53.4.2 Course of RDS in Preterm Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 828
53.4.3 Extremely Preterm Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 828
53.4.4 Late-Preterm and Early-Term Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 829
53.5 Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 829
53.5.1 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 829
53.6 Predisposing Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 831
53.6.1 Surfactant System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 831
53.6.2 Secretion of Fetal Lung Liquid and Induction of Liquid Absorption . . . . . . . . . 833
53.6.3 Structural Lung Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835
M. Hallman (*)
Department of Children and Adolescents, Oulu University
Hospital, and PEDEGO Research Unit, Medical Research
Center Oulu, University of Oulu, Oulu, Finland
e-mail: mikko.hallman@oulu.fi
T. Saarela
Department of Children and Adolescents, Oulu University
Hospital, Oulu, Finland
e-mail: Timo.Saarela@ppshp.fi
L. J. I. Zimmermann
Department of Pediatrics and Neonatology, School for
Oncology and Developmental Biology (GROW),
Maastricht University Medical Center, Maastricht,
The Netherlands
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 823
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_289
824 M. Hallman et al.
53.7 Mechanisms of Lung Injury in RDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835
53.7.1 Primary and Secondary Surfactant Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835
53.7.2 Biotrauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 836
53.7.3 Volutrauma and Barotrauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 837
53.7.4 Delay in Clearance of Lung Liquid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 837
53.7.5 High-Permeability Lung Edema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 838
53.7.6 Pulmonary Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 838
53.7.7 Abnormalities in Lung Perfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 838
53.7.8 Patent Ductus Arteriosus (PDA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839
53.8 Prevention of RDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839
53.8.1 Prevention of Premature Birth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839
53.8.2 Pharmacological Acceleration of Fetal Lung
Maturity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839
53.8.3 Diagnosis of Lung Maturity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 840
53.8.4 Prevention of Low-Risk Elective Births Before Term . . . . . . . . . . . . . . . . . . . . . . . . 840
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 841
Abstract 53.1 Salient Points
Due to increased survival and new treatment
strategies, new phenotypes of respiratory dis- • RDS is the most common serious disease
tress syndrome (RDS) have emerged. RDS in affecting the newborn.
near-term to term infants is characterized by • Advances in neonatal care have led to a
seemingly effortless breathing and tendency to decrease in mortality rates.
pulmonary hypertension that can be avoided • Half of the infants with RDS are born between
by expectant management. Common prevent- 29 and 34 weeks of gestation; symptoms of
able cause is elective delivery before full respiratory distress appear soon after birth and
40 weeks of pregnancy. Sometimes these surfactant administration limits the progression
infants possess rare alleles retarding lung of the disease.
development. Extremely preterm infants are • In extremely preterm infants, RDS tends to have
often affected by intrauterine inflammation, a prolonged course and develops into BPD
accelerating surfactant maturity. Despite new through many intertwined mechanisms.
noninvasive treatment practices, initially mild • Antenatal steroid administration to the
RDS tends to become prolonged and develops pregnant women, by inducing structural
to BPD. This is due to deficient antioxidant, lung maturity and stimulating functional
anti-inflammatory, and antimicrobial capacity; maturity, are the cornerstone of prevention
predisposition to airway injury, alveolar of RDS.
flooding, and surfactant inactivation by multi-
ple mechanisms are discussed. Genetic factors
predisposing very preterm infants to RDS are
intertwined with acquired risks: lack of labor, 53.2 Introduction
non-presenting twin, and adverse metabolic
environment (e.g., hyperinsulinemia). Antena- Respiratory distress syndrome of newborn
tal steroid, inducing structural maturity and infants (RDS), called infantile RDS or IRDS,
stimulating functional maturity, is the corner- previously idiopathic RDS or hyaline mem-
stone of prevention of RDS and the develop- brane disease (HMD), is the most common seri-
mental diseases prior to week 34. Currently ous disease affecting the newborn. Since the
steroid supplementation in RDS is not description of hyaline membranes by Hochheim
recommended. in 1903, the pathogenesis and etiology were
53 Respiratory Distress Syndrome: Predisposing Factors, Pathophysiology, and Diagnosis 825
studied (Obladen 1992). During past 50 years, 53.3 Risk Factors
the advances in neonatal intensive have led to
striking improvement in prognosis in advanced RDS is characterized by typical features of respi-
perinatal centers, changing the phenotype of ratory insufficiency shortly after birth. The pri-
RDS and allowing the decrease in RDS mortal- mary cause in most cases is lung immaturity that
ity from nearly 50% to close to 5%. In addition, results in deficient gas exchange and acute
infants born extremely preterm (<28 weeks) lung injury. The clinical features depend on a
previously died at birth. Today nearly all sur- number of interactive constitutional, genetic,
vive long enough to develop RDS. and acquired factors and particularly on thera-
In 1926, Van Neergard described the hystere- peutic practices. The risk factors have decreased
sis of the lung. The significance of this finding as a result of improved antenatal anticipation of
was not appreciated until surface activity was preterm birth, pharmacologic acceleration of
described by Clements and Pattle in the 1950s fetal lung maturity, and of early treatment prac-
(Obladen 1992). As a consequence, Avery and tices at birth.
Mead (1959) discovered that the airways of The reported incidence of RDS among term-
infants dying of HMD had high surface tension born infants is one in 2000 (Marttila et al. 2004).
(Avery and Mead 1959). This finding was further Elective delivery without labor before 40th week
tested several years later when dipalmitoyl phos- of pregnancy is expected to increase the risk of
phatidylcholine was nebulized to the airways in RDS. The incidence increases by each week of
RDS with disappointing results (Chu et al. 1967). decreasing the length of gestation. At
It took the death of President Kennedy’s son Pat- 34–36 weeks, it has ranged from 5% to 10%, at
rick on HMD in 1963 to activate the research on 30–33 weeks from 10% to 35%, and at
RDS. After defining the surfactant system and 28–29 weeks from 30% to 50%, and in ELGA
lung structures in more detail, followed by thera- infants, the risk exceeds 50%. In the USA, the
peutic trials using natural surfactant, an increase reported incidence is often higher. More recently
in the survival and an acute, dramatic decrease in the gestational age of the RDS population has
the severity of RDS became evident (Robertson decreased. This has taken place because of the
and Taeusch 1995). Antenatal glucocorticoid ther- successful prevention of RDS in the preterm
apy (AGC) in threatened preterm birth was shown population and increased early survival of new-
by Liggins and Howie in 1971 to decrease the risk born infants with very low gestation. Figure 1
of RDS (Liggins and Howie 1972). The accep- shows schematically the risk and mortality of
tance of AGC in common clinical use was delayed RDS and application of therapies during the
until around the introduction of surfactant therapy past 45 years.
in the early 1990s. Increased risk of RDS is associated with elec-
Surfactant therapy, AGC, effective ventilator tive deliveries without labor in late-preterm
treatment practices, and several supplementary (34–36 weeks) and early-term (37–38 weeks) preg-
treatment strategies have improved the survival nancies (Gerten et al. 2005; Ramachandrappa and
and decreased the risk of RDS. Organ injuries Jain 2008), lack of AGC before 34 weeks of preg-
associated with RDS and the phenotype of RDS nancy (Roberts and Dalziel 2006), and Caucasian
have become remarkably less distinct (“the new (vs. African) ethnicity. Surfactant supplementation
RDS”). However, the risk of bronchopulmonary at preterm birth and continuous distending pressure
dysplasia (BPD) continues to be prevalent ventilation from birth may abolish typical symp-
among infants born extremely preterm (ELGA, toms (Morley et al. 2008; Sandri et al. 2010). Males
<28 weeks). Genetic and constitutional factors, have a higher risk than females, the difference
most notably the length of gestation as a proxy corresponding to a mean of 1 week of gestation
of the degree of lung development, influence (Table 1). The length of gestation interacts with
clinical management and outcome. other risk factors. Multiple birth increases the risk
826 M. Hallman et al.
Fig. 1 Demographics of RDS during development of bronchopulmonary dysplasia, patent ductus arteriosus,
perinatal-neonatal treatment practices. Trends in mortality necrotizing enterocolitis, intraventricular hemorrhage gr
and in birth weights during 1970–2014. The figures are 2–4. S surfactant trials, SS the incidence synthetic surfac-
from Finland with prematurity rate ranging from 5.2% to tant treatment of infants <32 week’s gestation, AS animal
6.0% and the incidence of RDS in the range of 0.4–0.6% surfactant (The figures are obtained from hospital records
during the past 25 years. WHO definition of live birth was and from the Finnish Perinatal Register (Finnish National
introduced in 1989. Serious associated morbidity includes Institute for Health and Welfare; Dr. Mika Gissler))
of RDS in ELGA births and is a protective factor at 53.3.1 Genetic Factors Influencing
30 weeks or later (Marttila et al. 2004). The pre- Susceptibility to RDS
senting twin has a lower risk of RDS (but higher
risk of infection) than the non-presenting one. According to available twin studies comparing the
Chorioamnionitis decreases the risk of RDS in concordance of RDS between monozygotic and
ELGA births (Watterberg et al. 1996; Kaukola dizygotic same sex preterm twins, a direct genetic
et al. 2009). Maternal diabetes and fetal hydrops contribution to the susceptibility to RDS has been
increase the risk of RDS. There is no consensus, small (~20%). Instead, detectable effects of indi-
whether preeclampsia or intrauterine growth vidual genes are due to gene-gene or gene-
restriction (IUGR) influences the risk. However, environment interactions. They undermine the esti-
chronic retroplacental bleeding (circumvallate pla- mates of the genetic effects on the basis of twin
centa) is associated with acceleration of lung studies. For instance, the presenting twin has
maturity. a lower risk of RDS compared to the
53 Respiratory Distress Syndrome: Predisposing Factors, Pathophysiology, and Diagnosis 827
Table 1 Pregnancy-related states and complications asso- insults. Genes with identified roles in lung func-
ciated with altered risk of RDS as compared to gestation tion have mutations or common allelic variants
controls
that influence surfactant function in stress or
Accelerated maturation Control or delayed have no detectable effect. Studies thus far show
or control maturation
that some genes expressed in type 2 cells influ-
Vaginal birth Elective birth with labor
ence the individual risk of RDS, including poly-
Elective birth with labor Elective low risk birth w/o
labor: late preterm or early morphism of SP-A, SP-B, SP-C, and ABCA3
term (37–38 weeks) (Hallman and Haataja 2007). According to
Female fetus Male fetus genetic studies, mediators influencing the risk
Closeness to cervix in Remote to cervix in twin of spontaneous premature birth and the risk of
twin pregnancy pregnancy (non-presenting) RDS are partly intertwined: SP-A and SP-D
(presenting)
influence cytokine responses mediating surfac-
First born twin pair Second born twin pair
>28 weeks, no infection >28 weeks tant synthesis and preterm labor process
Singleton <28 weeks Twin <28 weeks (Karjalainen et al. 2012).
Twin 30–36 weeks Singleton 30–36 weeks The genetic studies on the susceptibility to
Control <28 weeks Preeclampsia <28 weeks RDS have thus far been focused on major alleles
Chorioamnionitis Control 24–29 weeks of the likely candidate genes (i.e., surfactant pro-
24–29 weeksa teins). For more objective data on candidate genes
Gestation control Poor control of maternal and alleles, very large, non-biased, population-
diabetes, fetal hydrops,
based studies, their replicates, and meta-analyses
severe isoimmunization
a are required. Genome-wide association analyses
Mostly histologic chorioamnionitis. Clinical chorioam-
nionitis, when associated with fetal infection, is associated (GWAS) and whole-genome studies involving
with respiratory distress mimicking RDS siblings are appropriate. Eventually research
may help redefine the disease and its treatment.
non-presenting one, and the magnitude of this dif-
ference is influenced by gene-environment interac-
tion (Marttila et al. 2003; Hallman and Haataja 53.4 Symptoms and Clinical
2007). RDS in late-preterm and early-term infants Findings
has likely a different genetic background compared
to RDS infants with shorter gestation at birth. The 53.4.1 Respiratory Course and Lung
rare alleles with significant adverse effect to respi- Function in RDS
ratory function are more likely in RDS cases with
near-term or term gestation. Natural course of RDS is characterized by early
Mutations that may disrupt surfactant func- rapid progression of respiratory distress leading to
tion include SP-B, ABCA3, and SP-C genes. respiratory failure and often death in the absence
They cause fatal or severe chronic lung disease of treatment within 1–48 h. The stabilization
that initially resembles RDS (Wert et al. 2009). phase of respiratory distress is followed by the
Mutations involving transcription factors recovery phase, starting within 1–6 days after
TTF-1, C/EBPα, FOXA2, a glucocorticoid birth and continuing longer than progressive
receptor NR3C1, and some other genes gener- phase. The unifying features in RDS are the tran-
ally delay differentiation of specific functions, sient deficiency of surfactant in epithelial lining
including the surfactant system, causing serious and the early lung injury. Cyanosis is evaluated by
respiratory distress and often other symptoms oxygen saturation monitoring and right-to-left cir-
(Whitsett et al. 2010). Several other proteins, culatory shunt by measuring the arterial blood
including SP-A and SP-D, have important, gases and calculating the alveolar-arterial O2 ten-
partly redundant functions that influence the sion difference. Soon after birth, the breath sounds
susceptibility to infections and inflammatory are often diminished; later stridor may be evident.
828 M. Hallman et al.
Early RDS is characterized by low functional suggestive, unless pre-treatment surfactant diag-
residual capacity, low compliance, and high nostics are available or the patient has distinct
venous admixture, indicating diffuse atelectasis. favorable response to exogenous surfactant.
The early lung injury often involves peripheral The surfactant-induced remission is sometimes
airways causing obstructive small airway disease followed by relapse requiring retreatment.
in full-blown RDS. The short inspiratory time The response to exogenous surfactant is less pre-
constant early in the course of RDS increases as dictable and generally less striking if surfactant
a sign of airway obstruction (Baldwin et al. 2006). is given later (>6 h after birth). Some develop
Modest abnormalities in lung function may persist signs of patent ductus arteriosus (PDA). Apnea,
even weeks and will be evident at term after infection, and pneumothorax are rare complications.
the recovery from uncomplicated RDS, and par-
ticularly when it is complicated with BPD
(Hjalmarson et al. 2014). Surfactant therapy in 53.4.3 Extremely Preterm Infants
RDS increases acutely functional residual capac-
ity, decreases venous admixture, more gradually Infants born before 28 weeks of gestation have
increases the compliance, and has little effect on simplified saccular airways, no true alveoli, and
airway resistance. wide interstitial spaces. The highly compliant
The post-hospitalization course of children chest cage generates striking retractions despite
with RDS without development of BPD reveals moderate negative pleural pressures. The low sur-
increased incidence of wheezing during infections factant pool is susceptible to abundant inhibitors.
and therefore higher hospitalization rates during Without treatment, the infants often die before
first 2 years of life, suggesting residual lung injury development of RDS. Providing continuous
or excessive immune response during infection distending pressures and if necessary to gentle
(Koivisto et al. 2005; Jones 2009 Kotecha et al. ventilation limits the emerging lung injury. Sur-
2013). Very premature birth (<32 weeks, VLGA), factant treatment in delivery room or within few
followed by treatment of RDS with modern hours after birth typically induces a sustained
methods and no BPD, is associated with a barely remission characterized by acute lowering of sup-
detectable impact on FEV1 and diffusion capacity plemental O2 requirements and less acute lower-
in school children compared to term-born controls ing of airway pressure requirements. Relapse of
(Ronkainen et al. 2015). respiratory failure often takes place, indicating
retreatment. The course of RDS is characterized
by a high incidence of cardiopulmonary compli-
53.4.2 Course of RDS in Preterm cations, particularly PDA. Air leak syndrome
Infants (pneumothorax, interstitial emphysema), pulmo-
nary hypertension, and pulmonary hemorrhage
Half of the infants with RDS are born between are less common. RDS particularly in this group
29 and 34 weeks of gestation. First symptoms are is associated with complicating diseases: BPD,
observed very soon after birth. Tachypnea, nasal intraventricular hemorrhage (IVH), necrotizing
flaring, subcostal and intercostal retractions, cya- enterocolitis (NEC), and retinopathy of prematu-
nosis, and expiratory grunt are characteristic, rity (ROP). The incidence of complicating dis-
although not very specific, findings since transient eases varies from NICU to another.
tachypnea is initially nearly indistinguishable. In Despite AGC, noninvasive ventilation, early
RDS, the symptoms continue longer than 24 h, surfactant, and other adjunct treatments, such as
unless specific therapies are applied. late cord clamping, caffeine, and inhaled nitric
The progression of respiratory distress is oxide or selective postnatal glucocorticoid, a
decreased or prevented by continuous distending significant risk of BPD and other adverse effects
pressures and by surfactant therapy. As a result remain (Schmidt et al. 2008; Bassler et al.
of rather mild symptoms, the diagnosis remains 2015).
53 Respiratory Distress Syndrome: Predisposing Factors, Pathophysiology, and Diagnosis 829
53.4.4 Late-Preterm and Early-Term are superimposed on a background of atelectatic
Infants lung parenchyma. The severity of RDS on the
basis of the chest X-ray has been graded (Avery
Late-preterm (35–36 gw) and early-term infants et al. 1981). The grade is likely modified several
with RDS are mostly born electively without hours after exogenous surfactant. Pulmonary
active labor. Other risk factors include acute whiteout (grade 4) is generally a sign of a severe
asphyxia and poorly controlled maternal diabetes; disease; it is also observed in mild disease very
genetic predisposition is a likely underlying cause soon after birth (<1 h). Pulmonary edema and
(Ramachandrappa and Jain 2009). In RDS, the prominent heart shadow is a typical X-ray find-
breathing is rapid but apparently effortless as the ing in RDS complicated by PDA. In near-term
stable chest cage does not often reveal retractions RDS population, reticulogranularity tends to be
and chest X-ray finding may be inconclusive. less distinct and the lung fields may reveal
Ignoring early treatment of respiratory distress ground glass appearance. In some cases lung
and hypoxemia escalates the later respiratory fields appear hyper-expanded; this entity is
course. Persistence of pulmonary hypertension called type 2 RDS.
(PPHN) or pneumothorax are occasional compli- Lung ultrasound (LUS) diagnostics has been
cations. Studies reveal surfactant insufficiency recently reported as a tool for prediction of respi-
despite atypical presentation. ratory failure (Sundell et al. 1971). LUS examined
The developmental stage explains the pheno- within 1 h after the admission on 59 infants
type. The small size of newly developed true alveoli with respiratory distress accurately predicted
predisposes to therapy-resistant atelectasis. The sta- RDS (n = 23) with sensitivity and specificity of
ble chest cage and strong respiratory drive generates 95.6% and 94.4%, respectively (Vergine et al.
high transpulmonary pressures during inspiration, 2014). This method is still investigational.
expanding alveolar ducts, improving the clearance Analysis of surfactant component or surface
of edema fluid. The pulmonary vasculature has a activity of specimens performed on gastric or
prominent smooth muscular layer that extends dis- airway aspirates at birth differentiates RDS with
tally; hypoxemia-induced contractility predisposes specificity of and sensitivity of 50–75% and
to pulmonary hypertension. 80–97%, respectively (Verder et al. 2003;
The clinical recovery often takes place within a Hallman et al. 1986). The false-positive prediction
rather short period. Continuing severe respiratory can be due to blood contamination or to surfactant
symptoms much beyond early neonatal period raises retention due to airway liquid adsorption. A sim-
the possibility of a rare lung disease, particularly ple, rapid, and accurate bedside method would be
hereditary interstitial lung disease due to multiple useful, if available.
specific causes (▶ Chap. 59, “Rare Lung Diseases
of Newborns”).
53.5.1 Differential Diagnosis
53.5 Diagnostics Transient tachypnea (wet lung) becomes clearly
distinguishable from RDS within several hours
The diagnosis is based on a combination of after birth. Bacterial pneumonia, mostly due to
characteristic symptoms, clinical findings, and Group B Streptococcus, often coincides with
the chest X-ray. Typical chest X-ray features RDS. In pulmonary infection, pleural exudate,
reveal a diffuse reticulogranularity with super- focal infiltrates, and sepsis are common. Amniotic
imposed air bronchograms (Fig. 2), indicating aspiration pneumonia, particularly meconium aspi-
atelectasis and edema of respiratory units, distal ration, is easily distinguished by the appearance of
to respiratory bronchioles. The prominent air viscous, often green aspirate, typically in post-term
bronchogram representing aerated bronchi and or term infant. Congenital chylothorax is distin-
larger bronchioles become distinct when they guished by typical milky appearance of lipid-rich
830 M. Hallman et al.
Fig. 2 Typical radiographic and pathological findings of RDS. Typical chest X-rays representing RDS of infant during
surfactant (a) and pre-surfactant era (b). Autopsy findings from normal (c) and HMD (d) lungs
pleural exudate after enteral feeding. Rare cases of hernia, other causes of lung hypoplasia, cystic
small preterm infants with minimal respiratory dis- adenomatous malformation, esophagus atresia,
tress develop cystic interstitial emphysema soon isolated fistula, lung sequestration, tumors, and
after birth (Wilson-Mikity syndrome) (Hoepker malformations require early diagnosis and specific
et al. 2008), a form of obstructive inflammatory treatment strategies.
lung disease that resembles “new BPD” with min- A slow recovery from RDS may be a constitu-
imal respiratory distress at birth. tional feature with likely genetic involvement.
Congenital cardiac diseases associated with Failure to recover is a feature of congenital inter-
respiratory distress and congestive edema, most stitial lung disease due to a mutation in genes that
notably anomalous pulmonary venous return with are essential in postnatal lung function (Wert et al.
abnormal infra diaphragmatic pulmonary vein 2009). PPHN mostly develops as a consequence
return (Scimitar syndrome), require early diagno- of primary lung disease, often RDS. Alveolar
sis and surgery. Equally critical is the prompt diag- capillary dysplasia with misalignment of pulmo-
nosis and early onset of prostaglandin E2 infusion nary vessels is suspected on the basis of persis-
for maintenance of ductal patency and pulmonary tence of acute severe defect in gas exchange;
circulation of ductus-dependent cardiac defects. autopsy diagnosis increasingly has identified
Early respiratory distress due to diaphragmatic genetic background (Bishop et al. 2011).
53 Respiratory Distress Syndrome: Predisposing Factors, Pathophysiology, and Diagnosis 831
Acute (also called acquired or adult) respiratory hydrophobic surfactant proteins (SP-B and
distress syndrome (ARDS) may develop in severe SP-C). The latter contain stretches of hydrophobic
infection or asphyxia also in newborn infants. amino acids interrupted by hydrophilic amino
These patients often have beneficial response to a acids with cationic charge. Natural surfactant
high dose of exogenous surfactant. However, sur- additionally contains SP-A and SP-D: they are
factant therapy has not significantly improved the collagen-containing lectins that have roles in
outcome of this severe, heterogeneous syndrome innate immunity, surfactant metabolism, and for-
that requires proper antibiotics and comprehensive mation of tubular myelin.
cardiopulmonary management. The hydrophobic components are synthesized
in ER, followed by serial cleavage of hydrophilic
stretches of SP-B- and SP-C proproteins, and they
are transported to intracellular lamellar bodies
53.6 Predisposing Factors (LB) (Fig. 3). After secretion from LB into
the alveolar lining, hydrophobic surfactant binds
The lung has developed relatively late in evolu- Ca++ and SP-A, transforming to aggregates that
tion (250 million years), and human evolution is resemble tubular myelin and have instantaneous
recent (5 million years). The regulation of the surface adsorption. During breathing movements,
expression of individual genes generates much of surfactant aggregates are transformed to smaller
the diversity in human genome. The regulation of vesicles. Only a minor fraction of the surfactant
the birth process and the involvement of the fetus complex is removed by cilia, and most of it is taken
in the transition is particularly species specific. up by both alveolar macrophages (AM) and type
Preterm birth is exceptionally common in human 2 (T2) alveolar cells. Surfactant is catabolized in
species. Spontaneous preterm birth particularly in these cells and additionally reutilized in T2 cells.
chorioamnionitis (CA) accelerates surfactant
maturity decreasing the risk of RDS. The periph- Lowering of Surface Tension Surfactant greatly
eral lining of air spaces at 20–22 weeks of gesta- reduces surface tension thus preventing the col-
tion contains epithelial cells that morphologically lapse of small airspaces. Surface tension during
resemble type 2 cells, and pulmonary capillaries expiration is assumed to be close to zero, and it
align with future potential airways. Later in ges- rarely rises above 20 mN/m during normal expi-
tation, both the number of type 2 cells and the ration. Surfactant additionally serves as a lubri-
content of lamellar bodies increase. At term, the cant that reduces barotrauma.
surfactant content of the lungs reaches maximum
and has a critical role in adaptation. Other pulmo- Immune Functions and Ancillary Pro-
nary host defense systems have distinct perinatal teins Individual surfactant components serve as
developmental patterns as well. immune modulators influencing together with
AM and other systems in defense against
microbes and other insults. Several surfactant
53.6.1 Surfactant System components inhibit the signaling of the Toll-like
receptors.
The major surfactant component, dipalmitoyl The coincidence of pneumonia and RDS
phosphatidylcholine (DPPC), concentrates at the reflects the immaturity of the innate immune
air liquid interphase as a tightly packed lipid system. The major defense functions of surfactant
film (Fig. 3). Other surfactant components provide components are focused against airborne microbes,
the extraordinary rapid surface adsorption of DPPC. involving in their destruction without evoking
These include phosphatidylcholine (PC) containing excessive inflammatory response: most surfactant
unsaturated fatty acids, often unsaturated phospho- components are involved (PG, PI, SP-C, SP-B,
lipids containing anionic charge [phosphatidyl- SPPC, and PC). Surfactant collections, SP-A and
glycerol (PG), phosphatidylinositol (PI)] and SP-D, inhibit Toll-like receptor (TLR) signaling,
832 M. Hallman et al.
Fig. 3 Surfactant metabolism in alveolar epithelial cells SP-A and transforms to tubular myelin (TM) figures. In ELF,
and in epithelial lining fluid (ELF). Surfactant is synthesized surfactant is transformed to smaller vesicles that are taken up
endoplasmic reticulum (ER) of type 2 (T2) cells. Surfactants by alveolar macrophages (AM) and T2 cells for either catab-
(DPPC, PC, PG, PI, SP-B, and SP-C) are synthesized in olism in lysosomes (LS) or for reprocessing into LB
endoplasmic reticulum (ER) and processed via Golgi and (recycling). In RDS, surfactant in ELF is deficient at birth,
multivesicular bodies (MVB) into lamellar bodies (LB). and it increases to near-control level within a few days after
SP-A and SP-A are processed by constitutional pathway. birth. At the same time, acquired surfactant defects appear as
After release of LB content into alveoli, surfactant binds a result of airway and alveolar injury
aggregate viruses, and stimulate phagocytosis of glucocorticoid activity in fetus leads to lung
bacteria. Collectins, absent in exogenous surfac- hypercellularity, lack of functional differentiation,
tants, are proposed to serve important functions in and respiratory failure at birth. Other hormones
innate immunity (Wright 2005). contributing to biochemical lung maturity include
adrenergic agents, thyroid hormone, and prolac-
Regulation of Surfactant System: An Example tin, whereas testosterone delays lung maturity.
of Antenatal Regulation of Functional Maturity - Several other growth factors and cytokines also
Glucocorticoid is the main hormone regulating influence the differentiation and growth of alveo-
spontaneous functional differentiation of the lar tissue (Torday and Rehan 2015).
lung (Bird et al. 2015). The effects of glucocorti- Besides regulation of normal differentiation,
coid on the surfactant system are mediated by inflammatory cytokine and corticosteroid signal
several pathways, one being fibroblast-derived both the acceleration of lung maturation and
growth factor that influences the differentiation spontaneous preterm labor in chorioamnionitis
of type 2 alveolar epithelial cells involved in sur- (Kallapur et al. 2014). IL-1 has been identified
factant synthesis and secretion. Glucocorticoid as a primary agonist upregulating the surfactant
typically promotes differentiation of other func- system in intrauterine inflammation (Bry et al.
tions in lung and in other organs and structural 1997). Lipopolysaccharide from cell wall of
maturation of the lung. High persistent glucocor- Gram bacteria (LPS or endotoxin) or inflamma-
ticoid activity decreases the growth. Absent tory cytokine introduced to the amniotic fluid
53 Respiratory Distress Syndrome: Predisposing Factors, Pathophysiology, and Diagnosis 833
accelerates differentiation of the surfactant and makes periodic breathing movements with a
induces lung inflammation that extends systemi- small tidal volume (0.2–3 mL), resulting in trans-
cally. Severe systemic infections and very high fer of liquid in and out from the airways. Toward
cytokine levels associate with adverse fetal the end of the second trimester, most of the amni-
consequences. otic fluid originates from hypotonic fetal urine,
and it is cleared by fetal swallowing, with a turn-
Secondary Injuries Affecting Lung and Surfactant over time of 48 h.
System Pulmonary interstitium, individual lung The secretion of the lung liquid, tidal respira-
cells, including T2 cells, and the surfactant system tory movements, and airway contractility dilate
are exposed to multiple inflammatory and bio- the future peripheral airways. The tidal move-
chemical insults as part of the manifestation of ments of the chest wall deliver some of the amni-
lung injury in RDS: disruption of ER processing otic fluid content to the airways. Experimental
of surfactant components, inhibition, inactivation, ligation of the fetal airways expands the future
degradation, de-aggregation, and displacement of airways and inhibits lung maturity. Lack of fetal
surfactant complex have been documented breathing movements leads to poor lung growth.
(Mulugeta et al. 2015; Sáenz et al. 2010). Despite Lack of amniotic fluid or compression of lungs
lung injury, RDS is mostly a self-healing disease, as (diaphragmatic hernia, intrathoracic tumor, small
the activation of differentiation-promoting inflam- chest cage) causes lung hypoplasia if present from
matory cytokines and of the anti-inflammatory midpregnancy (Potter syndrome from fetal anuria
endocrine axis promotes spontaneous maturation in particular).
and healing. Chloride ion exits the epithelial cells of the
In infants developing RDS, generally very low airways and alveoli through apical anion-selective
although variable quantities of surfactant are pre- channels, including cystic fibrosis transmembrane
sent in the airways at birth. Surfactant sufficiency regulator protein (CFTR). The driving force of the
is established within 2–7 days in most cases pump is linked to the Na+,K+-ATPase activity,
(Hallman et al. 1994; Carnielli et al. 2009). In generating the electrical potential difference allo-
infants at risk of BPD, the surfactant proteins wing basolateral entry of Cl (Fig. 4).
and surface activity in the air spaces continue to
be deficient after the first week of life. Excessive Absorption of the Fetal Lung Liquid is Linked
inflammation and other toxins suppress surfactant to Surfactant Function Toward term the secre-
synthesis and function. The inactivated surfactant tion of lung liquid secretion decreases dramati-
is degraded and replaced by newly synthesized cally. The lung liquid during active term labor
surfactant. As yet unidentified step(s) in surfactant decreases by 40–50% as a result of active absorp-
turnover is deficient in infants developing BPD. tion of lung water and surfactant concentrates in
air spaces. Lung extracellular water further
decreases by another 40% during the first 6 h of
53.6.2 Secretion of Fetal Lung Liquid life after term birth. A bulk of it exits the lung
and Induction of during the first breaths as the permeability of
Liquid Absorption epithelium in small airways and air spaces
increases acutely (Fig. 4). Both T2 and T1 epi-
During the second trimester, the rapidly growing thelial cells contain amiloride-sensitive ENaC
fetal lung secretes Cl (150 mEq/L) from epithe- protein complex, attached in the apical plasma
lial lining of air spaces and airways (Olver et al. membrane. Besides the luminal transporters,
2004). This results in osmosis-driven liquid secre- basolateral Na+,K+-ATPase and voltage gated
tion of 0.2–0.5 l per 24 h of protein-poor liquid or Cl channels transport Na+ and Cl ions to
5–15% of total liquid intake into the amniotic lung interstitium. Aquaporins facilitate the
cavity. At the same time, 6–9% of the cardiac movement of water across cell membranes. In
output is perfusing lung tissue. A normal fetus addition, a large transepithelial leak is induced
834 M. Hallman et al.
Fig. 4 Fetal lung liquid secretion (risk of RDS) and lung K+-ATPase. Constitutional liquid secretion is driven by
liquid absorption during labor (protective). Both are energy Na+,K+-Cl cotransporter (CLC). Cl exits the apical
dependent driven by various transporters in the epithelial membrane through cystic fibrosis transmembrane conduc-
membranes. Glucocorticoid and adrenergic agents tance regulator (CFTR) and other channels. A paracellular
upregulate sodium channels (ENaC), promoting liquid leak across the epithelium is induced during first breaths
absorption, together with aquaporins [AQP5] and Na+, after birth
at birth promoting bulk liquid from the airways symptoms of RDS, and activation of ion
(Van Driessche et al. 2007). channels involved in liquid adsorption is associ-
Adrenaline via cyclic AMP and corticosteroid ated with the recovery. Wet lung syndrome is
induces the absorptive state of the fetal lung. characterized by insufficient clearance of lung
Corticosteroid increases the synthesis of ENaC liquid and apparently critical deficiency of the
protein and adrenaline activates ENaC, particu- active clearance mechanism (O’Brodovich 2005;
larly the rate-limiting ENaC-α. Cortisol increases Helve et al. 2009).
as a result of activation of the pituitary-adrenal Induction of the active adsorptive state of
axis toward the term. Adrenalin increases during fetal lung liquid during normal labor leads to
labor, and a further increase takes place shortly retention and accumulation of surfactant in
after birth. future air spaces and airways, providing the
In infants developing RDS, the ion channels critical surfactant pool available at birth, thus
responsible for clearance of the lung liquid are facilitating the liquid clearance from airways
not active at birth. This is likely to aggravate the and air spaces.
53 Respiratory Distress Syndrome: Predisposing Factors, Pathophysiology, and Diagnosis 835
53.6.3 Structural Lung Development is either transient or in rare cases missing altogether.
Transient effect endogenous surfactant is a sign of
During fetal development, there are changes in lung perturbed endogenous metabolism of surfactant and
structure, including in the microanatomy and in the surfactant inhibitors. This emphasizes the interac-
amount and composition of the extracellular matrix. tive nature of factors influencing the alveolar stabil-
These factors influence the phenotype of RDS. ity, pulmonary circulation, and structural integrity,
During the canalicular phase between 16th and essential to the gas exchange function. These fac-
25th weeks of gestation, the airway branching tors also include the conducting airways that are
is complete and the lung transforms to organ, poten- intimately involved in lung injury, pulmonary per-
tially capable of gas exchange (chapter by Moretti). fusion, and cardiac contractility. Ductus arteriosus
This is accomplished by formation of cartilage, increasingly remains open as the duration of preg-
bronchial grands, and growth of the distal ends of nancy shortens, perturbing cardiopulmonary func-
the preacinar terminal bronchioles that grow and tion and increasing lung edema. Regardless of
branch to two to four respiratory bronchioles. The length of gestation and pregnancy complications,
potential gas exchange surface enlarges as a result of diffuse atelectasis, lung edema, and hyaline mem-
simultaneous vascular sprouting and acinar growth. branes are a consequence of functional immaturity
Future airways and capillaries also approach each of alveolar epithelium. Infections and severe
other, decreasing the length of gas diffusion path. asphyxia, extreme immaturity, and other adverse
The epithelium undergoes thinning from columnar events complicate and dominate the symptoms of
to cuboidal form as type 2 cells differentiate. cardiorespiratory distress. Figure 5 illustrates fac-
During the saccular phase between 23 and tors involved in pathogenesis.
28–36 weeks, clusters of thin-walled saccules form
the acinus that simultaneously expands and grows
in length as the respiratory bronchioles divide into 53.7.1 Primary and Secondary
six–seven further generations by branching. Elastic Surfactant Deficiency
fibers are deposited along the airways and capil-
laries. The capillaries still form a double capillary High surface tension retracts the air spaces with
network between individual saccules. very small principal radii (R1 and R2) according
Toward the end of gestation and particularly to the law of Laplace: P (collapsing surface pres-
after birth, the elongated T1 alveolar cells expand sure) = γ (surface tension constant) {1/R1 + 1/R2}.
and increasingly cover the alveolar lining, In true alveoli or at the tip of respiratory ducts
whereas surfactant-secreting T2 cells arrange of immature lung, the two principal radii are very
around the alveolar corners. The alveolar stage similar (P = 2 γ/R), whereas in tubular surfaces,
involves microvascular maturation that starts pre- the second radius is indefinite (P = γ/R). During
term and continues during the first years. True inspiration, surfactant components adsorb to the
alveoli grow from the walls of terminal saccules lining, while during expiration, unsaturated lipids
as spherical structures. They grow in size, and the with higher surface tension are squeezed out from
inter-saccular tissue containing a double capillary the lining, helping the surface tension to reach
network transforms into a single capillary network near-zero level. During tidal ventilation, surface
in close apposition to alveoli (Burri 2006). tension increases slightly during inspiration
and returns to near-zero during expiration (i.e.,
hysteresis) preventing atelectasis and decreasing
53.7 Mechanisms of Lung Injury alveolar edema. In the absence of surfactant, the
in RDS tendency to atelectasis is due to the high surface
pressures that increase during expiration. Surface
Although the effect of surfactant therapy is often tension in vitro is measured quantitatively using
dramatic in reducing or even abolishing the symp- captive bubble or pulsating bubble surfactometer.
toms of respiratory distress, in some cases its effect These measurements have been confirmed in
836 M. Hallman et al.
SURFACTANT DEFICIENCY POOR SURFACTANT FUNCTION
INFLAMMATION SURFACTANT
Surfactant INACTIVATION
FREE RADICALS
therapy
Management
LUNG DEVELOPMENT LEAKY CELLULAR
BARRIERS EDEMA Lung function
Gestational age
Corticosteroids Chronization
Genetic risk Management
Intrauterine
inflammation Lung congestion, PDA
Gender
Twin gestation Defects in ion transport
LUNG STRUCTURE REPROGRAMMING
SPECIFIC FUNCTIONS Tissue damage, remodeling of growth air
leaks, cytokines, metaplasia, fibrosis
Fig. 5 Pathogenesis of RDS. Primary surfactant defi- (e.g., asphyxia, volutrauma). Persistence of lung injury is
ciency that is augmented by other defects in differentiation opposed by the lung healing, plasticity, and differentiation
(e.g., lack of absorptive ion transport) and acquired factors (e.g., induction/increase in surfactant)
situ by microscopy of the alveolar surface surfactant function in vitro. Fibrin monomer is
containing droplets of specific fluorocarbons one of the most potent surfactant inhibitors
with constant, generally low surface tension described. Other mechanisms of surfactant inacti-
(Schürch et al. 2001). vation include excess of proteolytic and phospho-
During the first breaths, surfactant in lung liq- lipase activities. Finally, oxidant injury by
uid rapidly adsorbs and concentrates on the hydroxyl radicals and peroxynitrite and other nox-
emerging air liquid interface. Lowering the sur- ious factors deteriorate surfactant function and
face tension (72 mN/m in isotonic saline) toward metabolism (Sáenz et al. 2010; Hallman et al.
0 mN/m decreases the force required for liquid 1994; Carnielli et al. 2009). Many of these nox-
clearance from narrow tubular structures and alve- ious agents originate from inflammatory cells as a
olar saccules; additional force required is due to consequence of lung injury by barotrauma, hyper-
viscous resistance of the small airways. Transient oxia, and endotoxins. ER stress and associated
negative interstitial pressures generated during defect in intracellular processing and dysfunction
the first few forceful inspirations (as high as of surfactant proteins is consistent with the
50–70 cm H2O) and airway pressures during observed abnormalities in surfactant composition
forced expirations with semi-closed vocal cords, and metabolism in infants developing BPD
i.e., “first cry” (25–50 cm H2O), are exceptionally (Mulugeta et al. 2015).
high and contribute to the rapid paracellular
increase in epithelial permeability and possibly
injure immature airways. Low surface tension 53.7.2 Biotrauma
facilitates clearance of lung liquid and decreases
airway injury. As a consequence of ante-, intra-, and postnatal
Secondary surfactant defects emerge after events particularly those taking place at birth, the
birth. The leakage of proteinous liquid across the innate immune system is activated. The inflamma-
epithelial lining dilutes surfactant and inactivates tory reaction as a result of biotrauma induces both
surfactant (Hallman et al. 1991). Proteins, cationic healing and tissue destruction (e.g., phagocytosis,
amino acids, carbohydrates, and lipids inhibit oxidants, lytic proteins, oxidants, free radicals).
53 Respiratory Distress Syndrome: Predisposing Factors, Pathophysiology, and Diagnosis 837
The degree of biotrauma depends on management Lack of lubricant property of surfactant contrib-
practices, constitution, and hereditary factors. Both utes to barotrauma.
antenatal (e.g., antenatal steroid and antibiotics
after preterm rupture of fetal membranes), delivery
room (e.g., early introduction of PEEP, limitation 53.7.4 Delay in Clearance of Lung
of inspiratory pressures, noninvasive surfactant Liquid
administration), and neonatal (early extubation,
noninvasive ventilation, anti-inflammatory airway Prenatal events influence the lung liquid adsorption
therapies, prevention of infections) treatment and the amount of lung liquid at birth (Olver et al.
practices are primary aimed to decrease biotrauma. 2004; Van Driessche et al. 2007; O’Brodovich
An experimental study by Jobe et al. illustrates 2005). Spontaneous labor, advanced gestation,
an example of research on biotrauma (Hillman and vaginal birth additively decrease the liquid in
et al. 2007). the airways at birth. In healthy human infants, the
Besides the components of the surfactant system, clearance of most airway liquid to lung
other proteins, including Clara cell protein 16, SOD, interstitium takes place within seconds to minutes
eNAC, number of other anti-inflammatory peptides after the first breaths. Both active, energy-
(e.g., defensins), signaling receptors, transcription requiring, and passive pressure-driven mecha-
factors, hormones, and growth factors, control the nisms are stretch activated.
development of innate immunity. In normal adaptation, the clearance of liquid
from lung interstitium takes place during the first
day as the solute directly enters the circulation or
53.7.3 Volutrauma and Barotrauma is cleared via lymphatics. The bulk of the liquid
removed from the airways accumulates in disten-
Intubation and the associated bagging and sible perivascular spaces of large lung vessels and
mechanical ventilation without full control of airways, away from the gas exchange path.
the tidal volumes and pressures are the most In very premature lung, low activities of devel-
important source of volutrauma and barotrauma. opmentally regulated sodium and water transport
By increasing the airway pressure requirements, weaken the absorptive state of premature fetal
high surface tension influences volutrauma, lung, delaying the accumulation of the surfactant
i.e., overstretching of patent air spaces. Volu- pool before birth and the liquid clearance after
trauma predominates when large tidal volumes birth (Van Driessche et al. 2007; Helve et al.
(>6–12 mL/kg) are delivered during mechanical 2009; Bland 2001). This is a major problem in
ventilation shortly after birth (Hillman et al. elective late-preterm and early-term births: the
2007). It manifests as rupture, laceration, increase alveolar surfactant pool at birth is small as a result
in permeability and compliance of central air- of surfactant secretion into amniotic fluid and lack
ways, perivascular edema, bronchiolar obstruc- of adsorption of lung liquid.
tion, and inflammatory response (biotrauma). Lung immaturity adversely affects lung liquid
In RDS the minimum surface tension ranges clearance as the compliant chest cage complicates
from 20 to 50 mN/m. Distending pressures that generation of high negative interstitial pressures,
maintain patency of alveoli with a radius of 50 μm and the activities involving ion and water transport
or of alveolar ducts (very preterm) with radius of across the epithelium toward lung interstitium are
100 μm is estimated to be 8–20 cm H2O and low. Diaphragmatic fatigue and particularly lack of
4–10 cm H2O, respectively. High surface tension respiratory drive due to deficient respiratory center
and high viscous resistance caused by airway responses contribute for alveolar edema and respi-
edema and particles deteriorate lung homogeneity ratory distress.
and predispose to volutrauma. The passive stretch-activated bulk solute trans-
Volutrauma and barotrauma are decreased con- fer takes place in both directions. It is thus respon-
siderably by avoiding mechanical ventilation. sible for either the clearance of lung fluid or the
838 M. Hallman et al.
formation of alveolar edema after very preterm left cardiac failure resulting in flooding of alveolar
birth. Edema is imminent, in case hydrostatic capillaries (e.g., in hypothermia). Hemorrhage
pressures (interstitial pressure and the airway may be precipitated by surfactant therapy as it
distending pressure) fail to compensate for the lowers pulmonary vascular resistance increasing
high surface pressures in surfactant deficient lung. the left-to-right shunt through ductus arteriosus.
Inadequate continuous positive airway pressure
levels may further decrease pulmonary vascular
53.7.5 High-Permeability Lung Edema resistance, allowing hydrostatic congestion and
eventually rupture of capillaries and airway epi-
The injury of capillary endothelium and airway thelium (▶ Chap. 55, “Pulmonary Hemorrhage,
epithelial cells and their basement membranes is Transient Tachypnea, and Neonatal Pneumonia”).
a characteristic early feature. The injury mecha-
nisms include mechanical trauma, biotrauma, and
toxins (oxygen). An important functional conse- 53.7.7 Abnormalities in Lung
quence is an increase in permeability to macro- Perfusion
molecules soon after preterm birth. An increase in
permeability exceeds the capacity of pulmonary Acetylcholine, nitric oxide (NO), and potentially
lymphatics, resulting in interstitial edema. Small other vasoactive agents triggered dilate pulmo-
airways, bronchioles, and air spaces are suscepti- nary arterioles during normal neonatal transition.
ble to flooding and obstruction, and alveolar During the early hours in RDS, the failure of
edema further decreases gas exchange. alveolar capillary gas exchange may in part be
Increased epithelial permeability leads to due to poor perfusion of alveoli, whereas mainly
protein-rich alveolar edema and accumulation of in later stages of RDS, symptoms of pulmonary
surfactant inhibitors. Accumulation of fibrinogen vascular congestion prevail. Pulmonary perfusion
into alveolar space precedes the formation of hya- needs to be carefully considered throughout the
line membranes. A residue of inactivated surfac- respiratory course.
tant components and other residues are In extremely immature lung, the marginal size
incorporated into the matrix of fibrin-rich hyaline capillary bed barely provides a reservoir against
membranes. They interfere with gas exchange, hypo-hypervolemia and excessive distending
obstruct the air spaces, and may initiate intra- pressures.
alveolar coagulation. Hyaline membranes are Besides lung hypoplasia, predisposition to
eventually cleared by phagocytosis and fibrino- PPHN can be the result of acute biotrauma, caused
lytic activity (Idell et al. 1994). by microbes and inflammatory agents.
Continuous distending pressure to the airways; Prolonged rupture of fetal membranes in pre-
avoidance of mechanical ventilation; avoidance of term infants is occasionally complicated by severe
fluid overload, cardiac failure, and of infections; surfactant-nonresponsive respiratory distress,
and activation of anti-inflammatory mechanisms associated pulmonary hypertension, and low air-
(steroid) all contribute toward decreasing high- way nitrite and inflammatory cytokine levels,
permeability lung edema. suggesting transient immune paralysis. A dra-
matic, acute favorable response to inhaled NO
has been demonstrated in several small studies.
53.7.6 Pulmonary Hemorrhage However, the actual improvement in the outcome
has not been shown in a randomized trial (Aikio
Pulmonary hemorrhage complicates RDS mostly et al. 2012).
in extremely preterm infants. It may be seen as an Increase in pulmonary vascular resistance in
extreme form of high-permeability lung edema severe acute lung disease is well recognized
that is associated with PDA, decrease in pulmo- (Steinhorn 2010). This applies also to RDS.
nary vascular resistance, and rapidly developing Toward term, the muscularity of pulmonary
53 Respiratory Distress Syndrome: Predisposing Factors, Pathophysiology, and Diagnosis 839
arteries increases. Treatment of RDS in near-term Available therapies convert RDS from lethal
infants is often delayed, allowing progression of to manageable or preventable disease. The cost
respiratory distress and development of PPHN of treatment is high, and the disease may asso-
that favorably responds to inhaled NO. ciate with complications that may be life-
threatening (Gilbert 2006). In very preterm
infants, RDS is a common disease that has a
53.7.8 Patent Ductus Arteriosus (PDA) major influence in the risk of both acute and
chronic morbidity.
Prostaglandin inhibitor-induced contraction of the
fetal ductus arteriosus is detectable in the begin-
ning in the third trimester and increases toward 53.8.1 Prevention of Premature Birth
term. After birth, the cascade of events leading to
permanent constriction followed by anatomical Elimination of prematurity would be most effec-
closure of the ductus takes place in nearly all tive in prevention. There are remarkable variation
term-born infants, whereas the degree of in the risk of prematurity based on the lifestyle,
prematurity progressively increases the risk of working conditions, risk behavior, ethnicity,
hemodynamically significant PDA (Hamrick and socioeconomic status, and the healthcare system.
Hansmann 2010). In vitro fertilization practices increase the risk of
PDA particularly in ELGA infants continues to premature birth.
be a challenge and an important factor influencing Tocolytic agents have a limited capacity to
the duration of the course of RDS. A large left-to- prolong the pregnancy in threatened preterm
right shunt through PDA causes pulmonary con- labor. Despite side effects, they are shown to be
gestion at the expense of systemic perfusion. This efficacious in delaying the preterm birth for a few
sometimes happens within few days after birth, as days required for full effect of ACG. Ca-channel
a result of surfactant-induced remission of RDS antagonists delay preterm birth without causing
that decreases pulmonary vascular resistance. serious adverse effects.
Attempts to close ductus arteriosus during the Supplementation of progesterone acetate from
first days after birth by indomethacin or ibuprofen midterm pregnancies has reduced the prematurity
or by ligation have been associated with serious rate only in rare cases of cervix insufficiency.
side effects, including pulmonary hypertension Thus far, no long-term risks have been observed,
and IVH. Appropriate emergency treatment of and the follow-up continues (WHO 2015).
early PDA is to promote the treatment of lung
edema, particularly by increasing inappropriately
low continuous distending airway pressure and 53.8.2 Pharmacological Acceleration
reducing excessive liquid intake. Adverse effects of Fetal Lung Maturity
associating with PDA include pulmonary edema/
IVH, NEC, ROP, and BPD. Antenatal glucocorti- AGC became an accepted therapy for prevention
coid, neonatal caffeine, and inhaled budesonide of RDS first in the 1990s when the concerns of
decrease the risk of PDA. The potential benefit of serious adverse long-term effects were not mate-
paracetamol in early treatment of PDA is currently rialized (Liggins and Howie 1972; Roberts and
investigated. Dalziel 2006). Glucocorticoid influences the
development of the fetal lung, gastrointestinal
tract, cardiovascular system, liver, kidney, and
53.8 Prevention of RDS central nervous system. It accelerates the differ-
entiation of the surfactant system, promotes the
Obstetric and early neonatal management of pre- absorptive state of fetal lung, enhances the closure
term infants influence the risk and severity of ductus after birth, increases the generally low
of RDS. blood pressure of preterm infants shortly after
840 M. Hallman et al.
birth, improves the performance of the immature amniotic fluid. This amniotic surfactant pool starts
left ventricle, and has beneficial effects on the emerging with imminent functional maturity of
immune and antioxidant systems. fetal lung. Surfactant increases in concentration
According to meta-analysis of randomized trials and quality in a characteristic fashion as the preg-
on AGC, it resulted in overall reduction of the risk nancy proceeds. Surfactant indices, measured in
of RDS (relative risk, RR 0.66, 95% CI 0.59–0.73). the amniotic fluid [lecithin/sphingomyelin (L/S)
The most beneficial effect was observed when ratio, PG, the lung profile, saturated lecithin, LB],
AGC was started 1–7 days before threatened pre- are used to evaluate the risk of RDS of an unborn
term birth prior to 34 full weeks of pregnancy. fetus, particularly in the era when AGC or exog-
According to cohort studies, AGC was efficacious enous surfactant were not used (Hallman 1992).
of improving the postnatal survival and decreasing Assessment of fetal maturity in preterm and near-
the risk of RDS among ELGA and preterm twin term pregnancies is still indicated when there is a
pregnancies, respectively. AGC further decreased need to balance the risk of continuing a risk preg-
the risks of RDS in preterm infants exposed to nancy against the risk of iatrogenic RDS. The
chorioamnionitis and rupture of fetal membranes. reported specificity and sensitivity of the surfac-
Although AGC decreases the risk of respiratory tant indices in amniotic fluid have ranged from
distress in near-term pregnancies, most fetuses are 92–100% to 30–70%, respectively. Due to surfac-
exposed only to potential adverse effects (e.g., tant retention in active labor, the sensitivity of
hypoglycemia); ACG is not routinely indicated at surfactant indices in amniotic fluid or gastric aspi-
34 weeks or later. rate at birth is likely rather low.
AGC and exogenous surfactant supplement
each other in decreasing the risk of RDS and
IVH (Hallman et al. 2010). According to meta- 53.8.4 Prevention of Low-Risk Elective
analysis, glucocorticoid decreased neonatal Births Before Term
mortality, IVH, and NEC and tended to decrease
early neonatal infections. The cognitive and neu- A significant fraction of near-term (34–36 weeks)
rological problems observed in rodents following and early-term-born infants (37–38 weeks)
AGC have not been replicated as there is a trend develop RDS if delivered electively before the
toward improved neurological outcome. Expo- onset of active labor (Tita et al. 2009). In infants
sure to AGC is associated with mild insulin resis- born at 39 weeks of pregnancy or later, RDS is very
tance in young adults (Dalziel et al. 2005). rare (<1%) regardless of the mode of delivery,
Repeating the AGC dosage in threatened pre- whereas the risk of meconium aspiration syndrome
term birth decreases the risk of RDS and of severe and acute asphyxia continues to increase after term.
RDS (Peltoniemi et al. 2011). Repeating the drug In elective near-term births without onset of
weekly decreased the birth weight and head cir- labor, the fetus is exposed to increased risk of
cumference dose-dependently. Although no transient tachypnea, spontaneous pneumothorax,
adverse influence on growth or on neurologic or RDS, and persistence of fetal circulation. The
cognitive function has been detected, longer induction of the adsorptive state of lung liquid
follow-up studies are required. Currently a single allows the accumulation of surfactant in future
repeat dosage of AGC is recommended in threat- air spaces before birth. The labor-associated hor-
ened very preterm birth (<32 weeks) in case the mones, cortisol, and adrenalin additionally
fetus remains undelivered for more than week. increase the secretion of surfactant. According to
available trials, AGC in elective near-term births
decreases the risk of transient respiratory distress.
53.8.3 Diagnosis of Lung Maturity Before ACG treatment is accepted as a therapy
in elective late-preterm and early-term births with-
Lung surfactant secreted into liquid-filled air out labor, it is important to know that the mostly
spaces is carried by the lung liquid into the healthy fetuses exposed to steroid are not
53 Respiratory Distress Syndrome: Predisposing Factors, Pathophysiology, and Diagnosis 841
adversely affected long term. In near-term births, betamethasone: 30-year follow-up of a randomised
AGC is indicated when the risk of respiratory controlled trial. Lancet 365:1856–1862
Gerten KA, Coonrod DV, Bay RC, Chambliss LR (2005)
distress is considerable. These cases include Cesarean delivery and respiratory distress syndrome:
maternal diabetes with poor metabolic control, does labor make a difference? Am J Obstet Gynecol
severe Rh immunization, diaphragmatic hernia, 193:1061–1064
near-term RDS in the family, and documentation Gilbert WM (2006) The cost of preterm birth: the
low cost versus high value of tocolysis. BJOG
of immaturity of fetal lung. 113(Suppl 3):4–9
Hallman M (1992) Antenatal diagnosis of lung maturity.
In: Robertson B, Van Golde LMG, Batenburg JJ
(eds) Pulmonary surfactant. From molecular biology
References to clinical practice. Elsevier, Amsterdam, pp
425–445
Aikio O, Metsola J, Vuolteenaho R et al (2012) Transient Hallman M, Haataja R (2007) Genetic basis of respiratory
defect in nitric oxide generation after rupture of fetal distress syndrome. Front Biosci 12:2670–2682
membranes and responsiveness to inhaled nitric oxide Hallman M, Arjomaa P, Romu M, Tahvanainen J (1986)
in very preterm infants with hypoxic respiratory failure. The lung profile in diagnosis of fetal and neonatal
J Pediatr 161:397–403 surfactant defects. In: Vignali M, Cosmi EV, Luerti M
Avery ME, Mead J (1959) Surface properties in relation to (eds) Diagnosis and treatment of fetal lung immaturity.
atelectasis and hyaline membrane disease. AMA Am J Masson, Milan, pp 41–49
Dis Child 97(5 Part 1):517–523 Hallman M, Merritt TA, Akino T, Bry K (1991) Surfactant
Avery ME, Fletcher BD, Williams RG (1981) The lung and protein A, phosphatidylcholine, and surfactant inhibi-
its disorders in the newborn infant, Major problems tors in epithelial lining fluid. Correlation with surface
in clinical pediatrics, vol 1, 4th edn. Saunders, activity, severity of respiratory distress syndrome, and
Philadelphia, pp 1–367 outcome in small premature infants. Am Rev Respir
Baldwin DN, Pillow JJ, Stocks J, Frey U (2006) Lung- Dis 144:1376–1384
function tests in neonates and infants with chronic lung Hallman M, Merritt TA, Bry K (1994) The fate of exoge-
disease: tidal breathing and respiratory control. Pediatr nous surfactant in neonates with respiratory distress
Pulmonol 41:391–419 syndrome. Clin Pharmacokinet 26:215–232
Bassler D, Plavka R, Shinwell ES et al (2015) Early inhaled Hallman M, Peltoniemi O, Kari MA (2010) Enhancing
budesonide for the prevention of bronchopulmonary functional maturity before preterm birth. Neonatology
dysplasia. N Engl J Med 373:1497–1506 97:373–378
Bird AD, McDougall AR, Seow B et al (2015) Glucocor- Hamrick SE, Hansmann G (2010) Patent ductus arteriosus
ticoid regulation of lung development: lessons learned of the preterm infant. Pediatrics 125:1020–1030
from conditional GR knockout mice. Mol Endocrinol Helve O, Pitkänen O, Janér C, Andersson S (2009) Pulmo-
29:158–171 nary fluid balance in the human newborn infant.
Bishop NB, Stankiewicz P, Steinhorn RH (2011) Alveolar Neonatology 95:347–352
capillary dysplasia. Am J Respir Crit Care Med Hillman NH, Moss TJ, Kallapur SG et al (2007) Brief,
184:172–179 large tidal volume ventilation initiates lung injury and
Bland R (2001) Loss of liquid from the lung lumen in a systemic response in fetal sheep. Am J Respir Crit
labor: more than a simple “squeeze”. Am J Physiol Care Med 176:575–581
Lung Cell Mol Physiol 280:L602–L605 Hjalmarson O, Brynjarsson H, Nilsson S, Sandberg KL
Bry K, Lappalainen U, Hallman M (1997) Intraamniotic (2014) Persisting hypoxaemia is an insufficient mea-
interleukin- 1 accelerates surfactant protein synthesis in sure of adverse lung function in very immature infants.
fetal rabbits and improves lung stability after premature Arch Dis Child Fetal Neonatal Ed 99:F257–F262
birth. J Clin Invest 99:2992–2999 Hoepker A, Seear M, Petrocheilou A et al (2008) Wilson-
Burri PH (2006) Structural aspects of postnatal lung devel- Mikity syndrome: updated diagnostic criteria based on
opment – alveolar formation and growth. Biol Neonate nine cases and a review of the literature. Pediatr
89:313–322 Pulmonol 43:1004–1012
Carnielli VP, Zimmermann LJ, Hamvas A, Cogo PE Idell S, Kumar A, Koenig KB, Coalson JJ (1994) Pathways
(2009) Pulmonary surfactant kinetics of the newborn of fibrin turnover in lavage of premature baboons with
infant: novel insights from studies with stable isotopes. hyperoxic lung injury. Am J Respir Crit Care Med
J Perinatol 29(Suppl 2):S29–S37 149:767–775
Chu J, Clements JA, Cotton EK et al (1967) Neonatal Jones M (2009) Effect of preterm birth on airway function
pulmonary ischemia. I. Clinical and physiological stud- and lung growth. Paediatr Respir Rev 10(Suppl 1):9–11
ies. Pediatrics 40:709–782 Kallapur SG, Presicce P, Rueda CM, Jobe AH, Chougnet
Dalziel SR, Walker NK, Parag V et al (2005) Cardiovas- CA (2014) Fetal immune response to chorioamnionitis.
cular risk factors after antenatal exposure to Semin Reprod Med 32:56–67
842 M. Hallman et al.
Karjalainen MK, Huusko JM, Tuohimaa A et al (2012) A Ronkainen E, Dunder T, Peltoniemi O, Kaukola T,
study of collecting genes in spontaneous preterm birth Marttila R, Hallman M (2015) New BPD predicts
reveals an association with a common surfactant pro- lung function at school age: follow-up study and
tein D gene polymorphism. Pediatr Res 71:93–99 meta-analysis. Pediatr Pulmonol 50:1090–1098
Kaukola T, Tuimala J, Herva R et al (2009) Cord Sáenz A, López-Sánchez A, Mojica-Lázaro J et al (2010)
immunoproteins as predictors of respiratory outcome in Fluidizing effects of C-reactive protein on lung surfac-
preterm infants. Am J Obstet Gynecol 200(100):e1–e8 tant membranes: protective role of surfactant protein
Koivisto M, Marttila R, Saarela T et al (2005) Wheezing A. FASEB J 24:3662–3673
illness and re-hospitalization in the first two years of Sandri F, Plavka R, Ancora G et al (2010) Prophylactic or
life after neonatal respiratory distress syndrome. J early selective surfactant combined with nCPAP in very
Pediatr 147:486–492 preterm infants. Pediatrics 125:e1402–e1409
Kotecha SJ, Edwards MO, Watkins WJ (2013) Effect of Schmidt B, Roberts R, Millar D, Kirpalani H (2008) Evi-
preterm birth on later FEV1: a systematic review and dence based neonatal drug therapy for prevention of
meta-analysis. Thorax 68:760–766 bronchopulmonary dysplasia in very-low-birth-weight
Liggins GC, Howie RN (1972) A controlled trial of ante- infants. Neonatology 93:284–287
partum glucocorticoid treatment for prevention of the Schürch S, Bachofen H, Possmayer F (2001) Surface activ-
respiratory distress syndrome in premature infants. ity in situ, in vivo, and in the captive bubble
Pediatrics 50:515–525 surfactometer. Comp Biochem Physiol A Mol Integr
Marttila R, Haataja R, Rämet M et al (2003) Surfactant Physiol 129:195–207
protein B polymorphism and respiratory distress syn- Steinhorn RH (2010) Neonatal pulmonary hypertension.
drome in premature twins. Hum Genet 112:18–23 Pediatr Crit Care Med 11(2 Suppl):S79–S84
Marttila R, Kaprio J, Hallman M (2004) Respiratory dis- Sundell H, Garrott J, Blankenship W et al (1971) Studies on
tress syndrome in twin infants compared with single- infants with type II respiratory distress syndrome. J
tons. Am J Obstet Gynecol 191:271–276 Pediatr 78:754–764
Morley CJ, Davis PG, Doyle LW et al (2008) Nasal CPAP Tita AT, Landon MB, Spong CY et al (2009) Timing of
or intubation at birth for very preterm infants. N Engl J elective repeat cesarean delivery at term and neonatal
Med 358:700–708 outcomes. N Engl J Med 360:111–120
Mulugeta S, Nureki S, Beers MF (2015) Lost after Torday JS, Rehan VK (2015) On the evolution of the
translation: insights from pulmonary surfactant for pulmonary alveolar lipofibroblast. Exp Cell Res
understanding the role of alveolar epithelial dys- 340:215. pii: S0014-4827(15)30174-9
function and cellular quality control in fibrotic lung Van Driessche W, Kreindler JL, Malik AB et al (2007)
disease. Am J Physiol Lung Cell Mol Physiol 309: Interrelations/cross talk between transcellular transport
L507–L525 function and paracellular tight junctional properties in
O’Brodovich H (2005) Pulmonary edema in infants and lung epithelial and endothelial barriers. Am J Physiol
children. Curr Opin Pediatr 17:381–384 Lung Cell Mol Physiol 293:L520–L524
Obladen M (1992) History of surfactant research. In: Verder H, Ebbesen F, Linderholm B et al (2003) Predic-
Robertson B, Van Golde LMG, Batenburg JJ (eds) tion of respiratory distress syndrome by the micro-
Pulmonary surfactant. From molecular biology to clin- bubble stability test on gastric aspirates in newborns
ical practice. Elsevier, Amsterdam, pp 1–18 of less than 32 weeks’ estation. Acta Paediatr 92:
Olver RE, Walters DV, Wilson SM (2004) Developmental 728–733
regulation of lung liquid transport. Annu Rev Physiol Vergine M, Copetti R, Brusa G, Cattarossi L (2014) Lung
66:77–101 ultrasound accuracy in respiratory distress syndrome
Peltoniemi OM, Kari MA, Hallman M (2011) Repeated and transient tachypnea of the newborn. Neonatology
antenatal corticosteroid treatment: a systematic review 106:87–93
and meta-analysis. Acta Obstet Gynecol Scand Watterberg KL, Demers LM, Scott SM, Murphy S (1996)
90:719–727 Chorioamnionitis and early lung inflammation in
Ramachandrappa A, Jain L (2008) Elective cesarean sec- infants in whom bronchopulmonary dysplasia
tion: its impact on neonatal respiratory outcome. Clin develops. Pediatrics 97:210–215
Perinatol 35:373–393 Wert SE, Whitsett JA, Nogee LM (2009) Genetic disorders of
Ramachandrappa A, Jain L (2009) Health issues of the late surfactant dysfunction. Pediatr Dev Pathol 12:253–274
preterm infant. Pediatr Clin North Am 56:565–577 Whitsett JA, Wert SE, Weaver TE (2010) Alveolar surfac-
Roberts D, Dalziel S (2006) Antenatal corticosteroids tant homeostasis and the pathogenesis of pulmonary
for accelerating fetal lung maturation for women disease. Annu Rev Med 61:105–119
at risk of preterm birth. Cochrane Database Syst Rev WHO (2015) WHO recommendations on interventions to
3:CD004454 improve preterm birth outcomes. ISBN 978 924
Robertson B, Taeusch HW (1995) Surfactant therapy for 1508988
lung disease. In: Lefant C (ed) Lung biology in health Wright JR (2005) Immunoregulatory functions of surfac-
and disease, vol 84. Marcel Dekker, New York tant proteins. Nat Rev Immunol 5:58–68
Treatment of Respiratory Failure
in Newborn: Mechanical Ventilation 54
Colin Morley and Gianluca Lista
Contents
54.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845
54.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845
54.3 Problems with Mechanical Ventilation
of Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 846
54.4 What Are the Indications for Mechanical Ventilation? . . . . . . . . . . . . . . . . . . 846
54.4.1 Apnea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 846
54.4.2 Respiratory Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 846
54.4.3 Oxygenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
54.5 Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
54.5.1 Arterial Blood Gas Measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
54.5.2 A Chest X-Ray . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
54.5.3 Investigate Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
54.6 The Basic Principles of Mechanical Ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . 847
54.6.1 Improving Oxygenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
54.6.2 Controlling the Blood Level of Carbon Dioxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . 848
54.6.3 Heating and Humidification of Ventilation Gases . . . . . . . . . . . . . . . . . . . . . . . . . . . 849
54.6.4 Measuring Blood Gases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 849
54.6.5 Monitoring Ventilator Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 849
54.6.6 Pressure Wave . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 849
54.6.7 Flow Wave . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 849
54.6.8 Tidal Volume Wave . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 850
C. Morley (*)
Dept Obstetrics and Gynecology, University of Cambridge
at Rosie Maternity Hospital, Cambridge, UK
e-mail: [email protected]
G. Lista (*)
Neonatology and Neonatal Intensive Care Unit, Ospedale
dei Bambini V. Buzzi, Milan, Italy
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 843
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_202
844 C. Morley and G. Lista
54.7 Techniques of Mechanical Ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 851
54.7.1 Conventional Mandatory Ventilation (CMV) or Intermittent Mandatory
Ventilation (IMV) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 851
54.7.2 Triggered Ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 854
54.7.3 Synchronized Intermittent Mandatory Ventilation (SIMV) . . . . . . . . . . . . . . . . . . 856
54.7.4 Assist/Control (A/C) Also Called Synchronized Intermittent
Positive Pressure Ventilation (SIPPV) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856
54.7.5 Volume Guarantee Ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 857
54.7.6 Pressure Support Ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859
54.7.7 Neurally Adjusted Ventilator Assist (NAVA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859
54.7.8 High-Frequency Oscillatory Ventilation (HFOV) . . . . . . . . . . . . . . . . . . . . . . . . . . . 859
54.8 Weaning the Infant from Ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861
54.9 Managing Complications of Ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861
54.9.1 Endotracheal Tube Not in the Trachea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861
54.9.2 Endotracheal Tube Inserted Too Far Down into
the Right Main Bronchus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861
54.9.3 Accidental Extubation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
54.9.4 Pneumothorax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
54.9.5 Pulmonary Interstitial Emphysema (PIE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
54.10 Drug Treatments During Ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863
54.10.1 Muscle-Relaxing Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863
54.10.2 Caffeine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863
54.10.3 Sedation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863
Abstract
Premature delivery is always associated with the Pressure-limited ventilation continues to be
failure of respiratory transition and a delayed the primary mode of ventilation in neonates
achievement of an adequate functional residual because of its relative simplicity and ability to
capacity. For this reason preterm babies (espe- ventilate effectively despite large endotracheal
cially the extremely low for gestational age – tube (ETT) leaks.
ELGA – infants) frequently need respiratory sup- The major disadvantage of pressure-limited
port. Noninvasive ventilation (NIV) is in wide- ventilation is that the tidal volume (VT) varies
spread use in the management of respiratory as the baby alters its breathing pattern and with
distress even in ELGA infants without increasing changes in lung compliance (e.g., after surfac-
neonatal mortality or neurological impairment. tant therapy). The consequences of such rapid
The most recent meta-analysis and reviews improvements in compliance are inadvertent
of NIV demonstrated that NIV is a valid alter- hyperventilation and lung injury from exces-
native to mechanical ventilation (MV) in the sively large VT (volutrauma); hyperventilation
management of respiratory failure and resulted may induce hypocapnia, with high risk of cere-
in significant reductions in the incidence of bral damage. There is strong evidence that
bronchopulmonary dysplasia (BPD) among excessive tidal volumes, rather than the ventila-
surviving infants. tor pressure, are the key determinant of
Nevertheless, preterm babies, mainly ventilator-induced lung injury (VILI). Inade-
ELGA infants, require MV because they have quate (too small) VT also causes significant
unresponsive apnea, or a high and rising problems (atelectrauma): in particular ineffi-
PaCO2, and/or a high and rising FiO2 despite cient gas exchange due to increased dead
treatment with continuous positive airway space to VT ratio. Therefore, in the last few
pressure (CPAP). years, tidal volume-targeted ventilation has
54 Treatment of Respiratory Failure in Newborn: Mechanical Ventilation 845
become an important standard of care in neona- • Ventilation parameters may have to be modi-
tal and pediatric respiratory support. fied in accordance with changes in lung
There are many volume-targeted ventilation mechanics of the neonates.
modes used in neonatal period, but volume • When the neonatologist decides to use conven-
guarantee (VG) ventilation is the most exten- tional mechanical ventilation (CMV), volume-
sively studied. targeted ventilation has better outcomes than
The Cochrane review on volume-targeted pressure-limited ventilation.
ventilation showed significant reductions in • High-frequency oscillatory ventilation
duration of ventilation, rates of pneumothorax (HFOV) is very useful in improving oxygena-
(PTX), and intraventricular hemorrhage (IVH) tion and removing carbon dioxide especially in
and a borderline significant reduction in the infants with very stiff lungs.
incidence of BPD in surviving infants. Also • To reduce the occurrence of complications due
VG ventilation plus adequate PEEP, with an to MV and to reduce the risk of BPD, it is
open lung strategy, is an alternative to high- important to wean infants from the ventilator
frequency oscillatory ventilation (HFOV) in and extubate as soon as possible.
infants ventilated for severe RDS. Nevertheless
in a baby with very stiff lungs, pulmonary inter-
stitial emphysema (PIE) or PTX, the use of
54.2 Introduction
HFOV still remains the best ventilator approach.
To optimize ventilatory management of
Respiratory diseases, with different etiologies,
infants with respiratory failure and to adjust
are one of the major problems in neonatal
the ventilatory settings, it is important to mon-
medicine and one of the main reasons for an infant
itor the blood gases and perform chest X-ray.
receiving intensive respiratory support. Without
As most modern ventilators have numerical
respiratory support many ill newly born infants
and graphical displays of ventilator parame-
would die.
ters, these should be used to guide ventilation
Respiratory support can be given with several
management and reduce the risk of lung injury.
different techniques. From the least intensive to the
It is important to wean babes from the venti-
most intensive, they are: additional oxygen, high-
lator and extubate them as soon as possible to
flow nasal cannula oxygen, continuous positive
reduce the risk of pulmonary infections and BPD.
airway pressure (CPAP), bi-level CPAP or nasal
In many cases early caffeine administration can
intermittent ventilation, untriggered mechanical
reduce the duration of mechanical ventilation,
ventilation, triggered mechanical ventilation, tidal
BPD, and the occurrence of respiratory and neu-
volume-targeted ventilation, and high-frequency
rological adverse outcome. It is therefore impor-
oscillatory ventilation. This chapter will only pre-
tant to have a respiratory protocol that helps the
sent information about mechanical ventilation.
neonatologist to manage both the acute and the
In any discussion of mechanical ventilation, it
recovery phase of respiratory failure.
is important to define the terminology of sponta-
neous breathing and mechanical ventilation
because this can be confusing.
54.1 Salient Points It is important to realize that patients have
breaths and ventilators deliver inflations.
• Mechanical ventilation (MV) is often used to
treat babies with respiratory failure initially man- A breath is a spontaneous inspiration by an infant.
aged with a noninvasive respiratory support. An inspiration is a breath taken by the baby.
• MV has to be tailored to optimize lung volume An inflation is a pressure applied to the airways by a
and improve gas exchange with less lung injury. ventilator with the intention of inflating the lungs.
846 C. Morley and G. Lista
Spontaneous expiration is gas leaving the lung • Ventilation increases infection.
after a breath. • Mechanical ventilation may interfere with the
Ventilator exhalation is gas leaving the lung after baby’s control of breathing and blood gases.
an inflation. • Unfortunately, we still do not have good evi-
Inspiratory time is the time during which a baby dence about when to start ventilation, how to
inspires. prevent lung damage, the optimal way to wean
Inflation time is the duration of a mechanical the ventilation and extubate the infant, or when
inflation. to stop ventilation.
Ventilator exhalation time is the exhalation time
set on the ventilator.
Expiration time is the time gas leaves the lungs 54.4 What Are the Indications
after an inspiration or inflation until a new for Mechanical Ventilation?
inflation or inspiration occurs.
The major reason for ventilating an infant is
apnea. However, the difficult decision comes in
54.3 Problems with Mechanical deciding when to ventilate an infant who is very
Ventilation of Infants premature, or breathing with retraction of the
lower chest wall, or requiring oxygen treatment,
Mechanical ventilation is associated with a number or having numerous apneic episodes.
of problems, so it is most important not to ventilate Intubation and ventilation of very premature
an infant unless it is absolutely necessary. babies with respiratory difficulty soon after
The problems with ventilation are: birth used to be considered mandatory. How-
ever, it is now realized that even very premature
• Gas is pushed into the lungs rather than sucked babies can often be supported with CPAP
in. This is unphysiological. It is much more (Ammari et al. 2005) or other modes of nonin-
effective for lung aeration and blood circula- vasive ventilation, particularly if treated early
tion through the lungs to have a negative pres- with caffeine.
sure with each inspiration.
• The endotracheal tube (ETT) bypasses the lar-
ynx. This may lower the residual lung volume 54.4.1 Apnea
because the larynx is very important for
maintaining lung volume during lung disease. Apnea unresponsive to stimulation, nasal CPAP,
During expiration without an ETT it may nar- caffeine, and hand ventilation for a short time is an
row or close to reduce the expiratory flow and absolute indication for mechanical ventilation.
maintain lung volume (Carlo et al. 1987). There are few other absolute indications about
• An ETT increases resistance to gas flow and when to ventilate a baby. It is often a matter of
breathing. clinical judgment and local policy, consideration
• Inflations can injure the airways and alveoli of the infant’s gestational age, and other factors.
(Bjorklund et al. 1997). This is by several mech-
anisms: (1) volutrauma where the tidal volume
is too high and the overdistension injures the 54.4.2 Respiratory Failure
lungs (Attar and Donn 2002); (2) repeated
expansion and collapse of atelectatic areas of The first question is does the infant have respiratory
the lung – called atelectrauma (Donn and Sinha failure? An arterial PaCO2 that has risen above
2003); (3) barotrauma where repeated high ven- 60 mmHg (~8 kPa) is a good sign of respiratory
tilator pressures damage the lungs; and (4) injury failure. However, this judgment should not be
from the ETT in the airway. made on the first blood gas measurement, unless
54 Treatment of Respiratory Failure in Newborn: Mechanical Ventilation 847
the baby is obviously very ill, because many babies should be inserted to enable easy and repeated
improve over the first hour or two with careful and measurement of arterial blood gases. A ventilated
gentle management, after the baby has been appro- baby will require several accurate blood gases in
priately positioned and nasal CPAP has been used. the first days and so an arterial line is optimal for
A capillary CO2 is not accurate enough for the baby and carers. Capillary blood gases can be
making the decision to ventilate an infant because misleading, and venous blood gases should not be
it might be spuriously high in an infant with poor used to assess the respiratory function unless the
peripheral circulation. CO2 or pH is near the normal range.
A severe uncompensated metabolic acidosis
may be an indication for ventilation.
54.5.2 A Chest X-Ray
54.4.3 Oxygenation An anterior/posterior chest X-ray should be done
as early as possible to confirm the respiratory
A high and rising FiO2, despite treatment with diagnosis and exclude diagnoses that may need
CPAP, is a strong pointer to the need for ventilation. different treatment. If umbilical arterial and/or
There is little consensus about the FiO2 that should venous lines have been used, the X-ray should
be used to determine when a baby should be ven- include the abdomen to show their position.
tilated. To a certain extent, the FiO2 does not matter
if the PaO2 is maintained. However, a high FiO2 is
usually a sign that there is a low lung volume if 54.5.3 Investigate Infection
there is not a cardiac cause. Oxygen is toxic to the
lungs and the higher the more likely lung injury Infection must always be suspected in babies
occurs. Pragmatically, the indication for ventilation presenting with respiratory failure soon after birth
in a very premature infant being treated with CPAP because it can be present even in babies born by
is an FiO2 > 0.40–0.45, especially when surfactant Cesarean section. Infection at this age usually
is still to be given, and a pH < 7.2 and paCO2 > causes septicemia and can be quickly life threaten-
65–70 mmHg (Morley et al. 2008). ing if antibiotics are not given early. Blood cultures,
The criteria for ventilation may vary depending gastric aspirate microscopy and culture, and blood
on the size of the baby. Babies born at <26 weeks tests for indicators of infection should be taken and
gestation may need earlier ventilator support then intravenous antibiotics given. Penicillin and
because of their extreme immaturity. More mature gentamicin are safe and effective.
babies are stronger and ventilation should not be
used unless absolutely necessary.
54.6 The Basic Principles
of Mechanical Ventilation
54.5 Investigations
Several aspects of ventilation need to be adjusted to
54.5.1 Arterial Blood Gas optimize the blood gases, lung volume, tidal vol-
Measurements ume, and minute volume and minimize lung injury.
Understanding and assessing arterial blood gases
is one of the most important aspects of the care of 54.6.1 Improving Oxygenation
a baby with respiratory failure.
Unless the baby has mild RDS, as indicated by a Oxygenation can be improved by increasing the
low FiO2 and minimal dyspnea, an arterial line FiO2. However, the higher the FiO2, the greater
848 C. Morley and G. Lista
the chance of lung injury because high levels Primary pulmonary hypertension, with right to
are toxic to the epithelium. Therefore other tech- left shunting of venous blood past the lungs, can
niques should be used to improve oxygenation be recognized when a baby has a high FiO2 to
and reduce the need for a high FiO2. obtain a satisfactory PaO2, yet the PaCO2 is easily
Oxygenation is not dependent on the move- controlled. The chest X-ray shows lungs with a
ment of gas in and out of the lungs. It only requires relatively normal volume and reduced vascular
oxygen to enter the lungs and an appropriate sur- markings. Echocardiography is used to confirm
face area for diffusion. the diagnosis.
Adequate oxygenation depends on ensuring One problem to be aware of is when the peak
the lungs are well aerated with enough surface inflating pressure (PIP) is progressively
area for gas exchange (Thome et al. 1998). Oxy- increased to try and improve oxygenation, and
genation is closely related to the PEEP or mean the oxygenation deteriorates. This may be
airway pressure (MAP) used because this is the because the pressure is causing overdistension
key factor to maintain lung volume in an intubated and interfering with pulmonary blood flow. A
infant with lung disease. The level of PEEP pointer to this is that oxygenation improves
should be between 5 and 8 cm H2O. There is no when the baby is transiently disconnected from
easy guide to the exact level to use in any baby at the ventilator.
any time. PEEP can be increased when a high
FiO2 is being used or when the chest X-ray
shows low lung volume. 54.6.2 Controlling the Blood Level
Adjusting the PEEP depends on clinical assess- of Carbon Dioxide
ment, chest X-ray appearance, and FiO2 and the
PaCO2 or transcutaneous PCO2 levels. PEEP can CO2 control is related to moving gas in and out of
be increased to open the lungs if the FiO2 is high, the lung. Inadequate spontaneous breathing is the
and the chest X-ray also shows the lungs to be primary reason for ventilation. Altering the tidal
underinflated. The levels of PEEP to use in differ- volume and ventilator rate controls the PaCO2.
ent situations have not been determined. Careful control of the PaCO2 is very important.
Altering peak pressure or inflation and expira- Overventilation causing hypocarbia (PaCO2 <
tion times will alter the mean airway pressure, and 30 mmHg) is strongly associated with chronic
have some effect on oxygenation, but adjusting lung disease and adverse neurodevelopmental
these is not as effective at altering oxygenation as outcomes (Okumura et al. 2001). Hypercarbia
changing PEEP. (PaCO2 > 60 mmHg) may also be damaging
In a normal lung, high PEEP may cause because it causes acidosis and increased cerebral
oxygenation and PaCO2 to deteriorate by perfusion. The normal PaCO2 range for a venti-
overdistending the lung and reducing effective lated baby is about 35–60 mmHg.
tidal volume and compressing the alveolar capil- During ventilation the tidal volume is deter-
laries. Sometimes this is the first “clinical mined by the applied pressure, i.e., PIP, PEEP,
alarm”, indicating too much PEEP is cardiovas- and the baby’s breathing. Neonatologists think
cular impairment by lung overinflation. However, of neonatal ventilation in terms of applied pres-
there is no evidence this is a problem in babies sures and the effect they have on the PaCO2;
ventilated for respiratory failure, because little of however, the pressure is only a proxy for the
the inflating pressure is transmitted to the lungs delivered tidal volume. The higher the PIP, the
unless it is increased to a very high level. greater the tidal volume delivered. Most modern
Oxygenation is dependent on the lungs being neonatal ventilators measure and display tidal
appropriately perfused. Inadequate oxygenation volume, so this can now be targeted. Large tidal
may be due to low blood pressure, pulmonary hyper- volumes can damage the lungs very quickly –
tension, or pulmonary atresia. Therefore, to ensure called volutrauma. The appropriate tidal volume
optimal pulmonary perfusion and oxygenation, the for ventilated spontaneously breathing babies is
blood pressure must be maintained. around 3.5–6 ml/kg depending on the ventilator
54 Treatment of Respiratory Failure in Newborn: Mechanical Ventilation 849
rate. If the PaCO2 is too high or too low, the tidal avoided by using a heated inspiratory ventilator
volume (or peak inflating pressure) is altered a circuit.
little (0.5 ml/kg or 2 cm H2O) and the PaCO2
rechecked in about 30 min.
The ventilator rate should be adequate to 54.6.4 Measuring Blood Gases
ensure the PaCO2 is in the normal range. Most
babies are ventilated while breathing. They During mechanical ventilation, adjusting the
breathe between 50 and 90/min. Modern ventila- ventilator settings in response to frequently
tors enable inflations to be triggered and synchro- measured blood gases is necessary for control
nized with each breath to assist the baby’s of PaCO2 and pH. The frequency depends on the
respiratory efforts. This is called assist/control stability of ventilation. In the acute phase, when
mode of ventilation. This means that the baby the lung function is changing, blood gases
triggers inflations and so controls the ventilator should be measured no more than 30 min after
rate and to some extent the minute volume. With a change in ventilator settings. Transcutaneous
triggered ventilation, the backup rate should be set measurements of CO2 can be useful, give quick
at about 30/min, well below the baby’s spontane- feedback about changes in CO2, and reduce the
ous rate. If it is set too close to the spontaneous number of blood gases measured but are prone
rate, this will reduce the proportion of triggered to drift.
inflations. The product of ventilator rate and tidal
volume is the minute volume. The minute volume
should be ~ 200–300 ml/kg/min. 54.6.5 Monitoring Ventilator
The PaCO2 is related to the minute volume and Parameters
so it can be increased or decreased by altering the
ventilator rate. However, because ventilated Most modern ventilators have numerical and graph-
babies are spontaneously breathing and triggering ical displays of ventilator parameters. It is important
the ventilator, altering the set rate may have little these are understood and interpreted correctly. The
effect on the delivered minute volume in this most useful graphical display is pressure, flow, and
mode. Then the only control is adjusting the tidal volume against time with a horizontal axis
tidal volume. showing about 10 s worth of waveforms. See
Figs. 1, 2, 3, 4, 5, and 6 for recordings during
different ventilator modes and their interpretation
54.6.3 Heating and Humidification (Schmolzer et al. 2010). Pressure volume loops are
of Ventilation Gases only useful when the baby is not breathing.
Inspired gases are heated and humidified by the
nose, pharynx, and upper respiratory mucosa. 54.6.6 Pressure Wave
They are delivered to the lungs at 37 C and
with a saturation of 100%. This shows the ventilator pressure wave changing
Medical gases are 100% dry and cold. An ETT with inflations. It shows the level of PEEP and
bypasses the upper airway and so all heating and how this changes with spontaneous inspirations,
humidification of the gases must be from a heater the onset of inflation, the rate of rise of the pres-
humidifier in the circuit. Even slightly cold or dry sure, whether the set PIP is achieved, and whether
gases quickly thicken the mucus, reduce cilial there is any pressure plateau.
action, and damage the mucosa. It is important to
ensure that all gas reaches the lungs at no less than
37 C and carries 44 mg% H2O (100% relative 54.6.7 Flow Wave
humidity) (Schulze 2007). Any condensation of
water vapor in the ventilator circuit, from the This shows the gas flow changing as the baby
inspired gas, is a loss of humidity and must be breathes and the ventilator inflates. Flow
850 C. Morley and G. Lista
Fig. 1 This shows about 3.8 s of a recording of pressure falls slightly, and there is an inspiratory tidal volume. At
limited fixed rate untriggered ventilation with the flow “B” the ventilator pressure rises to a plateau for the infla-
wave at the top with gas going down the ETT above the tion time of about 0.3 s. This result is an inflation tidal
zero line and gas coming out of the ETT below the zero volume about the same size as the baby’s inspiratory vol-
line. The pressure wave is in the middle showing 5 cm H2O ume. It can be seen that ventilator inflations and baby’s
PEEP pressure and 16 cm H2O peak pressure. The bottom inspirations and expirations are completely out of
line shows the tidal volume wave. At “A” the baby is synchrony
inspiring and the ventilator pressure not rising, the PEEP
above the zero line is down the ETT; flow below there is gas trapping, diaphragmatic braking, or
the zero line is flow out of the tube. With spon- any obstruction or splinting against the
taneous breathing triggering ventilation, it dis- inflations.
plays a small inspiratory flow immediately
before inflation that triggers inflation. The dis-
play also shows any flow from spontaneous 54.6.8 Tidal Volume Wave
breaths not associated with inflations, the gas
flow during inflations, any gas leak during infla- This shows the volume of gas passing down the
tion, any interaction between the spontaneous ETT as an upstroke, the volume of gas leaving the
breaths and inflations, whether the inflation time lung as a downward curve, and any gas leak
is adequate, whether the expiratory time is around the ETT as a vertical line at the end of
appropriate for full expiration, and whether each inflation.
54 Treatment of Respiratory Failure in Newborn: Mechanical Ventilation 851
Fig. 2 This shows about 9 s of a recording of results in an inflationary tidal volume about 20% larger
synchronised intermittent mandatory ventilation (SIMV) than the baby’s tidal volume. What cannot be seen is that
at a rate of 35/min with the flow wave at the top with gas these inflations were triggered by the baby’s inspiratory
going down the ETT above the zero line and gas coming flow, and so the tidal volumes are a combination of the
out of the ETT below the zero line. The pressure wave is in baby’s breathing and synchronous inflation. The baby is
the middle showing about 6 cm H2O PEEP pressure and breathing at about 75 breaths per minute. It can be seen that
14 cm H2O peak pressure. The bottom line shows the tidal the baby makes about seven inspirations without ventilator
volume wave. At “A” the baby is inspiring without venti- support and four with ventilator support. Out of a com-
lator inflations. There is an inspiratory and expiratory tidal bined tidal volume during this time of about 34 ml, the
volume of about 2–3 ml. At “B” the ventilator pressure ventilator has contributed only 4 ml. It would appear that
rises to a plateau for the inflation time of about 0.3 s. This this baby probably does not need to be ventilated
Other neonatal ventilators may have slightly dif-
54.7 Techniques of Mechanical
ferent modes but the general principles of use are
Ventilation
the same.
This section will be illustrated from our experi-
ence and studies using the Drager Babylog 8000þ 54.7.1 Conventional Mandatory
ventilator and the Sensormedics 3100A high- Ventilation (CMV) or
frequency oscillating ventilator for many years Intermittent Mandatory
(South and Morley 1986a, b, c, 1992; South Ventilation (IMV)
et al. 1987, 1988; Greenough et al. 1986;
Hoellering et al. 2008; Kamlin et al. 2006; CMV and IMV are exactly the same mode and
McCallion et al. 2005a, b, 2008; Pellicano et al. use pressure-limited, time-cycled ventilation.
2009; Tingay et al. 2007; Wheeler et al. 2009a, b). The ventilator is adjusted to deliver a set PIP
852 C. Morley and G. Lista
Fig. 3 This shows about 9 s of a recording of assist control inspirations triggered an inflation and drove the ventilator
ventilation A/C (SIPPV) and volume guarantee mode at a at about 65/min. There is an inspiratory and expiratory tidal
set rate of 50/min with the flow wave at the top with gas volume varying slightly between 4 ml and 6 ml with
going down the ETT above the zero line and gas coming variable a leak. This shows how well A/C ventilation
out of the ETT below the zero line. The pressure wave is in supports each of the baby’s breaths and how volume guar-
the middle showing about 6 cm H2O PEEP pressure and antee changes the pressure to try and maintain the tidal
the PIP changing from 13 down to 11 cm H2O. The bottom volume as the baby changes its breathing
line shows the tidal volume wave. Each of the baby’s
and a set PEEP with all inflations. There is no appropriate PEEP for a baby and this usually
single PIP or PEEP that can be used for all babies starts at 5 cm H2O.
under all circumstances. The starting PIP is cho- The inflation time is usually set to 0.3 s, as this
sen by experience, e.g., 20 cm H2O and the is the mean inspiratory time of a ventilated pre-
infant’s chest wall movement assessed by obser- term infant. However, as every baby is different, it
vation. If this is considered to be too much, the is best to adjust the inflation time by observing the
PIP is reduced. If there is none, or too little chest flow wave. The inflation flow wave should arrive
wall movement, the PIP is increased. When at the zero flow line when the inflation pressure
changing PIP by observing chest movement, finishes and then there should be little or no zero
remember in normal babies the movement with flow before expiration begins. If it is set longer,
each breath is barely discernable. Subsequently, the infant may breathe out during the ventilator
the PIP is adjusted according to the PaCO2. inflation. The expiratory time is set to provide the
There is no easy way to determine the desired respiratory rate, ~60 per minute.
54 Treatment of Respiratory Failure in Newborn: Mechanical Ventilation 853
Fig. 4 This shows about 9 s of a recording of assist control separately. The pressures are changing slightly to try and
ventilation A/C (SIPPV) and volume guarantee mode at a produce the set tidal volume of 4.5 ml. Note that even
set rate of 50/min with the flow wave at the top with gas though there is a large difference in the driving pressure,
going down the ETT above the zero line and gas coming the tidal volume for triggered and untriggered inflations is
out of the ETT below the zero line. The pressure wave is in similar and sometimes the untriggered inflations with the
the middle showing about 6 cm H2O PEEP pressure. The higher PIP have the smaller tidal volumes. There is an
PIP changes from about 15 cm H2O to about 30 cm inspiratory and expiratory tidal volume varying slightly
H2O. The bottom line shows the tidal volume wave. The between 4 ml and 6 ml with variable a leak. This shows
waves marked A are triggered inflations with a lower PIP, the problem of having the backup rate very close to the
and the waves marked B are untriggered inflations with a baby’s spontaneous rate. The ventilator frequently changes
much higher PIP. This is happening because the volume from triggered to untriggered inflations
guarantee program targets triggered and untriggered PIP
See Fig. 1 for a recording of ventilator, flow, and it may inflate on top of a large inspiration
tidal volume waves during CMV showing the asyn- resulting in a very large tidal volume.
chrony between inflations and inspirations. 2. The set PIP may be too high or too low for the
IMV is the only ventilator mode available on infant resulting in over- or underventilation.
transport ventilators. Overventilation can cause high tidal volumes
There are many problems with this mode of and acute lung injury, and the resulting
ventilation: hypocarbia is associated with periventricular
leukomalacia.
1. It is unresponsive to the infant’s respiratory 3. It provides little or no monitoring of the actual
efforts because it is not triggered or synchro- ventilation the baby receives.
nized with the infant’s breathing. It may deliver 4. The ventilator rate cannot match the infant’s
an inflation when the infant is breathing out, or respiratory rate, particularly as it changes.
854 C. Morley and G. Lista
Fig. 5 This shows about 13 s of a recording of A/C inflation tidal volume of more than 130% of the set tidal
(SIPPV) and volume guarantee mode at a set rate of volume. The volume guarantee program reacts by stopping
about 50/min with the flow wave at the top with gas the inflations. Note their inflation times are shorter. The PIP
going down the ETT above the zero line and gas coming is lower and reducing each inflation to try and bring the
out of the ETT below the zero line. The pressure wave is in tidal volumes back to the set level. At C there are three
the middle showing about 7 cm H2O PEEP pressure. The large inflations at a slower rate. These are untriggered
PIP changes to try and maintain the set tidal volume 5 ml. inflations at the backup rate and have PIPs that correspond
The bottom line shows the tidal volume wave. The group to the PIP of previous untriggered inflations. At D the baby
of waves marked A are all triggered inflations with a stable inspires and a much smaller triggered PIP is delivered. This
tidal volume. The group of waves marked B are all trig- all shows the dynamic nature of the volume guarantee
gered inflations, but here the tidal volume has suddenly program responding to large changes in the infants’ breath-
increased because the baby started breathing hard with ing pattern
54.7.2 Triggered Ventilation piece of the ventilator circuit and the ETT. Two
fine tungsten wires heated to 400 C detect the gas
The purpose of triggered ventilation is for the flow by the cooling effect of the gas. It detects
ventilator to inflate the infant in synchrony with inspiratory gas flow, and when this has reached
the infant’s inspiration and augment the inspira- about 0.2 l/min, ~ 30 ms after the beginning of
tory gas flow and tidal volume. With the Drager inspiratory flow, an inflation is started. The delay
Babylog 8000þ ventilator, triggering is from a hot time depends on the set trigger sensitivity on a
wire flow sensor that is placed between the wye scale of 1–10 with 1 being the most sensitive. This
54 Treatment of Respiratory Failure in Newborn: Mechanical Ventilation 855
Fig. 6 This figure shows A/C volume guarantee ventila- inflations and increases the PIP by 3 cm H2O every infla-
tion. At A the inflations are all triggered and the PIP tion until the baby starts breathing again at C, except for
changes a little to maintain the tidal volume. At B the one untriggered inflation. Note at D there are expiratory
infant splints against the ventilator inflations and stops tidal volumes larger than the inspiratory ones. This often
the flow and tidal volumes even though an inflation is happens just as the baby starts splinting and blowing down
being delivered. As the tidal volume is lower than set, the the lung volume
volume guarantee program uses untriggered, backup
sensitivity should always be set to 1 so that the Two other trigger mechanisms have been used:
inflation occurs as close as possible to the onset of
the baby’s inspiration. A higher number will mean 1. A capsule stuck on the abdomen to detect
a longer delay between the onset of inspiration abdominal movement. This may be unreliable.
and the start of inflation resulting in a The effectiveness and accuracy depends on
nonsynchronous inflation. where it is placed on the abdomen.
A potential problem with flow triggering is that 2. Using a change in the pressure in the ventilator
the sensor detects gas flow from condensed water circuit depends on the baby making a sufficiently
bubbling in the ventilator circuit and this triggers large inspiration to change the circuit pressure
an inflation even though the baby may not be (~0.5 cm H2O). It is inaccurate if the baby is very
inspiring at this time – the so-called auto-trigger- small or has a low inspiratory effort.
ing. Some people reduce the sensitivity to prevent
this; however, this causes an unacceptable delay Some people worry that adding a flow sensor
between the onset of inspiration and the inflation. increases the dead space and thereby increases the
Ensuring the ventilator circuit is free of condensed infant’s PaCO2. For this reason, for the very pre-
water can prevent this. term babies, the Vte can be increased a bit to
856 C. Morley and G. Lista
5–6 ml/Kg for babies <1 Kg. Increased dead space supported by the ventilator, it is inappropriate to
is rarely a big problem because, as an uncuffed use SIMV when the baby is initially ventilated or
ETT is used, there is almost always a leak around in respiratory failure. It may have a place when
the ETT. Even with no leak, the effect on PaCO2 is weaning ventilation but this can be a problem if
small and not of clinical significance compared the ventilator rate is set so low that the majority of
with the clinical gain from using the sensor. the baby’s breaths are unsupported through the
endotracheal tube. It is inferior to A/C synchronized
intermittent positive pressure ventilation (SIPPV).
54.7.3 Synchronized Intermittent To reduce the work of breathing of the
Mandatory Ventilation (SIMV) unsupported breaths and overcome the resistance
of breathing through the ETT, pressure support
In this mode the ventilator is pressure-limited, (PS) can be added to SIMV to partially assist the
and time-cycled, but inflations are triggered by spontaneous breaths (Osorio et al. 2005). The ini-
the baby’s inspiratory gas flow in synchrony tial preset pressure level above PEEP is generally
with a prior set number of inspirations. This set using the formula (PS = PIP-PEEP/2) and then
means that not all the baby’s inspirations are reduced according to the clinical status of the baby
supported by a ventilator inflation, e.g., if the (e.g., respiratory rate, FiO2 to maintain the SpO2
baby is breathing at 80/min and the ventilator is target, respiratory effort). The pressure used is
set to deliver 30/min, only 30 of the breaths will guessed by clinical experience and not interactive
coincide with an inflation. For all other breaths, with the baby’s breathing. On the ventilator screen,
the inspiration is through the endotracheal tube the PS has a sinusoidal flow waveform between the
with only PEEP for support. If the baby is apneic, SIMV inflations (Singh et al. 2007). When com-
the set ventilator rate is delivered. pared with SIMV alone, SIMV þ PS reduced
The ventilator divides each minute by the set respiratory rate (Osorio et al. 2005), duration of
number of inflations, called the ventilator interval. mechanical ventilation, and oxygen need in pre-
For example, if set to 60/min because the inflation term infants (Reyes et al. 2006; Patel et al. 2009).
time is 0.3 s and the expiratory time 0.7 s, then the
ventilator interval is 1 s. If the rate is set to 30/min,
inflation time 0.3 s, and expiratory time 1.7 s, the 54.7.4 Assist/Control (A/C) Also Called
ventilator interval is 2 s. The ventilator will Synchronized Intermittent
deliver each inflation, triggered or untriggered, Positive Pressure Ventilation
within each set ventilator interval. (SIPPV)
See Fig. 2 for a recording of the pressure, flow,
and tidal volume waves during SIMV. In this mode inflations are triggered by all the
The problems with SIMV ventilation are: baby’s inspirations. So it inflates the baby in syn-
chrony with each spontaneous inspiration. This
• Not all inspirations are supported by an is the most appropriate mode to use when the
inflation. baby requires full ventilatory support (Abubakar
• The unsupported breaths through the ETT and Keszler 2005; Mrozek et al. 2000; Herrera
increase the work of breathing and can lead to et al. 2002).
exhaustion. A/C is pressure-limited, time-cycled ventilation,
• The tidal volume delivered may vary consider- and the PIP, PEEP, inflation time, and expiratory
ably from the triggered inflations to the sponta- time are set. However if the rate is less than the
neous breaths and also due to the set PIP being baby’s breathing rate, the baby’s inspiration controls
delivered on top of the baby’s tidal volumes. the rate. It is important to realize the purpose of A/C
is to support all inspirations. If the ventilator rate (the
When should SIMV be used? Because of the backup) is set too high, the baby does not have
problems with spontaneous breaths not being enough time to make a breath before the mandatory
54 Treatment of Respiratory Failure in Newborn: Mechanical Ventilation 857
inflation starts, the spontaneous breaths are overrid- changes the tidal volume. The delivered PIP can
den by the ventilator, and the ability to trigger infla- now be changed automatically to target a specified
tions and assist the infant is lost, e.g., if the backup tidal volume. This should be in the range
rate is 60/min, then the infant will only trigger 3.5–6.0 ml/kg depending on the baby’s breathing
inflations if it breathes faster than 60/min. At this rate and the ventilator backup rate.
backup rate, only about half the baby’s breaths will The volume guarantee mode specifically targets
trigger an inflation (McCallion et al. 2008). It is the delivery of an expiratory tidal volume set by the
“confusing” for the baby to be trying to breathe clinicians (Patel et al. 2009). It works in all trig-
and suddenly have inflation asynchronous with its gered modes: SIMV, A/C, and pressure support
inspiration. The main purpose of the A/C ventilation ventilation (PSV). The ventilator monitors expired
is then lost. Therefore, it is important to set the tidal volume and determines whether it is higher,
backup rate slower, about 30/min, so all the baby’s lower, or identical to the set expired tidal volume. If
breaths can trigger inflation. If the baby stops breath- it is higher, the PIP is reduced for the next inflation,
ing, the ventilator rate will be 30/min. Spontane- and if the tidal volume is lower, the PIP is increased
ously breathing ventilated babies rarely become to try and ensure the set tidal volume is achieved.
completely apneic for very long, but obviously a The volume guarantee mode controls the
rate of 30/min for several minutes after a spontane- expired tidal volume very closely to the set tidal
ous triggered rate of about 70/min would need care- volume (Keszler and Abubakar 2004). Analyses
ful monitoring. from 6693 inflations: mean (SD) for triggered
See Fig. 3 for a recording of the pressure, flow, expired tidal volume =102% (29%) of set and
and tidal volume waves during A/C ventilation. range 0–378%; for untriggered = 97% (31%) and
Some people think that with A/C mode babies range 0–322% (McCallion et al. 2008). It can be
are more likely to become overventilated if they seen that there can be large variations in the
trigger the ventilator too fast. In my experience this tidal volume. This is due to the infant’s breathing.
is no more of a problem than with other modes if If the infant takes breaths larger than the set tidal
the PIP is set to ensure reasonable average tidal and volume, the ventilator cannot, and will not, prevent
minute volumes. The clinicians need to carefully this. The ventilator response is to lower the PIP for
monitor the tidal volume and minute volume. subsequent inflations. If the inspired tidal volume is
In A/C mode the baby mainly controls the more than 130%, then the inflation is stopped.
ventilator rate, and so if the PaCO2 is low, it is Sometimes ventilated infants “splint” or contract
inappropriate to reduce the rate to reduce minute their abdominal muscles very hard and completely
volume because the baby is controlling the rate. stop an inflation. The response of the ventilator will
To control PaCO2 PIP is the parameter to change. be to increase the PIP in a stepwise fashion to try
and restore the tidal volume. This overcomes the
splinting, and consequent hypoxia, quicker than
54.7.5 Volume Guarantee Ventilation ventilation continuing with a set PIP.
See Figs. 3, 4, 5, and 6 for recordings of assist/
One of the major complications from ventilating control with volume guarantee.
infants is acute lung injury leading to Some pressure-limited ventilators have two
bronchopulmonary dysplasia. Volutrauma is one inflating pressures called pressure support venti-
of the main causes of this. Tidal volumes of more lation. In this mode the PIPs are set and not related
than 8 ml/kg may cause volutrauma and so it is to the delivered tidal volume for many inflations.
important to measure and control the tidal volume. However, in volume guarantee mode, the PIP
This mode reduces volutrauma. changes all the time to try and maintain the tidal
Traditionally, during neonatal ventilation alter- volume in response to the infant’s breathing.
ing the PIP has been used to change the PaCO2. It There are several safety features with volume
is often forgotten, or not realized, that the PIP is a guarantee that ensure the tidal volume is safe and
proxy for tidal volume and altering the PIP as accurate as possible:
858 C. Morley and G. Lista
1. If the inflating tidal volume is more than 130% the Pmax. If it is set high, e.g., 30 cm H2O, to allow
of the set expired tidal volume, the current the ventilator to use pressures up to that level, then
inflation is stopped. it may occasionally deliver this pressure, which
2. The PIP does not change, up or down, by more may concern some neonatologists. What is impor-
than 3 cm H2O from one inflation to the next. tant is that the clinical team need to be vigilant and
This works independently for triggered and consider why the PIP has risen and whether there is
untriggered inflations (McCallion et al. 2008). a problem that needs correcting. Reasons may be:
3. There is a separate control of PIP for triggered there is an increased leak around the ETT and so a
and untriggered inflations. This is because the higher pressure is needed to compensate and
baby is contributing to the delivered tidal vol- deliver the set Vte; the lung disease has deterio-
ume and the PIP required with triggered infla- rated; and pneumothorax, PIE, atelectasis, and ETT
tions will be lower than with untriggered either dislodged into the right main bronchus or
inflations where the tidal volume has to be nearly extubated. As the baby’s condition changes,
achieved totally by the PIP. so the Pmax may need to be reset. Some experts set
4. Sudden large changes in PIP can occur from the Pmax about 3–5 cm H2O above the PIP being
one inflation to the next if the backup rate is set used to maintain the set Vt. This gives a more
too close to the infant’s spontaneous rate sensitive control over the PIP delivered. If the
because the ventilator changes from triggered Pmax is set too low, the ventilator may frequently
to untriggered inflations with the untriggered alarm “low tidal volume” because it is limiting the
inflations having a larger PIP than triggered PIP needed to deliver the set tidal volume. This can
ones. However, importantly it does not result be a problem either because the frequencies of the
in sudden large changes in tidal volume alarms frustrate the staff or because they ignore the
because these are being controlled. This over- alarms and don’t look for the cause of the alarm. It
rides the algorithm for the PIP not changing is important that the Pmax level is considered and
from one inflation to the next by more than reset if needed both if it is too high and too low.
3 cm H2O. During weaning the Pmax should be reduced to
5. The expired tidal volume is used for the set avoid an inappropriately high PIP being delivered.
tidal volume rather than inspired tidal volume We consider the baby ready to be extubated
because part of the inflation tidal volume is lost from VG when the set Vt is 4–6 ml/Kg and
through leak around the ETT. (a) when the PIP is less than 16–14 cm H2O),
6. Volume guarantee automatically weans the PIP (b) the FiO2 is <0.3, (c) there is no tachypnea or
as the lungs heal, compliance and resistance other signs of respiratory difficulty such as retrac-
improve, and the baby breathes more effec- tion, and (d) pH > 7.2 and pCO2 < 65 mmHg.
tively. If a baby generates a tidal volume larger When ventilating with volume guarantee, A/C
than the set tidal volume, the PIP may reach the mode is best so that every spontaneous breath
PEEP level. triggers an inflation. With this combination of
A/C and volume guarantee, the baby’s spontaneous
54.7.5.1 Setting the Maximum Inflating rate controls the ventilator rate and the volume
Pressure That Can Be Delivered guarantee controls the PIP. Therefore to control
in VG the PaCO2, the important control is the set tidal
In VG the maximum PIP the ventilator is allowed volume. This can be increased to reduce the PaCO2
to deliver is called the Pmax. The Pmax should be or lowered to increase the PaCO2, especially in
set above the PIP being used to ventilate the baby. chronically ventilated infants with increased pul-
In VG it is important that the ventilator can pick an monary dead space and distension of the trachea.
appropriate PIP to deliver the target Vt set. It Evidence from systematic review and meta-
should be set to a level the clinicians would like analysis demonstrated that preterm infants man-
to be alerted about and are comfortable with. There aged with tidal volume-targeted ventilation (e.g.,
is a debate about what pressure should be used for VG ventilation) had reduced incidence of BPD,
54 Treatment of Respiratory Failure in Newborn: Mechanical Ventilation 859
duration of mechanical ventilation, severe IVH and be choosing expiratory times nearer 0.3 s in
PVL, pneumothorax, and risk of hypocarbia, when response to the flow curve.
compared with preterm babies ventilated with The shape and timing of the inflation flow
pressure-limited ventilation (Wheeler et al. 2010; curve is dependent on the gas flow in the circuit.
Peng et al. 2014). Nevertheless, the authors con- A high gas flow will result in a shorter inflation
cluded that further multicenter RCTs are required time and a low gas flow a longer inflation time.
to evaluate the impact of this ventilatory approach When ventilating a baby with a low gas flow, e.g.,
on long-term neurodevelopmental outcome, death, 4 L/min, then the pressure support mode is very
and other complications related to mechanical ven- valuable to pick the appropriate expiratory time.
tilation. We can hypothesize that a further positive The advantage of this mode is that the infant
effect to volume-targeted ventilation could be cannot exhale against inflation.
given by the optimization of the PEEP level. In
the past PEEP has been defined as a “cheap” and
effective lung protection, and the research for 54.7.7 Neurally Adjusted Ventilator
appropriate levels of PEEP (the so-called best Assist (NAVA)
PEEP) guided by SpO2, blood gas levels, transcu-
taneous CO2 monitoring, and chest X-ray To reduce possible asynchrony with ventilator
(Monkman and Kirpalani 2003) is used not only inflations, a new mode of mechanical ventilation
in adults with ARDS but also in preterm infants has been introduced called neurally adjusted venti-
with respiratory failure. It seems to be an intriguing lator assist (NAVA) (Hummler and Schuze 2009).
approach to implement the protective effect of Using electrodes on a specially designed nasogas-
volume-targeted ventilation (Castoldi et al. 2011). tric tube, it detects and analyzes the diaphragmatic
A recent Cochrane review concluded, “there is EMG and uses this signal to trigger ventilator infla-
insufficient evidence to guide selection of appro- tions in proportion and in synchrony with the pha-
priate PEEP levels for RDS or CMV. There is a sic inspiratory diaphragmatic electrical activity.
need for well designed clinical trials evaluating the Backup pressure control is provided when there is
optimal application of this important and fre- no diaphragm signal. Small preliminary studies
quently applied intervention” (Bamat et al. 2012). have shown that NAVA can be successfully used
in term and preterm infants (Beck et al. 2009; Stein
et al. 2013). NAVA is contraindicated in some
54.7.6 Pressure Support Ventilation specific conditions (e.g., esophageal malformation,
coagulation disorders, pace makers in use, or
With the Drager 8000þ ventilator, there is apnea). Large multicenter trials are needed to deter-
another triggered mode called pressure support mine the usefulness and accuracy of NAVA and
ventilation (PSV). This is a confusing term compare it with tidal volume-targeted assist/control
because all the other modes are pressure ventilation and pressure-controlled ventilation and
supported. It is a mode that triggers ventilator whether it decreases duration of ventilation and
exhalation and therefore automatically controls reduces BPD, rate of pneumothorax, and other
the inflation time. The ventilator tracks the infla- major complications of prematurity.
tion flow curve as it rises and falls. As the flow
decreases from the peak flow to 15% of the peak
flow, this triggers the ventilator to stop inflation. 54.7.8 High-Frequency Oscillatory
It automatically takes account of any leak flow. It Ventilation (HFOV)
is therefore important the inflation time is set
much longer than normal ventilation to allow This mode of ventilation is used when other modes
the ventilator to increase the expiratory time if of ventilation is unable to ensure satisfactory CO2
needed. An expiratory time of 0.6 s would be exchange without using a high PIP (e.g., 30 cm
appropriate even though the program will usually H2O or more) to deliver the tidal volume.
860 C. Morley and G. Lista
HFOV is done in different ways by different controller of CO2. The higher is the ΔP, the more
ventilators and so I will concentrate on the CO2 is removed. The best way to judge whether
principles: the ΔP is correct is to start low and increase it
until the chest is seen to be just wriggling with
1. The lung volume is produced and maintained the ventilator. It is very easy to quickly
by a continuous high mean airway pressure overventilate babies with HFOV and drive the
~10–20 cm H2O, not just an end expiratory PaCO2 down to dangerous levels in a few
pressure of ~5 cm H2O. minutes. To monitor, use a transcutaneous CO2
2. The tidal volume delivered is approximately sensor before HFOV is started. As the PaCO2
equal to the infants dead space volume ~2 ml/kg falls, ΔP is reduced accordingly. The ΔP is not
3. The ventilator rate is much higher than con- very powerful with the Drager 8000þ and
ventional ventilation at between 5 and 15 Hz increasing it above 60% has little added benefit.
(300 and 900/min). 3. The high-frequency rate also affects the PaCO2.
It is important to realize this is the opposite of
Adjusting three main parameters controls the conventional ventilation: as the rate is reduced,
ventilation: the PaCO2 is likely to fall, and as the rate is
increased, the PaCO2 rises. This is because at a
1. The mean airway pressure (MAP). As this con- lower rate, the ΔP has more time and therefore is
trols the lung volume, and oxygenation is likely to increase removing more CO2; as the rate
approximately proportional to lung volume, increases, the ΔP is reduced. It is best to start at
the MAP is increased until the FiO2 required ~8–10 Hz, adjust the MAP and ΔP to optimize
to produce an appropriate PaO2 is at the lowest the blood gases, and only adjust the frequency if
that can be achieved. If the MAP is increased the PaCO2 cannot be controlled at the frequency
too much, the oxygenation will deteriorate. It is chosen. With the Drager Babylog 8000þ, chang-
best to start with a MAP slightly higher than that ing the rate has more effect on PaCO2 than
used on conventional ventilation and increase it changing ΔP.
until the FiO2 is optimized. It has been
recommended (Dargaville and Tingay 2012) The advantages of HFOV are:
that lung volume optimization during HFOV
may be best done by stepwise increments in 1. Improvement in oxygenation by using a higher
MAP, starting from a low MAP (e.g., 6–8 cm mean airway pressure than is acceptable during
H2O) and increasing the MAP to until the FiO2 conventional ventilation
is reduced to 0.3–0.25 to obtain for the target 2. Better CO2 removal in infants with very stiff
SpO2 and normal transcutaneous CO2, until lungs where an unacceptably high PIP would be
FiO2 is reduced to 0.3–0.25 (De Jaegere et al. required to produce an appropriate tidal volume
2006). By stepwise reductions of MAP, with
transcutaneous CO2 monitoring, the minimal The disadvantages of HFOV are:
MAP can be found to maintain the SpO2 targets
with reduced FiO2 and normal CO2. Frequent 1. It does not synchronize with the baby’s
chest X-rays will provide some information breathing.
about the lung inflation, particularly whether 2. It is very easy to overventilate and produce
the lungs are underinflated, one lung is col- hypocarbia with HFOV.
lapsed, the lungs are seriously overinflated, or 3. The Sensormedics ventilator provides no feed-
there is air leak. Changing MAP has the same back to the clinicians.
effect on all HFOV ventilators. 4. The Sensormedics ventilator has few alarms
2. The amplitude of the ventilating pressure swing about the adequacy of ventilation. In fact the
(ΔP). This is the change in the pressure that is ETT can be clamped and no gas delivered to
driving the change in tidal volume. This is one the baby and yet there is no alarm.
54 Treatment of Respiratory Failure in Newborn: Mechanical Ventilation 861
5. It is not clear how well the infant is breathing or bradycardic or hypoxic during this time is
when the infant is ready for weaning. unlikely to breathe well after extubation.
Preterm babies should be treated with caffeine
The Drager VN500 has a new HFOV mode of (Schmidt et al. 2006, 2007) or theophylline before
HFOV volume guarantee. More research is extubation. This increases the chance of success-
needed to determine if this controls and delivers ful extubation. They should be extubated to nasal
the HFOV more accurately. CPAP, or NIPPV, or high-flow nasal cannula oxy-
gen, rather than straight to unsupported breathing.
These modes have been shown to reduce the inci-
54.8 Weaning the Infant from dence of reintubation (Davis et al. 1998).
Ventilation
The longer the baby is intubated and ventilated, 54.9 Managing Complications
the more likely infection will occur and neonatal of Ventilation
chronic lung disease develops. It is therefore
important to wean babies from the ventilator and 54.9.1 Endotracheal Tube Not
extubate them as soon as possible. in the Trachea
The FiO2 is reduced to maintain appropriate
PaO2 and SpO2 and the PIP (tidal volume) is In order for a baby to be ventilated, an ETT has to
reduced to maintain the PaCO2 in the normal range be passed into the trachea. This is not a simple
When the FiO2 and PIP have been reduced to ~ procedure and it has been shown that this takes
<0.40 and <16 cm H2O, respectively, the lungs two or more attempts (Lane et al. 2004; O’Donnell
are improving, and if the baby breathes ade- et al. 2006). It has also been shown that the person
quately, extubation may be possible. In the VG intubating the baby often thinks (hopes) that ETT is
mode, the ventilator automatically weans the PIP in the trachea, and it may take several minutes
to deliver the set Vt. before they realize that the baby’s failure to respond
Some people advocate reducing the ventila- to the ventilation is because the ETT is not in the
tor rate in SIMV mode so that the baby has trachea. Some infants have been seriously
more spontaneous and less supported breaths. compromised because the clinicians failed to
One problem is the unsupported breaths are appreciate they had intubated the esophagus. It is
made through the ETT. This increases the so important to ensure the ETT is in the trachea that
work of breathing. This becomes significant after every intubation a CO2 detector (Kamlin et al.
if the ventilator rate is reduced below about 2005) or a gas flow detector is connected to the
30/min. Lower rates are unnecessary because ETT so that expired CO2 or the inspiratory and
to maintain a normal PaCO2, the baby will be expiratory gas flow can be detected to ensure the
breathing well. ETT is properly placed.
Many babies can be extubated from A/C ven-
tilation when the FiO2 and PIP are low without the
need for SIMV. Similarly, babies can be extubated 54.9.2 Endotracheal Tube Inserted Too
from SIMV at 30/min. Far Down into the Right Main
To help decide whether a baby will breathe Bronchus
adequately after extubation, the ventilator can be
switched to ETT CPAP for ~ 3 min, and see how If the ETT is either inserted too far or it slips down
well the heart rate, SpO2, and respiratory pattern after insertion, it will enter the right main bron-
are maintained (Kamlin et al. 2006). A baby who chus. The left lung and right upper lobe will then
can maintain the SpO2 and heart rate on a few not be ventilated. The diagnosis is made from a
minutes of ETT CPAP has a high chance of suc- chest X-ray. The treatment is to withdraw the ETT
cessful extubation. A baby who becomes to the appropriate level.
862 C. Morley and G. Lista
54.9.3 Accidental Extubation suction applied to the outlet. The insertion site
should be the fourth or fifth intercostal place in
Accidental extubation of a ventilated baby is a the anterior axillary line but away from the
serious problem because the baby’s condition breast bud. The baby should be placed on his
may deteriorate quickly. Securing the ETT so it back with the affected side elevated so the body
does not come loose can prevent it. Accidental is at approximately 45o to the mattress. The
extubation can be difficult to differentiate from drain is then inserted from the posterior lateral
other causes of a rapid deterioration. There are aspect. This ensures the drain passes anteriorly
several ways to make the diagnosis. The quickest, rather than posteriorly and therefore drains the
most accurate technique is to watch the display of air at the front of the chest. Under local anes-
the ETT flow wave. If the ETT becomes thetic a small hole is made in the chest wall, just
dislodged, the flow pattern immediately changes above a rib, and then enlarged appropriately
so there is flow down the ETT but not back with small artery forceps. These are used to
up. Placing a carbon dioxide detector on the distal introduce the catheter. A trocar should not be
end of the ETT will also rapidly show whether used because this increases the chance of perfo-
CO2-containing gas is coming out of the ETT rating the lung.
(Aziz et al. 1999). This is rapid and sensitive.
Other techniques, such as auscultation of both
lungs and misting of the ETT, are not so accurate. 54.9.5 Pulmonary Interstitial
Inspection of the larynx with a laryngoscope is Emphysema (PIE)
invasive but the only way to determine the posi-
tion of the ETT if other methods are unavailable. This mostly occurs in ventilated very premature
babies. It can be a serious problem and may cause
death if not treated promptly and effectively. In
54.9.4 Pneumothorax this condition gas tracks into the interstitial tis-
sues and compresses the airways. It commonly
A tension pneumothorax is one cause of deteriora- occurs throughout one or both lungs and proba-
tion in a ventilated baby. This is manifest by an bly comes from a tear in the hilum where the gas
increased FiO2 and/or a rising PaCO2 and increased is forced into the tissues. It causes a serious
ventilatory pressures when in volume guarantee deterioration in the respiratory and clinical status
mode. Occasionally it presents with apnea. of the baby. The diagnosis is made from the chest
Seeing a pneumothorax on an urgent chest X-ray.
X-ray confirms the diagnosis. Occasionally, the There are two important aspects to the treat-
pneumothorax is not very obvious because the ment of PIE (Swingle et al. 1984). (1) Reduce the
gas is anterior, and with the baby lying supine, ventilator PIP, PEEP, or set Vt, even if the PaCO2
the lung appears to fill the chest. One of the best or FiO2 rises as a consequence. However, do not
radiological signs is an obvious clear demarcation compromise the baby’s clinical and physiologi-
around the heart, diaphragm, or mediastinum. cal stability to an extent where the baby may
These are normally blurred in a baby with RDS. deteriorate. (2) Lay the baby with the affected
Transillumination of the chest with a bright light side down and with the back at right angles to the
in darkened surroundings usually shows the mattress. The affected lung is dependent and
hemithorax glowing. Although this is useful in slowly looses the PIE. This is one of the best
an emergency, it is not completely reliable and ways of treating PIE. If both lungs are affected,
so a chest X-ray should always be obtained to lay the baby so the worst lung is dependent. This
confirm the diagnosis if possible. treatment may lead to complete collapse of the
The treatment is an intercostal drain, placed dependent lung. This is a transient problem and
under strict sterile conditions, with the distal with repositioning the lung usually reinflates
tubing underwater in a sealed bottle with without PIE.
54 Treatment of Respiratory Failure in Newborn: Mechanical Ventilation 863
54.10 Drug Treatments During References
Ventilation
Abubakar K, Keszler M (2005) Effect of volume guaran-
tee combined with assist/control vs synchronized
54.10.1 Muscle-Relaxing Drugs intermittent mandatory ventilation. J Perinatol 25
(10):638–642
In the past muscle-relaxing drugs were commonly Ammari A et al (2005) Variables associated with the early
used for ventilated babies. This has now become failure of nasal CPAP in very low birth weight infants.
J Pediatr 147(3):341–347
uncommon, as neonatologists have realized that it
Attar MA, Donn SM (2002) Mechanisms of ventilator-
is better to support the spontaneous breathing of induced lung injury in premature infants. Semin
the baby rather than take overventilation Neonatol 7(5):353–360
completely. There is no evidence that the use of Aziz HF et al (1999) The pediatric disposable end-tidal
carbon dioxide detector role in endotracheal intubation
muscle-relaxing drugs improves the outcome for
in newborns. J Perinatol 19(2):110–113
babies with RDS (Cools and Offringa 2005). In Bamat N et al. (2012) Positive end expiratory pressure for
fact their use reduces venous return, causes preterm infants requiring conventional mechanical ven-
edema, increases the ventilator pressure required, tilation for respiratory distress syndrome or
bronchopulmonary dysplasia. Cochrane Database Syst
and prolongs ventilation. They should only be
Rev CD004500.pub2
used when babies are very difficult to ventilate Beck J et al (2009) Patient-ventilator interaction during
and oppose inflation. neurally adjusted ventilatory assist in very low birth
weight infants. Pediatr Res 65(6):663–668
Bellu R et al (2009) Opioids for neonates receiving
mechanical ventilation. A systematic review and
54.10.2 Caffeine meta-Analysis. Arch Dis Child Fetal Neonatal Ed 95
(4):F241–F251
Caffeine when given to ventilated very prema- Bhandari V et al (2005) Morphine administration and
ture babies has been shown to reduce the short-term pulmonary outcomes among ventilated pre-
term infants. Pediatrics 116(2):352–359
incidence of apnea; reduce the duration of ven- Bjorklund LJ et al (1997) Manual ventilation with a few
tilation, duration of oxygen treatment, and the large breaths at birth compromises the therapeutic
incidence of BPD; and reduce the incidence of effect of subsequent surfactant replacement in imma-
neurodevelopmental problems (Schmidt et al. ture lambs. Pediatr Res 42(3):348–355
Carlo WA et al (1987) Control of laryngeal muscle activity
2006). It appears to have few serious side effects in preterm infants. Pediatr Res 22(1):87–91
(Schmidt et al. 2007). Caffeine should be given Castoldi F et al (2011) Lung recruitment maneuver during
early to all ventilated very preterm infants, not volume guarantee ventilation of preterm infants with
just for treating apnea. acute respiratory distress syndrome. Am J Perinatol 28
(7):521–528
Cools F, Offringa M (2005) Neuromuscular paralysis for
newborn infants receiving mechanical ventilation.
54.10.3 Sedation Cochrane Database Syst Rev (2): p CD002773
Dargaville PA, Tingay DG (2012) Lung protective venti-
Many people sedate ventilated infants to make lation in extremely preterm infants. J Paediatr Child
Health 48:740–746
them feel less stressed and more comfortable.
Davis P et al (1998) Randomised controlled trial of nasal
Several different sedatives have been used. The continuous positive airway pressure in the extubation
appropriate sedative and dose has not been eluci- of infants weighing 600 to 1250 g. Arch Dis Child Fetal
dated. There is no good evidence that they Neonatal Ed 78:F1–F4
De Jaegere A et al (2006) Lung recruitment using oxygena-
improve the outcomes for the babies, and they
tion during open lung high-frequency ventilation in pre-
may adversely affect the baby’s respiratory drive term infants. Am J Respir Crit Care Med 174:639–645
so that it takes longer for the baby to breathe Donn SM, Sinha SK (2003) Can mechanical ventilation
sufficiently to be extubated (Bhandari et al. strategies reduce chronic lung disease? Semin Neonatol
8(6):441–448
2005; Bellu et al. 2009). The best way to keep
Greenough A et al (1986) Fighting the ventilator–are fast
the baby comfortable is with good nursing care rates an effective alternative to paralysis? Early Hum
and appropriate positioning. Dev 13(2):189–194
864 C. Morley and G. Lista
Herrera CM et al (2002) Effects of volume-guaranteed infants: a systematic review and meta-analysis. Arch
synchronized intermittent mandatory ventilation in pre- Dis Child Fetal Neonatal Ed 99:F158–F165
term infants recovering from respiratory failure. Pedi- Reyes ZC et al (2006) Randomized, controlled trial com-
atrics 110(3):529–533 paring synchronized intermittent mandatory ventilation
Hoellering AB et al (2008) Lung volume and cardiorespi- and synchronized intermittent mandatory ventilation
ratory changes during open and closed endotracheal plus pressure support in preterm infants. Pediatrics
suction in ventilated newborn infants. Arch Dis Child 118(4):1409–1417
Fetal Neonatal Ed 93(6):F436–F441 Schmidt B et al (2006) Caffeine therapy for apnea of
Hummler H, Schuze A (2009) New and alternative modes prematurity. N Engl J Med 354(20):2112–2121
of mechanical ventilation in neonates. Semin Fetal Schmidt B et al (2007) Long-term effects of caffeine ther-
Neonatal Med 14(1):42–48 apy for apnea of prematurity. N Engl J Med 357
Kamlin CO et al (2005) Colorimetric end-tidal carbon (19):1893–1902
dioxide detectors in the delivery room: strengths and Schmolzer GM et al (2010) Respiratory monitoring of
limitations. A case report. J Pediatr 147(4):547–548 neonatal resuscitation. Arch Dis Child Fetal Neonatal
Kamlin CO et al (2006) Predicting successful extubation of Ed 95(4):F295–F303
very low birthweight infants. Arch Dis Child Fetal Schulze A (2007) Respiratory gas conditioning and humid-
Neonatal Ed 91(3):F180–F183 ification. Clin Perinatol 34(1):19–33
Keszler M, Abubakar K (2004) Volume guarantee: stability Singh J et al (2007) Volume-targeted ventilation of new-
of tidal volume and incidence of hypocarbia. Pediatr borns. Clin Perinatol 34:9–1053
Pulmonol 38(3):240–245 South M, Morley CJ (1986a) Synchronous mechanical
Lane B et al (2004) Duration of intubation attempts during ventilation of the neonate. Arch Dis Child 61
neonatal resuscitation. J Pediatr 145(1):67–70 (12):1190–1195
McCallion N et al (2005) Volume-targeted versus pressure- South M, Morley CJ (1986b) Monitoring spontaneous
limited ventilation in the neonate. Cochrane Database respiration in the ventilated neonate. Arch Dis Child
Syst Rev (3): CD003666 61(3):291–294
McCallion N et al (2005b) Volume guarantee ventilation, South M, Morley CJ (1986c) Ventilator settings and active
interrupted expiration, and expiratory braking. Arch expiration. Arch Dis Child 61:310–311
Dis Child 90(8):865–870 South M, Morley CJ (1992) Respiratory timing in
McCallion N et al (2008) Neonatal volume guarantee ven- intubated neonates with respiratory distress syndrome.
tilation: effects of spontaneous breathing, triggered and Arch Dis Child 67(4):446–448
untriggered inflations. Arch Dis Child Fetal Neonatal South M et al (1987) Expiratory muscle activity in preterm
Ed 93(1):F36–F39 babies. Arch Dis Child 62(8):825–829
Monkman S, Kirpalani H (2003) PEEP – a “cheap” and South M et al (1988) A simple technique for recording
effective lung protection. Pediatr Resp Rev 4(1):15–20 the electromyogram of the external abdominal
Morley CJ et al (2008) Nasal CPAP or intubation at birth oblique muscle in the newborn. Early Hum Dev 16
for very preterm infants. N Engl J Med 358(7):700–708 (1):55–60
Mrozek JD et al (2000) Randomized controlled trial of Stein H et al (2013) Prospective crossover comparison
volume-targeted synchronized ventilation and conven- between NAVA and pressure control ventilation in pre-
tional intermittent mandatory ventilation following initial mature neonates less than 1500 grams. J Perinatol 33
exogenous surfactant therapy. Pediatr Pulmonol 29 (6):452–456
(1):11–18 Swingle HM et al (1984) New approach to management of
O’Donnell CP et al (2006) Endotracheal intubation attempts unilateral tension pulmonary interstitial emphysema in
during neonatal resuscitation: success rates, duration, premature infants. Pediatrics 74(3):354–357
and adverse effects. Pediatrics 117(1):e16–e21 Thome U et al (1998) The effect of positive end expiratory
Okumura A et al (2001) Hypocarbia in preterm infants with pressure, peak inspiratory pressure, and inspiratory
periventricular leukomalacia: the relation between time on functional residual capacity in mechanically
hypocarbia and mechanical ventilation. Pediatrics 107 ventilated preterm infants. Eur J Pediatr 157(10):
(3):469–475 831–837
Osorio W et al (2005) Effects of pressure support during an Tingay DG et al (2007) Effects of open endotracheal suc-
acute reduction of synchronized intermittent mandatory tion on lung volume in infants receiving HFOV. Inten-
ventilation in preterm infants. J Perinatol 25 sive Care Med 33(4):689–693
(6):412–416 Wheeler KI et al (2009a) Assist control volume guarantee
Patel DS et al (2009) Work of breathing and different levels ventilation during surfactant administration. Arch Dis
of volume-targeted ventilation. Pediatrics 123(4): Child Fetal Neonatal Ed 94(5):F336–F338
e679–e684 Wheeler KI et al (2009b) Volume-guarantee ventilation:
Pellicano A et al (2009) Comparison of four methods of lung pressure may decrease during obstructed flow. Arch
volume recruitment during high frequency oscillatory Dis Child Fetal Neonatal Ed 94(2):F84–F86
ventilation. Intensive Care Med 35(11):1990–1998 Wheeler KK et al (2010) Volume-targeted or pressure-
Peng WS et al (2014) Volume-targeted ventilation is more limited ventilation in the neonate. Cochrane Database
suitable than pressure-limited ventilation for preterm Syst Rev 11:CD003666
Pulmonary Hemorrhage, Transient
Tachypnea, and Neonatal Pneumonia 55
Mary Elaine Patrinos and Richard J. Martin
Contents
55.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 865
55.2 Pulmonary Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866
55.3 Transient Tachypnea of the Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 867
55.4 Neonatal Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870
Abstract 55.1 Salient Points
The intent of this chapter is to address three
other common pulmonary causes of respiratory • Pulmonary hemorrhage occurs as a result of
distress in the high-risk infant. These other extreme pulmonary vascular congestion
forms of parenchymal lung disease range in where blood-tinged secretions suctioned from
severity from mild, as seen in transient the endotracheal tube may quickly evolve into
tachypnea, to severe as is often the case in frank blood. The volume of blood loss can be
pulmonary hemorrhage. It is worth noting life-threatening, resulting in hypovolemic
that on occasion, one or more of these condi- shock.
tions may coexist in the same patient. The • The management of pulmonary hemorrhage is
treatment for all conditions is largely support- largely supportive with the goals of correcting
ive or involves the use of targeted antimicro- hypoxic and hypercapnic respiratory failure,
bial therapy. maintaining cardiac output, replacing blood
and volume loss, and correcting abnormalities
in clotting studies.
• Transient tachypnea of the newborn (TTN) is a
M. E. Patrinos
transient early-onset respiratory distress with
Case Western Reserve University School of Medicine,
Cleveland, OH, USA radiographic findings of lung hyperinflation
e-mail: [email protected] increased pulmonary vascular markings and
R. J. Martin (*) cardiomegaly.
Rainbow Babies and Children’s Hospital, Division of • Risk factors for developing TTN include elec-
Neonatology, Case Western Reserve University School of tive cesarean section without labor, prematu-
Medicine, Cleveland, OH, USA
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 865
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_203
866 M. E. Patrinos and R. J. Martin
rity, multiple gestation, male gender, maternal patent ductus arteriosus (PDA) with high pulmo-
diabetes, macrosomia, prolonged maternal nary blood flow (references Kluckow and Evans
administration of hypotonic fluid, and maternal 2000).
asthma. Pulmonary hemorrhage occurs when a buildup
• Neonatal pneumonia may be acquired pre- or of filtrate containing plasma and whole blood pro-
post-natally and may be of bacterial, viral, duces hemorrhagic edema fluid leading to an
fungal, or protozoal origin. increase in capillary pressure and subsequent rup-
• The incidence of neonatal pneumonia is ten ture (Cole et al. 1973). The presence of blood in
times higher for preterm infants then term the sputum of an otherwise stable intubated infant
infants. should raise the possibility of erosion or ulcera-
• The onset of neonatal pneumonia can be con- tion of the carina/upper airway by an endotracheal
genital, early onset, and late onset. Congenital tube or trauma from a suction catheter.
or intrauterine pneumonia is usually caused by Pulmonary hemorrhage was present in the
organisms ascending from the maternal uro- lungs of up to 68% of infants who died in the
genital tract before or during labor or via the first week of life and was associated with the
transplacental route. Early-onset pneumonia need for cardiopulmonary resuscitation in the
is usually acquired in the perinatal period. neonatal intensive care unit (Kostelanetz and
Late-onset pneumonia is diagnosed when Dhanireddy 2004). Blood aspiration syndrome is
symptoms arise after 48 h of life and the path- a distinct and separate entity associated with
ogens are typically acquired from the infant’s maternal hemorrhage and early-onset respiratory
environment. distress (Gordon et al. 2003).
• It is difficult to diagnose pneumonia, especially The clinical picture of pulmonary hemorrhage
when it coincides with RDS. If the index of is quite dramatic and warrants immediate atten-
suspicion for infection is high, the accepted tion. The infant may present with signs of hypo-
treatment is antibiotics for 48 h while awaiting volemic shock, cyanosis, bradycardia, and apnea.
culture results and following other clinical and Red or pink-tinged secretions suctioned from the
laboratory parameters. oropharynx or endotracheal tube may, at any time,
progress to massive bleeding. The radiographic
picture demonstrates patchy infiltrates, as seen in
55.2 Pulmonary Hemorrhage Fig. 1, or a complete white out.
The management of pulmonary hemorrhage is
Pulmonary hemorrhage (PH) occurs as a result of largely supportive with the goals of correcting hyp-
extreme pulmonary congestion where blood- oxic and hypercapnic respiratory failure,
tinged secretions suctioned from the endotracheal maintaining cardiac output, replacing blood and
tube may quickly evolve into frank blood. The volume loss, and correcting abnormalities in
volume of blood loss can be life-threatening, clotting studies. The initiation of mechanical ven-
resulting in hypovolemic shock. PH usually pre- tilation with settings adjusted to achieve high mean
sents in the second to fourth day of life and may be airway pressures may tamponade small pulmonary
associated with lung tissue damage from respira- vessels. High-frequency oscillatory ventilation is
tory distress syndrome, infection, mechanical often helpful. There is increasing evidence that
ventilation, and oxygen-induced lung injury. closure of the patent ductus arteriosus with early
Patients at highest risk for a PH include extremely medical therapy may reduce the risk of pulmonary
preterm infants (<28 weeks’ gestation) and mul- hemorrhage. It is widely accepted that pulmonary
tiples. Other predisposing factors include hyp- hemorrhage in the preterm infant is secondary to a
oxia, acidosis, hypervolemia, hypoproteinemia, patent ductus arteriosus coupled with an acute
congestive heart failure, and coagulation abnor- change in pulmonary compliance and fall in pul-
malities. Kluckow confirmed an association monary vascular resistance, resulting in pulmonary
between pulmonary hemorrhage and a large over circulation and edema. Recent data indicate
55 Pulmonary Hemorrhage, Transient Tachypnea, and Neonatal Pneumonia 867
lung fluid (Avery et al. 1966). In her work, Avery
characterized early-onset respiratory distress in
eight late premature infants with radiographic
findings of lung hyperinflation increased pulmo-
nary vascular markings and cardiomegaly. Symp-
toms were mild and transient with infants
improving in a 2–5-day period. Until recently, it
was believed that once TTN resolves, there are no
long-term consequences for the infant (Avery et al.
1966; Martin et al. 2015; Miller et al. 1980).
However, a large retrospective study of term
infants suggests that TTN might be significantly
associated with childhood asthma with increased
propensity in males. This study also suggests that
Fig. 1 Diffuse, patchy infiltrates, and right-sided atelecta-
sis caused by pulmonary hemorrhage
TTN is a marker of diminished pulmonary func-
tion, which may reflect an inherited susceptibility
to develop asthma (Liem et al. 2007).
that small-for-gestational-age preterm infants with The incidence of TTN is approximately 1% of
a moderate to large PDA are at greatest risk (Scholl live births. Risks for developing TTN include
and Yanowitz 2015). elective cesarean section without labor, prematu-
While surfactant therapy has been implicated in rity, multiple gestation, male gender, maternal
the pathogenesis of pulmonary hemorrhage, it also diabetes, and macrosomia (Gross et al. 1983;
has a therapeutic role in its management (Findlay Rawlings and Smith 1984). Prolonged maternal
et al. 1995; Long et al. 1992; Pandit et al. 1995; administration of hypotonic fluid and maternal
Pappin et al. 1994; Raju and Langenberg 1993; asthma have also been suggested as a cause for
Amizuka et al. 2003). This is due to the deactiva- TTN (Martin et al. 2015; Hook et al. 1997;
tion of surfactant by the hemorrhagic fluid. Demissie et al. 1998) (Fig. 2).
In a small study, the introduction of Most of the published work related to the path-
hemocoagulase via the endotracheal tube every ophysiology of TTN is consistent with Avery’s
4–6 h in addition to mechanical ventilation original conclusions that TTN is the result of
increased survival, decreased the length of pulmo- delayed fetal lung fluid clearance (Jain and Dudell
nary hemorrhage, and decreased the need for pro- 2006; Birnkrant et al. 2006). The lung’s functional
longed mechanical ventilation due to the residual capacity comprises a potential air space
pulmonary hemorrhage (Shi et al. 2005). The of 20–30 mL/kg body weight. This space is filled
outcome of pulmonary hemorrhage depends on in utero with fetal lung fluid containing high
the severity of the infant’s underlying cardiorespi- potassium and chloride and low bicarbonate and
ratory status. Mortality rates as high as 50% occur protein. Shifts between body compartments are
in ELBW infants. Morbidities include peri- controlled by a chloride active pump (Liem et al.
ventricular leukomalacia, intraventricular hemor- 2007; Adams et al. 1963; Barker and Olver 2002;
rhage, cerebral palsy, and cognitive delays. Bland 1988; Cummings et al. 1993). Two to three
days prior to delivery, the fetus begins to clear
lung fluid in anticipation of transition to extrauter-
55.3 Transient Tachypnea ine life. This process begins with a decrease in
of the Newborn fetal lung fluid secretion. The major clearance
takes place with the onset of labor. At this time,
Transient tachypnea of the newborn (TTN) was the lung epithelium becomes a sodium-absorbing
originally described by Avery et al. in 1966 as the membrane, and lung fluid flow is directed from
clinical manifestation of delayed clearance of fetal the air space to the interstitium via the epithelial
868 M. E. Patrinos and R. J. Martin
TTN commonly presents soon after birth with
100% tachypnea, grunting, nasal flaring, subcostal
Rates of respiratory
retractions, and possible cyanosis. An arterial
blood gas is likely to show mild respiratory aci-
inefficient fluid absorption
distress
dosis with hypoxemia. Chest radiographs demon-
strate perihilar streaking due to periarterial
lymphatic engorgement. TTN may also present
Surfactant deficiency in premature infants in association with respira-
tory distress syndrome. TTN is transient in nature
24 27 30 33 36 39 with resolution of symptoms often within 8–12 h,
Gestational age (weeks) but tachypnea may persist for up to 5 days. Infants
may require oxygen support but rarely over 40%
Fig. 2 Relative contribution of surfactant deficiency and inspired oxygen. In the case of rare respiratory
insufficient fluid absorption [TTN] to neonatal respiratory
distress (Adapted from Helve et al. (2009))
acidosis, CPAP may be instituted. Due to diffi-
culty in distinguishing TTN from pneumonia,
infants may receive a course of antibiotics. The
sodium channel (ENaC). The importance of radiographic findings of TTN should spontane-
endogenous steroids in this process is demon- ously resolve by 48 h (Martin et al. 2015). Lung
strated by the relationship between low expres- ultrasound has been used for early diagnosis of
sion of serum and glucocorticoid-inducible TTN and may allow a less-invasive approach to
kinase, ENaC, and poor lung liquid clearance respiratory support in infants exhibiting early
(Janér et al. 2015). The expression of these epi- signs of respiratory distress (Copetti and
thelial ion transport channels is also directly Cattarossi 2006; Raimondi et al. 2014).
related to gestational age so that TTN, like RDS,
is largely a developmental condition with decreas-
ing incidence as gestation progresses. In addition, 55.4 Neonatal Pneumonia
low protein containing lung fluid exhibits low
oncotic pressure, which is another driving force The lungs are often a portal of entry for early onset
for lung fluid to enter the vascular system. sepsis/pneumonia in the neonatal period. Pneu-
Mechanical compression via vaginal delivery monia may be acquired pre- or postnatally and
plays a relatively minor role in lung fluid clearance. be of bacterial, viral, fungal, or protozoal origin.
Milner et al. (1978) showed that when infants were Morbidity is high, prompting a high index of
not delivered through the vaginal canal and were suspicion when facing an infant with signs of
not exposed to vaginal compression, they had respiratory distress. An immature immune system
higher interstitial and alveolar fluid volume. Fur- and poor mechanical defense mechanisms may
thermore, these infants also had a decrease in their increase susceptibility to invasion of pathogens
lung gas volume. This hypothesis is not supported into the lungs. Furthermore, when an infant has
by later animal and human studies that showed no comorbidities such as respiratory distress syn-
increase in functional residual capacity (FRC) in drome (RDS), meconium aspiration syndrome,
vaginally delivered infants (Jain and Dudell 2006; or chronic lung disease (CLD), both vulnerability
Hägnevik et al. 1991). Results by Birnkrant and a to and consequences of pneumonia may be
retrospective study by Liem et al. (2007; Birnkrant enhanced.
et al. 2006) found an association between TTN and The incidence of neonatal pneumonia is ten
the development of wheezing syndromes. These times higher for preterm infants then term infants.
data support the hypothesis of fetal lung fluid clear- Barnett and Klein (Barnett and Klein 2001)
ance at the cell pump level and not the mechanical reported intrauterine and early-onset pneumonia
compression theory as the pathophysiologic basis in 10–38% of stillbirths and in 20–63% of autop-
for TTN. sies from live births that died in the first 28 days of
55 Pulmonary Hemorrhage, Transient Tachypnea, and Neonatal Pneumonia 869
life. The difficulty of reporting incidence is in the pneumonia. Group B Streptococcus [GBS]
inconsistency of defining pneumonia in infants remains the primary cause of pneumonia in the
less than 1 month of age. The majority of late- term neonate (Apisarnthanarak et al. 2003). Overt
onset pneumonias are diagnosed in premature GBS sepsis was seen in 1% of colonized infants or
infants, and most were on ventilatory support at 1–4/1000 live births if no intrapartum antibiotic
the time of diagnosis. A small single center study prophylaxis was given. In the USA, guidelines for
by Apisarnthanarak et al. (2003) showed 28% of intrapartum chemoprophylaxis have proven suc-
ventilated infants developed ventilator-associated cessful with a significant decrease in GBS sepsis
pneumonia (VAP), and, in 1986, Halliday et al. to 0.41 per 1000 births (Stoll et al. 2011). Algo-
(1984) reported a 35% incidence of pneumonia in rithms provide for the management of
intubated patients with RDS. Despite efforts by GBS-positive mothers as well as infants exposed
the Center for Disease Control (CDC) and to prophylaxis treatment. Unfortunately, other
National Nosocomial Infection Surveillance Sys- microorganisms known to cause early-onset pneu-
tem (NNIS), there is still no gold standard for monia have increased in importance since the
diagnosing VAP in the neonatal period. For implementation of the GBS guidelines. The com-
infants <1 year of age, the CDC has published mon pathogens that may influence the infant in the
clinical, radiographic, and laboratory criteria for immediate postpartum period are Escherichia coli
VAP (Buonocore Chap. 55, “Pulmonary Hemor- [E.coli], Klebsiella spp., Proteus mirabilis,
rhage, Transient Tachypnea, and Neonatal Pneu- H. influenzae, group D Streptococci, Listeria
monia”). The incidence in developed countries monocytogenes, and pneumococci. In very low
ranges from 2.7 to 10.9 episodes per 1000 venti- birth weight infants, rates of E. coli sepsis
lator days. In developing countries, the incidence (5/1000) exceed that of GBS (2/1000). In addition,
has been reported as high as 37.2 cases per 1000 nonbacterial pneumonia may be seen in the early
ventilator days (Cernada et al. 2014). Over the last postnatal period such as caused by Candida
decade, VAP prevention bundles have been (Gerberding et al. 1989; Aldana-Valenzuela et al.
largely successful in reducing the incidence of 2005), viruses (Takahashi et al. 2007; Barker et al.
hospital-acquired pneumonias. 1990; Faden et al. 2005), and Chlamydia
The etiology of neonatal pneumonia can be (Numazaki et al. 2003).
divided into three categories: congenital, early Late-onset pneumonia is diagnosed when
onset, and late onset. Congenital or intrauterine symptoms arise after 48 h of life. The pathogens
pneumonia is usually caused by ascending organ- are commonly acquired from the environment or
isms from the maternal urogenital tract before or nosocomial. Late-onset pneumonia is more com-
during labor or via the transplacental route. Micro- mon in premature infants or infants on prolonged
organisms such as viruses (cytomegalovirus, ventilatory support (Yuan et al. 2007). Gram-
rubella, herpes simplex virus, adenovirus, varicella negative bacteria (E. coli, Serratia marcescens,
zoster virus, enteroviruses, and influenza A), bac- Proteus spp., Klebsiella spp., Pseudomonas
teria (Listeria monocytogenes, Mycobacterium spp.), coagulase-negative Staphylococci (Philip
tuberculosis, Treponema pallidum), and protozoa 1994; Chartrand and McCracken 1982), and
(Toxoplasma gondii) are known causes of congen- Staphylococcus aureus along with GBS are
ital pneumonia. Early-onset pneumonia is usually among the most common bacterial organisms iso-
due to introduction of bacteria from the birth canal lated in late-onset pneumonia. Viral organisms
during the delivery process, especially in a situa- such as CMV (Takahashi et al. 2007; Bradshaw
tion of prolonged membrane rupture (Levine 1991; and Moore 2003), VZV, RSV, parainfluenza, influ-
Airede 1992). Gasping due to asphyxia and/or enzas A and B (Yusuf et al. 2007), Rhinovirus
meconium aspiration may introduce organisms (Calvo et al. 2007), Enterovirus (Abzug 2004),
into the respiratory system. Other factors, such as and Coronavirus are also seen in this type of
prematurity and maternal urinary tract infection, pneumonia. Recent data indicate that with
have a major role in increasing the risk of neonatal increased testing, 6% of all NICU sepsis
870 M. E. Patrinos and R. J. Martin
evaluations may detect a respiratory virus via mul- positive gram stain to be more consistent with
tiplex polymerase chain reaction (Ronchi et al. early-onset bacterial pneumonia than RDS. How-
2014). In addition, fungal etiologies have been ever, diagnostic difficulty remains, and if the
implicated. Infections are acquired mainly index of suspicion for sepsis is high, the accepted
through skin colonization and breakdown, treatment route is antibiotics for 48 h while
through gastrointestinal translocation of organ- awaiting culture results and following the above
isms, and from the respiratory tract of family and markers trends. It is also appropriate to treat every
care providers. The colonization of an infant in the infant who deteriorates from a respiratory stand-
intensive care unit with common or unusual flora point, especially if the infant was asymptomatic
can be due to a weak immune system, health-care for the first 6 h of life.
provider exposure, and interventions (endotra- The recommended empiric choice for early-
cheal tube, mechanical ventilation, and multiple onset pneumonia is ampicillin in conjunction
courses of antibiotics) (Frakking et al. 2007; with an aminoglycoside (gentamicin). For late-
Gupta 2002; Webber et al. 1990; Garland et al. onset pneumonia, empiric therapy may constitute
1992). nafcillin or vancomycin and an aminoglycoside.
It is difficult to diagnose pneumonia with great When cultures are definitive and sensitivities are
certainty. Isolation of bacteria or viruses from the known, antimicrobial therapy should be tailored
trachea or the oropharynx does not necessarily cor- for the specific organism. The prognosis of neo-
relate with invasive infection, but may instead, natal pneumonia depends on the underlying etiol-
reflect colonization. Radiographic studies are diffi- ogy and overall condition of the infant.
cult to interpret and cannot differentiate atelectasis
or fluid from infiltrate secondary to pneumonia. The
Acknowledgment We acknowledge the contribution of
workup for suspected neonatal pneumonia includes Amitai Kohn to this section in the prior addition.
blood and airway cultures (nasopharyngeal or tra-
cheal if intubated). Sherman (Sherman et al. 1984)
showed that tracheal secretions with a positive gram References
stain in relation to neonatal bacteremia had a 74%
sensitivity and 47% positive predictive value and Abzug MJ (2004) Presentation, diagnosis, and manage-
concluded that gram stain of tracheal secretions may ment of enterovirus infections in neonates. Paediatr
be of practical value in the diagnosis of congenital Drugs 6:1–10
Adams FH, Fujiwara T, Rowshna G (1963) Surface prop-
bacteremia. Positive airway culture alone may be erties and lipids from lungs of infants with hyaline
more suggestive of early than late-onset pneumonia; membrane disease. J Pediatr 63:881–888
however, in neither case is it sensitive (Ruderman Airede AI (1992) Prolonged rupture of membranes and
et al. 1994; Brook et al. 1980). Although radio- neonatal outcome in a developing country. Ann Trop
Paediatr 12:283–288
graphic studies are frequently nonspecific, it is Aldana-Valenzuela C, Morales-Marquec M, Castellanos-
more common to find pleural effusions in bacterial MartMart J, Deanda-Gda-G M (2005) Congenital can-
and fungal infections. Other nonspecific laboratory didiasis: a rare and unpredictable disease. J Perinatol
values such as C-reactive protein (CRP) and WBC 25:680–682
Amizuka T, Shimizu H, Niida Y, Ogawa Y (2003) Surfac-
counts, especially immature to mature neutrophils tant therapy in neonates with respiratory failure due to
ratio (I/T), may aid in the diagnosis of pneumonia. haemorrhagic pulmonary oedema. Eur J Pediatr 162:
The difficulty in diagnosing pneumonia, espe- 697–702
cially when it coincides with RDS, presents the Apisarnthanarak A, Holzmann-Pazgal G, Hamvas A et al
(2003) Ventilator-associated pneumonia in extremely
clinician with a therapeutic dilemma. Low abso- preterm neonates in a neonatal intensive care unit:
lute neutrophil count (ANC), high I/T ratio characteristics, risk factors, and outcomes. Pediatrics
(>0.2), and CRP (>1) have shown to have posi- 112(6 Part 1):1283–1289
tive predictive values of bacterial sepsis (Makhoul Avery ME, Gatewood OB, Brumley G (1966) Transient
tachypnea of newborn. Possible delayed resorption of
et al. 2006; Berger et al. 1995). Leslie et al. (1981) fluid at birth. Am J Dis Child 111:380–385
showed high I/T, low total neutrophil counts, and
55 Pulmonary Hemorrhage, Transient Tachypnea, and Neonatal Pneumonia 871
Barker PM, Olver RE (2002) Invited review: clearance of Garland JS, Dunne WM Jr, Havens P et al (1992) Peripheral
lung liquid during the perinatal period. J Appl Physiol intravenous catheter complications in critically ill children:
93:1542–1548 a prospective study. Pediatrics 89(6 Part 2):1145–1150
Barker JA, McLean SD, Jordan GD et al (1990) Primary Gerberding KM, Eisenhut CC, Engle WA, Cohen MD (1989)
neonatal herpes simplex virus pneumonia. Pediatr Congenital candida pneumonia and sepsis: a case report
Infect Dis J 9:285285J and review of the literature. J Perinatol 9:159–161
Barnett ED, Klein JO (2001) Bacterial infections Gordon E, South M, McDougall PN, Dargaville PA (2003)
of the respiratory tract. In: Remington JS, Klein JO (eds) Blood aspiration syndrome as a cause of respiratory
Infectious diseases of the fetus and newborn infant. WB distress in the newborn infant. J Pediatr 142:200–202
Saunders, Pennsylvania, pp 1006–1018 Gross TL, Sokol RJ, Kwong MS et al (1983) Transient
Berger C, Uehlinger J, Ghelfi D et al (1995) Comparison of tachypnea of the newborn: the relationship to preterm
C-reactive protein and white blood cell count with delivery and significant neonatal morbidity. Am J
differential in neonates at risk for septicaemia. Eur J Obstet Gynecol 146:236–241
Pediatr 154:138–144 Gupta A (2002) Hospital-acquired infections in the neona-
Birnkrant DJ, Picone C, Markowitz W et al (2006) Asso- tal intensive care unit–Klebsiella pneumoniae. Semin
ciation of transient tachypnea of the newborn and child- Perinatol 26:340–345
hood asthma. Pediatr Pulmonol 41:978–984 Hägnevik K, Lagercrantz H, Sjöqvist BA (1991) Establish-
Bland RD (1988) Lung liquid clearance before and after ment of functional residual capacity in infants delivered
birth. Semin Perinatol 12:124 vaginally and by elective cesarean section. Early Hum
Bradshaw JH, Moore PP (2003) Perinatal cytomegalovirus Dev 27:103–110
infection associated with lung cysts. J Paediatr Child Halliday HL, McClure G, Reid MM et al (1984) Controlled
Health 39:563–566 trial of artificial surfactant to prevent respiratory dis-
Brook I, Martin WJ, Finegold SM (1980) Bacteriology of tress syndrome. Lancet 1:476–478
tracheal aspirates in intubated newborn. Chest 78: Helve O, Pitkänen O, Janér C et al (2009) Pulmonary fluid
875–877 balance in the human newborn infant. Neonatology
Calvo C, García-García ML, Blanco C et al (2007) 95:347–352
Role of rhinovirus in hospitalized infants with Hook B, Kiwi R, Amini SB et al (1997) Neonatal morbid-
respiratory tract infections in Spain. Pediatr Infect ity after elective repeat cesarean section and trial of
Dis J 26:904–908 labor. Pediatrics 100(3 Part 1):348–353
Cernada M, Brugada M, Golombek S et al (2014) Jain L, Dudell GG (2006) Respiratory transition in infants
Ventilator-associated pneumonia in neonatal patients: delivered by cesarean section. Semin Perinatol
an update. Neonatology 105:98–107 30:296–304
Chartrand SA, McCracken GH Jr (1982) Staphylococcal Janér C, Pitkänen OM, Süvari L et al (2015) Duration of
pneumonia in infants and children. Pediatr Infect Dis gestation and mode of delivery affect the genes of
1:19–23 transepithelial sodium transport in pulmonary adapta-
Cole VA, Normand IC, Reynolds EO, Rivers RP (1973) tion. Neonatology 107:27–33
Pathogenesis of hemorrhagic pulmonary edema and Kluckow M, Evans N (2000) Ductal shunting, high pul-
massive pulmonary hemorrhage in the newborn. Pedi- monary blood flow, and pulmonary hemorrhage.
atrics 51:175–187 J Pediatr 137:68–72
Copetti R, Cattarossi L (2006) The ‘double lung point’: an Kostelanetz AS, Dhanireddy R (2004) Survival of the
ultrasound sign diagnostic of transient tachypnea of the very low birth infants after cardiopulmonary resuscita-
newborn. Neonatology 91:203–209 tion in the neonatal intensive care unit. J Perinatol
Cummings JJ, Carlton DP, Poulain FR et al (1993) Hypo- 24:279–283
proteinemia slows lung liquid clearance in young Leslie GI, Scurr RD, Barr PA (1981) Early-onset bacterial
lambs. J Appl Physiol 74:153–160 pneumonia: a comparison with severe hyaline mem-
Demissie K, Marcella SW, Breckenridge MB, Rhoads GG brane disease. Aust Paediatr J 17:202–206
(1998) Maternal asthma and transient tachypnea of the Levine CD (1991) Premature rupture of the membranes
newborn. Pediatrics 102(1 Part 1):84–90 and sepsis in preterm neonates. Nurs Res 40:36–41
Faden H, Wynn RJ, Campagna L, Ryan RM (2005) Out- Liem JJ, Huq SI, Ekuma O et al (2007) Transient tachypnea
break of adenovirus type 30 in a neonatal intensive care of the newborn may be an early clinical manifestation
unit. J Pediatr 146:523–527 of wheezing symptoms. J Pediatr 151:29–33
Findlay RD, Taeusch HW, David-Cu R, Walther FJ (1995) Long W, Corbet A, Allen A (1992) Retrospective search
Lysis of red blood cells and alveolar epithelial toxicity for bleeding diathesis among premature newborns with
by therapeutic pulmonary surfactants. Pediatr Res pulmonary hemorrhage after synthetic surfactant treat-
37:26–30 ment. J Pediatr 120:S45–S48
Frakking FN, Brouwer N, van Eijkelenburg NK et al Makhoul IR, Yacoub A, Smolkin T et al (2006) Values of
(2007) Low mannose-binding lectin (MBL) levels in C-reactive protein, procalcitonin, and Staphylococcus-
neonates with pneumonia and sepsis. Clin Exp specific PCR in neonatal late-onset sepsis. Acta
Immunol 150:255–262 Paediatr 95:1218–1223
872 M. E. Patrinos and R. J. Martin
Martin RJ, Fanaroff AA, Walsh MC (eds) (2015) Neonatal- Ronchi A, Michelow IC, Chapin KC et al (2014) Viral
perinatal medicine diseases of the fetus and infant, 10th respiratory tract infections in the neonatal intensive
edn. Mosby/Elsevier, New York care unit: the VIRIoN-I study. J Pediatr 165:690–696
Miller LK, Calenoff L, Boehm JJ, Riedy MJ (1980) Ruderman JW, Srugo I, Morgan MA et al (1994) Pneumo-
Respiratory distress in the newborn. JAMA 243: nia in the neonatal intensive care unit. Diagnosis by
1176–1179 quantitative bacterial tracheal aspirate cultures. J Peri-
Milner AD, Saunders RA, Hopkin IE (1978) Is air trapping natol 14:182–186
important in the maintenance of the functional residual Scholl JE, Yanowitz TD (2015) Pulmonary hemorrhage in
capacity in the hours after birth? Early Hum Dev 27: very low birth weight infants: a case-control analysis. J
103–110 Pediatr 166:1083–1084
Numazaki K, Asanuma H, Niida Y (2003) Chlamydia Sherman MP, Chance KH, Goetzman BW (1984) Gram’s
trachomatis infection in early neonatal period. BMC stains of tracheal secretions predict neonatal bacter-
Infect Dis 3:2 emia. Am J Dis Child 138:848–850
Pandit PB, Dunn MS, Colucci EA (1995) Surfactant ther- Shi Y, Tang S, Li H et al (2005) New treatment of neonatal
apy in neonates with respiratory deterioration due to pulmonary hemorrhage with hemocoagulase in addition
pulmonary hemorrhage. Pediatrics 95:32–36 to mechanical ventilation. Biol Neonate 88:118–121
Pappin A, Shenker N, Hack M, Redline RW (1994) Exten- Stoll BJ, Hansen NI, Sánchez PJ et al (2011) Early onset
sive intraalveolar pulmonary hemorrhage in infants neonatal sepsis: the burden of Group B Streptococcal
dying after surfactant therapy. J Pediatr 124:621–626 and E. coli disease continues. Pediatrics 127:817–826
Philip AG (1994) The changing face of neonatal infection: Takahashi R, Tagawa M, Sanjo M et al (2007) Severe
experience at a regional medical center. Pediatr Infect postnatal cytomegalovirus infection in a very prema-
Dis J 13:1098–1102 ture infant. Neonatology 92:236–236
Raimondi F, Migliaro F, Sodano A et al (2014) Use of Webber S, Wilkinson AR, Lindsell D et al (1990) Neonatal
neonatal chest ultrasound to predict noninvasive venti- pneumonia. Arch Dis Child 65:207–211
lation failure. Pediatrics 134:e1089–e1094 Yuan TM, Chen LH, Yu HM (2007) Risk factors and
Raju TN, Langenberg P (1993) Pulmonary hemorrhage outcomes for ventilator-associated pneumonia in neo-
and exogenous surfactant therapy: a meta-analysis. natal intensive care unit patients. J Perinat Med 35:
J Pediatr 123:603–610 334–338
Rawlings JS, Smith FR (1984) Transient tachypnea of the Yusuf K, Soraisham AS, Fonseca K (2007) Fatal influenza
newborn. An analysis of neonatal and obstetric risk B virus pneumonia in a preterm neonate: case report
factors. Am J Dis Child 138:869–871 and review of the literature. J Perinatol 27:623–625
Pulmonary Air Leakage in Newborns
56
Paola Papoff and Corrado Moretti
Contents
56.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 874
56.2 Pulmonary Air Leaks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 874
56.3 Structure of the Lung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 874
56.4 Pulmonary Interstitial Emphysema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 875
56.4.1 Etiology and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 875
56.4.2 Clinical Aspects, Differential Diagnosis, and Prognosis . . . . . . . . . . . . . . . . . . . . 876
56.4.3 Therapy and Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 877
56.5 Pneumomediastinum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 877
56.5.1 Etiology and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 878
56.5.2 Clinical Aspects and Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 878
56.5.3 Therapy and Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 879
56.6 Pneumothorax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 879
56.6.1 Etiology and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 880
56.6.2 Clinical Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 880
56.6.3 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 881
56.6.4 Therapy and Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 881
56.6.5 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 882
56.7 Pneumopericardium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 882
56.7.1 Etiology and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 883
56.7.2 Clinical Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 883
56.7.3 Therapy and Treatments and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 883
P. Papoff
Pediatric Intensive Care Unit, Sapienza University of
Rome, Rome, Italy
e-mail: [email protected]
C. Moretti (*)
Università degli Studi di Roma “La Sapienza”, Rome, Italy
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 873
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_204
874 P. Papoff and C. Moretti
56.8 Pneumoperitoneum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 883
56.8.1 Etiology and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 883
56.8.2 Clinical Aspects, Therapy, and Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 884
56.9 Subcutaneous Emphysema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 884
56.10 Pulmonary Gas Embolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 884
56.10.1 Clinical Aspects, Therapy, and Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 884
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 884
Abstract 56.2 Pulmonary Air Leaks
In neonates, the most common air leaks include
pulmonary interstitial emphysema, pneumome- Pulmonary air leaks include a number of clinical
diastinum, and pneumothorax, while conditions characterized by overdistension and
pneumopericardium, pneumoperitoneum, and rupture of the alveolar wall with air leaking from
venous pulmonary embolism are less frequent. the intra-alveolar space into the surrounding tis-
Air leaks are more common and severe among sue. The air dissects along the perivascular con-
neonates with lung disease characterized by nective tissue sheath toward the hilum, resulting
either poor lung compliance needing high ven- in a pneumomediastinum, or into the pleural
tilatory pressures or lung overdistention. Many space, producing a pneumothorax. Less com-
affected neonates have minimal or no symp- monly, air may dissect into the pericardial space,
toms, while others present with signs of respi- subcutaneous tissue, peritoneal space, or venous
ratory distress and increased oxygen circulation causing pneumopericardium, subcuta-
requirement. Sudden collapse may occur in neous emphysema, pneumoperitoneum, and
case of hypertensive pneumothorax or venous pulmonary embolism, respectively. Air
pneumopericardium. The diagnosis is leaks are more common and more severe among
suspected clinically and confirmed by chest neonates with pulmonary diseases that are char-
X-ray. Treatment varies by type of air leak and acterized by poor lung compliance (e.g., respira-
severity of clinical condition. tory distress syndrome) requiring high ventilatory
pressures or by airway obstruction (e.g., meco-
nium aspiration syndrome) because of alveolar
overdistention.
56.1 Salient Points
The incidence of pulmonary air leaks is
inversely related to birth weight and increase in
• The most common neonatal air leaks include
infants who need resuscitation. Affected neonates
pulmonary interstitial emphysema,
may be asymptomatic or have various degrees of
pneumomediastinum, and pneumothorax.
respiratory distress. Diagnosis is suspected clini-
• Air leaks may occur spontaneously or develop
cally because of respiratory distress and increased
in association with other forms of lung disease
oxygen requirement and confirmed by X-ray.
often requiring ventilatory support.
Treatment varies by type and severity of air leak.
• Symptoms may vary from mild respiratory dis-
tress to severe hypoxia and hemodynamic
instability.
• Diagnosis is suspected clinically and con- 56.3 Structure of the Lung
firmed radiographically.
• Treatment varies by type and severity, ranging Macroscopically, the lung is divided into three
from watchful waiting to ventilatory pressure lobes on the right and two on the left, each of
reduction or chest drainage. which has autonomous ventilation and blood
56 Pulmonary Air Leakage in Newborns 875
supply. Each lobe comprises segments, which are resulting in pulmonary interstitial emphysema.
pyramidal in shape with the apex toward the hilum The extent of PIE can vary. PIE may occur
and the base toward the surface of the lung. The throughout the lungs or may be unilateral or
segments are supplied by a bronchus and by a lobar. In the former case, it may be difficult to
segmentary artery and are drained by a differentiate PIE from early bronchopulmonary
perisegmentary venous network. Each segment dysplasia (BPD).
comprises pulmonary lobules, each of which is The incidence of PIE has decreased because of
supplied by a lobular bronchiole, and a branch of treatments such as surfactant and the concept of
the pulmonary artery. The lobular bronchiole con- “gentle ventilation,” as well as the availability of
tinues branching until it reaches the level of termi- high-frequency oscillatory ventilation (HFOV)
nal bronchioles, which ventilate the alveolar sacs for infants who are difficult to maintain with con-
that comprise clusters of alveoli. There are 10–15 ventional ventilation (Helbich et al. 1998).
alveoli in each alveolar sac. These are the func- Risk factors for PIE are:
tional units of the lung where gas exchange occurs.
The bronchial tree and associated vessels are • Mechanical ventilation with high pressures or
wrapped in a sheath of collagen and elastic tissue. volumes (the most important factor)
The pressure on the pleural surface is transmitted • Low gestational age (PIE usually develops in
through the alveolar walls to the alveoli. Each infants younger than 32 weeks’ gestation, who
alveolar unit is interdependent with the adjacent weigh less than 1,200 g) (Hart et al. 1983)
one so that the expansion of one alveolus deter- • Pulmonary hypoplasia
mines the increase in wall tension of neighboring • Pulmonary diseases, e.g., severe respiratory
alveoli and ensures uniform pulmonary expansion. distress syndrome (RDS), meconium aspira-
Most of the development of the pulmonary elastic tion syndrome (MAS), and infectious or aspi-
structure occurs during the fetal saccular period, ration pneumonia (Campbell 1970)
which begins toward the 25th week of gestation. • Chorioamnionitis and funisitis (Jeffrey 2003)
The terminal bronchiole gives rise to two or • Malpositioned endotracheal tube (Greenough
more respiratory or alveolar bronchioles, which et al. 1984)
develop hemispheric evaginations called alveoli.
Alveoli are more numerous in the distal portion of
the respiratory bronchiolus, which ends by 56.4.1 Etiology and Pathogenesis
branching into alveolar ducts and finally the alve-
olar sacs, which form the terminal portion of the The mechanisms involved in spontaneous, inter-
respiratory airways. stitial, mediastinal, and subcutaneous emphysema
Each lung is enveloped by a serous membrane, have been described by Macklin and Macklin
the pleura. (Macklin 1939). Their experimental work with
various animal models led to the hypothesis that
overdistended alveoli resulting from uneven ven-
56.4 Pulmonary Interstitial tilation rupture into the pulmonary vascular
Emphysema sheaths and create PIE. Predisposing factors for
PIE are positive pressure ventilation (PPV) with
Pulmonary interstitial emphysema (PIE) may be high mean airway pressures (MAP) and reduced
defined as a collection of gas outside the airway lung compliance.
and inside the interstitial space. It is caused by The basic requirement for rupture is the exis-
alveolar and bronchiolar rupture. The perivascular tence of a pressure gradient between the alveo-
connective tissue is more abundant and less lus and its surrounding structure. However, in
dissectible in preterm than older infants. This pre- extremely premature infants, PIE can occur at
disposes to air trapping in the perivascular space, low mean airway pressures and probably
876 P. Papoff and C. Moretti
residual volume and dead space, and an increased
ventilation perfusion (V/Q) mismatch. It also
impedes pulmonary blood flow and obstructs the
lymphatic drainage. These changes account for
worsening oxygenation.
At an early stage of RDS, there is increased
interstitial and perivascular fluid that rapidly
decreases over the next few days. This fluid may
obstruct the movement of gas from ruptured alve-
oli to the mediastinum through the
bronchovascular sheaths, causing an increase of
PIE. Another possible mechanism for entrapment
of air in the interstitium is the increased amount of
connective tissue in the immature lung. Entrap-
ment of air in the interstitium may result in a
Fig. 1 Distal bronchovascular sheath surrounded by alve-
vicious cycle that causes compression of the adja-
oli after expiratory airflow obstruction. Pressure gradient cent alveoli and a further increase in ventilation
between airspace and perivascular interstitium leads to pressure with more air escaping from the
alveolar rupture (arrows) and direct introduction of air overdistended alveoli into the interstitial tissues.
into bronchovascular sheath. Modified from (Maunder
1984)
56.4.2 Clinical Aspects, Differential
reflects increased sensitivity to stretch by the Diagnosis, and Prognosis
immature lung. The pressure within adjacent
alveoli is generally assumed to be similar and PIE may occur during the first 72 h of life or as a
the interalveolar wall remains intact. As illus- complication of prolonged positive pressure ven-
trated schematically in Fig. 1 (Maunder 1984), tilation in older premature infants.
if a pressure difference develops between the The clinical presentation of PIE varies with size
alveoli, the risk of alveolar rupture is increased, and location of gas accumulation. PIE may cause
causing interstitial emphysema. Since the mean compression of small airways with wheezing or
pressure within the mediastinum is always diminished breath sounds because of decreased
rather lower than in peripheral lung paren- lung compliance. There may be changes in venti-
chyma, air dissects proximally along the lator requirements, increased respiratory rate, and
bronchovascular sheaths to the lung hilum and variations in heart rate and blood pressure. Trapped
mediastinal soft tissue. Having reached the gas reduces pulmonary perfusion by compressing
mediastinum, accumulated air may decompress blood vessels, causing hypoxemia, hypercapnia,
into cervical and subcutaneous tissue or to the and respiratory acidosis.
retroperitoneum, dissecting along the fascial The air collection along the bronchovascular
planes. If mediastinal pressure rises abruptly sheaths is visible radiologically as small rounded,
or decompression via these routes is not suffi- nonconfluent, microradiolucencies throughout the
cient to relieve the tension, the mediastinal lungs (Fig. 2). PIE may be unilateral (Fig. 3). If
parietal pleura may rupture, resulting in pneu- there is mechanical ventilation and because of
mothorax. This mechanism, rather than rupture rupture of interlobular septa, PIE tends to form
of subpleural blebs, is thought to be responsible hypertransparent bubbles that may be quite large
for spontaneous pneumothorax in a majority of and look like pseudocysts. Small areas of PIE
cases (Caldwell et al. 1979). alternating with pneumatoceles have the effect of
The presence of air in the interstitial tissue making the pulmonary parenchyma look like a
causes reduced compliance, an increase in honeycomb.
56 Pulmonary Air Leakage in Newborns 877
Fig. 2 Diffuse pulmonary interstitial emphysema
Possible complications of PIE include other air
leaks, such as pneumomediastinum, pneumotho- Fig. 3 Pulmonary interstitial emphysema, especially
marked in the right lung
rax, pneumopericardium, pneumoperitoneum,
subcutaneous emphysema, and pulmonary
venous embolism, intraventricular hemorrhage, HFOV has been found to be effective in the treat-
possible epithelialization of the interstitial air ment of PIE (Helbich et al. 1998).
pockets, and chronic lung disease. Treatment of the localized form includes posi-
PIE may be confused with severe respiratory tioning the infant with the affected side down or
distress syndrome (RDS), early bronchopulmonary selectively intubating the main bronchus of the
dysplasia (BPD), cystic adenomatoid malforma- unaffected side (Brooks et al. 1977; Chan and
tion, lymphangiectasia, bronchogenic cysts, con- Greenough 1992). Severely ill premature neo-
genital lobar emphysema, and pulmonary nates may not tolerate the latter treatment because
infection. PIE may take several weeks to resolve. it is difficult for them to compensate for distress
The condition can therefore increase the length of with one functioning lung. Physiotherapy may be
time of mechanical ventilation and the incidence of useful as the presence of mucus may contribute to
BPD (Hart et al. 1983). Some infants may develop the formation of cysts and bubbles through a valve
chronic lobar emphysema and may require surgical mechanism (Swingle et al. 1984). A short course
lobectomies. of dexamethasone has been shown to be as an
effective treatment in infants with PIE, possibly
by reducing airway edema and inflammation and
56.4.3 Therapy and Treatments airway obstruction (Fitzgerald et al. 1998).
In mechanically ventilated infants, initial treat-
ment of PIE should be aimed at obtaining maxi- 56.5 Pneumomediastinum
mum patient-ventilator synchrony, securing the
endotracheal tube in the appropriate position, Pneumomediastinum is defined as a collection
and reducing peak inspiratory pressure (PIP) and of gas in the mediastinal space. Free air may
positive end expiratory pressure (PEEP) as much not be confined solely to the mediastinum
as possible, consistent with blood gas values. A but may penetrate through tissue planes, causing
short inspiratory time (Ti) and a triangular pres- pneumopericardium, pneumothorax, subcutane-
sure wave morphology should be set to avoid ous emphysema, or pneumoperitoneum. Pneumo-
inflating the parenchymal cysts that have a long mediastinum occurs in approximately 2.5 per
time constant (Meadow and Cheromcha 1985). 1,000 live births.
878 P. Papoff and C. Moretti
Risk factors for pneumomediastinum are: pneumomediastinum may exhibit bulging in the
midthoracic area, distended neck veins, and low
• Gas trapping associated either with several blood pressure.
lung diseases, including RDS, pneumonia, The pneumomediastinum is characterized
and MAS, or with mechanical ventilation radiologically by the presence of cardiac margins
• Birth asphyxia requiring resuscitation that are clearly delimited by a thin black streak.
• Chest trauma The edges of the right atrium and the left ventricle
• Mechanical obstruction as seen with a foreign are generally well distinguished from the pulmo-
body or a tumor nary parenchyma. In cases of pneumome-
diastinum with small quantities of air, the only
sign is a radiolucent band (hyperlucency) in the
56.5.1 Etiology and Pathogenesis retrosternal area on the lateral view (Fig. 4)
(Macklin 1939; Hoffer and Ablow 1984). The
Pneumomediastinum is in most cases a complica- main diagnostic element of pneumomediastinum
tion of a pre-existing pulmonary disease and may is prominence of lobes of the thymus that may be
be preceded by PIE. The air that leaks out of the more or less marked depending on the amount of
alveoli makes its way along the bronchovascular air in the mediastinum (the image resembles the
sheaths toward the hilum and into the mediastinum. wings of a seagull or a spinnaker sail, Fig. 5)
Pneumomediastinum may appear spontaneously at (Moseley 1960; Lawal et al. 2009). When there
birth or may occur later, secondary to the formation is a pneumomediastinum, the lobes of the thymus
of a valve-like mechanism and consequent rupture are surrounded by air, and in the lateral view, this
of the alveoli. The air moving from the mediasti- peculiar radiographic aspect is sufficient to diag-
num toward the neck causes the dissection of the nose an anteromedial pneumothorax. The air in
cervical aponeurosis and the supraclavicular tissue the mediastinum may push both thymus lobes
planes, forming subcutaneous emphysema. The air toward the pulmonary apices, thus simulating
in the mediastinum may also spread to the upper lobar collapse or pneumonia. The presence
subpleural space and simulate a basal pneumotho- of other signs suggesting pneumomediastinum
rax. Air may also leak into the peritoneal cavity allows this condition to be differentiated from
through areas of lower resistance, such as the ster- pulmonary consolidation.
nocostal trigone, and cause subdiaphragmatic air
collections (pneumoperitoneum).
56.5.2 Clinical Aspects and Differential
Diagnosis
Pneumomediastinum rarely leads to clinically sig-
nificant complications. However, compression of
mediastinal structures may occur when there is
extensive subcutaneous and mediastinal gas. The
infant with pneumomediastinum is usually
asymptomatic or has mild respiratory distress. In
the absence of other pulmonary disorders, it tends
to regress spontaneously.
A large accumulation of trapped air may com-
promise ventilation and cardiac output. The first
sign may be subcutaneous emphysema in the
neck, face, or chest. The infant with a large Fig. 4 Pneumomediastinum, lateral view
56 Pulmonary Air Leakage in Newborns 879
56.6 Pneumothorax
Pneumothorax is defined as an accumulation of air
in the pleural space. Pneumothoraces have been
termed small, moderate, or large if they occupy
15% or less, 15–60%, or more than 60% of the
pleural space.
Spontaneous pneumothoraces develop in up to
1–1.5% of normal term infants around the time of
birth owing to high transpulmonary pressure dur-
ing the first breaths (only about 10% of these are
symptomatic) (Steele et al. 1971). Males are more
affected than females, whereas there is no differ-
ence between term and preterm infants. In the
Fig. 5 Pneumomediastinum with the raised thymus lobes presence of lung disease, especially if mechanical
(spinnaker sail)
ventilation is required, the incidence of pneumo-
thorax increases dramatically (10%). Fifteen to
20% of pneumothoraces are bilateral. Two-thirds
of unilateral pneumothoraces affect the right side.
There is no correlation between the incidence of
pneumothorax and gestational age (Greenough
et al. 1984). Reports of familial spontaneous
pneumothoraces in neonates are rare (Bagchi and
Nycyk 2002).
Risk factors for pneumothorax are:
• Lung diseases, such as wet lung (following
cesarean section) (Benterud et al. 2009),
MAS, congenital bullae, and pulmonary hypo-
Fig. 6 Pneumomediastinum with the air collected in the plasia, which result in uneven lung compliance
triangular ligament and alveolar overdistension
• PIE
• Ventilatory support. Predisposing factors dur-
Air may collect in some mediastinum recesses, ing mechanical ventilation are:
suchlike the triangular ligament. In such cases, the – Lack of synchronization. Asynchrony is
chest X-ray shows a hyperlucent paravertebral usually secondary to trigger delay, long Ti,
area extending from the diaphragm up to the pul- and an inspiratory/expiratory ratio (I/E)
monary hilum (Fig. 6; Volberg et al. 1979). 1:1 (Primhak 1983)
Pneumomediastinum should be differentiated – High ventilation pressures
from bronchogenic cysts (Shah et al. 1999), – High PEEP (Klinger et al. 2008)
esophageal perforation, and pneumothorax. – High ventilation tidal volumes (more
important than increase in pressure)
(McCallion et al. 2005)
56.5.3 Therapy and Treatments – Intubation of the right main bronchus
• Nasal CPAP (the risk is lower than during
A conservative approach is usually adopted. Only mechanical ventilation)
tension pneumomediastinum with tamponade • Low temperature of inhaled gases (<36.5 C).
needs immediate drainage. In infants weighing 1,500 g at birth, the
880 P. Papoff and C. Moretti
incidence of pneumothorax increases if the collection of air shifts the mediastinum to the con-
temperature of inhaled gases is below tralateral hemithorax and compresses the contralat-
36.5 C. It is likely that lower temperatures eral lung and great vessels, compromising both
cause a reduced content of water in the venti- cardiovascular and respiratory function. Whether
lation gas, which alters the mucociliary clear- air enters the pleural space through a defect in the
ance (Tarnow-Mordi et al. 1989) precipitating chest wall, a lacerated bronchus, or alveolus, a
airway obstruction one-way valve effect is created so that air enters
• Direct injury (suction catheter and central during inspiration but cannot escape during expira-
venous catheter positioning) tion. Accumulation of air continues until the intra-
thoracic pressure of the affected hemithorax
equilibrates with atmospheric pressure. At this
point, the accumulation of pressure within the thorax
56.6.1 Etiology and Pathogenesis leads to collapse of the ipsilateral lung and displace-
ment of the mediastinum (and associated great ves-
In an overdistended lung, air passes from a rup- sels) toward the contralateral hemithorax. While the
tured alveolus up the bronchovascular sheath into superior vena cava is able to move to some extent,
the mediastinum and from there into the pleural the inferior vena cava is relatively fixed within the
cavity causing pneumothorax. The pathogenesis diaphragm and will be distorted. As two-thirds of
of pneumothorax is comparable to that of the the venous return in children comes from below the
pneumomediastinum. Rarely pneumothorax is diaphragm, compression of the inferior vena cava
the result of the rupture of subpleural blebs. In leads to a dramatic reduction in venous return to the
the neonate, the susceptibility to pulmonary rup- heart and cardiovascular collapse.
ture is further enhanced by a reduced number of
alveolar connecting channels (pores of Kohn) that
allow air to redistribute between ventilated and 56.6.2 Clinical Aspects
nonventilated units.
Diagnosis of pneumothorax is based on clinical
56.6.1.1 Classification signs, physical examination, arterial blood gases,
Pneumothoraces are commonly classified into transillumination, and imaging. Pneumothorax pre-
three types: simple, communicating, and tension. sents with signs of respiratory distress (grunting,
Simple or noncommunicating pneumothorax increased respiratory rate, retractions), chest asym-
occurs when there is no direct communication metry, cyanosis, episodes of apnea and bradycardia,
with the atmosphere. There is no mediastinal tachycardia, and hypotension. During mechanical
shift resulting from the accumulated air. A simple ventilation, pneumothorax is frequently tension
pneumothorax may occur spontaneously or as a accompanied by compression of the mediastinal
consequence of barotrauma or volutrauma during structures, which may cause impaired venous
positive pressure mechanical ventilation. return and cardiocirculatory collapse (Ogata
Communicating or open pneumothorax may et al. 1976). On auscultation of the chest, breath
occur in association with an open defect in the sounds are decreased or absent in the affected side,
chest wall as in patent ductus arteriosus (PDA) and it may be difficult to identify the heart sounds.
surgery. As intrathoracic pressure is less than A pneumothorax should be suspected when there is
atmospheric pressure during spontaneous breath- sudden worsening of the clinical condition. How-
ing, air rapidly accumulates in the pleural space. ever, its exact location by auscultation is not always
Loss of negative intrathoracic pressure results in as straightforward, especially in very low weight
varying degrees of lung collapse and further respi- infants. Arterial blood gases may show a respira-
ratory compromise. tory or mixed acidosis and hypoxemia.
Tension pneumothorax is caused by progressive Transillumination is an effective method for
accumulation of air in the pleural space. This demonstrating increased transmission of light on
56 Pulmonary Air Leakage in Newborns 881
Fig. 8 Right antero-medial pneumothorax with a slight
contra-lateral shift of the mediastinum
Fig. 7 Right tension pneumothorax
the affected side (Kuhns et al. 1975). However, • Bronchogenic cyst
chest X-ray remains the gold standard for the diag- • Esophageal-pleural fistula (Boerhaave
nosis of pneumothorax. Large pneumothoraces are syndrome)
generally easy to identify radiologically. The
affected hemithorax is larger than the contralateral The most common complications of pneumotho-
hemithorax, with larger intercostal spaces, and the rax in the neonate are respiratory or cardiac arrest,
diaphragmatic dome is lowered. The profile of the intraventricular hemorrhage, bronchopleural fis-
collapsed lung is sharply outlined (Fig. 7). tula, hemopneumothorax, and infection.
In tension pneumothoraces, the contralateral
shift of the mediastinum is generally considerable.
In the most severe cases, the diaphragm is flattened 56.6.4 Therapy and Treatments
or even concave (Moseley 1960). Anterior or
anteromedial collections of air inside the pleural 56.6.4.1 Asymptomatic Pneumothorax
cavity may easily be missed. The appearances are The asymptomatic pneumothorax does not
those of a lung with decreased markings and slight require any specific treatment other than close
contralateral shift of the mediastinum (Fig. 8). In observation and may be managed conservatively.
patients in whom an anteromedial pneumothorax is In small to moderate pneumothoraces, treatment
suspected, a lateral supine chest X-ray is useful. with 100% oxygen may accelerate air
The thymus gland on the side of the pneumothorax reabsorption. High inspired oxygen concentra-
may appear closely adherent to the mediastinum. A tions facilitate nitrogen washout from the blood-
large thymus may give a false impression of a stream (PN2 drops from 573 mmHg at room air to
space-occupying mass in the upper mediastinum. 0 mmHg under 100% oxygen) creating a concen-
Ultrasonography has been shown to be accurate tration gradient between pleural gas and pleural
and efficient for the early detection of clinically venous circulation. This gradient favors the
important pneumothoraces (Brook et al. 2009). reabsorption of nitrogen within the pleural
pockets. This technique has proved to be effective
in animal models or in adult individuals with
56.6.3 Differential Diagnosis spontaneous pneumothorax (Northfield 1971),
whereas in neonates 100% oxygen does not
• Lobar emphysema seem to offer significant advantage (Clark
• Cystic adenomatoid malformation of the lung et al. 2014); therefore, due to the risk of oxygen
• Congenital diaphragmatic hernia toxicity, its use in neonates is controversial.
882 P. Papoff and C. Moretti
When mechanical ventilation is used, even small • Lung puncture
pneumothoraces are usually drained. • Bronchopleural fistula, which is evidenced by
persisting pneumothorax
56.6.4.2 Needle Aspiration • Chylothorax (secondary to lesions of the tho-
Needle aspiration can be used to treat a symptom- racic duct)
atic pneumothorax. It is frequently curative in • Paralysis of the diaphragm (due to lesions of
infants who are not mechanically ventilated and the phrenic nerve)
may be a temporizing treatment in infants who are • Breast deformity (Rainer et al. 2003)
mechanically ventilated.
56.6.4.4 Selective Intubation
56.6.4.3 Thoracotomy Selective intubation of the contralateral main
Chest tube drainage (thoracotomy) is usually bronchus should be reserved for cases where
needed for continuous drainage of pneumothoraces there is a bronchopleural fistula. In addition, a
that develop in infants receiving positive pressure technique of single-lung ventilation using a
ventilation because the air leak may persist. In Swan-Ganz catheter to block the main bronchus
these cases, continuous aspiration with negative on the disease side has been successfully used on
pressures of 5–10 cmH2O may be useful. neonates unresponsive to conventional therapy
Technique of pleural drainage: (Rastogi et al. 2007).
(a) Select a chest tube of appropriate size. For
small infants, 8 Fr chest tubes are adequate. 56.6.5 Prevention
For larger infants, 10 Fr chest tubes are better.
(b) Locate the fifth intercostal space in the ante- Pneumothorax may be prevented by using venti-
rior axillary line on the affected side (Brook lation techniques that allow for synchronization
et al. 2009). between spontaneous and mechanical breaths
(c) Prepare the site with antibacterial solution. so as to reduce transpulmonary pressure fluctua-
(d) Administer analgesic to the infant. Be ready tions. HFOV may reduce the incidence of
for resuscitation. pneumothorax in infants with severe pulmonary
(e) Inject the area with a small amount of 1% disease.
lidocaine (1–2 mg/kg).
(f) Make a small incision (approximately the size
of the tube) along the intercostal space directly 56.7 Pneumopericardium
over the sixth rib.
(g) Insert the trocar by blunt dissection. Pneumopericardium is a collection of air in the
(h) Advance the chest tube a few centimeters and pericardial space. It frequently occurs in associa-
check the position radiographically. tion with pneumomediastinum. It is likely that gas
(i) Suture the tube in place. The tube should be enters the pericardium through a defect in the
kept for 24–48 h from the moment the pneumo- pericardial sac, probably at the pericardial reflec-
thorax has stopped draining, i.e., when the inter- tion near the ostia of the pulmonary veins. The
mittent air leakage stops. In the case of residual incidence has been estimated around 1.3% of term
air, attach the tube to a drainage system under and preterm infants (Burt 1982). Pneumoper-
low continuous suction (–10 to –20 cm H2O). icardium rarely occurs spontaneously (Itani and
Mikati 1998).
Complications of pleural drainage include: Risk factors for pneumopericardium are:
• Infection • Prematurity
• Hemorrhage (laceration of intercostal vessels) • Birth asphyxia requiring resuscitation
56 Pulmonary Air Leakage in Newborns 883
• Mechanical ventilation (PIP >32 cm H2O,
MAP >17 cm H2O)
• Lung disease
• Anatomic predisposition (maldevelopment of
the left pleuropericardial membrane)
56.7.1 Etiology and Pathogenesis
Pneumopericardium is frequently associated
with a pneumomediastinum and/or pneumotho-
rax since the pathogenic mechanism is the same,
i.e., diffusion of air from the pulmonary inter-
stices through the bronchovascular sheaths to the
Fig. 9 Pneumopericardium: a hypertransparent image that
planes of pleural reflection at the level of the entirely delimits the heart except for the emergence of the
large vessels, where air under tension flows great vessels
directly into the pericardium sac. Pericardial con-
nective tissue is discontinuous at the reflection of
56.7.3 Therapy and Treatments
parietal onto visceral pericardium near the ostia
and Prognosis
of the pulmonary veins so that there is a site of
potential weakness where a microscopic dissec-
Treatment is conservative if asymptomatic.
tion of air into the pericardial sac is possible.
Oxygen administration will help the
Moreover, congenital defects can be an explana-
reabsorption of air in cases with mild respira-
tion for pneumopericardium.
tory distress (Hummler et al. 1996). If cardiac
tamponade occurs, drainage with a cannula nee-
dle will be performed via the subxiphoid route.
56.7.2 Clinical Aspects Relapses are frequent and require the position-
ing of an indwelling drainage tube (Pfenninger
Because of the speed at which it occurs, et al. 1982). Mortality is high, between 70%
pneumopericardium is usually a dramatic and 90%.
event, causing cardiac tamponade. Symptoms
appear when the pressure in the pericardium
exceeds the ventricular filling pressure and car- 56.8 Pneumoperitoneum
diac output is reduced (Itani and Mikati 1998;
Long 1990). Sometimes the presenting signs of Pneumoperitoneum is defined as the presence of
pneumopericardium may be confused with air within the peritoneal cavity.
those of a tension pneumothorax (sudden hypo-
tension, bradycardia, and hypoxia). The heart
sounds are muffled, but a friction rub is occa- 56.8.1 Etiology and Pathogenesis
sionally audible. There are low voltages on
electrocardiography. The radiological appear- Pneumoperitoneum usually results from perfora-
ances of pneumopericardium are of a tion of the gut, although in some instances it can
hypertransparent image, which outlines the be caused by air under pressure dissecting from
heart entirely, except for where the great vessels the chest (pneumomediastinum, bronchopleural
emerge (Fig. 9). Gas surrounding the heart may fistula) through the diaphragmatic apertures
be confused with pneumomediastinum. into the peritoneal space (Aranda et al. 1972;
884 P. Papoff and C. Moretti
Knight and Abdenour 1981). The diagnosis is 56.10 Pulmonary Gas Embolism
made on an abdominal radiograph and usually
has little clinical significance. However, it must The presence of intravascular gas is a rare com-
be differentiated from intraperitoneal air due to plication of positive pressure ventilation (Lee and
perforated bowel. Tanswell 1989). This condition is usually fatal and
results from direct communication between air-
way lumen, interstitium, and small vascular chan-
56.8.2 Clinical Aspects, Therapy, nels, as demonstrated by barium studies at autopsy
and Treatments (Bowen et al. 1973). It can be a consequence of air
leaks syndromes or lung trauma.
Pneumoperitoneum may be an incidental finding
or may present with abdominal distension or in
most severe cases with cardiovascular collapse. 56.10.1 Clinical Aspects, Therapy,
On the posteroanterior radiograph, pneumo- and Treatments
peritoneum may be difficult to see if free intraper-
itoneal gas accumulates between intestinal loops. Affected infants are usually premature and have
If gas is present on both sides of the bowel, it may severe respiratory failure necessitating very high
outline the bowel wall, rendering it visible as a ventilatory pressures. Pulmonary gas embolism
thin, linear stripe (double wall sign or Rigler’s causes a catastrophic deterioration of the patient’s
sign). If there is doubt about the diagnosis of condition with cardiocirculatory collapse.
pneumoperitoneum, consider a lateral shoot- The radiographs of thorax and abdomen show
through abdominal X-ray (with the baby lying on pulmonary interstitial emphysema and pulmonary
his back and the X-ray film at right angles to the venous air embolism (i.e., air within the heart and
mattress) or a lateral decubitus abdominal X-ray, many vessels).
both of which will demonstrate the liver clearly Treatment is directed to sustain cardiopulmo-
separates from the abdominal wall. Free abdomi- nary function.
nal air requires a surgical opinion. Either peritoneal
drainage or laparotomy may be required.
References
56.9 Subcutaneous Emphysema Aranda JV, Stern L, Dunbar JS (1972) Pneumothorax with
pneumoperitoneum in a newborn infant. Am J Dis
Subcutaneous emphysema occurs more com- Child 123:163–166
Bagchi I, Nycyk J (2002) Familial spontaneous pneumo-
monly in the face, neck, or supraclavicular region.
thorax. Arch Dis Child Fetal Neonatal Ed 87:F70
It typically presents as crepitus detected by palpa- Benterud T, Sandvik L, Lindemann R (2009) Cesarean
tion. Clinically, patients can develop dysphonia section is associated with more frequent pneumothorax
and dyspnea. Simple subcutaneous emphysema and respiratory problems in the neonate. Acta Obstet
Gynecol Scand 88:359–361
that does not compromise respiration can be
Bowen FW Jr, Chandra R, Avery GB (1973) Pulmonary
treated with conservative management (oxygen, interstitial emphysema with gas embolism in hyaline
analgesia, antibiotic prophylaxis, reassurance, membrane disease. Am J Dis Child 126:117–118
and close monitoring). More severe subcutaneous Brook OR, Beck-Razi N, Abadi S et al (2009) Sonographic
detection of pneumothorax by radiology residents as
emphysema that causes respiratory obstruction is
part of extended focused assessment with sonography
an emergency, and methods of management for trauma. J Ultrasound Med 28:749–755
include infraclavicular incisions, placement of Brooks JG, Bustamante SA, Koops BL et al (1977) Selec-
14G fenestrated subcutaneous catheters, insertion tive bronchial intubation for the treatment of severe
localized pulmonary interstitial emphysema in new-
of subcutaneous drains with or without suction,
born infants. J Pediatr 91:648–652
tracheostomy, or subcutaneous chest tubes (John- Burt TB (1982) Neonatal pneumopericardium. Radiology
son et al. 2014). 142:81–84
56 Pulmonary Air Leakage in Newborns 885
Caldwell EJ, Powell RD Jr, Mullooly JP (1979) Interstitial Long WA (1990) Pneumopericardium. In: Long WA
emphysema: a study of physiologic factors involved in (ed) Fetal and neonatal cardiology. WB Saunders, Phil-
experimental induction of the lesion. Am Rev Resp Dis adelphia, pp 377–388
102:516–525 Macklin CC (1939) Transport of air along sheaths of pul-
Campbell RE (1970) Intrapulmonary interstitial emphy- monic blood vessels from alveoli to mediastinum. Arch
sema: a complication of hyaline membrane disease. Intern Med 64:913–926
Am J Roentgenol Radium Ther Nucl Med 110:449–456 Maunder RJ (1984) Subcutaneous and mediastinal emphy-
Chan V, Greenough A (1992) Severe localised pulmonary sema pathophysiology, diagnosis, and management.
interstitial emphysema–decompression by selective Arch Intern Med 144:147
bronchial intubation. J Perinat Med 20:313–316 McCallion N, Davis PG, Morley CJ (2005) Volume-
Clark SD, Saker F, Schneeberger MT et al (2014) Admin- targeted versus pressure-limited ventilation in the neo-
istration of 100% oxygen does not hasten resolution of nate. Cochrane Database Syst Rev 3, CD003666
symptomatic spontaneous pneumothorax in neonates. J Meadow WL, Cheromcha D (1985) Successful therapy of
Perinatol 34:528–531 unilateral pulmonary emphysema: mechanical ventila-
Fitzgerald D, Willis D, Usher R, Outerbridge E et al (1998) tion with extremely short inspiratory time. Am J
Dexamethasone for pulmonary interstitial emphysema Perinatol 2:194–197
in preterm infants. Biol Neonate 73:34–39 Moseley JE (1960) Loculated pneumomediastinum in the
Greenough A, Dixon AK, Roberton NR (1984) Pulmonary newborn. A thymic “spinnaker sail” sign. Radiology
interstitial emphysema. Arch Dis Child 59:1046–1051 75:788–790
Hart SM, McNair M, Gamsu HR, Price JF (1983) Pulmo- Northfield TC (1971) Oxygen therapy for spontaneous
nary interstitial emphysema in very low birthweight pneumothorax. Br Med J 4:86–88
infants. Arch Dis Child 58:612–615 Ogata ES, Gregory GA, Kitterman JA et al (1976) Pneu-
Helbich TH, Popow C, Dobner MP et al (1998) Newborn mothorax in the respiratory distress syndrome: inci-
infants with severe hyaline membrane disease: radiolog- dence and effect on vital signs, blood gases, and
ical evaluation during high frequency oscillatory versus pH. Pediatrics 58:177–183
conventional ventilation. Eur J Radiol 28:243–249 Pfenninger J, Bossi E, Biesold J, Blumberg A (1982)
Hoffer FA, Ablow RC (1984) The cross-table lateral view Treatment of pneumothorax, pneumopericardium and
in neonatal pneumothorax. AJR Am J Roentgenol pneumomediastinum. Helv Paediatr Acta 37:353–360
142:1283–1286 Primhak RA (1983) Factors associated with pulmonary air
Hummler HD, Bandstra ES, Abdenour GE (1996) Neona- leak in premature infants receiving mechanical ventila-
tal fellowship.Neonatal pneumopericardium: success- tion. J Pediatr 102:764–768
ful treatment with nitrogen washout technique. J Rainer C, Gardetto A, Fr€ uhwirth M et al (2003) Breast
Perinatol 16:490–493 deformity in adolescence as a result of pneumothorax
Itani MH, Mikati MA (1998) Early onset neonatal sponta- drainage during neonatal intensive care. Pediatrics
neous pneumopericardium. J Med Liban 46:165–167 111:80–86
Jeffrey IJ (2003) The critical role of perinatal pathology. Rastogi S, Gupta A, Wung JT et al (2007) Treatment of
BJOG 110(Suppl 20):128–130 giant pulmonary interstitial emphysema by ipsilateral
Johnson CH, Lang SA, Bilal H et al (2014) In patients with bronchial occlusion with a Swan- Ganz catheter.
extensive subcutaneous emphysema, which technique Pediatr Radiol 37:1130e4
achieves maximal clinical resolution: infraclavicular inci- Shah DS, Lala R, Rajegowda B, Bhatia J (1999) Broncho-
sions, subcutaneous drain insertion or suction on in situ genic cyst and its progress in a premature infant. J
chest drain? Interact Cardiovasc Thorac Surg 18:825–829 Perinatol 19:150–152
Klinger G, Ish-Hurwitz S, Osovsky M et al (2008) Risk Steele RW, Metz JR, Bass JW, DuBois JJ (1971) Pneumo-
factors for pneumothorax in very low birth weight thorax and pneumomediastinum in the newborn. Radi-
infants. Pediatr Crit Care Med 9:398–402 ology 98:629–632
Knight PJ, Abdenour G (1981) Pneumoperitoneum in the Swingle HM, Eggert LD, Bucciarelli RL (1984) New
ventilated neonate: respiratory or gastrointestinal ori- approach to management of unilateral tension pulmo-
gin? J Pediatr 98:972–974 nary interstitial emphysema in premature infants. Pedi-
Kuhns LR, Bednarek FJ, Wyman ML et al (1975) Diag- atrics 74:354–357
nosis of pneumothorax or pneumomediastinum in Tarnow-Mordi WO, Reid E, Griffiths P, Wilkinson AR
the neonate by transillumination. Pediatrics 56: (1989) Low inspired gas temperature and respiratory
355–360 complications in very low birthweight infants. J Pediatr
Lawal TA, Gl€uer S, Reismann M et al (2009) Spontaneous 114:438–442
neonatal pneumomediastinum: the “spinnaker sail” Volberg FM Jr, Everett CJ, Brill PW (1979) Radiologic
sign. Eur J Pediatr Surg 19:50–52 features of inferior pulmonary ligament air collections
Lee SK, Tanswell AK (1989) Pulmonary vascular air in neonates with respiratory distress. Radiology 130:
embolism in the newborn. Arch Dis Child 64:507–510 357–360
Bronchopulmonary Dysplasia/Chronic
Lung Disease of the Newborn 57
Vineet Bhandari
Contents
57.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 888
57.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 888
57.3 Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 889
57.4 Etiology and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 889
57.5 Biomarkers in BPD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 892
57.6 Clinical Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 898
57.7 Differential Diagnoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 899
57.8 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 899
57.9 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 902
57.10 Novel Approaches/Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 904
57.11 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 906
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 906
Abstract profile of infants with BPD has changed and it is
Bronchopulmonary dysplasia (BPD) is a uncommon in infants over 1,200 g birth weight
chronic lung disease associated with premature and >30 weeks gestational age. Understanding
birth and characterized by early lung injury. of the basic biology of lung development and
Over the past four decades, there have been use of antenatal steroids, postnatal surfactant,
significant changes in the definition, pathology, new ventilatory strategies, and aggressive nutri-
and radiological findings of BPD. The clinical tion have resulted in major improvements in the
clinical course and outcomes. Management of
the early, evolving and established phases of
V. Bhandari (*) BPD continues to improve. Despite many
Neonatology/Pediatrics, St. Christopher’s Hospital for advances in care, however, infants with BPD
Children/Drexel University College of Medicine, have significant neurodevelopmental and pul-
Philadelphia, PA, USA
monary sequelae.
Drexel University, Philadelphia, PA, USA
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 887
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_205
888 V. Bhandari
Abbreviations
TIMP Tissue inhibitor of
α1P1 Alpha-1 proteinase inhibitor metalloproteinases
BPD Bronchopulmonary dysplasia TNF Tumor necrosis factor
BW Birth weight TNF-α Tumor necrosis factor-α
CC10 Clara cell 10-kD protein VEGF Vascular endothelial growth factor
CCSP Clara cell secretory protein
CMV Conventional mechanical
ventilation 57.1 Salient Points
CT Computed tomography
CTGI Continuous tracheal gas insufflation • BPD is the most common chronic lung disease
ET-1 Endothelin-1 of infancy.
FGF-2 Fibroblast growth factor-2 • A consensus definition of BPD, with categori-
GA Gestational age zation of severity, has been validated with
HFOV High-frequency oscillatory neurodevelopmental outcomes.
ventilation • While the multitude of animal studies and bio-
HGF Hepatocyte growth factor markers associated with BPD continue to
ICAM-1 Soluble intercellular adhesion expand our scientific knowledge and under-
molecule-1 standing of the pathogenesis of BPD, there is
ILs Interleukins limited data on their causal role and transla-
IL-1RA IL-1 receptor antagonist tional extension to the human premature neo-
iNO Inhaled nitric oxide nate. Progress in this area is crucial to make an
KGF Keratinocyte growth factor impact on BPD.
LFA-1 Lymphocyte function-associated • Identification and quantification of the genetic
antigen 1 contribution to BPD has been done.
LPS Lipopolysaccharide • There is an increasing use of noninvasive ven-
MCP Monocyte chemoattractant proteins tilation techniques (SNIPPV/NCPAP) with or
MIF Macrophage migration inhibitory without less invasive modes of surfactant
factor administration in the prevention and manage-
MMPs Matrix metalloproteinases ment of BPD.
NAC N-acetyl cysteine • The efficacy and safety of caffeine in the pre-
NCPAP Nasal continuous positive airway vention of BPD has been established.
pressure • Pulmonary and neurodevelopmental outcome
NF-kB Nuclear factor-kappa B studies of the neonates surviving the “new”
NIPPV Nasal intermittent positive pressure BPD will need to be done to assess the poten-
ventilation tial health impact of BPD in the long term.
PAI-1 Plasminogen activator inhibitor-1
PDA Patent ductus arteriosus
PMA Postmenstrual age 57.2 Introduction
PTHrP Parathyroid hormone-related
protein Bronchopulmonary dysplasia (BPD) is the
RCT Randomized controlled trial commonest cause of chronic lung disease in
RDS Respiratory distress syndrome infancy (Balany and Bhandari 2015). Recent
RSV Respiratory syncytial virus international data report an incidence of BPD of
SOD Superoxide dismutase 12–34% in very low birth weight (VLBW;
TA Tracheal aspirates <1,500 g) infants (Jensen and Schmidt 2014).
TATI Tumor-associated trypsin inhibitor Despite many advances in neonatal ventilation
TGF-ß1 Transforming growth factor-ß1 techniques and the widespread use of surfactant
57 Bronchopulmonary Dysplasia/Chronic Lung Disease of the Newborn 889
Table 1 Diagnostic criteria for BPD
Mild – supplemental O2 Moderate – supplemental O2 Severe – supplemental O2 (for 28 days)
(for 28 days) and (for 28 days) and and
<32 weeks RA at 36 weeks corrected <0.3 FiO2 at 36 weeks 0.3 FiO2
GA at birth GA or at discharge corrected GA or at discharge +/ positive pressure support at
36 weeks corrected GA or at discharge
32 weeks RA by postnatal day 56 or <0.3 FiO2 by postnatal day 0.3 FiO2
GA at birth at discharge 56 or at discharge +/ positive pressure support by
postnatal day 56 or at discharge
BPD bronchopulmonary dysplasia, FiO2 fraction of inspired oxygen, GA gestational age, RA room air (From Bhandari
and Bhandari (2009), with permission)
and antenatal corticosteroids, the incidence of angiogenesis proportionate to the growth of the
BPD has remained the same (Smith et al. 2005) air-exchanging lung parenchyma, abnormal dis-
or even increased slightly (Bhandari and Bhandari tribution of alveolar capillaries, prominent corner
2011; Trembath and Laughon 2012). In a recent vessels with variable capillary density in adjacent
evaluation of the utility of the various definitions alveoli, or vessels that are more distant from the
of BPD, the number of unclassified infants was air surface.
lowest with the consensus definition (Walsh
et al. 2006) (summarized in Table 1) (2.1%) and
highest with the physiologic definition (Walsh 57.4 Etiology and Pathogenesis
et al. 2004) (16.1%) (Poindexter et al. 2015).
Newer management strategies with high flow Genetic predisposition, baro- and volu-trauma
nasal cannula (up to 8 L/min) to provide positive from mechanical ventilation in surfactant-
pressure support are impacting the definition of deficient premature lungs, pulmonary edema,
BPD. Currently, the status of the respiratory sup- pre- and postnatal infections, and reactive oxygen
port, with or without “physiologic” testing to species from prolonged oxygen use and high oxy-
ascertain the supplemental oxygen requirement, gen concentrations have been associated with the
at 36 weeks postmenstrual age (PMA) is the development of BPD (Fig. 1).
most commonly used definition.
1. Genetics: Genetic factors contribute 53–82%
57.3 Pathology susceptibility (Bhandari et al. 2006a; Lavoie
et al. 2008), making BPD a disease occurring
Pre-surfactant era or “old” BPD lung pathology secondary to “gene-environmental” factors. In
showed severe airway injury, inflammation, and the first study, it was observed that in prema-
parenchymal fibrosis with marked heterogeneity. ture twins (63 monozygotic and 189 dizygotic
Post-surfactant use, the “new” BPD lung revealed twin pairs), <32 weeks gestational age (GA),
a more uniform impairment of acinar develop- BPD occurred at a rate of 29% in one or more
ment with alveolar simplification characterized of a twin pair. After controlling for other
by enlargement and decreased septation of the covariates, 53% ( p = 0.004) of BPD was
airspaces, resulting in large-sized, thin-walled, explained by genetic factors alone (Bhandari
and decreased number of alveoli. Importantly, et al. 2006a). These results were independently
there is absence of small and large airway epithe- confirmed (Lavoie et al. 2008). Multiple
lial metaplasia, smooth muscle hypertrophy, and genetic variants have been assessed in the eval-
fibrosis. In addition, the pulmonary microvascu- uation of carrier states that predispose to the
lature in new BPD is undoubtedly dysregulated development of BPD (Bokodi et al. 2007;
(Coalson 2006; Baraldi and Filippone 2007). The Bhandari and Gruen 2006; Bhandari 2012;
vascular changes observed include marked Prosnitz et al. 2013).
890 V. Bhandari
Antenatal factors: chorioamnionitis Postnatal factors: ventilator trauma, oxygen
toxicity, pulmonary edema, sepsis
CYTOKINES
GENETIC SUSCEPTIBILITY
Pro -inflammatory Anti -inflammatory
(e.g. IL- 1) (e.g. IL-10)
IMMATURE LUNG
CELL DEATH
Normal lung RESOLUTION REPAIR
Impaired Alveolarization Dysregulated Angiogenesis
BRONCHOPULMONARY DYSPLASIA
Fig. 1 Pathogenesis of “new” BPD (From Bhandari and Bhandari (2009), with permission)
2. Prenatal infections: Chorioamnionitis may be 24–38 weeks and accounts for the majority of
a risk factor for the development of BPD. Clin- infants who later develop BPD. The last phase,
ical observation studies suggest chorioam- the alveolar phase, starts from ~32 weeks PMA
nionitis, and the fetal inflammatory response till about 2–8 years after birth, with the majority
(FIR) syndrome increases the risk of BPD of the alveolarization process occurring
(Thomas and Speer 2014). In contrast, histolog- 5–6 months after birth. Alveolarization incorpo-
ical chorioamnionitis with FIR has been associ- rates the processes of “elastogenesis and angio-
ated with decreased BPD (Plakkal et al. 2013). genesis,” with multiple cell to cell interactions
Given the effect of various confounding between fibroblasts, epithelial (type I and II
factors, the issue of antenatal infection/inflam- pneumocytes), interstitial, and endothelial
mation causing BPD in human infants remains cells. Premature birth, with its subsequent med-
controversial (Balany and Bhandari 2015; ical disorders and their management, alters the
Ericson and Laughon 2015). postnatal development of lungs, via changes in
3. Lung immaturity: Intrinsic to the develop- the molecular signal transduction pathways.
ment of BPD is prematurity. Normal lung devel- Factors that disrupt normal angiogenesis, con-
opment occurs in phases which correspond to trol of inflammation (i.e., imbalance between
structural differences. The first phase, the “pro-” and “anti-inflammatory” cytokines),
embryonic phase (3–7 weeks PMA) is followed and appropriate fibrin deposition or removal
by the pseudoglandular phase (5–17 weeks). are at play in the pathogenesis of BPD.
Many premature neonates are born during the 4. Hyperoxia: Excessive oxygen induces oxida-
late canalicular phase (16–26 weeks) of lung tive stress with production of reactive oxygen
development. The saccular phase occurs at species with increased production of
57 Bronchopulmonary Dysplasia/Chronic Lung Disease of the Newborn 891
inflammatory cytokines from epithelial, endo- that a causal role for the PDA in the devel-
thelial, and inflammatory cells. Initial opment of BPD could not be inferred based
hyperoxic cellular damage induces alveolar or on data reported in controlled clinical trials
interstitial macrophages to express early cyto- (Clyman 2013). Early ductus ligation was
kines such as IL-1 and tumor necrosis factor said to be an independent risk factor for the
(TNF). Chemoattractants are then induced from development of BPD (Clyman 2013). In con-
multiple cell types in the lung, in turn recruiting trast, another recent study concluded that sur-
other inflammatory cells, such as neutrophils gical ligation of PDA itself was not an
(Bhandari and Elias 2006). An immature lung independent risk factor for BPD (Schena
which is exposed to ante- and postnatal envi- et al. 2015).
ronmental factors contributes to the release of a 6. Postnatal infections: Systemic infections pre-
variety of “pro- and anti-inflammatory” cyto- dispose to the development of BPD (Van
kines. An imbalance in these mediators leads Marter et al. 2002). The inflammatory response
to activation of the cellular death pathways in occurring secondary to infection increases
the lung. Thus, direct (via reactive oxygen spe- release of inflammatory and vasoactive cyto-
cies) or indirect (via cytokines) damage to the kines on an already damaged pulmonary
respiratory endothelium and epithelium occurs organ, increasing the need for mechanical ven-
by inducing necrotic and/or apoptotic cell death tilation. Airway colonization with increased
(Bhandari and Elias 2006). This is followed by neutrophilic presence and “pro-inflammatory”
healing (resolution of injury) or repair of the cytokines may also predispose to the develop-
lung (Bhandari and Bhandari 2003, 2007). The ment of BPD (Speer 2006).
latter process is characterized by impaired 7. Role of cytokines: The common theme of
alveolarization and dysregulated angiogenesis inflammation noted above is underscored by
leading to fewer, larger simplified alveoli and a the role played by cytokines. Cytokines are
dysmorphic pulmonary vasculature (Fig. 1) – chemicals produced by virtually all cell types
the pathologic hallmarks of BPD (Baraldi and including fibroblasts, white blood cells, and
Filippone 2007). endothelial and epithelial cells. They mediate
5. Ventilator-induced injury (baro-, volu-, and immune, inflammatory, and hematopoietic
atelecto-trauma): Mechanical ventilation has functions in response to various stimuli. In
long been associated with the development of preterm infants, inciting events cause an
BPD. The initiating biophysical injury due to inflammatory response, either systemically or
excessive tissue stretch leads to a cascade of localized to the pulmonary organ. We have
inflammation-induced lung injury (Keszler and only a partial understanding of how inflamma-
Sant’Anna 2015). Intubated neonates who ulti- tion in the setting of prematurity causes BPD.
mately develop BPD often have significantly Soon after birth, upon initiation of oxygen
increased levels of “pro-inflammatory” cyto- exposure and/or mechanical ventilation, there
kines, possibly from microbial colonization is an influx of neutrophils and macrophages
and increased distention of alveolar tissue with into pulmonary interstitium. Neutrophils
subsequent baro-, volu-, and/or atelecto-trauma adhere to the endothelium, with interaction
leading to increased inflammation (Speer 2006). between these two cell types occurring via
The association of presence of a patent adhesion molecules (e.g., selectins and
ductus arteriosus (PDA) and BPD is likely integrins). This allows for extravasation of
due to the increase in pulmonary circulation neutrophils and macrophages toward the spe-
and subsequent pulmonary edema. This usu- cific areas of injury. These inflammatory cells
ally instigates increased ventilatory support produce cytokines and other signaling mole-
and oxygen administration, both being impor- cules for augmentation of the inflammatory
tant contributory factors to the development response in an attempt to mitigate the damage
of BPD. However, a recent review concluded of the inciting insult. There is subsequent
892 V. Bhandari
disruption of the alveolar capillary unit and neonates who will likely go on to develop this
pulmonary tissue integrity. The imperfect chronic disorder. A majority of the biomarkers
attempt at repair, differentiation, and growth discussed below are likely abnormal due to dam-
of these tissues acts in concert with the inflam- age that has already occurred. Some biomarkers
mation to produce the biochemical profile, are capable of being perceived as either “pro-” or
signs, and symptoms we see in patients with, “anti-inflammatory” depending on their concen-
and those at risk, for BPD (Speer 2006; Ryan tration in relation to their physiologic role. Given
et al. 2008). the proximity to the lung, the primary focus of
It is important to highlight the concept that most investigators has been to access pulmonary
the immature lung in the late canalicular/saccu- secretions to evaluate putative biomarkers
lar phase of development is most predisposed to for BPD.
BPD, when exposed to the pre- and postnatal The initial TA studies focused on the cytology of
factors, as described above (Balany and the secretions. The exfoliation of dysplastic, meta-
Bhandari 2015). While some markers of inflam- plastic bronchial cells was found to be 95% specific
mation may not be detectable within days to and 71% sensitive for the subsequent development
weeks of exposure to noxious stimuli, they of BPD. Categories of pulmonary biomarkers that
have already initiated and propagated the sig- are deranged in BPD include IL and other
naling pathways of the inflammatory process/ chemoattractant molecules, markers indicative of
immune cascade (Bhandari 2014a). This activa- abnormal angiogenesis, those signifying abnormal
tion and persistence of inflammation predispose fibrin deposition or degradation, markers of oxida-
to the permanent structural and functional defi- tive damage, and peptide growth factors. While a
cits in BPD lungs (Balany and Bhandari 2015). study has shown that TA specimens may be suitable
Many studies have been conducted to eval- substitutes for bronchoalveolar lavage samples in
uate the presence of cytokines in the amniotic preterm infants, there has been some controversy
fluid, cord blood, plasma, and tracheal secre- whether measurements of the markers in the TA are
tions of preterm neonates at risk or who have valid without “normalization.” While some have
BPD in an effort to determine a biochemical advocated use of total protein, secretory component
profile of the condition. Many of the pulmo- of IgA, and serum urea, others have espoused that
nary biomarkers relate to the possible disrup- no “normalization” is required.
tion in the above described mechanisms. A Table 2 summarizes the results of various TA
multitude of biomarkers detected in tracheal analytes, focusing more on recent reports that
aspirates (TA), blood, and urine have been would be more reflective of the “new” BPD, usu-
proposed for early identification of infants ally obtained in the first week of life, from babies
who subsequently develop BPD. at risk of developing BPD. More details are avail-
able from recent reviews (Thomson and Bhandari
2008; Bhandari and Bhandari 2013; Lal and
Ambalavanan 2015).
Interferon-γ (IFN-γ): Increased TA levels of
57.5 Biomarkers in BPD IFN-γ and the downstream signaling molecules
interferon-γ-inducible proteins 9 and 10 (IP-9,
Though there are many clinical associations indic- IP-10) have been shown to be associated with
ative of an increased risk for the eventual devel- increased risk of BPD and/or death (Bhandari
opment of BPD, currently there exists no one and Bhandari 2013).
factor or marker that uniformly and accurately Interleukins (ILs): ILs are chemicals made by
predicts its development. The inciting events that one cell type that act on other inflammatory cells.
predispose to development of BPD likely occur They may induce growth, differentiation, and pro-
fairly soon after birth, and we are limited by a lack liferation of other leukocytes. They may also act
of ability to distinguish very early in these as chemoattractants for recruitment of other cell
57 Bronchopulmonary Dysplasia/Chronic Lung Disease of the Newborn 893
Table 2 Use of tracheal aspirate analytes as biomarkers response to injury, while IL-8 is a potent chemo-
for BPD tactic agent for recruitment of neutrophils. These
Levels associated with cytokines are typically viewed as “pro-inflamma-
increased risk of BPD Analytes tory” and have been shown to be elevated in the
Increased Cytokines and chemokines: TA very early in the respiratory course of the
IL-1β, IL-6, IL-8, IL-16,
TNF-α, IFN-γ, MCP-1, preterm population that ultimately develops
MCP-2, MCP-3 BPD. IL-16 acts as a chemoattractant for CD4+
Proteases/antiproteases: T lymphocytes, monocytes, and eosinophils.
MMP-8, MMP-9, trypsin-2 Levels of IL-16 correlated significantly with neu-
Adhesion molecules: trophil counts in the TA and subsequent develop-
sICAM-1, L-selectin
ment of BPD.
Oxidative injury markers:
3-chlorotyrosine,
IL-10, IL-4, and IL-13: These cytokines usu-
malondialdehyde, LOOH ally act in an “anti-inflammatory” capacity and are
Peptide growth factors: responsible for the production, differentiation, and
TGFβ1, angiopoietin-2, proliferation of B cells and macrophages. It has
endothelin-1, FGF2 been suggested that decreased levels of “anti-
Miscellaneous: NF-kB,
inflammatory” cytokines would predispose to the
fibronectin, PAI-1, NGAL,
pepsin development of BPD given the role that inflam-
Decreased Cytokines and chemokines: mation likely has in this disorder. However, there
IL-10, MIF are discrepant findings regarding the levels of
Proteases/antiproteases: “anti-inflammatory” cytokines in the TA of pre-
TIMP2, cathepsin K term infants at risk for BPD.
Oxidative injury markers: IL-10: IL-10 was found to be decreased in TA
YKL-40
samples taken in the first 7 days of life in those
Peptide growth factors: KGF,
HGF infants who developed BPD. Other investigators
Miscellaneous: CCSP, found detectable levels of IL-10 in TA of preterm
PTHrP, lysozyme, PUFA, ventilated infants, but could not correlate the
DMA levels with development of BPD. When lipopoly-
Biphasic/variable Peptide growth factors: saccharide (LPS), a potent inducer of inflamma-
VEGF, sVEGFR1
tion, was used to induce production of IL-10 from
For more details, see Thomson and Bhandari (2008) and
lung inflammatory cells (obtained from premature
Bhandari and Bhandari (2013)
IL interleukin, TNF tumor necrosis factor, INF interferon, infants), there was a decreased ability to induce
MCP monocyte chemoattractant, MMP matrix IL-10 in those infants who went on to develop
metalloproteinase, sICAM soluble intracellular adhesion BPD. A majority of preterm infants (97%) unable
molecule, LOOH lipid hydroperoxide, TGF transforming
to constitutively express the IL-10 gene devel-
growth factor, FGF fibroblast growth factor, NF-kB nuclear
factor-kappa B, PAI plasminogen activator inhibitor, NGAL oped BPD.
neutrophil gelatinase-associated lipocalin, MIF macrophage IL-4 and IL-13: IL-4 is produced by T lym-
migration inhibition factor, TIMP tissue inhibitor of phocytes and alveolar macrophages. Levels of
metalloproteinase, YKL-40 also known as chitinase-3-like
these potentially “anti-inflammatory” cytokines
protein1, human homologue of breast regression protein
39 (BRP39), KGF keratinocyte growth factor, HGF hepato- (IL-4, IL-13) could not be significantly correlated
cyte growth factor, CCSP Clara cell secretory protein, with the development of BPD.
PTHrP parathyroid hormone-related protein, PUFA polyun- Angiopoietin-2: Angiopoietin-2 is an angio-
saturated fatty acid, DMA dimethylacetals, VEGF vascular
genic growth factor that destabilizes blood ves-
endothelial growth factor, sVEGFR soluble VEGF receptor 1
sels, enhances vascular leak, and induces
types (immune and nonimmune cells) to a site of epithelial cell necrosis in hyperoxic conditions.
injury and may exert “pro- or anti-inflammatory” Angiopoietin-2 concentration was observed to be
effects. IL-1ß, IL-6, IL-8, and IL-16: IL-1ß and increased in infants with BPD and/or death in the
IL-6 are particularly active in the acute phase first week of life, when compared to those infants
894 V. Bhandari
with RDS who recovered (Bhandari et al. 2006b; Fibronectin: An extracellular matrix compo-
Aghai et al. 2008). Furthermore, the levels nent, fibronectin, is important in maintaining the
decreased after exposure to dexamethasone integrity of pulmonary tissues and microvascula-
(Aghai et al. 2008). ture. Researchers have found a higher fibronectin
Cathepsin K: Cathepsin K is a cysteine prote- level in those infants who developed BPD.
ase, which degrades existing extracellular matrix Lactoferrin and lysozyme: Lactoferrin is said
and regulates the release of matrix proteins from to be a marker of inflammation by regulating
fibroblasts. In one study, infants who developed granulocyte and macrophage proliferation, and
BPD had declining cathepsin K levels by day may also have some antioxidant properties. Lyso-
13, when compared to neonates who did not. zyme is a bactericidal protein that degrades the
Chemokines: There are four families of walls of susceptible bacteria. Both are hypothe-
chemokines (chemotactic cytokines); they play a sized to be released from the serous cells of the
role in regulating inflammation by recruiting submucous glands of the respiratory tract. Both
inflammatory cells to the area of injury. The “CC” lactoferrin and lysozyme when measured in the
family consists of monocyte chemoattractant pro- first 3 days of life were decreased in patients with
teins (MCP) 1, 1α, 1β, 2, and 3. These chemokines BPD as compared to those without BPD, with the
were measured in a study to assess the role of decrease in lysozyme being significant.
CC chemokines in acute lung injury in the L-selectin: Concentrations of soluble L-selectin
preterm, ventilated infant over the first 21 days of in TA from infants are increased at 7 postnatal days
life. MCP-1, MCP-1α, MCP-1β, MCP-2, of life, in infants who develop BPD (Bhandari and
and MCP-3 were all increased in those infants Bhandari 2013).
developing BPD. However, only MCP-1, MCP-2, Lipid hydroperoxide (LOOH): More
and MCP-3 were statistically significant, with recently, increased LOOH levels have been
MCP-3 being the most significant (Baier noted in BPD (Fabiano et al. 2015).
et al. 2004). Macrophage migration inhibitory factor
Clara cell secretory protein (CCSP): CCSP (MIF): MIF is an upstream regulator of the innate
is produced by Clara cells, which are non-ciliated immune response. It has been implicated in the
epithelial cells lining the respiratory and terminal pathogenesis of a number of inflammatory disor-
bronchioles. This protein may act to modulate ders including sepsis, acute RDS (in adults),
acute pulmonary inflammatory processes. In pre- asthma, and inflammatory/autoimmune diseases.
term infants with TA samples taken up to 2 weeks MIF was quantified in TA obtained during the first
after birth, CCSP increased with maturity and in 2 days of life in a cohort of neonates with RDS.
those neonates who had evidence of infection. In There was a reduction in the concentration of MIF
another study, the results indicated that lower in the lungs of those infants who went on to
levels of CCSP predisposed to development of develop BPD (Kevill et al. 2008).
BPD. Malondialdehyde: Malondialdehyde is a
3-Chlorotyrosine: 3-Chlorotyrosine is a bio- marker of oxidative damage, possibly from oxy-
marker of the neutrophil oxidant, hypochlorous gen radicals produced under hyperoxic conditions
acid, which is utilized in the inflammatory process. or the respiratory burst from inflammatory cells
Its only source is from neutrophils and monocytes present in the pulmonary organ. In one study of
which release myeloperoxidase to catalyze oxida- ventilated infants, its pulmonary concentrations
tion of chloride by hydrogen peroxide to give were noted to be elevated, but weakly correlated
hypochlorous acid. In support of data that neutro- with the development of BPD.
philic infiltration and subsequent oxidative injury Matrix metalloproteinases (MMPs): MMPs
is closely related to the development of BPD, are a family of endoproteinases that aid in the
investigators assessed levels of 3-chlorotyrosine remodeling and degradation of extracellular
and found that an increase in their concentration matrix and basement membranes. They are
correlated with development of BPD. secreted in inactive form and activated in
57 Bronchopulmonary Dysplasia/Chronic Lung Disease of the Newborn 895
extracellular spaces and cell surfaces by oxidants initiate protease cascades, causing tissue destruc-
and serine proteinases. They also have the capac- tion. It was hypothesized that when trypsin is
ity to activate each other. The development of ineffectively inhibited by its natural inhibitor
BPD is partially characterized by disordered pul- tumor-associated trypsin inhibitor (TATI), it may
monary repair after inflammation. Patients who play a role in the development of BPD. Results in
went on to develop BPD had increased levels of TA samples from preterm infants indicated that
tracheal MMP-8, with decreased levels of its there was significantly higher trypsin-2 to TATI
inhibitor, “tissue inhibitor of metalloproteinases” ratio during first 2 weeks in those infants devel-
(TIMP) (Cederqvist et al. 2001). oping BPD.
Neutrophil gelatinase-associated lipocalin Polyunsaturated fatty acid (PUFA) and
(NGAL): TA levels of NGAL, which is part of a dimethylacetals (DMA): These have been
macromolecular complex that includes MMP9, reported to be significantly decreased in infants
are increased in infants with BPD (Bhandari and developing BPD, but only on day 1 (Bhandari and
Bhandari 2013). Bhandari 2013).
Nuclear factor-kappa B (NF-kB): NF-kB is a Soluble intercellular adhesion molecule-1
transcription factor activated by cellular stress, (sICAM-1): sICAM-1 plays a role in early
subsequently promoting expression of multiple inflammation and is the ligand for lymphocyte
genes including “pro-inflammatory” cytokines. function-associated antigen 1 (LFA-1). sICAM-1
TA levels of NF-kB were significantly elevated is expressed by lymphocytes, eosinophils, mast,
in the infants who developed BPD or died. How- endothelial, and bronchial epithelial cells. Infants
ever, this difference did not persist when GA was who developed BPD had significantly higher
taken into account. levels of soluble sICAM-1 in TA at 6–14 days of
Parathyroid hormone-related protein age.
(PTHrP): PTHrP is secreted by type II Transforming growth factor-ß1 (TGF-ß1):
pneumocytes and plays a role in normal alveolar TGF-ß1 is produced mostly by alveolar macro-
growth and development. Its signaling was phages and acts on fibroblasts to increase the
shown to be downregulated in alveolar transcription of fibronectin and procollagen. It
overdistention and under hypoxic conditions. also inhibits synthesis of proteases and increases
Infants developing BPD had significantly lower the synthesis of antiproteases, thus resulting in a
levels of PTHrP in the first week of life, when net increase in fibrosis. Infants who developed
compared to those who did not (Rehan and BPD had significantly increased levels of
Torday 2006). TGF-β1 in TA.
Pepsin: TA levels of pepsin (derived from Tumor necrosis factor-α (TNF-α): TNF-α is
gastric microaspirations) have been reported to a pro-inflammatory cytokine that induces cell
be significantly higher in infants who had BPD death and enhances expression of other cytokines.
and/or died in the first week and month of post- In a study of premature infants, TNF-α was noted
natal life (Bhandari and Bhandari 2013). to be increased early in the patients who devel-
Plasminogen activator inhibitor-1 (PAI-1): oped BPD.
PAI-1 is a regulator of fibrinolysis. It was hypoth- Peptide growth factors: Peptide growth fac-
esized that inhibition of fibrinolysis may play a tors are important for normal lung development,
role in the development of BPD. Infants who maturation, and repair. This group includes
developed BPD had significantly higher levels of endothelin-1 (ET-1), fibroblast growth factor-2
PAI-1 than non-BPD patients. (FGF-2), keratinocyte growth factor (KGF), hepa-
Pulmonary trypsin-2: Trypsin-2 is a serine tocyte growth factor (HGF), and vascular endo-
protease expressed in a variety of human epithe- thelial growth factor (VEGF).
lial cell types, including in the lung. It can directly ET-1: ET-1 is a potent endothelium-derived
attack extracellular protein matrix, basement vaso- and broncho-constricting factor, produced
membrane proteins, and can activate MMPs and in virtually all tissues, though its largest
896 V. Bhandari
concentration is in the lung. Under the influence Conversely, no difference in TA VEGF levels
of cytokines (IL-1β, IL-6, IL-8), production of ET were noted between BPD and no BPD infants in
can be induced in macrophages and monocytes. another study (Ambalavanan and Novak 2003). In
ET-1 has also been hypothesized to increase the a recent study, a phasic pattern of VEGF concen-
production of oxygen radicals from alveolar mac- trations was noted in infants who go on to develop
rophages. In preterm infants with RDS, TA con- BPD. These infants had an initial spike over the
centrations of ET-1 in the first week of life were first 12 h of postnatal life, followed by a decrease
significantly elevated in infants developing BPD over the next few days and then a subsequent
(Niu et al. 1998). This was, however, not con- significant increase (Bhandari et al. 2008a).
firmed by others (Ambalavanan and Novak 2003). sVEGFR1: While sVEGFR1 levels were
FGF-2: FGF plays a role in angiogenesis, by higher on day 1 in infants who developed BPD,
stimulating endothelial cell proliferation, they subsequently declined on days 3 and
degrading extracellular matrix, and appears to 7 (Bhandari and Bhandari 2013).
interact with VEGF. There was a significant ele- YKL-40: This is also known as chitinase-3-like
vation in the levels of FGF-2 in the TA in the protein 1, and low levels have been reported in
BPD/death population on day 1 of life infants who go on to develop BPD (Bhandari and
(Ambalavanan and Novak 2003). Bhandari 2013).
KGF: A member of the FGF family, KGF Other biomarkers: Given the complexity of
regulates proliferation of alveolar epithelial cells the pathogenesis of BPD, investigators have also
and enhances synthesis of surfactant and acceler- attempted to use the relative concentration of TA
ates wound closure in airway epithelium. It was markers to predict BPD. Infants who developed
noted that in premature infants who developed BPD had higher IL-1β concentrations and IL-1β/
BPD, KGF was lower than in those who did not IL-6 ratios. Premature infants who developed
develop it. BPD had higher levels of IL-1 receptor antagonist
Pulmonary HGF: HGF in fetal rat lungs stim- (IL-1RA) in their airways on the first day of life.
ulates branching of both alveolar and bronchial IL-1β also increased significantly for BPD
epithelia and contributes to growth, maturation, patients early, both compared to non-BPD patients
and maintenance of tissue homeostasis. It has and also within the BPD group. While the early
been suggested that HGF also mediates repair of (day 1) IL-1 antagonist/agonist molar balance
type II pneumocytes after acute lung injury. offered protection, by days 5 and 7, a threshold
Infants who developed BPD had significantly for IL-1RA in the presence of increasing IL-1β
lower levels of HGF in the first 2 weeks of life, expression favored “pro-inflammation” in the
when compared to non-BPD counterparts. BPD group. Others have demonstrated a sustained
VEGF: VEGF promotes endothelial cell increase of TGFβ1 levels in TA from preterm
growth and remodeling. In the pulmonary system, infants who developed BPD, combined with an
it appears to be essential for the appropriate devel- absent or irregular secretion of IL-4, IL-10, and
opment of alveolar tissue; in rats its antagonism IL-12. Babies who developed BPD or died had
has been shown to result in dramatically impaired lower IL-6/VEGF ratios in the TA, than those who
alveolarization (Thebaud and Abman 2007). In did not have such an adverse outcome (Thomson
heavily vascularized tissues, such as the lung, and Bhandari 2008). In other studies, BPD infants
VEGF exists in high concentrations. During had significantly lower TIMP-1 level with higher
hyperoxic episodes when damage to the micro- MMP-9/TIMP-1 ratio during the first 2 weeks of
vasculature occurs, VEGF plays a role in the life and low TIMP-2 and MMP-2 levels during the
remodeling process, and its levels are increased, first 3 days of life compared with no BPD infants
sometimes disproportionately. In preterm infants (Ekekezie et al. 2004).
with RDS, infants developing BPD had signifi- Cord blood (and TA) soluble E-selectin has
cantly lower levels of TA VEGF closer to 1 week been noted to be increased in infants who devel-
of life (Thomson and Bhandari 2008). oped BPD. Increased serum levels of soluble
57 Bronchopulmonary Dysplasia/Chronic Lung Disease of the Newborn 897
E-selectin were associated with the development complexity than control subjects. Increased end-
of BPD. In another study, low levels of soluble tidal carbon monoxide (CO) and exhaled nitric
L-selectin and increasing levels of soluble oxide (NO) levels have been reported in infants
E-selectin were reported to be potential risk fac- with BPD in the first month of life (Bhandari and
tors for BPD. The cord blood placental growth Bhandari 2013).
factor concentrations were noted to be increased A majority of these studies comprise of a small
in infants developing BPD. Serum C-IV number of babies. Appropriately so, most
(an antigen marker of type IV collagen, a compo- attempts to identify biomarkers have been to
nent of basement membranes) levels were ele- access the pulmonary compartment by collecting
vated in the first week of life in infants TA. However, TA have been collected at a vari-
subsequently diagnosed with BPD. In another able number of time points, measurements done
study of serial measurements of the C-terminal usually of single markers, with or without “nor-
fragment of type I procollagen, levels at week malization” and with variable definitions of BPD
4 were significantly lower in infants who subse- (oxygen requirement for 28 days or at 36 weeks
quently developed BPD. Patients with both the PMA, with or without radiographic criteria). Few
old and new categories of BPD had elevated have been replicated in different cohorts. Those
serum levels of TGF-β1, though these were not with consistent results include: elastase, IL-1β,
statistically significant (Vento et al. 2006). Other IL-6, MCP-1, ET-1, and angiopoietin-2 (Table 2).
blood markers include measures of eosinophilic VEGF has been replicated but showed variable
activation (eosinophilic cationic protein and the results (Table 2). Most of the above comments
cellular surface antigen CD9), which were are also true of the blood and urinary markers.
increased in BPD. The plasma KL-6 Not surprisingly, none of the aforementioned
(a circulating high molecular weight mucinous markers for BPD are in general clinical use.
glycoprotein which is the extracellular soluble The majority of the above biomarkers show
region of MUC-1 mucin possessing an undefined only an association with BPD. In order to prove a
sialylated carbohydrate chain that is recognized causal relationship, they need to be studied in
by KL-6 antibody) was noted to be increased in developmentally appropriate animal models and
patients with moderate/severe BPD. The plasma human lungs with BPD. Some progress in this
levels of 8-iso-prostaglandin F2alpha (a stable direction has been made with the following: elastin
metabolite of F2-isoprostanes, a marker for oxi- (Bland et al. 2007), cathepsin-S (Hirakawa
dant injury) have been noted to be increased in et al. 2007), HGF (Padela et al. 2005), KGF
infants who developed BPD/died. In another (Frank 2003), IFN-γ (Harijith et al. 2011; Choo-
study, however, urinary levels of the same metab- Wing et al. 2013), IL-1β (Bry et al. 2007), IL-6
olite were not correlated with BPD. (Choo-Wing et al. 2007), MCP-1 (Vozzelli
Older infants with established BPD had higher et al. 2004), TGF-β1 (Vicencio et al. 2004),
levels of urinary leukotriene E 4 when compared VEGF (Thebaud et al. 2005), bombesin-like pep-
to healthy infants of the same age; however, it was tide (Subramaniam et al. 2007), YKL-40 (Sohn
not found to be an early marker of BPD. Elevated et al. 2010), and angiopoietin-2 (Bhandari
urinary elevated bombesin-like peptide levels in et al. 2006b), but additional work is needed.
infants at 1–4 days after birth were associated with There has been an increasing focus on using
a tenfold increased risk of developing BPD “omic” techniques (genomics, epigenomics,
(Cullen et al. 2002). Given the importance of microbiomics, transcriptomics, proteomics,
vascular development in the pathogenesis of and metabolomics) for detecting markers for
BPD, investigators have postulated evaluating BPD (Lal and Ambalavanan 2015; Piersigilli
the vascularity of the lower gingival and vestibu- and Bhandari 2016). Using these approaches,
lar oral mucosa as a marker for BPD. Infants with biomarkers in human studies recently reported
BPD showed a significantly lower blood vessel include SPOCK2, VEGF-624C > G, VEGF-460
area as well as a higher vascular network T > C, mast cell-specific markers, miR-219
898 V. Bhandari
pathway, miR-152, miR-30a-3p, miR-133b, growth may be related to undiagnosed hypoxia,
miR-206, miR-7, lactate, taurine, cardiac disease, gastroesophageal reflux, and
trimethylamine-N-oxide, gluconate, myoinositol, swallow dysfunction or recurrent aspiration.
and alterations in surfactant lipid profile Radiological findings: In the early phase of
(Piersigilli and Bhandari 2016). BPD, the chest X-ray shows RDS or, in some
case, minimal respiratory disease. In the evolving
phase, the lung fields become more hazy and
57.6 Clinical Aspects dense suggesting pulmonary edema, atelectasis,
or infiltrates. Recently there has been a change in
Clinical diagnosis: The classical presentation is a the radiographic findings associated with
history of a premature infant with RDS who has established BPD. This change has likely been
been intubated and mechanically ventilated and brought about by the younger GA of surviving
exposed to supplemental oxygen for the first week infants, widespread use of surfactant, and less
of life or longer. Usually these infants experience aggressive respiratory management strategies.
bouts of postnatal sepsis and have inadequate Traditionally, in the pre-surfactant era, BPD was
nutritional intake. Over time, these infants fulfill represented on radiographic imaging by emphy-
the diagnostic criteria for BPD, as defined earlier. sematous areas with other portions of the lung
In the early phase of BPD (up to the first displaying volume loss. This correlated with the
postnatal week of life), the clinical presentation pathology of a pulmonary specimen that would
may be indistinguishable from an infant with also exhibit signs of increased inflammation,
RDS. Such infants may require intubation and fibrosis, and small airway disease. Over the clin-
surfactant administration. Occasionally, prema- ical course of evolving “new” BPD, the radiolog-
ture infants may require minimal respiratory sup- ical signs are fairly nonspecific, and the lung fields
port with nasal continuous positive airway appear hazy and dense secondary to pulmonary
pressure (NCPAP) or nasal intermittent positive edema (called the leaky lung syndrome, LLS)
pressure ventilation (NIPPV), with a supplemen- (Hyodynmaa et al. 2012) and atelectasis (Fig. 2).
tal oxygen requirement of <40%. In the evolving Once the “new” BPD is well established, the
phase of BPD (after 1 week of life to 36 weeks
PMA), such infants have not been able to be
successfully extubated or have been re-intubated.
These infants usually require escalation of venti-
latory support and higher concentrations of sup-
plemental oxygen. Signs and symptoms of
established BPD (after 36 weeks PMA) include
tachypnea, dyspnea, and chronic or intermittent
crackles and wheezing. In children with subglottic
stenosis secondary to prolonged intubation, there
may be presence of a stridor on exam. Noisy
breathing exacerbated with high airflow activities
such as feeding and agitation may be heard in
infants with tracheomalacia and bronchomalacia.
BPD spells are episodes of tracheal obstruction
associated with episodes of cyanosis and oxygen
desaturations and bradycardia, usually occurring
secondary to agitation, and are thought to be
related to tracheomalacia and bronchomalacia.
Cardiac complications of severe BPD include pul-
monary hypertension and cor pulmonale. Poor Fig. 2 Chest X-ray of an infant with established BPD
57 Bronchopulmonary Dysplasia/Chronic Lung Disease of the Newborn 899
appearance of the lungs progresses to hyperinfla- leading to interstitial lung disease are most likely
tion and cystic areas (“bubbly appearance” or to be considered in the differential diagnoses of
cystic BPD) (Hyodynmaa et al. 2012), but without BPD. These include specific conditions that affect
the large cysts typical of the older form of BPD surfactant function, i.e., mutations in surfactant
(Speer 2006; Agrons et al. 2005). proteins B, C, and ABCA3. Confirmation of diag-
noses may require lung biopsy and genetic testing.
Pulmonary lymphangiectasia: It is a rare
57.7 Differential Diagnoses developmental disorder that results in dilated and
obstructed lymphatics. Confirmation of the diag-
Aspiration pneumonia: In the early phase of nosis requires a lung biopsy. There is an associa-
BPD, respiratory distress can be secondary to tion with Noonan and Turner syndromes.
aspiration of amniotic fluid or maternal blood Wilson-Mikity syndrome: There is significant
during delivery (Table 3). The radiological picture overlap between Wilson-Mikity syndrome and the
may show localized lobar infiltrates or an intersti- premature infants with BPD who do not have
tial pattern. With supportive care that usually significant respiratory disease at birth (vide
includes supplemental oxygen with or without supra). Infants with Wilson-Mikity syndrome do
mechanical ventilation, intravenous fluids, and not develop RDS. The exact etiology is unknown.
antibiotics, such infants show significant clinical Proposed predisposing factors include air trap-
improvement within the first week of life. ping, fluid overload secondary to chronic PDA,
Congenital heart disease: Infants with cya- recurrent aspiration, infection, rickets, and surfac-
notic congenital heart disease will show evidence tant deficiency. Clinical features are characterized
of hypoxemia, not responsive to supplemental by features of respiratory distress. This syndrome
oxygen. In addition, there may be signs sugges- is commonly seen between 1 and 2 months of age,
tive of a cardiovascular etiology (hypotension, and most cases slowly resolve. Chest radiographic
heart murmurs, heart rhythm disturbances). findings are normal in the first week, but later they
Chest X-rays may be helpful in terms of the size are similar to those of BPD, with hyperinflation,
and shape of the cardiac silhouette. Cardiac echo- streaky infiltrates, and cystic changes. Radio-
cardiography will be diagnostic. graphic changes persist for a few months to
Infectious pneumonia: These are mostly viral years after clinical findings resolve. It is perhaps
or bacterial in the immediate newborn period. a genetic variant of the “new” BPD.
There may be maternal history (e.g., chorioam-
nionitis) that may predispose an infant to an infec-
tious pneumonia. Chest X-rays show lobar or 57.8 Prognosis
perihilar infiltrates. Neonates usually improve
with supportive care (as mentioned above) within This is primarily dependent on pulmonary and
the first week of life. neurodevelopmental outcomes.
Interstitial lung disease: In the neonatal Pulmonary outcomes (pulmonary hyperten-
period, genetic and developmental disorders sion): A major pulmonary morbidity is the devel-
opment of pulmonary hypertension (PH) which is
Table 3 Differential Aspiration pneumonia
noted in ~20% of infants with birth weights
diagnoses of BPD
Congenital heart <1,000 g, primarily those with moderate/severe
disease BPD, and this persists to discharge in many
Infectious pneumonia infants (Ambalavanan and Mourani 2014). The
Interstitial lung disease gold standard for diagnosis of PH is cardiac cath-
Pulmonary eterization. But given the concern that the inva-
lymphangiectasia sive procedure would not be well tolerated in these
Wilson-Mikity sick BPD infants, it is usually avoided, at least, at a
syndrome
younger postnatal age. Echocardiography is
900 V. Bhandari
generally used for diagnosis. Objective measures pneumonia, respiratory syncytial virus (RSV)
of PH by echocardiogram include estimated right infection, and worsening BPD (Bhandari and
ventricular systolic pressure (RVSP) derived from Panitch 2006). Although recurrent respiratory
the tricuspid regurgitant jet velocity (TRJV) symptoms needing hospitalization decrease over
(Mourani and Abman 2015). A threshold of time, this increase in respiratory symptoms persists
RVSP greater than 35 mmHg (TRJV >3 m/s) to beyond the first 2 years of life into preschool years,
define PH has been used (Mourani and Abman adolescence, and early adulthood (Bhandari and
2015). Lack of a TRJV does not preclude the Panitch 2006). It is unclear whether it is the severity
diagnosis of PH; the right ventricular myocardial of BPD or prematurity per se that influences the
performance index (MPI; also known as the Tei persistence and severity of symptoms.
index) has been used as a surrogate for increased Radiological findings: In children with a his-
pulmonary vascular resistance in BPD (Mourani tory of BPD, abnormal chest x-rays with subtle
and Abman 2015). Biochemical monitoring radiological abnormalities have been noted later
(B-type natriuretic peptide) has been suggested in adolescence and adulthood (Bhandari and
to diagnose and/or monitor BPD-associated PH Panitch 2006). The chest radiograph is relatively
(Cuna et al. 2014; Montgomery et al. 2016). Man- insensitive to the structural changes present in the
agement is primarily focused on maintaining oxy- BPD lung. In contrast, high resolution computed
gen saturation in the targeted range of 90–95%, in tomography (HRCT) is much more sensitive for
combination with inhaled nitric oxide (iNO) at visualizing radiological abnormalities in patients
5–20 ppm (Ambalavanan and Mourani 2014). If with BPD. Investigators have reported that there is
there is a limited or no response and/or in an effort little difference in the radiological appearance of
to wean off iNO, sildenafil is usually started “old” versus “new” BPD, with the absence of
(0.5–1 mg/kg/dose every 8 h) (Ambalavanan and bronchial involvement being the only striking dif-
Mourani 2014). Infants who do not respond to the ference. The common findings include regions of
above therapy are then usually started on a pros- hypoattenuation, linear opacities initiating at the
tacyclin analog (epoprostenol, iloprost, or pleural surface and radiating inward toward the
treprostinil) or an endothelin-receptor antagonist hilum, and triangular subpleural opacities
(bosentan or ambrisentan) (Ambalavanan and (Walkup and Woods 2015). A positive correlation
Mourani 2014). There are limited data on the use between abnormal radiographic findings and pul-
of these agents in infants with BPD and PH, and monary function has been reported, with severity
hence these need to be used with careful monitor- of the clinical course being associated with exten-
ing for efficacy and toxicity (Ambalavanan and sive CT scan abnormalities (Bhandari and Panitch
Mourani 2014). Infants with BPD-associated PH 2006). Chest HRCT scan scoring systems have
on treatment should be closely monitored. These been proposed that correlated well with clinical
include assessments of oxygenation and serial scores at 36 weeks PMA and duration of oxygen
echocardiograms (every 2–4 weeks initially and dependence (Walkup and Woods 2015). Magnetic
then 4–6 monthly), with cardiac catheterization resonance imaging (MRI) is also being used and
indicated for select patients (Mourani and has shown focal high-density areas and
Abman 2015). Weaning of medications should low-density cyst-like abnormalities in infants
only be done with improvement being with BPD (Walkup and Woods 2015).
documented by serial echocardiograms, in addi- Pulmonary function: Despite many advances
tion to assessment of pulmonary function and in neonatal care, patients with BPD continue to
growth, over weeks (Mourani and Abman 2015). have significant impairment in lung function, and
Respiratory morbidity: Compared to their lung function may continue to deteriorate
non-BPD, infants with BPD have higher rates of into late adolescence (Doyle et al. 2006). Fortu-
rehospitalizations (up to 50%) in the first year and nately, this impaired lung function typically does
36% in the second year of life. Reasons for not interfere with the patient’s ability to partici-
rehospitalization included reactive airway disease, pate in daily activities, including exercise.
57 Bronchopulmonary Dysplasia/Chronic Lung Disease of the Newborn 901
Persistent airway dysfunction likely reflects Most studies show no reduction in exercise
severity of neonatal disease. Although there is a capacity in children with BPD when compared to
plethora of literature describing abnormal lung children with healthy term infants or preterm
function in patients with BPD at all ages from babies without lung disease (Bhandari and Panitch
infancy to early adulthood, there are only a few 2006). Decreased gas transfer and oxyhemoglobin
studies correlating the extent of pulmonary func- saturations during exercise in school-aged children
tion impairment with various therapies used. An (6–9 years) have been reported in those with a
inverse relationship has been reported between history of BPD when compared with full-term
FEV1 at school age and duration of supplemental and preterm children with no BPD. Others have
oxygen. V’max25, a measure of flow through shown a decrease in maximal exercise in capacity
small airways, was reduced at school age in in BPD survivors aged 6–12 years when compared
inverse proportion to an oxygen score that quan- to healthy controls. Exercise tolerance continues
tified neonatal supplemental oxygen exposure. be relatively unchanged in young adulthood.
Conversely, others have reported poor correlation Higher airway obstruction and CO diffusing
between duration of mechanical ventilation and capacity and decreased exercise capacity but nor-
oxygen supplementation and forced expiratory mal mean lung function in former preemies at
flow in infants with BPD (Bhandari and Panitch young adulthood (mean age 19 years), when com-
2006). BPD infants had low forced expiratory pared to controls, has been reported. This suggests
flow measurements at 6 and 12 months who that the impaired exercise tolerance in these young
were treated initially with either high-frequency adults was not related to pulmonary function but
oscillatory ventilation (HFOV) or conventional perhaps poor physical fitness (Bhandari and
mechanical ventilation (CMV) compared with Panitch 2006).
published reference values (Hofhuis et al. 2002). Many changes occur in pulmonary function
Infants treated initially with HFOV had signifi- with growth and development. While lung
cantly better lung function at 12 months than mechanics and some volumes may normalize
those treated with CMV (Hofhuis et al. 2002), over time, small airway dysfunction persists.
suggesting that early HFOV in combination with While some investigators have suggested that
surfactant treatment could lessen the neonatal the abnormal lung function catches up in the first
lung injury that leads to BPD (Hofhuis year (Mello et al. 2015), others have reported no
et al. 2002). It is not known if this difference catch up during 2 years (Sanchez-Solis
persists into adulthood. Others have found no et al. 2016). Recent data suggest that adults with
significant difference in the degree of mild history of BPD are more likely to have airflow
obstructive lung disease as a function of mode of obstruction, bronchial hyperresponsiveness, and
ventilation at 8–9 years of age. This suggests that pulmonary gas trapping (Landry et al. 2016;
other factors influence long-term pulmonary out- Saarenpaa et al. 2015).
come (Bhandari and Panitch 2006). Other studies Neurodevelopmental outcomes: BPD chil-
have noted a correlation in the V’max FRC, dren have a greater fine and gross motor skill
FEV1, and FEF25–75% measured at 2 years and impairment as well as cognitive function and lan-
school age (Bhandari and Panitch 2006). guage delay as compared to infants without BPD.
Large airways can also be affected in BPD. Children with severe BPD had worse outcomes
Prolonged endotracheal intubation and mechani- and required more interventions at age 8 years
cal ventilation result in tracheomalacia and than did children with mild or moderate BPD
bronchomalacia which are associated with (Short et al. 2007).
increased airway compliance. Other problems Most studies of BPD have been cross-sectional
commonly encountered are subglottic stenosis, in nature, and the independent effect of BPD is
airway granulomas, and pseudopolyps that may difficult to assess, given the high likelihood of the
require surgical intervention (Bhandari and presence of additional medical complications in
Panitch 2006). these infants. While preterm infants have an
902 V. Bhandari
increased risk of neurodevelopmental impair- 57.9 Therapy
ment, BPD is an additional risk factor (Anderson
and Doyle 2006). BPD does not appear to be The current status of the various therapeutic
associated with a specific neuropsychological approaches in the three (early, evolving, and
but rather a global impairment (Anderson and established) phases of BPD is shown in Tables 4,
Doyle 2006). Importantly, the spectrum of 5, and 6. The robustness of the evidence has been
neurodevelopmental impairment appears to corre- classified based on the type of clinical studies
late well with the BPD disease severity using the system developed by the US Preventive
(Ehrenkranz et al. 2005; Jeng et al. 2008). Services Task Force:
Recently, a single-center recent retrospective
study reported that BPD (with or without chronic • Level I: Evidence obtained from at least one
oxygen dependency) in children predicted abnor- properly designed randomized controlled trial.
mal neurodevelopmental outcomes at 36 months • Level II-1: Evidence obtained from well-
corrected age (Lodha et al. 2014). However, designed controlled trials without
chronic oxygen dependency did not lead to randomization.
worse neurodevelopmental outcomes in those • Level II-2: Evidence obtained from well-
with BPD (Lodha et al. 2014). designed cohort or case-control analytic
Table 4 Management of BPD: early phase (up to 1 postnatal week)
Therapeutic Level of Level of
intervention Current status evidence recommendation
Oxygen Controversy in the acceptable oxygen saturation levels still exists I A
supplementation across centers, but generally <95% (Samiee-Zafarghandy
et al. 2015; Manja et al. 2015); usually between 87% and 93%
(Lakshminrusimha et al. 2015)
Ventilatory Avoid intubation. If intubated, give “early” surfactant (Yost and I A
strategy Soll 2000)
Use short inspiratory times (0.24–0.4 s), (Kamlin and Davis I A
2004) rapid rates (40–60/min) III B
Low PIP (14–20 cm H2O) III B
Moderate PEEP (4–6 cm H2O) III B
Low tidal volume (3–6 mL/kg) (Ambalavanan and Carlo 2006) III B
Extubate early to SNIPPV/NCPAP (Bhandari 2006) I A
Blood gas targets: pH 7.25–7.35 III B
PaO2 40–60 mmHg III B
PaCO2 45–55 mmHg (Miller and Carlo 2007) I C
High-frequency ventilation for “rescue,” if conventional I A
ventilation fails (Greenough 2007)
Methylxanthines Improves successful extubation rate (Henderson-Smart and Davis I A
2003)
Decreases BPD (Schmidt et al. 2006) I A
Vitamin A If considering use, dose is 5,000 IU administered intramuscularly I A
3 times per week for 4 weeks. 1 additional infant survived without
BPD for every 14–15 infants who received vitamin A (Tyson
et al. 1999; Darlow and Graham 2007)
Fluids Restrictive fluid intake may decrease BPD (Bhandari et al. 2005; II-2 B
Oh et al. 2005)
Nutrition Provide increased energy intake (Lai et al. 2006) I B
PIP peak inspiratory pressure, PEEP positive end expiratory pressure, SNIPPV synchronized nasal intermittent positive
pressure ventilation, NCPAP nasal continuous positive airway pressure (From Bhandari and Bhandari (2009), with
permission)
57 Bronchopulmonary Dysplasia/Chronic Lung Disease of the Newborn 903
Table 5 Management of BPD: evolving phase (>1 postnatal week to 36 weeks PMA)
Therapeutic Level of Level of
intervention Current status evidence recommendation
Oxygen Same as in Table 4 I A
supplementation
Ventilatory Avoid endotracheal tube ventilation. Maximize noninvasive I A
strategy ventilation (SNIPPV/NCPAP) for respiratory support (Bhandari
2006)
Blood gas targets: pH 7.25–7.35 III B
PaO2 50–70 mmHg III B
PaCO2 50–60 mmHg (Ambalavanan and Carlo 2006) III B
Methylxanthines Same as in Table 4 I A
Vitamin A Same as in Table 4. If using, continue for 4 postnatal weeks I A
Steroids Dexamethasone effective in weaning off mechanical ventilation I A
when used “moderately early” and “delayed” (Halliday
et al. 2003a, b)
Increased incidence of neurological sequelae with early use I D
(<96 h) (Halliday et al. 2003c)
Diuretics Furosemide: may use daily or every other day with transient I B
improvement in lung function (Baveja and Christou 2006)
Spironolactone and thiazides: chronic therapy improves lung I B
function and decreases oxygen requirements (Baveja and
Christou 2006)
Nutrition Same as in Table 4 I B
PMA postmenstrual age, SNIPPV synchronized nasal intermittent positive pressure ventilation, NCPAP nasal continuous
positive airway pressure (From Bhandari and Bhandari (2009), with permission)
Table 6 Management of BPD: established phase (>36 weeks PMA)
Therapeutic Level of Level of
intervention Current status evidence recommendation
Oxygen For prevention of pulmonary hypertension and cor pulmonale. A III C
supplementation wide variation in the acceptable oxygen saturation levels exists
across centers, but generally ~95% (Greenough 2007; Khemani
et al. 2007)
Ventilatory Blood gas targets: pH 7.25–7.35 III B
strategy PaO2 50–70 mmHg
PaCO2 50–65 mmHg (Ambalavanan and Carlo 2006)
Steroids Oral prednisolone may be helpful in weaning oxygen (Bhandari II-2 C
et al. 2008b)
Diuretics Chronic therapy as in Table 5 I B
Beta agonists Transient relief: increased compliance and reduced pulmonary I C
resistance (Baveja and Christou 2006)
No significant effect on incidence or severity of BPD I C
(Ng et al. 2001)
Anticholinergics Used in combination with beta agonists in infants with II-3 C
bronchospasm. Increased compliance and decreased respiratory
system resistance (Brundage et al. 1990)
Nutrition Same as in Table 4 I B
Immunization Prophylaxis against RSV and influenza decreases incidence of I A
rehospitalization and morbidity
PMA postmenstrual age (From Bhandari and Bhandari (2009), with permission)
904 V. Bhandari
studies, preferably from more than one center Continuous tracheal gas insufflation
or research group. (CTGI): In a prospective RCT in 34 premature
• Level II-3: Evidence obtained from multiple infants, CTGI was not found to decrease death or
time series with or without the intervention. BPD, compared to controls.
Dramatic results in uncontrolled trials might Cromolyn: Two trials did not show any
also be regarded as this type of evidence. decrease in the incidence of BPD with the use of
• Level III: Opinions of respected authorities, cromolyn (a mast cell stabilizer), which was con-
based on clinical experience, descriptive stud- firmed in a meta-analysis.
ies, or reports of expert committees. Hydrocortisone: Low-dose hydrocortisone
did not improve survival without BPD
The recommendation for use in the clinical (Watterberg et al. 2004). The RCT had to be
setting is also based on the guidelines developed terminated early due to the hydrocortisone-treated
by the US Preventive Services Task Force: infants receiving indomethacin having more gas-
trointestinal perforations (Watterberg et al. 2004).
• Level A: Good scientific evidence suggests Inositol: In a meta-analysis of RCT using ino-
that the benefits substantially outweigh the sitol supplementation in premature infants, the
potential risks. outcome of death or BPD was reported in two
• Level B: At least fair scientific evidence sug- trials and was found to be significantly reduced
gests that the benefits outweigh the potential (Howlett and Ohlsson 2003).
risks. Liquid ventilation: In an uncontrolled study
• Level C: At least fair scientific evidence sug- of 13 premature neonates treated with partial liq-
gests that there are benefits provided, but the uid ventilation, among eight infants who survived
balance between benefits and risks are too till 36 weeks PMA, four had BPD.
close for making general recommendations. Macrolide antibiotics: Erythromycin has
• Level D: At least fair scientific evidence sug- not been shown to decrease BPD in infants
gests that the risks outweigh potential benefits. when treated prophylactically or after known
• Level I: Scientific evidence is lacking, of poor Ureaplasma colonization. Azithromycin, in a
quality, or conflicting, such that the risk versus pilot study, did not reduce the incidence of BPD.
benefit balance cannot be assessed. N-Acetylcysteine (NAC): In a large RCT, the
use of a 6-day course of NAC did not prevent
BPD or death in infants with BW <1,000 g.
Nasal continuous positive airway pressure
57.10 Novel Approaches/Therapies (NCPAP): Early surfactant replacement therapy
with extubation to NCPAP compared with later
Allopurinol: In a randomized controlled trial selective surfactant replacement and continued
(RCT) of 400 preterm infants, allopurinol given mechanical ventilation with extubation from low
for 1 week did not impact on the incidence of BPD ventilator support was associated with less need
(at 28 days). for mechanical ventilation, lower incidence of
Alpha-1 proteinase inhibitor (α1P1): Sys- BPD, and fewer air leak syndromes (Stevens
temic treatment with α1P1 did not reveal any et al. 2007). Use of a cutoff value of FiO2 of
statistically significant differences in the rates of 0.45 to decide on transient intubation and surfac-
BPD between the treated and placebo groups of tant replacement appeared to decrease the inci-
preterm infants. dence of air leaks and BPD (Stevens et al. 2007).
Budesonide: Inhaled as well as intratracheal The Cochrane review, however, did not include the
administration of budesonide (the latter in con- results of the COIN trial which reported that in
junction with surfactant) has shown to decrease infants born at 25–28-weeks gestation, early nasal
BPD in 2 recent RCTs (Bassler et al. 2015; Yeh CPAP did not significantly reduce the rate of death
et al. 2016). or BPD, as compared with intubation, and the
57 Bronchopulmonary Dysplasia/Chronic Lung Disease of the Newborn 905
CPAP group had a higher incidence of decreased hospitalizations and emergency room
pneumothorace (Morley et al. 2008). In the SUP- visits and less frequent use of bronchodilator ther-
PORT study, the rates of BPD or death did not differ apy at age 1 year, as compared to infants that did
significantly between the CPAP group and the not receive it (Davis et al. 2003).
surfactant group (47.8% and 51.0%) after Stem cells: Intratracheal delivery of stem cells
adjustment for confounding factors (Network in human preterm infants is being studied to pre-
SSGotEKSNNR et al. 2010). Follow-up studies vent BPD (Chang et al. 2014).
reported improved pulmonary morbidity in the Synthetic surfactant: A new synthetic surfac-
NCPAP group (Stevens et al. 2014), with no differ- tant (lucinactant) which contains the novel pep-
ence in neurodevelopmental outcomes (Vaucher tide, sinapultide, a surfactant-associated protein B
et al. 2012). mimic, appears to be similar to animal-derived
Nasal intermittent positive pressure ventila- surfactant in two multicenter randomized clinical
tion (NIPPV): NIPPV, both in the synchronized trials. A meta-analysis of the studies revealed no
(SNIPPV) (Bhandari et al. 2007) and statistically different differences in the outcomes
non-synchronized (Kugelman et al. 2007) modes, of death and BPD (Pfister et al. 2007).
has been found to decrease BPD in RCT. The NIP Surfactant delivery: Use of minimally or less
trial did not show any difference in outcomes invasive modes of surfactant administration have
(Kirpalani et al. 2013), but concerns with the shown initial promise (Dargaville et al. 2013;
study design have been raised (Bhandari 2013). Kribs et al. 2015). Another attractive alternative
Combining NIPPV with a less invasive mode of to intubation and delivery of intratracheal surfac-
surfactant administration has shown promise in a tant would be aerosol delivery. To date, no effec-
pilot RCT in decreasing the need for invasive ven- tive aerosolized surfactant preparation is available
tilation, but no impact on BPD, after controlling for for routine use in the clinical setting.
confounding factors (Oncel et al. 2015). Thyroxine: In a RCT, postnatal supplementa-
Nitric oxide: Inhaled nitric oxide (iNO) may tion of thyroxine in preterm newborns did not
or may not be beneficial in preventing BPD decrease the incidence of BPD.
(Barrington and Finer 2007). Late treatment Vitamin E: In a RCT, oral vitamin E supple-
with up to five doses of surfactant in ventilated mentation did not reduce BPD in infants with BW
premature infants being administered iNO <1,500 g.
(TOLSURF study) did not improve survival Volume-targeted ventilation: In a meta-
without BPD at 36 or 40 weeks (Ballard analysis comparing volume-targeted ventilation
et al. 2016). It does appear to be safe in this to pressure-limited ventilation, there was no dif-
population, though it does not appear to impact ference in the incidence of BPD between the two
on surfactant composition or pulmonary func- groups.
tion. Routine use of iNO to decrease BPD in the More research is needed with these approaches
preterm population is not recommended, pend- before definite recommendations can be made.
ing long-term outcome data. Prevention: Among the antenatal factors, pre-
Patient-triggered ventilation: Studies done to vention of premature birth is the single most effec-
date have not shown any reduction in the inci- tive preventive measure for BPD. Understanding
dence of BPD. the biology of, and targeting therapies to inhibit,
Recombinant CC10: Use of an anti- preterm labor safely would be an important goal.
inflammatory protein, recombinant human Clara The use of progesterone in prevention of prema-
cell 10-kD protein (CC10), has shown some initial ture labor has shown promise, although the pro-
promise. longation of gestation with this approach has yet
Recombinant SOD: Although the antioxidant to improve infant outcomes.
recombinant Cu-Zn superoxide dismutase (SOD) Antenatal steroids still remain the single
did not show any difference in outcome, infants most effective intervention for lung maturation
<27 weeks of gestation that received SOD had and are recommended for clinical use.
906 V. Bhandari
The impact of antenatal steroids on BPD has our ability to identify the genetic components of
been somewhat controversial with studies BPD and to target specific and novel therapies
reporting no or some benefit; other factors (Bhandari 2014b).
may perhaps mask the benefit of antenatal ste-
roids. Weekly courses of antenatal steroids are
not recommended. Betamethasone is preferred References
over dexamethasone.
Considerable research has gone into under- Aghai ZH, Faqiri S, Saslow JG, Nakhla T, Farhath S,
standing the role of antenatal and postnatal Kumar A et al (2008) Angiopoietin 2 concentrations
in infants developing bronchopulmonary dysplasia:
inflammation in the pathogenesis of BPD attenuation by dexamethasone. J Perinatol 28:149–155
(Speer 2006; Ryan et al. 2008; Bhandari Agrons A, Courtney S, Stocker J, Markowitz R (2005)
2014a). Antenatal interventions to treat From the archives of the AFIP: lung disease in prema-
chorioamnionitis have not decreased BPD; post- ture neonates: radiologic-pathologic correlation.
Radiographics 25(4):1047–1073
natal interventions may be too late to be effec- Ambalavanan N, Carlo WA (2006) Ventilatory strategies in
tive. In most circumstances, maintenance of the prevention and management of bronchopulmonary
target oxygen saturation ranged >85 and <95% dysplasia. Semin Perinatol 30(4):192–199
is prudent in preterm neonates to avoid oxygen Ambalavanan N, Mourani P (2014) Pulmonary hyperten-
sion in bronchopulmonary dysplasia. Birth Defects Res
toxicity in an attempt to prevent the development Part A Clin Mol Teratol 100(3):240–246. https://doi.
of BPD, though achieving intended targets may org/10.1002/bdra.23241
be difficult. Restrictive fluid intake to meet phys- Ambalavanan N, Novak ZE (2003) Peptide growth factors
iological needs without resulting in significant in tracheal aspirates of mechanically ventilated preterm
neonates. Pediatr Res 53(2):240–244
dehydration showed a trend toward a lower risk Anderson PJ, Doyle LW (2006) Neurodevelopmental out-
for BPD (Bell and Acarregui 2008). Attempts at come of bronchopulmonary dysplasia. Semin Perinatol
early extubation (Berger et al. 2014) (Jensen 30(4):227–232
et al. 2015) and use of noninvasive methods of Baier RJ, Majid A, Parupia H, Loggins J, Kruger TE
(2004) CC chemokine concentrations increase in respi-
ventilation appear to show early promise in the ratory distress syndrome and correlate with develop-
prevention of BPD. ment of bronchopulmonary dysplasia. Pediatr
Given the complex nature of BPD (Fig. 1), it is Pulmonol 37(2):137–148
unlikely that a single “magic bullet” (with the Balany J, Bhandari V (2015) Understanding the impact of
infection, inflammation, and their persistence in the
possible exception of prevention of preterm pathogenesis of bronchopulmonary dysplasia. Front
birth) will make a highly significant impact on Med (Lausanne) 2:90. https://doi.org/10.3389/
BPD. Incremental improvements are possible by fmed.2015.00090
targeting multiple aspects of this condition which Ballard RA, Keller RL, Black DM, Ballard PL, Merrill JD,
Eichenwald EC et al (2016) Randomized trial of late
include early diagnosis and treatment of antenatal surfactant treatment in ventilated preterm infants
and postnatal sepsis, optimal maintenance of oxy- receiving inhaled nitric oxide. J Pediatr 168:23–29.
genation and fluid/electrolyte status, and aggres- https://doi.org/10.1016/j.jpeds.2015.09.031, e4
sive early parenteral/enteral nutrition, along with Baraldi E, Filippone M (2007) Chronic lung disease after
premature birth. N Engl J Med 357(19):1946–1955
appropriate ventilatory strategies. Barrington KJ, Finer NN (2007) Inhaled nitric oxide
for preterm infants: a systematic review. Pediatrics
120(5):1088–1099
57.11 Conclusions Bassler D, Plavka R, Shinwell ES, Hallman M, Jarreau PH,
Carnielli V et al (2015) Early inhaled budesonide for
the prevention of bronchopulmonary dysplasia. N Engl
Focusing on aspects of basic biology (lung devel- J Med 373(16):1497–1506. https://doi.org/10.1056/
opment, identification of biomarkers, genetics, NEJMoa1501917
animal models) and pharmacotherapeutic Baveja R, Christou H (2006) Pharmacological strategies in
the prevention and management of bronchopulmonary
approaches (Walsh et al. 2006) has the maximum dysplasia. Semin Perinatol 30(4):209–218
potential to make an impact on BPD. Significant Bell EF, Acarregui MJ (2008) Restricted versus liberal
improvements in the future will likely depend on water intake for preventing morbidity and mortality in
57 Bronchopulmonary Dysplasia/Chronic Lung Disease of the Newborn 907
preterm infants. Cochrane Database Syst Rev 2-mediated acute lung injury and necrotic cell death.
1, CD000503 Nat Med 12(11):1286–1293
Berger J, Mehta P, Bucholz E, Dziura J, Bhandari V (2014) Bhandari V, Gavino RG, Nedrelow JH, Pallela P,
Impact of early extubation and reintubation on the Salvador A, Ehrenkranz RA et al (2007) A randomized
incidence of bronchopulmonary dysplasia in neonates. controlled trial of synchronized nasal intermittent pos-
Am J Perinatol 31(12):1063–1072. https://doi.org/ itive pressure ventilation in RDS. J Perinatol 27
10.1055/s-0034-1371702 (11):697–703
Bhandari V (2006) Non-invasive ventilation of the sick Bhandari V, Choo-Wing R, Lee CG, Yusuf K, Nedrelow
neonate: evidence-based recommendations. J Neonatol JH, Ambalavanan N et al (2008a) Developmental reg-
20(3):214–221 ulation of NO-mediated VEGF-induced effects in the
Bhandari V (2012) Genetic influences in lung development lung. Am J Respir Cell Mol Biol 39(4):420–430
and injury. In: Bancalari E (ed) The newborn lung: ques- Bhandari A, Schramm CM, Kimble C, Pappagallo M,
tions and controversies, 2nd edn. Neonatology: questions Hussain N (2008b) Effect of a short course of
and controversies. Saunders, Philadelphia, pp 29–55 prednisolone in infants with oxygen-dependent
Bhandari V (2013) The potential of non-invasive ventila- bronchopulmonary dysplasia. Pediatrics 121(2):
tion to decrease BPD. Semin Perinatol 37(2):108–114. e344–e349
https://doi.org/10.1053/j.semperi.2013.01.007 Bland RD, Xu L, Ertsey R, Rabinovitch M, Albertine KH,
Bhandari V (2014a) Postnatal inflammation in the patho- Wynn KA et al (2007) Dysregulation of pulmonary
genesis of bronchopulmonary dysplasia. Birth Defects elastin synthesis and assembly in preterm lambs with
Res Part A Clin Mol Teratol 100(3):189–201. https:// chronic lung disease. Am J Physiol Lung Cell Mol
doi.org/10.1002/bdra.23220 Physiol 292(6):L1370–L1384. https://doi.org/10.1152/
Bhandari V (2014b) Drug therapy trials for the prevention ajplung.00367.2006
of bronchopulmonary dysplasia: current and future tar- Bokodi G, Treszl A, Kovacs L, Tulassay T, Vasarhelyi B
gets. Front Pediatr 2:76. https://doi.org/10.3389/ (2007) Dysplasia: a review. Pediatr Pulmonol
fped.2014.00076 42:952–961
Bhandari A, Bhandari V (2003) Pathogenesis, pathology Brundage KL, Mohsini KG, Froese AB, Fisher JT (1990)
and pathophysiology of pulmonary sequelae of Bronchodilator response to ipratropium bromide in
bronchopulmonary dysplasia in premature infants. infants with bronchopulmonary dysplasia. Am Rev
Front Biosci 8:e370–e380 Respir Dis 142(5):1137–1142
Bhandari A, Bhandari V (2007) Bronchopulmonary dys- Bry K, Whitsett JA, Lappalainen U (2007) IL-1beta dis-
plasia: an update. Indian J Pediatr 74(1):73–77 rupts postnatal lung morphogenesis in the mouse. Am J
Bhandari A, Bhandari V (2009) Pitfalls, problems and Respir Cell Mol Biol 36(1):32–42
progress in bronchopulmonary dysplasia. Pediatrics Cederqvist K, Sorsa T, Tervahartiala T, Maisi P,
123:1562–1573 Reunanen K, Lassus P et al (2001) Matrix
Bhandari A, Bhandari V (2011) “New” bronchopulmonary metalloproteinases-2, -8, and -9 and TIMP-2 in tracheal
dysplasia: a clinical review. Clin Pulm Med aspirates from preterm infants with respiratory distress.
18(3):137–143 Pediatrics 108(3):686–692
Bhandari A, Bhandari V (2013) Biomarkers in Chang YS, Ahn SY, Yoo HS, Sung SI, Choi SJ, Oh WI
bronchopulmonary dysplasia. Paediatr Respir Rev 14 et al (2014) Mesenchymal stem cells for
(3):173–179. https://doi.org/10.1016/j.prrv.2013.02.008 bronchopulmonary dysplasia: phase 1 dose-escalation
Bhandari V, Elias JA (2006) Cytokines in tolerance to clinical trial. J Pediatr 164(5):966–972. https://doi.org/
hyperoxia-induced injury in the developing and adult 10.1016/j.jpeds.2013.12.011, e6
lung. Free Radic Biol Med 41(1):4–18 Choo-Wing R, Nedrelow JH, Homer RJ, Elias JA,
Bhandari V, Gruen JR (2006) The genetics Bhandari V (2007) Developmental differences in the
of bronchopulmonary dysplasia. Semin Perinatol responses of IL-6 and IL-13 transgenic mice exposed to
30(4):185–191 hyperoxia. Am J Physiol Lung Cell Mol Physiol 293
Bhandari A, Panitch HB (2006) Pulmonary outcomes (1):L142–L150
in bronchopulmonary dysplasia. Semin Perinatol Choo-Wing R, Syed MA, Harijith A, Bowen B,
30(4):219–226. https://doi.org/10.1053/j.semperi.2006. Pryhuber G, Janer C et al (2013) Hyperoxia and
05.009 interferon-gamma-induced injury in developing lungs
Bhandari V, Brodsky N, Porat R (2005) Improved outcome occur via cyclooxygenase-2 and the endoplasmic retic-
of extremely low birth weight infants with Tegaderm ulum stress-dependent pathway. Am J Respir Cell Mol
application to skin. J Perinatol 25(4):276–281 Biol 48(6):749–757
Bhandari V, Bizzarro MJ, Shetty A, Zhong X, Page GP, Clyman RI (2013) The role of patent ductus arteriosus and
Zhang H et al (2006a) Familial and genetic susceptibil- its treatments in the development of bronchopulmonary
ity to major neonatal morbidities in preterm twins. dysplasia. Semin Perinatol 37(2):102–107. https://doi.
Pediatrics 117(6):1901–1906 org/10.1053/j.semperi.2013.01.006
Bhandari V, Choo-Wing R, Lee CG, Zhu Z, Nedrelow JH, Coalson JJ (2006) Pathology of bronchopulmonary dys-
Chupp GL et al (2006b) Hyperoxia causes angiopoietin plasia. Semin Perinatol 30(4):179–184
908 V. Bhandari
Cullen A, Van Marter LJ, Allred EN, Moore M, Parad RB, Halliday HL, Ehrenkranz RA, Doyle LW (2003b) Moder-
Sunday ME (2002) Urine bombesin-like peptide ately early (7–14 days) postnatal corticosteroids for
elevation precedes clinical evidence of preventing chronic lung disease in preterm infants.
bronchopulmonary dysplasia. Am J Respir Crit Care Cochrane Database Syst Rev 1, CD001144
Med 165(8):1093–1097 Halliday HL, Ehrenkranz RA, Doyle LW (2003c) Early
Cuna A, Kandasamy J, Sims B (2014) B-type natriuretic postnatal (<96 hours) corticosteroids for preventing
peptide and mortality in extremely low birth weight chronic lung disease in preterm infants. Cochrane Data-
infants with pulmonary hypertension: a retrospective base Syst Rev 1, CD001146
cohort analysis. BMC Pediatr 14:68. https://doi.org/ Harijith A, Choo-Wing R, Cataltepe S, Yasumatsu R,
10.1186/1471-2431-14-68 Aghai ZH, Janer J et al (2011) A role for
Dargaville PA, Aiyappan A, De Paoli AG, Kuschel CA, matrix metalloproteinase 9 in IFNgamma-mediated
Kamlin CO, Carlin JB et al (2013) Minimally-invasive injury in developing lungs: relevance to
surfactant therapy in preterm infants on continuous bronchopulmonary dysplasia. Am J Respir Cell Mol
positive airway pressure. Arch Dis Child Fetal Neona- Biol 44(5):621–630
tal Ed 98(2):F122–F126. https://doi.org/10.1136/ Henderson-Smart DJ, Davis PG (2003) Prophylactic meth-
archdischild-2011-301314 ylxanthines for extubation in preterm infants. Cochrane
Darlow BA, Graham PJ (2007) Vitamin A supplementa- Database Syst Rev 1, CD000139
tion to prevent mortality and short and long-term mor- Hirakawa H, Pierce RA, Bingol-Karakoc G, Karaaslan C,
bidity in very low birthweight infants. Cochrane Weng M, Shi GP et al (2007) Cathepsin S deficiency
Database Syst Rev 4, CD000501 confers protection from neonatal hyperoxia-induced
Davis JM, Parad RB, Michele T, Allred E, Price A, lung injury. Am J Respir Crit Care Med
Rosenfeld W (2003) Pulmonary outcome at 1 year 176(8):778–785
corrected age in premature infants treated at birth with Hofhuis W, Huysman MW, van der Wiel EC, Holland WP,
recombinant human CuZn superoxide dismutase. Pedi- Hop WC, Brinkhorst G et al (2002) Worsening of
atrics 111(3):469–476 V’maxFRC in infants with chronic lung disease in the
Doyle LW, Faber B, Callanan C, Freezer N, Ford GW, first year of life: a more favorable outcome after high-
Davis NM (2006) Bronchopulmonary dysplasia in frequency oscillation ventilation. Am J Respir Crit Care
very low birth weight subjects and lung function in Med 166(12 Pt 1):1539–1543
late adolescence. Pediatrics 118(1):108–113 Howlett A, Ohlsson A (2003) Inositol for respiratory dis-
Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, tress syndrome in preterm infants. Cochrane Database
Wright LL, Fanaroff AA et al (2005) Validation of Syst Rev 4, CD000366
the National Institutes of Health consensus Hyodynmaa E, Korhonen P, Ahonen S, Luukkaala T,
definition of bronchopulmonary dysplasia. Pediatrics Tammela O (2012) Frequency and clinical correlates
116(6):1353–1360 of radiographic patterns of bronchopulmonary dyspla-
Ekekezie II, Thibeault DW, Simon SD, Norberg M, Merrill sia in very low birth weight infants by term age. Eur J
JD, Ballard RA et al (2004) Low levels of tissue inhib- Pediatr 171(1):95–102. https://doi.org/10.1007/
itors of metalloproteinases with a high matrix s00431-011-1486-6
metalloproteinase-9/tissue inhibitor of Jeng SF, Hsu CH, Tsao PN, Chou HC, Lee WT, Kao HA
metalloproteinase-1 ratio are present in tracheal aspi- et al (2008) Bronchopulmonary dysplasia predicts
rate fluids of infants who develop chronic lung disease. adverse developmental and clinical outcomes in
Pediatrics 113(6):1709–1714 very-low-birthweight infants. Dev Med Child Neurol
Ericson JE, Laughon MM (2015) Chorioamnionitis: impli- 50(1):51–57
cations for the neonate. Clin Perinatol 42(1):155–165. Jensen EA, Schmidt B (2014) Epidemiology of
https://doi.org/10.1016/j.clp.2014.10.011, ix bronchopulmonary dysplasia. Birth Defects Res Part
Fabiano A, Gavilanes AW, Zimmermann LJ, Kramer BW, A Clin Mol Teratol 100(3):145–157. https://doi.org/
Paolillo P, Livolti G et al (2015) The development of 10.1002/bdra.23235
lung biochemical monitoring can play a key role in the Jensen EA, DeMauro SB, Kornhauser M, Aghai ZH,
early prediction of bronchopulmonary dysplasia. Acta Greenspan JS, Dysart KC (2015) Effects of multiple
Paediatr. https://doi.org/10.1111/apa.13233 ventilation courses and duration of mechanical ventila-
Frank L (2003) Protective effect of keratinocyte tion on respiratory outcomes in extremely low-birth-
growth factor against lung abnormalities associated weight infants. JAMA Pediatr 169(11):1011–1017.
with hyperoxia in prematurely born rats. Biol Neonate https://doi.org/10.1001/jamapediatrics.2015.2401
83(4):263–272 Kamlin CO, Davis PG (2004) Long versus short inspira-
Greenough A (2007) How has research in the past 5 years tory times in neonates receiving mechanical ventila-
changed my clinical practice. Arch Dis Child Fetal tion. Cochrane Database Syst Rev 4, CD004503
Neonatal Ed 92(5):F404–F407 Keszler M, Sant’Anna G (2015) Mechanical ventilation and
Halliday HL, Ehrenkranz RA, Doyle LW (2003a) Delayed bronchopulmonary dysplasia. Clin Perinatol 42
(>3 weeks) postnatal corticosteroids for chronic lung (4):781–796. https://doi.org/10.1016/j.clp.2015.08.006
disease in preterm infants. Cochrane Database Syst Rev Kevill K, Bhandari V, Kettuman M, Leng L, Fan J,
1, CD001145 Mizue Y et al (2008) A role for macrophage migration
57 Bronchopulmonary Dysplasia/Chronic Lung Disease of the Newborn 909
inhibitory factor in the neonatal respiratory distress J 133(5):401–407. https://doi.org/10.1590/1516-
syndrome. J Immunol 180(1):601–608 3180.2014.00101812
Khemani E, McElhinney DB, Rhein L, Andrade O, Lacro Miller JD, Carlo WA (2007) Safety and effectiveness of
RV, Thomas KC et al (2007) Pulmonary artery permissive hypercapnia in the preterm infant. Curr
hypertension in formerly premature infants with Opin Pediatr 19(2):142–144
bronchopulmonary dysplasia: clinical features and out- Montgomery AM, Bazzy-Asaad A, Asnes JD, Bizzarro
comes in the surfactant era. Pediatrics 120(6):1260–1269 MJ, Ehrenkranz RA, Weismann CG (2016) Biochemi-
Kirpalani H, Millar D, Lemyre B, Yoder BA, Chiu A, cal screening for pulmonary hypertension in
Roberts RS et al (2013) A trial comparing preterm infants with bronchopulmonary dysplasia.
noninvasive ventilation strategies in preterm infants. Neonatology 109(3):190–194. https://doi.org/10.1159/
N Engl J Med 369(7):611–620. https://doi.org/ 000442043
10.1056/NEJMoa1214533 Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM,
Kribs A, Roll C, Gopel W, Wieg C, Groneck P, Laux R Carlin JB (2008) Nasal CPAP or intubation at birth for
et al (2015) Nonintubated surfactant application vs con- very preterm infants. N Engl J Med 358(7):700–708
ventional therapy in extremely preterm infants: a ran- Mourani PM, Abman SH (2015) Pulmonary hypertension
domized clinical trial. JAMA Pediatr 169(8):723–730. and vascular abnormalities in bronchopulmonary dys-
https://doi.org/10.1001/jamapediatrics.2015.0504 plasia. Clin Perinatol 42(4):839–855. https://doi.org/
Kugelman A, Feferkorn I, Riskin A, Chistyakov I, 10.1016/j.clp.2015.08.010
Kaufman B, Bader D (2007) Nasal intermittent Network SSGotEKSNNR, Finer NN, Carlo WA, Walsh
mandatory ventilation versus nasal continuous positive MC, Rich W, Gantz MG et al (2010) Early CPAP
airway pressure for respiratory distress syndrome: a versus surfactant in extremely preterm infants. N Engl
randomized, controlled, prospective study. J Pediatr J Med 362(21):1970–1979. https://doi.org/10.1056/
150(5):521–526 NEJMoa0911783
Lai NM, Rajadurai SV, Tan KH (2006) Increased energy Ng GY, da S, Ohlsson A (2001) Bronchodilators for the
intake for preterm infants with (or developing) prevention and treatment of chronic lung disease in
bronchopulmonary dysplasia/chronic lung disease. preterm infants. Cochrane Database Syst Rev
Cochrane Database Syst Rev 3, CD005093 3, CD003214
Lakshminrusimha S, Manja V, Mathew B, Suresh GK Niu JO, Munshi U, Siddiq M, Parton LA (1998) Early
(2015) Oxygen targeting in preterm infants: a physio- increase in endothelin-1 in tracheal aspirates of preterm
logical interpretation. J Perinatol 35(1):8–15. https:// infants: correlation with bronchopulmonary dysplasia.
doi.org/10.1038/jp.2014.199 J Pediatr 132:965–970
Lal CV, Ambalavanan N (2015) Biomarkers, early diagno- Oh W, Poindexter BB, Perritt R, Lemons JA, Bauer CR,
sis, and clinical predictors of bronchopulmonary dys- Ehrenkranz RA et al (2005) Association between fluid
plasia. Clin Perinatol 42(4):739–754. https://doi.org/ intake and weight loss during the first ten days of life
10.1016/j.clp.2015.08.004 and risk of bronchopulmonary dysplasia in extremely
Landry JS, Tremblay GM, Li PZ, Wong C, Benedetti A, low birth weight infants. J Pediatr 147(6):786–790
Taivassalo T (2016) Lung function and bronchial Oncel MY, Arayici S, Uras N, Alyamac-Dizdar E, Sari FN,
hyperresponsiveness in adults born prematurely. A Karahan S et al (2015) Nasal continuous positive air-
cohort study. Ann Am Thorac Soc 13(1):17–24. way pressure versus nasal intermittent positive-
https://doi.org/10.1513/AnnalsATS.201508-553OC pressure ventilation within the minimally invasive sur-
Lavoie PM, Pham C, Jang KL (2008) Heritability of factant therapy approach in preterm infants: a
bronchopulmonary dysplasia, defined according to the randomised controlled trial. Arch Dis Child Fetal Neo-
consensus statement of the national institutes of health. natal Ed. https://doi.org/10.1136/archdischild-2015-
Pediatrics 122(3):479–485 308204
Lodha A, Sauve R, Bhandari V, Tang S, Christianson H, Padela S, Cabacungan J, Shek S, Belcastro R, Yi M,
Bhandari A et al (2014) Need for supplemental Jankov RP et al (2005) Hepatocyte growth factor is
oxygen at discharge in infants with bronchopulmonary required for alveologenesis in the neonatal rat. Am J
dysplasia is not associated with worse neurodeve- Respir Crit Care Med 172(7):907–914
lopmental outcomes at 3 years corrected age. PLoS Pfister RH, Soll RF, Wiswell T (2007) Protein containing
One 9(3), e90843. https://doi.org/10.1371/journal. synthetic surfactant versus animal derived surfactant
pone.0090843 extract for the prevention and treatment of respiratory
Manja V, Lakshminrusimha S, Cook DJ (2015) distress syndrome. Cochrane Database Syst Rev
Oxygen saturation target range for extremely 4, CD006069
preterm infants: a systematic review and meta-analysis. Piersigilli F, Bhandari V (2016) Biomarkers in neonatol-
JAMA Pediatr 169(4):332–340. https://doi.org/ ogy: the new “omics” of bronchopulmonary dysplasia.
10.1001/jamapediatrics.2014.3307 J Matern Fetal Neonatal Med 29:1758–1764. https://
Mello RR, Silva KS, Costa AM, Ramos JR (2015) Longi- doi.org/10.3109/14767058.2015.1061495
tudinal assessment of the lung mechanics of very Plakkal N, Soraisham AS, Trevenen C, Freiheit EA,
low birth weight preterm infants with and Sauve R (2013) Histological chorioamnionitis and
without bronchopulmonary dysplasia. Sao Paulo Med bronchopulmonary dysplasia: a retrospective cohort
910 V. Bhandari
study. J Perinatol 33(6):441–445. https://doi.org/ Speer CP (2006) Inflammation and bronchopulmonary
10.1038/jp.2012.154 dysplasia: a continuing story. Semin Fetal Neonatal
Poindexter BB, Feng R, Schmidt B, Aschner JL, Ballard Med 11(5):354–362
RA, Hamvas A et al (2015) Comparisons and limita- Stevens TP, Harrington EW, Blennow M, Soll RF (2007)
tions of current definitions of bronchopulmonary dys- Early surfactant administration with brief ventilation
plasia for the prematurity and respiratory outcomes vs. selective surfactant and continued mechanical ven-
program. Ann Am Thorac Soc 12(12):1822–1830. tilation for preterm infants with or at risk for respiratory
https://doi.org/10.1513/AnnalsATS.201504-218OC distress syndrome. Cochrane Database Syst Rev
Prosnitz A, Gruen JR, Bhandari V (2013) The genetics of 4, CD003063
disorders affecting the premature newborn. In: Rimoin Stevens TP, Finer NN, Carlo WA, Szilagyi PG, Phelps DL,
DL, Connor JM, Pyeritz RE, Korf BR (eds) Emery and Walsh MC et al (2014) Respiratory outcomes of the
Rimoin’s principles and practice of medical genetics, surfactant positive pressure and oximetry randomized
6th edn. Elsevier, Philadelphia, pp 1–22 trial (SUPPORT). J Pediatr 165(2):240–249. https://
Rehan V, Torday J (2006) Lower parathyroid hormone doi.org/10.1016/j.jpeds.2014.02.054, e4
related protein content of tracheal aspirates in very low Subramaniam M, Bausch C, Twomey A, Andreeva S,
birth weight infants who develop bronchopulmonary Yoder BA, Chang L et al (2007) Bombesin-like pep-
dysplasia. Pediatr Res 60(2):216–220 tides modulate alveolarization and angiogenesis in
Ryan RM, Ahmed Q, Lakshminrusimha S (2008) Inflam- bronchopulmonary dysplasia. Am J Respir Crit Care
matory mediators in the immunobiology of Med 176(9):902–912. https://doi.org/10.1164/
bronchopulmonary dysplasia. Clin Rev Allergy rccm.200611-1734OC
Immunol 34(2):174–190 Thebaud B, Abman S (2007) Bronchopulmonary dyspla-
Saarenpaa HK, Tikanmaki M, Sipola-Leppanen M, Hovi P, sia- where have all the vessels gone? Role of angio-
Wehkalampi K, Siltanen M et al (2015) Lung function in genic growth factors in chronic lung disease. Am J
very low birth weight adults. Pediatrics 136(4):642–650. Respir Crit Care Med 175:978–985
https://doi.org/10.1542/peds.2014-2651 Thebaud B, Ladha F, Michelakis ED, Sawicka M,
Samiee-Zafarghandy S, Saugstad OD, Fusch C (2015) Do Thurston G, Eaton F et al (2005) Vascular endothelial
we have an answer when it comes to providing growth factor gene therapy increases survival, pro-
extremely preterm infants with optimal target oxygen motes lung angiogenesis, and prevents alveolar damage
saturation? Acta Paediatr 104(3):e130–e133. https:// in hyperoxia-induced lung injury: evidence that angio-
doi.org/10.1111/apa.12840 genesis participates in alveolarization. Circulation 112
Sanchez-Solis M, Perez-Fernandez V, Bosch-Gimenez V, (16):2477–2486
Quesada JJ, Garcia-Marcos L (2016) Lung function Thomas W, Speer CP (2014) Chorioamnionitis is essential
gain in preterm infants with and without in the evolution of bronchopulmonary dysplasia – the
bronchopulmonary dysplasia. Pediatr Pulmonol. case in favour. Paediatr Respir Rev 15(1):49–52.
https://doi.org/10.1002/ppul.23393 https://doi.org/10.1016/j.prrv.2013.09.004
Schena F, Francescato G, Cappelleri A, Picciolli I, May- Thomson A, Bhandari V (2008) Pulmonary biomarkers of
er A, Mosca F et al (2015) Association between hemo- bronchopulmonary dysplasia. Biomark Insights
dynamically significant patent ductus arteriosus and 3:361–373
bronchopulmonary dysplasia. J Pediatr 166 Trembath A, Laughon MM (2012) Predictors of
(6):1488–1492. https://doi.org/10.1016/j. bronchopulmonary dysplasia. Clin Perinatol 39
jpeds.2015.03.012 (3):585–601. https://doi.org/10.1016/j.clp.2012.06.014
Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington Tyson JE, Wright LL, Oh W, Kennedy KA, Mele L,
KJ, Ohlsson A et al (2006) Caffeine therapy for apnea Ehrenkranz RA et al (1999) Vitamin A supplementa-
of prematurity. N Engl J Med 354(20):2112–2121 tion for extremely-low-birth-weight infants. National
Short EJ, Kirchner HL, Asaad GR, Fulton SE, Lewis BA, Institute of Child Health and Human Development
Klein N et al (2007) Developmental sequelae in pre- Neonatal Research Network. N Engl J Med 340
term infants having a diagnosis of bronchopulmonary (25):1962–1968
dysplasia: analysis using a severity-based classification Van Marter LJ, Dammann O, Allred EN, Leviton A,
system. Arch Pediatr Adolesc Med 161(11):1082–1087 Pagano M, Moore M et al (2002) Chorioamnionitis,
Smith VC, Zupancic JA, McCormick MC, Croen LA, mechanical ventilation, and postnatal sepsis as modu-
Greene J, Escobar GJ et al (2005) Trends in severe lators of chronic lung disease in preterm infants. J
bronchopulmonary dysplasia rates between 1994 and Pediatr 140(2):171–176
2002. J Pediatr 146(4):469–473. https://doi.org/ Vaucher YE, Peralta-Carcelen M, Finer NN, Carlo WA,
10.1016/j.jpeds.2004.12.023 Gantz MG, Walsh MC et al (2012) Neurodeve-
Sohn MH, Kang MJ, Matsuura H, Bhandari V, Chen NY, lopmental outcomes in the early CPAP and pulse oxim-
Lee CG et al (2010) The chitinase-like proteins breast etry trial. N Engl J Med 367(26):2495–2504. https://
regression protein-39 and YKL-40 regulate hyperoxia- doi.org/10.1056/NEJMoa1208506
induced acute lung injury. Am J Respir Crit Care Med Vento G, Capoluongo E, Matassa PG, Concolino P,
182(7):918–928 Vendettuoli V, Vaccarella C et al (2006) Serum levels
57 Bronchopulmonary Dysplasia/Chronic Lung Disease of the Newborn 911
of seven cytokines in premature, ventilated newborns, bronchopulmonary dysplasia rates. Pediatrics 114
correlation with old and new forms of (5):1305–1311
bronchopulmonary dysplasia. Intensive Care Med Walsh MC, Szefler S, Davis J, Allen M, Van Marter L,
32:723–730 Abman S et al (2006) Summary proceedings from the
Vicencio AG, Lee CG, Cho SJ, Eickelberg O, Chuu Y, bronchopulmonary dysplasia group. Pediatrics 117
Haddad GG et al (2004) Conditional overexpression of (3 Pt 2):S52–S56
bioactive transforming growth factor-beta1 in neonatal Watterberg KL, Gerdes JS, Cole CH, Aucott SW, Thilo
mouse lung: a new model for bronchopulmonary dys- EH, Mammel MC et al (2004) Prophylaxis of early
plasia? Am J Respir Cell Mol Biol 31(6):650–656 adrenal insufficiency to prevent bronchopulmonary
Vozzelli MA, Mason SN, Whorton MH, Auten RL Jr dysplasia: a multicenter trial. Pediatrics 114
(2004) Antimacrophage chemokine treatment prevents (6):1649–1657
neutrophil and macrophage influx in hyperoxia- Yeh TF, Chen CM, Wu SY, Husan Z, Li TC, Hsieh WS
exposed newborn rat lung. Am J Physiol Lung Cell et al (2016) Intratracheal administration of budesonide/
Mol Physiol 286(3):L488–L493 surfactant to prevent bronchopulmonary dysplasia. Am
Walkup LL, Woods JC (2015) Newer imaging techniques J Respir Crit Care Med 193(1):86–95. https://doi.org/
for bronchopulmonary dysplasia. Clin Perinatol 42 10.1164/rccm.201505-0861OC
(4):871–887. https://doi.org/10.1016/j.clp.2015.08.012 Yost CC, Soll RF (2000) Early versus delayed selective
Walsh MC, Yao Q, Gettner P, Hale E, Collins M, Hensman surfactant treatment for neonatal respiratory distress
A et al (2004) Impact of a physiologic definition on syndrome. Cochrane Database Syst Rev 2, CD001456
Lung Ultrasound in Neonatal
Diagnostic 58
Francesco Raimondi, Fiorella Migliaro, and Letizia Capasso
Contents
58.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914
58.2 From Artifacts to Clinical Correlates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914
58.3 “Field Validation” of Lung Ultrasound in Neonatology . . . . . . . . . . . . . . . . . . . . . 915
58.4 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 916
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 916
Abstract appearing as a homogeneous, hyperechogenic
Neonatal respiratory disease is currently diag- line moving synchronous with respiration.
nosed on the basis of clinical signs and chest Adult emergency physicians have shown
radiographs. It has been estimated that the that the interpretation at the patient bedside of
average extremely low birth weight infant these findings together with some reproducible
will have 31 radiographs taken from birth to artifacts (see below) can be very useful in crit-
NICU discharge (Wilson-Costello et al., Pedi- ical situations where echography outperforms
atrics 97(3):369–374, 1996). The relevance of conventional radiology (Lichtenstein, Ann
this radiation exposure is still debated. More- Intensive Care 4(1):1, 2014; Lichtenstein,
over, the interpretation of a chest radiograph Chest 147(6):1659–1670, 2015).
has a significant interobserver variability. It has to be remarked that the use of artifacts
Ultrasound imaging of the lung has been tradi- (i.e., images that do not correspond to any
tionally neglected because the high acoustic anatomical structure) has raised a lot of con-
impedance of its air content prevents a clear cern in the scientific community. Strict meth-
image of the organ. The pleura is the only lung odology and close correlation with clinical data
structure clearly visible with ultrasounds have to be used when investigating with or
practicing lung ultrasound.
On this line of thought, international,
evidence-based recommendations have been
F. Raimondi (*) · F. Migliaro · L. Capasso published with age-related comments (Volpicelli
Division of Neonatology, Department of Translational et al., Intensive Care Med 38(4):577–591,
Medical Sciences, Università “Federico II” di Napoli, 2012). Neonatologists have learned the lesson
Naples, Italy
and are now applying point-of-care lung
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 913
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_206
914 F. Raimondi et al.
ultrasound to their practice (Rodríguez-Fanjul
et al., Ann Pediatr (Barc), 2015; Yousef,
Arch Pediatr. https://doi.org/10.1016/j.
arcped.2015.12.001, 2016; Raimondi et al.,
Neoreviews 15(1):e2–e6, 2014). This chapter
is a concise summary of their work.
58.1 Salient Points
• Ultrasound exam of the lung describes real
anatomic structures (e.g., the pleura) and arti- Fig. 1 Normal infant lung: the yellow square encircles the
facts in the lung parenchyma. hyperechoic image of the pleura in between two ribs.
• Artifacts and real images can be combined into Below the pleura, its horizontal reverberations (white
arrows) are visible. These artifacts are known as A-lines.
profiles that accurately diagnose adult respira- This image has been taken with a linear transducer
tory diseases.
• Neonatologists now use ultrasound mainly to
diagnose lung consolidations and respiratory
distress.
• Lung ultrasound is of valuable help in decision
making in neonatal respiratory medicine.
58.2 From Artifacts to Clinical
Correlates
A microconvex transducer is generally used to
explore the adult chest. A linear, high-frequency Fig. 2 B-lines: hyperechoic striae vertically departing
probe is often preferred in neonates where it from the pleura into the lung parenchyma (white arrows).
grants a wide view of the anterior, lateral, and This image has been taken with a microconvex transducer
possibly posterior fields both in the sagittal and
transverse projections. Useful information can be patient with heart failure (Blanco and Cianciulli
gained in B-mode as well as in M-mode. 2016). In the neonate, sporadic B-lines are often
In the healthy infant (Fig. 1), a periodically present after birth, especially after a C-section
moving line will be evident in B-mode below the (Martelius et al. 2013), but a white lung image is
superficial plans and between the rib images. This seldom regarded as normal (see below).
horizontal motion corresponds to the sliding of the Lung consolidation on ultrasonography is visu-
pleural leaflets (the sliding sign). Inferiorly, the alized as a subpleural echo poor or tissue-like region
pleural image is reflected a number of times in with blurred margins or wedge-shaped borders.
straight and short repetitions also known as Sonographic air bronchograms are hyperechoic lin-
A-lines. ear elements representing air in bronchioles that
A different artifact is named B-line, a vertical appear within the hypoechoic, consolidated lung.
hyperechoic image that recalls the tail of a comet In adults on mechanical ventilation, dynamic air
(Fig. 2). B-lines can be seen as individual or bronchograms have been proven to accurately dis-
multiple artifacts with a trend to coalesce into a criminate pneumonia from resorptive atelectasis
white lung image of sicker patients (Fig. 3). In the (Lichtenstein et al. 2009).
adult, B-lines have been linked to the interstitial The simultaneous absence of B-lines, lung slid-
syndrome and may also be useful in evaluating the ing, and lung point is diagnostic of pneumothorax,
58 Lung Ultrasound in Neonatal Diagnostic 915
Fig. 4 The double lung point: the white arrow marks a
sharp increase in B-lines echodensity going from the apical
to the basal lung fields
et al. 2010), chest ultrasound has limited value in
Fig. 3 White lung: thick B-lines merging in a completely
white image with no spared areas
the immediate follow-up of respiratory distress
syndrome. The same group found that the presence
of a double lung point (less hyperechogenic upper
even if the volume of the air leak is difficult to lung fields with thicker, brighter B-lines in depen-
quantitate (Migliaro et al. 2014). Pleural effusions dent areas) was highly sensitive and specific of
appear as an anechoic space between the pleural transient tachypnea of the newborn (Fig. 4)
leaflets. The conventional radiograph detects as (Vergine et al. 2014).
opacities images that will be differentiated as con- These results have been challenged by Liu
solidations or effusion only at ultrasound scan. It is et al. in a recent unmasked, monocentric, and
not surprising, then, that echography outperforms retrospective series of 1,358 infants; 358 neonates
the radiograph in ruling in and out both pneumo- were classified as having RDS, while the TTN
thorax and effusions. group had 228 patients (Liu et al. 2016). At ultra-
sound, all infants in both groups presented with an
abnormal pleural line and A-line disappearance,
58.3 “Field Validation” of Lung while the double lung point had a sensitivity for
Ultrasound in Neonatology TTN of only 45.6%.
These conflicting results cast a dim light on the
Respiratory distress syndrome was initially diag- ultrasound diagnosis of the most frequent neonatal
nosed by Copetti et al. with the simultaneous pres- respiratory diseases. An appropriately powered,
ence of three ultrasound findings: abnormalities of multicenter, prospective study is warranted to settle
the pleural line, white lung image, and absence of the issue.
spared areas in all lung fields. This profile had Irrespective of the nosologic description, lung
sensitivity and specificity of 100% in their series ultrasound can be applied to neonatal medicine for
of 55 premature infants (Copetti et al. 2008). Unfor- important functional questions like the need of
tunately, since the intratracheal administration of respiratory support or exogenous surfactant
surfactant does not clear the picture (Cattarossi administration. A population of 154 unselected
916 F. Raimondi et al.
term and late preterm newly born infants Copetti R, Cattarossi L, Macagno F et al (2008) Lung
underwent sequential chest ultrasound scans in a ultrasound in respiratory distress syndrome: a useful
tool for early diagnosis. Neonatology 94(1):52–59
well-baby nursery (Raimondi et al. 2012). The Lichtenstein DA (2014) Lung ultrasound in the critically
normal clearance of lung fluid was documented ill. Ann Intensive Care 4(1):1
with progressive transition from a B-lines pattern Lichtenstein DA (2015) BLUE-protocol and FALLS-
to an A-lines one. Also, a white lung image at 2 h protocol: two applications of lung ultrasound in the
critically ill. Chest 147(6):1659–1670
after birth was strictly associated with clinically Lichtenstein D, Mezière G, Seitz J (2009) The dynamic air
significant respiratory distress and need of venti- bronchogram. A lung ultrasound sign of alveolar consol-
lator support. Similarly, the persistence of a white idation ruling out atelectasis. Chest 135(6):1421–1425
lung image after a 2 h CPAP course has been Liu J, Chen XX, Li XW et al (2016) Lung ultrasonography
to diagnose transient tachypnea of the newborn. Chest.
shown to be a reliable predictor of intubation https://doi.org/10.1016/j.chest.2015.12.024
and surfactant administration (Raimondi Martelius L, Janér C, S€ uvari L et al (2013) Delayed lung
et al. 2014b). Brat et al. recently confirmed this liquid absorption after cesarean section at term. Neona-
observation building a lung hyperechogeneity tology 104(2):133–136
Migliaro F, Sodano A, Capasso L et al (2014) Lung
score that was correlated to oxygenation status ultrasound-guided emergency pneumothorax needle
and surfactant administration (Brat et al. 2015). aspiration in a very preterm infant. BMJ Case Rep.
https://doi.org/10.1136/bcr-2014-206803
Raimondi F, Migliaro F, Sodano A et al (2012) Can neonatal
lung ultrasound monitor fluid clearance and predict the
58.4 Conclusions need of respiratory support? Crit Care 16(6):R22
Raimondi F, Cattarossi L, Copetti R (2014a) International
Lung ultrasound is rapidly gaining an important perspectives: point-of-care chest ultrasound in the neo-
role in neonatal respiratory medicine. Future natal intensive care unit: an Italian perspective.
NeoReviews 15(1):e2–e6
research on individualized surfactant administra- Raimondi F, Migliaro F, Sodano A et al (2014b) Use of
tion and other common clinical situations will neonatal chest ultrasound to predict noninvasive venti-
make lung ultrasound a necessary tool in neonatal lation failure. Pediatrics 134(4):e1089–e1094
practice. Rodríguez-Fanjul J, Balcells Esponera C, Moreno
Hernando J et al (2015) Lung ultrasound as a tool to
guide the administration of surfactant in premature
neonate. Ann Pediatr (Barc). pii: S1695-4033(15)
References 00364-1
Vergine M, Copetti R, Brusa G et al (2014) Lung ultrasound
Blanco PA, Cianciulli TF (2016) Pulmonary edema accuracy in respiratory distress syndrome and transient
assessed by ultrasound: impact in cardiology and inten- tachypnea of the newborn. Neonatology 106(2):87–93
sive care practice. Echocardiography. https://doi.org/ Volpicelli G, Elbarbary M, Blaivas M et al (2012)
10.1111/echo.13182 International evidence-based recommendations for
Brat R, Yousef N, Klifa R et al (2015) Lung ultrasonogra- point-of-care lung ultrasound. Intensive Care Med
phy score to evaluate oxygenation and surfactant need 38(4):577–591
in neonates treated with continuous positive airway Wilson-Costello D, Rao PS, Morrison S et al (1996)
pressure. JAMA Pediatr 169(8), e151797 Radiation exposure from diagnostic radiographs
Cattarossi L, Copetti R, Poskurica B et al (2010) Surfactant in extremely low birth weight infants. Pediatrics
administration for neonatal respiratory distress does not 97(3):369–374
improve lung interstitial fluid clearance: echographic and Yousef N (2016) Lung ultrasound in the newborn. Arch
experimental evidence. J Perinat Med 38(5):557–563 Pediatr. https://doi.org/10.1016/j.arcped.2015.12.001
Rare Lung Diseases of Newborns
59
Paolo Tagliabue and Elena Ciarmoli
Contents
59.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 918
59.2 Rare Lung Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 918
59.3 Parenchymal Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 919
59.3.1 Bronchial Ultrastructural Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 919
59.3.2 Parenchymal Molecular Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 921
59.3.3 Vascular Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 924
59.4 Developmental Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927
59.4.1 Pulmonary Hypoplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927
59.5 Mechanical Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 930
59.5.1 Isomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931
Abstract Parenchymal diseases and cystic lung dis-
Rare causes of respiratory distress in the eases are briefly dealt with in order to favor the
newborn, mainly in term infants, need to be clinical approach and the diagnostic orienta-
considered in uncommon and atypical circum- tion in these rare and often life-threatening
stances. Embryological, pathological, surgical, conditions.
antenatal, or pediatric classifications for rare
lung diseases have been reported. The follow- Abbreviations
ing is a description of rare but not negligible ACD Alveolar capillary dysplasia
pulmonary diseases causing respiratory dis- BC Bronchogenic cyst
tress with neonatal presentation. BPS Bronchopulmonary sequestration
CCAM Congenital cystic adenomatoid
malformation
CDH Congenital diaphragmatic hernia
P. Tagliabue (*) · E. Ciarmoli CLE Congenital lobar emphysema
Neonatologia e Terapia Intensiva Neonatale, Fondazione CPL Congenital pulmonary
MBBM, ASST-Ospedale San Gerardo-Monza, Monza, lymphangiectasia
Italy
e-mail: [email protected];
[email protected]
# Springer International Publishing AG, part of Springer Nature 2018 917
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_207
918 P. Tagliabue and E. Ciarmoli
PCD Primary ciliary dyskinesia Numerous classifications and terminologies
PPHN Persistent pulmonary hypertension of have been suggested for rare congenital lung
the newborn malformations, attempting to incorporate a com-
mon origin and association of many of the lesions.
Indeed, the most commonly encountered anoma-
59.1 Salient Points lies can be classified into three broad categories:
bronchopulmonary anomalies, vascular anoma-
• Many large lung malformations seen at the lies, and combined lung and vascular anomalies.
routine 20 weeks gestation scan have largely Moreover, chest wall deformities and solid lesions
disappeared at term. as tumor masses or thoracic manifestations of
• There is even more confusion in terms of how complex syndromes, including ciliopathies, must
these malformations should be described; the be considered (Biyyam 2010; Liechty and Flake
abnormalities are often multiple, and clinical 2008; Shanti and Klein 2008).
and pathological descriptions should be kept Although these developmental lesions usually
separate. are isolated, there are too many examples of the
• There are today more informations about concurrent association of two or more in a single
genetic cause of these rare lung diseases. individual. These coexistent lesions suggest that a
• Advances in diagnostic imaging (including common pathogenetic mechanism may be
sonography, multi-detector computer tomogra- involved in the development of at least some of
phy, magnetic resonance imaging, and angiogra- these seemingly different lesions. According to one
phy) have increased their detection during both long-held theory, many of these lesions are due to
antenatal and postnatal periods, and radiological defective foregut budding and differentiation
characterization, which in turn influence patient (human lung originates as a ventral endodermal
counseling and management stratification. pouch from the primitive foregut (see ▶ Chap.
• For some of these rare diseases, fetal surgery is 47, “Neonatal Lung Development and Pulmonary
possible today. Malformations”). Another more recent theory of
causation is that these lesions are related to airway
obstruction with secondary pulmonary dysplastic
59.2 Rare Lung Disease changes (Langston 2003; Panicek and Heitzman
1987). It is possible that the level of airway obstruc-
Rare lung diseases include a wide spectrum of tion, the completeness of the obstruction, and the
conditions and are an important cause of morbid- timing of obstructive events may act together to
ity and mortality in newborn and infants. Despite produce varied patterns of malformation. Whereas
the low incidence of these lesions, neonatologists there is evidence for this mechanism, the modes
are likely to encounter these disorders through and timing of obstructive events and their out-
common respiratory symptoms and signs. For comes currently are poorly understood.
intensive care staff, radiologists, pathologists, For these reasons, definition and classifica-
and surgeons, the management and care of new- tion of these lesions are always somewhat prob-
borns affected by these diseases can require con- lematic, and in reviewing the literature it is not
siderable expenditures of time and resources unusual to find similar lesions called by
within a tertiary care center. Moreover, with completely different names and for the same
advances in both fetal ultrasonography (US) and names to be applied to very different lesions.
magnetic resonance (MR) imaging, abnormalities To address the confusing terminology used to
of the thorax are increasingly being recognized describe many of these lesions, we have decided
antenatally, allowing providers to (a) anticipate to classify here these heterogeneous diseases
management issues at the time of delivery or as: Parenchymal conditions (including bron-
later in neonatal life and (b) help parents compre- chial ultrastructural anomalies, parenchymal
hend the prognosis. molecular defects, and vascular malformations),
59 Rare Lung Diseases of Newborns 919
developmental abnormalities, and mechanical Table 1 Rare pulmonary causes for respiratory distress in
abnormalities (Table 1). neonates
It is a more realistic approach as reported pre- Parenchymal conditions
viously by Bush (2001). He proposed, using sim- Bronchial ultrastructural anomalies
ple language and avoiding embryologic Primary ciliary dyskinesia (S. Kartagener)
speculation, to describe the abnormalities actually Parenchymal molecular defects
present as well as the use of a systematic approach Congenital surfactant protein abnormalities
to search for potential multiple or associated Surfactant protein-B gene mutations
Surfactant protein-C gene mutations
anomalies. By reducing these lesions to their sim-
ABCA3 transporter gene mutations
plest components, a better understand of their
Vascular malformations
etiology, natural history, associated anomalies,
Abnormalities of the arterial tree (pulmonary and
and treatment recommendations can be achieved. systemic)
Finally, the approach to rare lung diseases in Abnormalities of the venous tree
neonates involves prenatal history, clinical features, Scimitar syndrome
and radiologic findings. Positive familiar history, Abnormalities of the connections between the
ultrasonographic chest findings, polyhydramnios, pulmonary, arterial, and venous trees
and associated congenital anomalies are suggestive Fistulae
elements. The main clinical features may be: Congenital alveolar capillary dysplasia
term newborn, unexpected respiratory distress, Abnormalities of the lymphatic tree
untreatable hypoxia without cyanotic heart defects, Congenital pulmonary lymphangiectasia
Congenital chylothorax
recurrent pulmonary infections, or chronic lung dis-
Developmental abnormalities
ease of unknown origin. The most relevant radio-
Lung underdevelopment (pulmonary agenesis/aplasia/
logic findings may present asymmetric chest hypoplasia)
imaging, dextrocardia, mediastinal shift, opacities Abnormalities of the bronchial tree (tracheal or
or hypertransparencies, cystic pulmonary masses, laryngeal agenesis or stenosis)
or fluid-filled lesions (Table 2). Disorders of the bronchial walls
Congenital tracheobronchomegaly
Congenital tracheobronchomalacia
59.3 Parenchymal Conditions tracheo-esophageal fistula
Alveolar disorders
59.3.1 Bronchial Ultrastructural Congenital large hyperlucent lobe
Anomalies Solid and cystic lung diseases (or congenital thoracic
malformations, CTM)
Cystic adenomatoid malformation
59.3.1.1 Primary Ciliary Dyskinesia Bronchopulmonary sequestration
(PCD) Bronchogenic cyst
Primary ciliary dyskinesia (PCD) is a rare, autoso- Other cystic lesions (Lymphatic cysts, enteric cysts,
mal recessive disorder of cilia structure, function, mesothelial cysts, simple parenchymal cysts, low-grade
and biogenesis leading to chronic infections of the pleuropulmonary blastoma)
respiratory tract, fertility problems, and disorders of Abnormally placed pulmonary tissue (APPT, or
“pulmonary ectopia”)
organ laterality. This genetically, functionally, and
Abnormal intrapleural tissue (AIPT)
ultrastructurally heterogeneous disease affects
Mechanical abnormalities
1:20–30,000 individuals (Noone et al. 2004). PCD
Rib cage anomalies
was first described by Kartagener et al. in 1936.
Skeletal
Today, Kartagener syndrome is a disorder charac- Muscular
terized by a triad of bronchiectasis, dextrocardia/ Central nervous
situs inversus, and sinusitis, with defective ciliary Diaphragmatic anomalies (CDH)
motility as the underlying cause but situs inversus is Extrapleural and mediastinal masses
present in only 50% of cases of PCD (McManus Isomerism
920 P. Tagliabue and E. Ciarmoli
Table 2 Approach to rare lung diseases in neonates within the first few weeks of life. Often
Prenatal history misdiagnosed with TTN or pneumonia, PCD infants
Positive familiar history frequently require supplemental oxygen for days to
Prenatal ultrasonographic chest findings weeks.
Polyhydramnios A spectrum of organ laterality defects occur
Associated congenital anomalies with PCD, including situs inversus totalis and
Neonatal clinical features situs ambiguus.
Term newborn The respiratory microbiology in PCD generally
Unexpected respiratory distress mirrors that of cystic fibrosis (CF); however, in
Untreatable hypoxia without cyanotic heart defects PCD colonization with Pseudomonas aeruginosa
Recurrent pulmonary infections generally occurs later, and the incidence of Strepto-
Chronic lung disease of unknown origin
coccus pneumoniae is much higher. Newborns with
Radiologic findings
airway colonization with Haemophilus influenzae,
Asymmetric chest imaging
Staphylococcus aureus, and S. pneumoniae were
Dextrocardia
recently reported (Kuehni et al. 2010).
Mediastinal shift
Radiological opacities or hypertransparencies
Cystic pulmonary masses Diagnostic Tests
Fluid-filled lesions As PCD can result from various defects in ciliary
biogenesis, structure, function, or organization,
no single test captures all PCD defects.
et al. 2003). Symptoms of PCD can occur at birth or Several older diagnostic tests are no longer
within the first several months of life (Ferkol and recommended for PCD evaluation, including
Leigh 2006). Normal ciliary function is critical in nasal saccharin testing, ciliary beat frequency cal-
the clearance of amniotic fluid from the fetal lung; culation, and visual assessment of ciliary motion
more than 80% of full-term neonates with PCD without high speed recording devices. Each of
have a syndrome of respiratory distress, with these tests has significant limitations, which can
increased work of breathing, tachypnea, and preva- lead to frequent false positive or false negative
lence of upper and middle lobe atelectasis on chest results, especially in uncooperative newborn and
radiographs (Hossain et al. 2003). Most PCD children; thus, these tests are not appropriate for
patients are well immediately after birth, but PCD diagnosis.
develop respiratory distress at 12–24 h of life Nasal nitric oxide (NO) measurements can
(as opposed to other causes of respiratory distress accurately identify patients with PCD 98.6% of
in term neonates (e.g., transient tachypnea of the the time. NO is produced by the paranasal sinus
newborn-TTN), which often present in the first epithelium via NO–synthase and low levels are
few hours after birth). An upper and middle lobar seen in PCD, CF, acute/chronic sinusitis, and
collapse in PCD patient was reported. One possibil- nasal polyposis. In patients with PCD, however,
ity is that PCD is an airway disease with preferential levels of exhaled NO are extremely low (10% of
gas trapping and hyperinflation in the lower lobes normal value) when compared with other diseases.
leading to atelectasis/compression in the upper Once the suspicion for PCD is high, the axo-
lobes. An alternative explanation for collapse in nemal structure of the respiratory cilia may be
the upper/middle lobes could be related to position- studied using transmission electron microscopy
ing. Because neonates spend the majority of their (TEM). Thus, until recently, the identification of
time supine, it could be that impaired mucociliary ultrastructural defects on TEM was the “gold
clearance leads to mucous build up and lobar col- standard” for the diagnosis; however, with
lapse preferentially in the dependent lobes advances in our molecular understanding in
(Mullowney et al. 2014). A small proportion of PCD, it is known that approximately 30% of
PCD patients are discharged home on day 1 of life patients with genetically proven PCD have nor-
but are then hospitalized with respiratory distress mal ciliary ultrastructure.
59 Rare Lung Diseases of Newborns 921
Today, the most effective test is light micros- and slow down the progression of the disease.
copy analysis of transnasal brushings for ciliary Airway clearance through daily chest physiother-
beat pattern. apy is highly recommended in PCD. Antibiotics
Transnasal brushing or nasal scrape ciliated should be given for acute respiratory exacerba-
epithelial samples can be analyzed with high- tions in PCD. Inhaled corticosteroids are not rou-
speed digital video imaging to get quantitative tinely recommend in PCD and should be reserved
measurements of the ciliary beat frequency for PCD patients with associated asthma or airway
(CBF) to help differentiate between abnormally reactivity (Lobo et al. 2015).
beating cilia and normal beat patterns. Normal Finally, PCD patients should receive
ciliary function excludes the diagnosis of PCD. recommended vaccinations per local schedules.
Ciliary ultrastructure may be abnormal as a pri-
mary defect or secondary to infections. Prognosis
Immunofluorescent analysis using antibodies The prognosis for a child with PCD is mainly
directed against the main axonemal components good and the outcome is very different from
has been used to identify structural abnormalities CF, but there is a large spectrum of disease sever-
of cilia; however, like many sophisticated tech- ity. These discrepancies in severity and survival
niques, it is restricted to a few centers that have may relate at least in part to the genetic and phe-
this technology. notypic heterogeneity of PCD as well as the
Finally, genetic testing for disease-causing usual aspects of access to care, socioeconomic
mutations associated with PCD is recommended backgrounds of patients, and accompanying
as part of a panel of diagnostic PCD tests. There comorbidities. Overall, the majority of patients
are currently 33 known genes associated with with PCD appear to have a near-normal life
PCD, with new genes being discovered at a expectancy when compliant with recommended
rapid pace. About 80% of the mutations are loss- therapies. A minority of patients develop progres-
of-function variants (nonsense, frame shift, or sive severe bronchiectasis, end-stage lung disease,
defective splice mutations), while the others are and early death, unless they undergo lung trans-
conservative missense mutations or in-frame dele- plant (Jain et al. 2007).
tions. Most mutations occur in only one patient/
family (“private” mutations); a few of the muta-
tions have been seen to recur in two or more 59.3.2 Parenchymal Molecular Defects
unrelated patients. At this point, with the use of
next generation sequencing, approximately 66% 59.3.2.1 Congenital Surfactant Protein
of patients with PCD can be identified, thus facil- Abnormalities
itating early diagnosis and treatment. This is espe- Advances in physiology, biochemistry, and
cially helpful in the cases where ciliary molecular biology have identified the chemical
ultrastructural analysis is equivocal or inadequate. composition of pulmonary surfactant as well as
Specific classes of mutations are associated with the genes and cellular processes involved in sur-
specific phenotypes. Mutations in genes that lead factant lipid and protein homeostasis. These stud-
to loss of function of the cilia also lead to low ies have provided molecular and genetic tools that
nasal NO levels (<77 nL/min). Mutations that are useful in identifying the genetic defects under-
affect the dynein arm’s ultrastructure lead to lying the pathogenesis of RDS and the genetic
situs abnormalities, while mutations that affect causes of respiratory disease in newborns, infants,
the central apparatus do not (Shapiro et al. 2016). and children.
Pulmonary surfactant is primarily composed of
Therapies phospholipids that are enriched with phosphati-
As there are currently no therapies available that dylcholine (PC) and phosphatidylglycerol (PG);
can reverse the underlying ciliary abnormalities, these phospholipids are produced in increasing
the goals of therapy are to prevent exacerbations amounts in late gestation by type II epithelial
922 P. Tagliabue and E. Ciarmoli
cells. Four surfactant proteins (SPs), SP-A, SP-B, associated with these mutations is unremitting
SP-C, and SP-D, have been identified as critical despite the use of intensive care and surfactant
components of alveolar surfactant, each contrib- replacement; this contrasts with RDS that is asso-
uting to lung homeostasis via their distinct protein ciated with premature newborns and responds to
structures and activities. SP-D and SP-A are mem- surfactant replacement.
bers of the collectin family of host defense pro- Other recessive mutations in ABCA3 and
teins that bind pulmonary microbial pathogens dominant mutations in the surfactant protein-C
and products, including viruses, fungi, and bacte- (SP-C) gene are associated with chronic ILD in
ria, and serve as critical innate host defense pro- older infants, children, and adults; infants and
teins with anti-inflammatory properties. SP-B and children with chronic ILD often present with
SP-C facilitate remodeling of newly secreted sur- symptoms of diffuse lung disease including
factant membranes by promoting the incorpora- tachypnea, retractions, hypoxemia, and digital
tion and spreading of lipids as the surface film clubbing.
expands during inhalation (For more details see Mutations in the genes encoding receptors for
▶ Chap. 51, “Molecular Structure of Surfactant: GM-CSF (CSF2RA, CSF2RB) are inherited as
Biochemical Aspects in Newborns”). autosomal recessive genes and are associated
The identification of the genes and cellular with progressive dyspnea and congenital PAP.
processes involved in maturation and function of These disorders are classified as surfactant
the pulmonary surfactant system, as well as in metabolism dysfunctions, pulmonary (SMDP)
alveolar development, has provided genetic tools types 1, 2, 3, and 4 (Whitsett et al. 2015).
that are useful for diagnosing rare lung diseases Deficiency of surfactant protein B (SP-B) is the
presenting in newborns, infants, and children. most common (Fig. 1). Infants who are deficient
Pathological and genetic analyses of full-term in SP-B may have a family history of perinatal
infants with refractory respiratory failure after respiratory failure in siblings because the muta-
birth have identified the role of mutations in the tions are inherited as autosomal recessive alleles.
genes encoding SP-B (SFTPB), SP-C (SFTPC), SFTPB-related lung disease (SMDP-1) is gener-
and ABCA3 (ABCA3) in the pathogenesis of ally fatal in the first months of life, although some
respiratory failure and diffuse, chronic interstitial infants have been supported by lung transplanta-
lung disease (ILD) in newborn infants and chil- tion. Surfactant replacement and other ventilatory
dren (Whitsett et al. 2010). support are not effective therapies for this disor-
Classification of the histopathology associated der. Histopathological diagnoses described in
with these disorders includes neonatal or congen- SP-B deficiency are associated primarily with
ital PAP, infantile desquamative interstitial pneu- neonatal PAP or infantile DIP (Wert et al. 2009;
monia (DIP), chronic pneumonitis of infancy, Nogee et al. 2000). Whereas neonatal lethality in
nonspecific interstitial pneumonia (NSIP), and knockout mice indicates that SP-B is indispens-
usual interstitial pneumonia (UIP) (in older chil- able for surfactant metabolism, SP-C deficiency is
dren and adolescents) (Flidel-Rimon and not lethal. The function of SP-C is less well under-
Shinwell 2005). The histopathology of these dis- stood, but it is likely required for optimal function
orders often overlaps and depends on the nature of of the surface film. A lack of SP-C causes pro-
the mutations, the age of the child, and the clinical gressive lung inflammation, emphysema, and
therapy provided (Table 3). remodeling as well as marked susceptibility to
Recessive mutations in the surfactant protein- infection, inflammation, and fibrosis, indicating
B (SP-B) and the ATP-binding cassette family its role in innate immune responses. Acute and
member A3 (ABCA3) genes present as lethal chronic lung diseases are associated with
surfactant deficiency in the newborn. Usually, mutations in SFTPC. SFTPC-related disease
these mutations were found in full-term newborn (SMDP-2) is typically inherited as an autosomal
infants, presenting with cyanosis, grunting, retrac- dominant disease with variable penetrance,
tions, and atelectasis. Pulmonary disease although sporadic mutations also have been
59 Rare Lung Diseases of Newborns 923
Table 3 Comparison of genetic disorders affecting surfactant metabolism (Downloaded from Whitsett et al. (2015))
CSF2RA and
Gene SFTPB SFTPC ABCA3 CSF2RB
Chromosome 2p11 8p21 16p13 Xp22 and 22q12
Protein SP-B SP-C ABCA3 CSF2RA and
CSF2RB
Phenotype Surfactant Surfactant Surfactant dysfunction 3 Surfactant
dysfunction 1 dysfunction 2 dysfunctions 4 and 5
Inheritance Autosomal Autosomal Autosomal recessive Autosomal recessive
recessive dominant or
sporadic, with
variable penetrance
Mechanism Loss of Dominant negative Loss of function Loss of function
function or toxic gain of
function
Pathogenesis Lack of SP-B Lack of mature Defective phospholipid Defective GM-CSF
SP-C; misfolded transport into LBs signaling
protein with ER
stress
Age of onset Neonatal Infancy to adult Neonatal > childhood Childhood or
neonatal > childhood
> adult
Clinical RDS ILD > RDS RDS > ILD Respiratory distress
syndrome and/or insufficiency;
dyspnea; tachypnea
Outcome Neonatal lethal Highly variable Lethal if neonatal; variable Variable severity
severity in childhood
Histopathology PAP > DIP Depends on age and Depends on age and mutation PAP
mutation Infants: PAP, DIP Children/
Infants: CPI > PAP adolescents: NSIP, UIP
or DIP
Children/adults:
NSIP, UIP
LB phenotypes Abnormal: Variable: normal Variable: small, dense LBs > NDa
large MVBs LBs and/or " in large normal LBs
with no normal fusing LBs
LBs
a
ND not determined for type II cells; large, foamy alveolar macrophages filled with surfactant material or large vacuoles
containing neutral lipids, or both, were observed with electron microscopy
Abbreviations: ABCA3 ATP-binding cassette transporter A3, CPI chronic pneumonitis of infancy, CSF2R granulocyte-
macrophage colony-stimulating factor receptor, DIP desquamative interstitial pneumonia, ER endoplasmic reticulum,
ILD interstitial lung disease, LB lamellar body, MVB multivesicular body, NSIP nonspecific interstitial pneumonia, PAP
pulmonary alveolar proteinosis, RDS respiratory distress syndrome, SP/SFTP surfactant protein, UIP usual interstitial
pneumonia
identified. Infants with SFTPC mutations usually secondary effects on processing SP-B and SP-C.
exhibit features of chronic pneumonitis of infancy Lung histology is consistent with congenital PAP
(Nogee 2004; Glasser et al. 2013). or infantile DIP. While ABCA3 is expressed in
Mutations in ABCA3 on chromosome 16 are various tissues, abnormalities are found only in the
the most common cause of hereditary respiratory lung. Pulmonary disease associated with ABCA3
failure in newborns. deficiency is generally fatal although a number of
Mutations have been identified throughout the infants have been treated by lung transplantation.
ABCA3 gene that cause abnormal processing, Prenatal and postnatal diagnoses are best made
misrouting, or impaired lipid transport as well as by identifying mutant ABCA3 alleles. Diseases
924 P. Tagliabue and E. Ciarmoli
Fig. 1 Histopathology of neonatal lung. (a) Normal neo- macrophages (arrow) filling the alveolar spaces. (c) Histo-
natal lung histology with thin alveolar septa and airspaces pathology of the lung from a child who had fatal ABCA3
devoid of debris. (b) Histopathology of the lung from a deficiency is similar to that for fatal SP-B deficiency, as
child who had fatal SP-B deficiency demonstrates thick- shown in panel b. Original magnification is 10
ened alveolar septa and eosinophilic, lipoproteinaceous (Downloaded from Gower et al. (2008))
material intermixed with large foamy alveolar
related to ABCA3 and SFTPB are similar in onset pulmonary artery from the right (pulmonary
and clinical course and are generally associated artery sling), sometimes with a cross-over arte-
with severe respiratory failure, although several rial segment, with the right upper lobe sup-
ABCA3 mutations have been associated with plied by a branch from the left pulmonary
chronic ILD in older infants, children, and adoles- artery.
cents. Histopathological findings vary depending The unilateral absence of a pulmonary artery
upon the age of the patient and the mutation and leads to the lung on that side receiving only sys-
often overlap with those found in deficiencies of temic blood, either through anomalous systemic
SP-B and SP-C (Bullard et al. 2006; Shulenin arteries or enlarged bronchial arteries.
et al. 2004; Doan et al. 2008). One or both pulmonary arteries may take ori-
gin from the aorta. Bilateral origin from the aorta
is part of the spectrum of common arterial trunk.
59.3.3 Vascular Malformations Unilateral origin of a pulmonary artery from the
aorta may be an isolated abnormality.
59.3.3.1 Abnormalities of the Arterial Finally, a congenitally small unilateral pulmo-
Tree (Pulmonary and Systemic) nary artery is usually seen in association with an
When a lung malformation was found, it is impor- ipsilateral congenitally small lung (CSL). Normal
tant that also abnormal vasculature is identified or pulmonary blood flow is needed for normal lung
excluded. development.
Regarding pulmonary arterial tree, the first Regarding systemic arterial tree, two groups of
abnormality that is often associated with lung abnormalities are relevant to the lung. The first
abnormality is the congenital origin of the left group consists of those producing a vascular ring.
59 Rare Lung Diseases of Newborns 925
The second group consists of collateral vessels incidentally because of radiographic abnormali-
which may arise from the aorta and supply all or ties. As a rule, patients with the infantile syn-
part of one or both lungs. This last group may be drome are diagnosed in the first few months of
seen in association with direct pulmonary arterio- life, the median age at presentation being
venous connections (pulmonary arteriovenous 2 months. Failure to thrive, tachypnea, and heart
malformations). Aneurysms of aortopulmonary failure are the dominant features at presentation in
collateral vessels were described (Chowdhury these severely ill patients although cyanosis may
et al. 2015). be observed if pulmonary hypertension and the
anatomy at hand predispose to right-to-left
59.3.3.2 Abnormalities of the Venous shunting of blood. The elevated Qp/Qs in the
Tree (Pulmonary and Systemic) infantile syndrome is often reported. Medical
Anomalous pulmonary veins result in blood from treatment is indicated in the infantile presentation
the lungs returning to the right side of the heart. to offset heart failure and allow growth before
The anomaly may be total or partial, unilateral undertaking surgical repair. However, the pres-
or bilateral, and isolated or associated with other ence of pulmonary hypertension or failure of
cardiopulmonary developmental defects. Anoma- response to medical therapy demands prompt sur-
lous pulmonary venous connections are often nar- gical intervention. Mortality is quoted at 45% in
row, and this may cause relatively mild pulmonary infantile presentation (Gudjonsson and Brown
hypertension. 2006).
Unilateral anomalous venous drainage may be Abnormalities of the connections between the
part of complex lung malformations; it may also pulmonary, arterial, and venous trees.
be seen in association with what appears to be a
simple lung cyst. 59.3.3.3 Fistulae
No congenital disorders of the systemic (bron- An important group of abnormalities which poten-
chial) venous tree have been described tially involves systemic and pulmonary arterial and
(Chowdhury et al. 2015). venous trees are the various forms of pulmonary
A particular clinical problem is Scimitar Syn- arteriovenous fistulae. They range from the diffuse
drome. Scimitar syndrome is a rare constellation, and microscopic to the single or multiple large
estimated to occur in two out of 100,000 births, abnormalities (Chowdhury et al. 2015).
with a 2:1 female preponderance. It consists in
part of right pulmonary venous return to the infe- 59.3.3.4 Congenital Alveolar Capillary
rior vena cava. In two thirds of cases, the Scimitar Dysplasia (ACD)
vein (SV) provides drainage for the entire right Congenital alveolar capillary dysplasia (ACD) is a
lung, but in one third the SV drains only the lower disorder of pulmonary vascular development
portion of the right lung. The developmental associated with persistent pulmonary hyperten-
errors accounting for the observed anatomy in sion in the newborn (PPHN) and unremitting
Scimitar syndrome are not understood at present. hypoxemia that is unresponsive to pulmonary
It is possible that some insult, occurring during vasodilators and various modes of mechanical
week 11 of gestation when normally pulmonary ventilation. The incidence or prevalence of ACD
venous drainage to the left atrium, results in the is not yet known; it seems likely that some cases
observed persistence of systemic arterial supply to originally classified as idiopathic persistent pul-
the right lung from the abdominal aorta. monary hypertension of the newborn (PPHN)
There are unequivocally two forms of Scimitar may actually have been ACD. A slight male pre-
syndrome in terms of clinical presentation: an dominance (60%) has appeared in reported cases.
infantile syndrome associated with significant No geographic pattern is apparent; cases have
mortality and a child/adult presentation that is a been distributed worldwide (Bishop et al. 2011).
milder form of the syndrome and in fact is fre- Autosomal recessive inheritance is suspected.
quently asymptomatic, with diagnosis being made DNA sequencing and comparative genomic
926 P. Tagliabue and E. Ciarmoli
hybridization have led to the identification of The clinical approach to infants with ACD is no
FOXF1 as one of the genes responsible for ACD different than that for other neonates presenting
and allowed for limited noninvasive diagnostic with PPHN. However, the response to therapy is
testing in some infants (Stankiewicz et al. 2009). often minimal and/or not sustained, which may
For several reasons, these case reports almost serve as an initial diagnostic clue. Most infants
certainly underestimate the true prevalence of with ACD will develop progressive hypotension
ACD. The evidence is mounting to suggest that due to right ventricular failure and/or refractory
a less severe phenotype compatible with hypoxemia. Because the hypoxemia and pulmo-
prolonged survival might exist, although defini- nary hypertension cannot be effectively reversed,
tive diagnostic criteria for this group are yet to be cardiotonic agents have only a minimal or transient
established. effect in infants with ACD. Although transient
The diagnosis of ACD is confirmed at responses to pulmonary vasodilator therapy can
autopsy in 90% of cases and in 10% by lung be observed in infants with ACD, no infant has
biopsy. Failure of development of alveolar been reported to have a sustained response to any
capillaries leads to absence of a normal available pulmonary vasodilator. ECMO is used at
air–blood barrier. ACD is characterized by some point in the clinical course in most case series
paucity of capillaries adjacent to the alveolar of ACD but deterioration and death followed
epithelium, anomalous distended veins, imma- within hours. Because none of the supportive ther-
ture alveolar development, and muscularisation apies described above has changed the expected
of the arterioles. The pathological features are mortality due to ACD, lung transplantation is cur-
diffuse in 85% and patchy in 15% of subjects rently the only option that might prolong survival.
(Melly et al. 2008). If here is a high index of suspicion, diagnostic
The symptoms and timing of presentation are lung biopsy could be considered. ACD is generally
related to the distribution of capillary dysplasia fatal (Kinugasa et al. 2002; Fliman et al. 2006).
and the extent of alveolar underdevelopment.
More than 95% are full-term with normal transi- 59.3.3.5 Abnormalities of the Lymphatic
tion. Respiratory distress progressing to Tree
untreatable respiratory failure is the most common Lymphatic tree disorders usually require histolog-
presentation. The onset of symptoms is within the ical confirmation. Lymphatic hypoplasia of varied
first hours of age in half the cases, while presen- distribution underlies yellow nail syndrome, in
tation at 2–6 weeks is reported in the 14% of cases which lymphedema is accompanied by discolor-
(Boggs et al. 1994). The chest radiograph may ation of the nails and pleural effusions.
show diffuse haziness or subtle ground-glass Klippel-Trenaunay syndrome, usually charac-
opacities but is often interpreted as normal. terized by varicosities of systemic veins, cutane-
Pneumothoraces have been reported frequently ous hemangiomas, and soft-tissue hypertrophy, is
in patients with fulminant disease, but it is not another congenital disorder. Pleuropulmonary
entirely clear whether this feature is related to abnormalities are described, including pulmonary
abnormalities in lung architecture or surfactant lymphatic hyperplasia, pleural effusions, pulmo-
function, a consequence of aggressive ventilator nary thromboembolism, and pulmonary vein var-
treatment to reverse hypoxemia, or is some com- icosities (Chowdhury et al. 2015).
bination of the two. To date, there are no reports of
computed tomography or magnetic resonance 59.3.3.6 Congenital Pulmonary
lung imaging in infants with documented ACD Lymphangiectasia (CPL)
(Cassidy et al. 2002). A congenital malformation with presentation from
There is an association with other congenital fetal to early adulthood. CPL results from failure of
malformations in 80% of cases, the commonest the pulmonary interstitial connective tissue to
being gastrointestinal (30%), cardiac (30%), and regress, leading to dilatation of lymphatic capil-
renal anomalies (23%). laries. Radiological findings include diffuse
59 Rare Lung Diseases of Newborns 927
thickening of the peribronchovascular interstitium Pulmonary aplasia is similar to agenesis,
and the interlobular septa with pleural effusions. except for the presence of a short blind-ending
Supportive therapy includes albumin infusions, rudimentary bronchus. Imaging findings are
diuretics, thoracocentesis, and paracentesis. Nutri- similar: postnatal radiography demonstrates dif-
tion plays an important role in reducing lymphatic fuse opacification of the involved hemithorax
production. Enteral nutrition with medium-chain with ipsilateral mediastinal shift (Biyyam
triglycerides and total parenteral nutrition have 2010).
been successfully employed. CPL often is associ-
ated with congenital and genetic diseases, includ-
ing Noonan, Ullrich-Turner, Ehlers-Danlos, and 59.4.1 Pulmonary Hypoplasia
Down syndromes. In rare localized disease, sur-
gical resection is curative. When present in the In this condition alveoli are reduced in number or
newborn, the clinical course might be fatal. For size. Severe hypoplasia may be incompatible with
the majority of patients with neonatal presenta- extrauterine life. Lung growth before birth is
tions, gradual improvement and survival are pos- dependent on blood supply, availability of space,
sible, particularly if there are no significant respiratory movements, and fluid filling the air-
co-existing abnormalities (Bouchard et al. 2000; ways in utero. Malformations of the rib cage,
Pinar 2004). pleural effusions, thoracic masses, or intestinal
loops in congenital diaphragmatic hernia (CDH)
59.3.3.7 Congenital Chylothorax compete with the developing lung for space. Ade-
Congenital chylothorax may be an isolated abnor- quate amniotic fluid is essential for normal
mality or else associated with a congenital abnor- lung development and any condition that
mality of the main lymphatic duct or pulmonary produces oligohydramnios leads to diminished
lymphatics. Associations with Noonan, Ullrich lung growth. Significant and prolonged
Turner, and Down syndrome, fetal thyrotoxicosis, oligohydramnios can result from chronic loss of
H-type tracheo-esophageal fistula, and mediastinal liquor after preterm premature rupture of mem-
neuroblastoma have been described; familial cases branes, or from inadequate production or excre-
have been reported (Chowdhury et al. 2015). See tion of urine because of renal and urinary tract
also ▶ Chap. 47, “Neonatal Lung Development malformations. In these conditions, airway and
and Pulmonary Malformations.”. arterial branching is inhibited, limiting the surface
for gas exchange. In the oligohydramnios
sequence, the common phenotype is a flattened
59.4 Developmental Abnormalities nose, contractures, and growth impairment of
extremities, known as Potter’s syndrome. The
Pulmonary underdevelopment has been classified condition of prolonged preterm premature rupture
into three categories: pulmonary agenesis, pulmo- of membranes is not universally lethal but
nary aplasia, and pulmonary hypoplasia. depends on the degree of pulmonary hypoplasia.
Pulmonary agenesis is a complete absence of The following conditions increase the risk of
the lung parenchyma, bronchus, and pulmonary mortality: (1) premature rupture of membranes
vasculature. at less than 25 weeks’ gestation, (2) severe
It has been hypothesized that abnormal blood oligohydramnios (amniotic fluid index <4) for
flow in the dorsal aortic arch during the 4th week more than 2 weeks, and (3) preterm delivery
of gestation (embryonic phase) is the cause. Uni- earlier than 28 weeks’ gestation. Serial
lateral pulmonary agenesis is difficult to diagnose amnioinfusions are helpful in case of oli-
with prenatal US; however, it can be suspected on gohydramnios. Abnormalities of the thoracic
the basis of mediastinal shift. More than 50% of cage, small, and bell shaped chest are typical
affected fetuses have other abnormalities involv- radiologic findings. The lung hypoplasia is usually
ing other systems. complicated by pulmonary hypertension therefore
928 P. Tagliabue and E. Ciarmoli
high-frequency ventilation and early use of inhaled become the esophagus and trachea is incomplete.
nitric oxide therapy are indicated (Biyyam 2010). Usually is associated with esophagus atresia.
See also ▶ Chap. 47, “Neonatal Lung Develop- Histological examination of a direct connection
ment and Pulmonary Malformations.”. between an otherwise normal esophagus and tra-
chea (H-type fistula) shows that abnormalities in
59.4.1.1 Abnormalities of the Bronchial the wall of the trachea extend beyond the fistula;
Tree (Tracheal or Laringeal there is often widespread loss of cartilage and squa-
Agenesis or Stenosis) mous metaplasia (For more details see ▶ Chap. 81,
Absent larynx results in normal appearances “Esophageal Atresia of Newborns”).
from above, but intubation is impossible. The
lungs are normal or hyperplastic. The
commonest cause of stridor characteristically 59.4.1.3 Alveolar Disorders
starting shortly after but not at birth is
laryngomalacia, with congenital laryngeal Congenital Large Hyperlucent Lobe
cysts and webs entering the differential diagno- Congenital large hyperlucent lobe (also know as
sis. With total or partial absence of the trachea congenital lobar overinflation (CLO) or congenital
(tracheal aplasia), the main bronchi either com- lobar emphysema (CLE)) is an example of a disor-
municates only with each other or with der of alveoli. CLHL is a rare anomaly of the lung
the esophagus. Congenital intrinsic tracheal development. It is defined as the postnatal over-
narrowing (stenosis) may take the form of a distention of the air spaces of one or more segments
gradual tapering or an isolated segmental or lobes of the lung that usually presents in the
narrowing or a membranous web, or it could neonatal period with respiratory distress. This over
be due to a nodule of ectopic esophageal tissue. distended portion of the lung compresses the adja-
Congenital extrinsic compression may be due to cent lung lobes and compromises the ventilation. In
a vascular ring or pulmonary artery sling about 50% of cases, the exact cause of CLE is not
(Biyyam 2010). known, in the remaining 50% several mechanisms
have been postulated. In some cases, it is due to
59.4.1.2 Disorders of the Bronchial Walls partial obstruction of a lobar bronchus, leading to
Bronchial wall caliber abnormalities may result in air-trapping. The obstruction may be caused by
all or part of the bronchial tree being too large or external compression or by intrinsic abnormalities
too small. Congenital tracheobronchomegaly is such as mucosal taps or mucus plugs. CLHL affects
associated with tracheomalacia and bronchiecta- the left upper lobe in about half the cases, the right
sis. There are saccular bulges between cartilages. middle and right upper lobes in most of the remain-
This is supported by the occasional association of der, and the lower lobes in less than 10%. Curiously,
Ehler-Danlos syndrome, cutis laxa, or Kenny- the lobes almost never become infected. CLO may
Caffey syndrome. be associated with cardiovascular anomalies in
Congenital tracheobronchomalacia is rare, 12 –14% of cases. Males are more frequently
and it is caused by the presence of esophageal affected than females.
remnants in the wall of the trachea, which is One half of the patients become symptomatic in
generally seen in association with esophageal the neonatal period, others may present months later.
atresia and tracheo-esophageal fistula. The presentation is with respiratory distress, which
Congenital bronchomalacia may be isolated, can be of varying severity. Physical examination
with a generally good prognosis, and has been reveals a hyper resonance in the affected area with
described in association with other congenital diminished air entry on auscultation.
abnormalities, especially connective tissue disor- Chest radiography is the best diagnostic tool.
ders (Biyyam 2010). Initial films may show an opaque mass on chest
A tracheo-esophageal fistula is present if the radiograph due to delayed clearance of lung fluid
separation of those parts of the primitive foregut to from affected lobe. The later films show a hyper
59 Rare Lung Diseases of Newborns 929
lucent overexpanded area of the lung with com- air and fluid trapping cause compression of the
pression or atelectasis of the adjacent lobes of the adjacent normal lung and mediastinum.
lung, depression of the diaphragm, and mediasti- CCAM is categorized into four types. Type 1 is
nal shift to the opposite side. characterized by a few large cysts and is the most
Most of the patients are symptomatic and common (75%). In type 2, there are evenly spaced
require treatment. The indication for surgical small cysts. Type 3 is very rare and appears solid on
treatment is life threatening, progressive, pulmo- gross examination. Type 4 is characterized by
nary insufficiency from compression of adjacent acinar-type epithelium rather than the bronchiolar
normal lung. Prompt resection of the involved epithelium. Usually only one lobe is involved.
lobe is the ideal treatment in symptomatic babies Enlarging lesions may cause progressive signs
(Ankermann et al. 2004; Olutoye et al. 2000; because of expansion of the cysts shortly after
Pariente et al. 2009). birth. Alternatively, abnormal signs may develop
later if there are intercurrent infections. The neo-
59.4.1.4 Solid and Cystic Lung Diseases natal presentation therefore ranges from respira-
(or Congenital Thoracic tory failure in approximately 50% of the cases to a
Malformations, CTM) healthy asymptomatic infant.
Cystic lung lesions are the most common pulmo- Large lesions may compromise the normal
nary lesions detected by routine antenatal ultra- development of the fetal lung, resulting in pulmo-
sound scanning. Different entities, such as nary hypoplasia or neonatal death. CCAM is a
congenital cystic adenomatoid malformation recognized cause of fetal hydrops and
(CCAM), bronchopulmonary sequestrations polyhydramnios. Infants with highly symptomatic
(BPS), bronchogenic cyst (BC), and congenital CCAMs require surgery. Most commonly, this
lobar emphysema (CLE), may be difficult to dif- occurs in neonates presenting with respiratory fail-
ferentiate, and antenatal MRI can provide more ure of sufficient severity to require ventilatory sup-
detail. A postnatal chest CT scan is useful in port. When considering the timing of surgery for
confirming the presence and extent of the lesions. asymptomatic infants, some neonatologists favor
Small lesions are usually asymptomatic both in operating during the neonatal period but others
utero and after birth. Large lesions may cause a suggest waiting until the child is between 6 months
mass effect resulting in esophageal compression and 2 years of age. The prognosis depends on the
and polyhydramnios, pulmonary hypoplasia, or size of the lesion, the degree of development of the
vena caval obstruction with fetal hydrops. In adjacent lung, and the presence of other congenital
these cases, fetal intervention may include anomalies (Shanti and Klein 2008; Narendra
thoracentesis or thoraco-amniotic shunting. The Kumar 2008; Fitzgerald 2007; Nicolai 2009;
postnatal presentation is variable and depends on Mendeloff 2004; Sfakianaki and Copel 2012);
the size, location, and type of lesion. Some infants For more details see ▶ Chap. 47, “Neonatal Lung
may develop PPHN and respiratory failure. If Development and Pulmonary Malformations.”.
there is associated pulmonary hypoplasia or A further type of CTM is mesenchymal cystic
ECMO is required, the mortality rate is increased. hamartoma (MCH). The lesions may be supplied by
bronchial, intercostal, or phrenic arteries. Patholog-
Congenital Cystic Adenomatoid ical examination shows them to consist of
Malformation (CCAM) multilocular, thin-walled cysts lined by primitive
A congenital hamartomatous lesion of the lung, mesenchymal cells that support a ciliated cuboidal
accounting for approximately 25% of congenital epithelium. In places, the epithelium is continuous
lung lesions. The incidence of CCAM is reported with that lining adjacent bronchioles. The mesen-
as between 1 in 11–35,000 live births. CCAM chymal cells have dark oval nuclei and inconspicu-
consists of a multicystic mass of dilated ous cytoplasm and show only rare mitoses.
bronchiolar-like spaces that proliferate at the Muscular hamartomas, which are small focal pro-
expense of alveoli. The cysts that enlarge following liferations of smooth muscle, are occasionally
930 P. Tagliabue and E. Ciarmoli
observed incidentally in the lung, sometimes asso- Lined with pseudostratified ciliated columnar
ciated with similar lesions in the bowel and liver epithelium with goblet cells and enlarged with
(Mark 1986). mucous, these are considered to be infected
peripheral lesions. Malignancies have been
Bronchopulmonary Sequestration (BPS) reported in these lesions. Most bronchogenic
Composed of abnormal lung tissue without con- cysts are found incidentally.
nection to the normal tracheobronchial tree. There Clinical presentations range from asymptom-
are two types of BPS based on their relationship to atic to recurrent nonspecific respiratory symp-
the pleurae, extra- and intra-lobar. Both receive an toms or infections to life-threatening respiratory
anomalous arterial supply from the systemic cir- distress. In infants, symptoms are generally
culation, usually a branch of the aorta. caused by compression of the trachea or bron-
With extralobar BPS, the mass of pulmonary chi and esophagus, leading to wheezing, stri-
parenchyma is outside the pleurae. The lesion is dor, dyspnea, and dysphagia. Intraparenchymal
found between the left lower lobe and the diaphragm cysts may manifest with recurrent infection.
in 66% of the cases. More common in males (3:1), Symptomatic cysts are generally resected
50% of newborns have respiratory distress because surgically.
of compression of the rest of the lung parenchyma. Plain chest radiograph is the standard initial
In more than 65%, there are associated anomalies, study. Ultrasound may show the fluid content.
including CDH (30%), pericardial defects, and CT and MRI are the best confirmatory studies.
anomalous pulmonary venous return. Antenatal intervention is therefore rarely indi-
Intralobar BPS is characterized by a lesion cated (Shanti and Klein 2008; Mendeloff 2004).
within the lobe of the lung without separate pleu-
rae. Intralobar BPS accounts for 75% of all BPS. 59.4.1.5 Abnormally Placed Pulmonary
Usually in the lower lobe (95%), on antenatal US, Tissue (APPT, or “Pulmonary
BPS appears as a solid mass. The presence of Ectopia”) and Abnormal
hydrops or polyhydramnios is a poor prognostic Intrapleural Tissue (AIPT)
factor. The majority of BPS (68%) undergo spon- AIPT constitutes ectopia of nonpulmonary tissues
taneous regression before birth and survival is in the thorax; APPT is ectopia of lung tissue
95%. Early complications are usually related to outside the thoracic cavity.
the degree of associated pulmonary hypoplasia AIPT of the adrenocortical tissue, thyroid, and
but also result from other associated anomalies. liver has been described in the lung, and pancre-
Large BPS or BPS with high systemic blood flow atic tissue has been noted within so-called
needs resection. Lobectomy is the treatment of intralobar sequestrations with gastrointestinal
choice for intralobar BPS (Liechty and Flake connections. There may be ectopic lung tissue in
2008; Shanti and Klein 2008; Mendeloff 2004). the neck, abdomen, or chest wall, often associated
See also ▶ Chap. 47, “Neonatal Lung Develop- with skeletal or diaphragmatic abnormalities.
ment and Pulmonary Malformations.”. Some examples of abdominal APPT have been
considered to represent extralobar sequestration.
Bronchogenic Cyst (BC) All these are very exceptional abnormalities
Bronchogenic cysts arise from abnormal buds (Shanti and Klein 2008).
from the primitive esophagus and tracheobron-
chial tree, which do not extend to the site were
alveolar differentiation occurs. 59.5 Mechanical Abnormalities
If this separation occurs early, the system
migrates into mediastinum. If it occurs late, it For more details about relevant abnormalities of
forms an intra pulmonary bronchogenic cyst. Bron- chest wall including the diaphragm (such as CDH)
chogenic cyst accounts for 20–30% of congenital see specific ▶ Chap. 47, “Neonatal Lung Devel-
bronchopulmonary foregut cystic malformation. opment and Pulmonary Malformations.”.
59 Rare Lung Diseases of Newborns 931
59.5.1 Isomerism et al (2002) The incidence and characteristics of neo-
natal irreversible lung dysplasia. J Pediatr 141:426–428
Chowdhury M et al (2015) Imaging of congenital lung
There is the usual arrangement (situs solitus) or a malformations. Semin Pediatr Surg 24(4):168–175
mirror-image arrangement (situs inversus); right Doan ML, Guillerman RP, Dishop MK, Nogee LM,
isomerism; left isomerism; indeterminate; and Langston C et al (2008) Clinical, radiological and path-
crossover segment. Additionally, there may be ological features of ABCA3 mutations in children.
Thorax 63:366–373
absence of one lung with contralateral normal Ferkol T, Leigh M (2006) Primary ciliary dyskinesia and
morphology. Abnormal connections may be to newborn respiratory distress. Semin Perinatol 30
the esophagus, to a mediastinal cyst, or to a pul- (6):335–340
monary parenchymal abnormality. Fitzgerald DA (2007) Congenital cyst adenomatoid
malformations: resect some and observe all? Paediatr
The term isomerism is entrenched but impre- Respir Rev 8:67–76
cise. Although atrial and bronchial arrangements Flidel-Rimon O, Shinwell ES (2005) Respiratory distress
are usually the same, they are not invariably and in the term and near-term infant. NeoRevew 6:289–297
“Bilateral righ lung (BRL)” is a more accurate Fliman P, deRegnier R, Kinsella J, Reynolds M, Rankin L,
Steinhorn RH (2006) Neonatal extracorporeal life sup-
term. Nearly 80% of children with BRL (right port: impact of new therapies on survival. J Pediatr
isomerism) have associated asplenia, with a risk 148:595–599
of overwhelming pneumococcal sepsis. A similar Glasser SW, Senft AP, Maxfield MD, Ruetschilling TL,
proportion with bilateral left lung (BLL, left isom- Baatz JE et al (2013) Genetic replacement of surfactant
protein-C reduces respiratory syncytial virus induced
erism) have associated polysplenia, a midline liver, lung injury. Respir Res 14:19
malrotation of the gut, partially anomalous pulmo- Gower WA, Wert SE, Nogee LM (2008) Inherited surfac-
nary venous drainage, and cardiac septal defects tant disorders. NeoReviews 9:e458–e467
(Ivemark syndrome) (Chowdhury et al. 2015). Gudjonsson U, Brown JW (2006) Scimitar syndrome.
Semin Thorac Cardiovasc Surg 9:56–62
Hossain T, Kappelman MD, Perez-Atayde AR, Young GJ,
Huttner KM, Christou H (2003) Primary ciliary dyski-
References nesia as a cause of neonatal respiratory distress: impli-
cations for the neonatologist. J Perinatol 23
Ankermann T, Oppermann HC, Engler S et al (2004) Con- (8):684–687
genital masses of the lung, cystic adenomatoid malfor- Jain K, Padleya SPG et al (2007) Primary ciliary dyskine-
mation versus congenital lobar emphysema: prenatal sia. Clin Radiol 62:986–993
diagnosis and implications for postnatal treatment. J Kartagener M, Horlacher A (1936) Situs viscerum inversus
Ultrasound Med 23:1379–84 and polyposisnasi in eineum Falle familiaerer
Bishop N, Stankiewicz P, Steinhorn R (2011) Alveolar Brouchiectasien. Beitr Klin Tub 87:331–333
capillary dysplasia. Am J Respir Crit Care Med Kinugasa H, Horigome H, Sugiura M, Saito T, Iijima T,
184:172–179 Matsui A (2002) Intravenous prostacyclin combined
Biyyam R (2010) Congenital lung abnormalities: with inhaled nitric oxide therapy for an infant with
embryologic features, prenatal diagnosis, and postnatal alveolar capillary dysplasia. Pediatr Int 44:525–527
radiologic-pathologic correlation. Radiographics Kuehni CE, Frischer T, Strippoli MP et al (2010) ERS Task
30:1721–1738 Force on Primary Ciliary Dyskinesia in Children. Fac-
Boggs S, Harris MC, Hoffman DJ, Goel R, McDonald- tors influencing age at diagnosis of primary ciliary
McGinn D, Langston C, Zackai E, Ruchelli E (1994) dyskinesia in European children. Eur Respir J 36
Misalignment of pulmonary veins with alveolar capil- (6):1248–1258
lary dysplasia: affected siblings and variable pheno- Langston C (2003) New concepts in the pathology of con-
typic expression. J Pediatr 124:125–128 genital lung malformations. Semin Pediatr Surg 12:17–37
Bouchard S, DiLorenzo M et al (2000) Pulmonary Liechty KW, Flake AW (2008) Pulmonary vascular
lymphangiectasia revisited. J Pediatr Surg 35:796–800 malformations. Semin Pediatr Surg 17:9–16
Bullard JE, Wert SE, Nogee LM (2006) ABCA3 defi- Lobo J, Zariwala M, Noone P (2015) Primary ciliary dys-
ciency: neonatal respiratory failure and interstitial kinesia. Semin Respir Crit Care Med 36:169–179
lung disease. Semin Perinatol 30:327–334 Mark EJ (1986) Mesenchimal cystic hamartoma of the
Bush A (2001) Congenital lung disease. A plea for clear lung. N Engl J Med 315:1255–1259
thinking and clear nomenclature. Pediatr Pulmonol McManus IC, Mitchison HM, Chung EM, Stubbings GF,
32:328–337 Martin N (2003) Primary ciliary dyskinesia (Siewert’s/
Cassidy J, Smith J, Goldman A, Haynes S, Smith E, Kartagener’s syndrome): respiratory symptoms and
Wright C, Haworth S, Davis P, Firmin R, Kasem K psycho-social impact. BMC Pulm Med 3:4
932 P. Tagliabue and E. Ciarmoli
Melly L, Sebire NJ et al (2008) Capillary apposition and and review of the literature. J Ultrasound Med
density in the diagnosis of alveolar capillary dysplasia. 28:1081–4
Histopathology 53:450–457 Pinar H (2004) Postmortem findings in term neonates.
Mendeloff E (2004) Sequestrations, congenital cystic Semin Neonatol 9:289–302
adenomatoid malformations, and congenital lobar Sfakianaki A, Copel JA (2012) Congenital cystic lesione of
emphysema. Semin Thorac Cardiovasc Surg 16:209–214 the lung: congenital cystic adenomatoid malformation
Mullowney T et al (2014) Primary ciliary dyskinesia and and bronchopulmonary sequestration. Rev Obstet
neonatal respiratory distress. Pediatrics 134:1160–1166 Gynecol 5(2):85–93
Narendra Kumar A (2008) Perinatal management of com- Shanti CM, Klein MD (2008) Cystic lung disease. Semin
mon neonatal thoracic lesions. Indian J Pediatr 75 Pediatr Surg 17:2–8
(9):931–937 Shapiro A et al (2016) Diagnosis, monitoring, and treat-
Nicolai T (2009) Management of the upper airway and ment of primary ciliary dyskinesia: pcd foundation
congenital cystic lung diseases in neonates. Semin consensus recommendations based on state of the art
Fetal Neonatal Med 14:56–60 review. Pediatr Pulmonol 51:115–132
Nogee LM (2004) Alterations in SP-B and SP-C expres- Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA,
sion in neonatal lung disease. Annu Rev Physiol Dean M (2004) ABCA3 gene mutations in newborns
66:601–623 with fatal surfactant deficiency. N Engl J Med
Nogee LM, Wert SE, Proffit SA, Hull WM, Whitsett JA 350:1296–1303
(2000) Allelic heterogeneity in hereditary surfactant Stankiewicz P, Sen P, Bhatt SS, Storer M, Xia Z, Bejjani BA,
protein B (SP-B) deficiency. Am J Respir Crit Care Ou Z, Wiszniewska J, Driscoll DJ, Maisenbacher MK
Med 161:973–981 et al (2009) Genomic and genic deletions of the FOX
Noone PG, Leigh MW, Sannuti A et al (2004) Primary gene cluster on 16q24.1 and inactivating mutations of
ciliary dyskinesia: diagnostic and phenotypic features. FOXF1 cause alveolar capillary dysplasia and other
Am J Respir Crit Care Med 169(4):459–467 malformations. Am J Hum Genet 84:780–791
Olutoye OO, Coleman BG, Hubbard AM et al (2000) Pre- Wert SE, Whitsett JA, Nogee LM (2009) Genetic disorders
natal diagnosis and management of congenital lobar of surfactant dysfunction. Pediatr Dev Pathol
emphysema. J Pediatr Surg 35:792–5 12:253–274
Panicek DM, Heitzman ER (1987) The continuum of pul- Whitsett JA, Wert SE, Weaver TE (2010) Alveolar surfac-
monary developmental anomalies. Radiographics tant homeostasis and the pathogenesis of pulmonary
7:747–772 disease. Annu Rev Med 61:105–119
Pariente G, Aviram M, Landau D et al (2009) Prenatal Whitsett JA et al (2015) Diseases of pulmonary surfactant
diagnosis of congenital lobar emphysema: case report homeostasis. Annu Rev Pathol 10:371–393
Persistent Pulmonary Hypertension of
the Newborn 60
Jason Gien, John P. Kinsella, and Steven H. Abman
Contents
60.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 934
60.2 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 934
60.3 PPHN: Clinical Physiology and Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 937
60.3.1 Insights into PPHN from the Laboratory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 938
60.3.2 Treatment of PPHN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 940
60.3.3 Nitric Oxide Therapy in PPHN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 942
60.3.4 PPHN: Ventilator Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 948
60.3.5 PPHN: Alternate Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 949
60.4 Pulmonary Hypertension in Congenital Diaphragmatic
Hernia (CDH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 950
60.4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 950
60.4.2 Pulmonary Hypertension in CDH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 951
60.4.3 Acute Pulmonary Hypertension in CDH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 951
60.4.4 Subacute (Late) Pulmonary Hypertension in CDH . . . . . . . . . . . . . . . . . . . . . . . . . . . 954
60.4.5 Chronic Pulmonary Hypertension in CDH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 955
60.4.6 Improving Outcomes in CDH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 955
60.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 956
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 956
Abstract
Persistent pulmonary hypertension of the new-
born (PPHN) is a clinical syndrome, character-
ized by failure of the pulmonary vasculature
J. Gien (*) resistance to fall after birth, resulting in post-
University of Colorado Denver, Denver, CO, USA
e-mail: [email protected] natal maintenance of a fetal circulation, which
in the absence of placental gas exchange
J. P. Kinsella
University of Denver, Denver, CO, USA results in hypoxemia with end organ damage.
e-mail: [email protected] Nitric oxide produced by the vascular endothe-
S. H. Abman lium is primarily responsible for vasodilation
University of Colorado Denver – Anschutz Medical after birth. When delivered exogenously,
Campus, Denver, CO, USA inhaled nitric oxide (iNO) is the mainstay of
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 933
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_208
934 J. Gien et al.
therapy for PPHN, with clinical studies dem- hypertension with right-to-left veno-arterial
onstrating improved survival and decreased admixture often complicates the course of new-
need for extracorporeal membrane oxygena- borns with diverse diseases, its recognition in
tion therapy (ECMO) with iNO treatment. term infants who were hypoxemic (but without
However, 25–30% of cases fail to respond to significant lung disease) was likely first identified
iNO, most commonly in the setting of lung by Roberton et al. (1967). These authors
hypoplasia and abnormal development of the described 13 infants born at or near-term who
pulmonary vasculature in utero. For these had marked hypoxemia but without other clinical
infants, alternate therapies are often needed. signs of “idiopathic respiratory distress syn-
In this chapter, we discuss the pathophysiology drome” or decreased lung compliance. They spec-
of PPHN, the history of PPHN therapies as ulated that the cause of hypoxemia was right-to-
they have evolved over time, mechanisms for left shunting, but did not specifically implicate
failed responses to iNO, and the approach to suprasystemic levels of pulmonary vascular resis-
PPHN that occurs in the setting of lung tance as the cause of the hypoxemia. The first
hypoplasia. clear description of the pathophysiology of
PPHN (associated with right-to-left shunting
across patent fetal channels) is attributed to
60.1 Salient Points Gersony et al. (1969), coined the phrase “persis-
tence of the fetal circulation” in describing two
• Persistent pulmonary hypertension of the new- newborns with “clear lung fields” who had critical
born (PPHN) is characterized by failure of hypoxemia associated with severe pulmonary
pulmonary vasculature resistance to fall after hypertension and right-to-left shunting across
birth, resulting in hypoxemia with end-organ the oval foramen and arterial duct (Gersony
damage. et al. 1969). One infant was treated with
• iNO is the mainstay of therapy in PPHN lead- tolazoline with only transient improvement in
ing to improved survival and decreased need oxygenation. In 1970, Lees used the term “pri-
for extracorporeal membrane oxygenation mary pulmonary hypertension” to describe this
therapy (ECMO). group of newborns (Lees 1970). In 1971, Siassi
• 25–30% of cases fail to respond to iNO; for et al. described five infants with “persistent pul-
these infants, alternative therapies are often monary vascular obstruction” associated with
needed (i.e., sildenafil, milrinone, bosentan). right-to-left shunting across the arterial duct, and
• Pulmonary hypertension is a major problem in in one case marked medial hypertrophy of the
newborns with congenital diaphragmatic her- muscular pulmonary arteries demonstrated on
nia (CDH). autopsy (SIassi et al. 1971). This observation of
• In the setting of CHD, early administration of a structural abnormality of the pulmonary circu-
pulmonary vasodilators plays a critical role in lation was further elucidated by Haworth and
management of late pulmonary hypertension, Reid in three infants who died with “persistent
with potential survival improvement. fetal circulation” and had extension of muscle into
smaller intra-acinar arteries (Haworth and Reid
1976). The phrase “persistent pulmonary hyper-
60.2 Background tension of the newborn” was first used by Levin
et al. to describe a group of newborns with severe
In the early 1960s, the association of respiratory pulmonary hypertension, clear chest radiographs,
distress syndrome with pulmonary hypertension and right-to-left shunting across the arterial duct
and right-to-left ductal shunting was shown in the demonstrated both by simultaneous temporal
landmark studies of Rudolph et al. (1961) and the arterial and umbilical arterial sampling (i.e., post-
clinical observations of Stahlman (1964). ductal desaturation) and cardiac catheterization
Although it is now recognized that pulmonary (Levin et al. 1976).
60 Persistent Pulmonary Hypertension of the Newborn 935
These initial descriptions of “PFC” focused on extrapulmonary shunting of blood flow across
a discreet subset of newborns who had adequate the ductus arteriosus (PDA) or foramen ovale
cardiac performance without structural heart dis- (PFO). In many clinical settings, hypoxemic
ease, absence of significant parenchymal lung respiratory failure in term newborns is often pre-
disease, and suprasystemic pulmonary vascular sumed to be associated with PPHN-type physiol-
resistance causing hypoxemia through right-to- ogy; however, hypoxemic term newborns can lack
left shunting of blood across the oval foramen echocardiographic findings of extrapulmonary
and/or the arterial duct. Due to the persistence of shunting across the PDA or PFO. Thus, PPHN
high PVR and blood flow through these “fetal should be reserved to describe neonates in whom
shunts,” the term “persistent fetal circulation” extrapulmonary shunting contributes to hypox-
was originally used to describe this group of emia and impaired cardiopulmonary function.
patients. Although there was initial appeal to the Recent estimates suggest an incidence for PPHN
acronym persistent fetal circulation (PFC) (Behr- of 1.9/1000 live births, or an estimated 7400
man 1976), this description is not quite accurate cases/year (Walsh-Sukys et al. 2000).
because of the absence of the placenta and onset Diseases associated with PPHN are often
of air breathing after delivery. It also soon became classified within one of three categories:
clear that “PFC” could complicate the course of (i) maladaptation: vessels are presumably of nor-
other diseases of the newborn, including meco- mal structural but have abnormal vasoreactivity;
nium aspiration (initially described by Stahlman (ii) excessive muscularization: increased smooth
(1964) and later by Fox et al. (1977), and pulmo- muscle cell thickness and increased distal exten-
nary hypoplasia/congenital diaphragmatic hernia sion of muscle to vessels which are usually non-
(Harrison and de Lorimier 1981). As a result, the muscular; and (iii) underdevelopment: lung
term “PPHN” has been considered as a syndrome hypoplasia associated with decreased pulmonary
and over time, most authors have embraced artery number. This designation is imprecise,
PPHN as the proper name for this syndrome, however, and high PVR in most patients likely
with the classic “PFC” subtype (idiopathic involves overlapping changes among these cate-
PPHN) representing a relatively small percentage gories. For example, neonates with congenital
of the cases now commonly encountered. diaphragmatic hernia (CDH) are primarily classi-
Pathophysiologic mechanisms and etiologic fied as having vascular “underdevelopment” due
classifications of PPHN described by Rudolph to lung hypoplasia, yet lung histology of fatal
(1980) and further characterized by Geggel and cases typically shows marked muscularization of
Reid (1984) and Gersony (1984) provided an pulmonary arteries, and clinically, these patients
important framework for understanding the com- can respond to vasodilator therapy. Similarly, neo-
plex nature of this syndrome as management strat- nates with meconium aspiration often have clini-
egies evolved over the last two decades. cal evidence of altered vasoreactivity, but
The clinical syndrome of persistent pulmonary excessive muscularization is often found at
hypertension of the newborn (PPHN) occurs in autopsy. As described above, autopsy studies of
association with various neonatal diseases, fatal PPHN demonstrate severe hypertensive
including meconium aspiration syndrome, group structural remodeling even in newborns who die
B streptococcal sepsis, and congenital diaphrag- shortly after birth, suggesting that many cases of
matic hernia, as well as from undetermined causes severe disease are associated with chronic intra-
(idiopathic). Striking differences exist between uterine stress. However, the exact intrauterine
these conditions, and mechanisms that contribute events that alter pulmonary vascular reactivity
to high PVR can vary between these diseases. and structure are poorly understood. Epidemio-
However, these disorders are included in the syn- logic studies have demonstrated strong associa-
drome of PPHN due to common pathophysiologic tions between PPHN and maternal smoking and
features, including sustained elevation of PVR ingestion of cold remedies that include aspirin or
leading to hypoxemia due to right-to-left other nonsteroidal anti-inflammatory products
936 J. Gien et al.
(Van Marter et al. 1996; Alano et al. 2001). Since understanding and clinical management of this
these agents can induce partial constriction of the syndrome. Indeed, the most striking change in
ductus arteriosus, it is possible that pulmonary the management of PPHN in the last decade
hypertension due to antenatal ductal narrowing evolved from improved understanding of the
contributes to PPHN. Other perinatal stresses, role of endogenous NO production and exoge-
including placenta previa and abruption, and nous NO delivery on pulmonary vasoregulation.
asymmetric growth restriction, are associated Because the successful transition from fetal pla-
with PPHN; however, most neonates who are cental dependence to survival at birth requires that
exposed to these prenatal stresses do not develop PVR rapidly declines and pulmonary blood flow
PPHN. Circulating levels of L-arginine, the sub- increases, the role of NO in the transitional circu-
strate for NO, are decreased in some newborns lation has been intensively investigated to under-
with PPHN, suggesting that impaired NO produc- stand its relationship to the pathophysiology and
tion may contribute to the pathophysiology of treatment of PPHN.
PPHN. It is possible that genetic factors increase NO was recognized as a potent vasodilator as
susceptibility for pulmonary hypertension. A early as 1979 (Furchgott and Zawadzki 1980), and
recent study reported strong links between in 1980, Furchgott and Zawadzki reported that
PPHN and polymorphisms of the carbamoyl acetylcholine-induced vasorelaxation was depen-
phosphate synthase gene (Pearson et al. 2001). dent on an intact endothelium through the elabo-
However, the importance of this finding is uncer- ration of an endothelial-derived relaxing factor
tain, and further work is needed in this area. Stud- (EDRF) that diffused to the subjacent vascular
ies of adults with idiopathic primary pulmonary smooth muscle. In 1987 investigators from two
hypertension have identified abnormalities of separate laboratories reported that the biologic
bone morphogenetic protein (BMP) receptor activity of EDRF was identical to NO or an
genes; whether polymorphisms of genes for the NO-containing substance. Palmer et al. (1987)
BMP or TGF-ß receptors, other critical growth induced the release of EDRF from porcine aortic
factors, vasoactive substances, or other products endothelial cells in culture and compared the
increase the risk for some newborns to develop effects on superfused aortic strips with that of
PPHN is unknown. NO in solution. They found that the effects of
Because of the role of pulmonary hypertension EDRF were indistinguishable from those of
in newborns with hypoxemic respiratory failure NO. Ignarro et al. (1987) used a bioassay cascade
(initially severe HMD and subsequently “PFC”, superfusion technique with intrapulmonary arter-
as described above), early approaches to manage- ies and veins, identified EDRF pharmacologically
ment included a focus on pulmonary vasodilation and chemically as NO, and found that EDRF and
using one of the few pharmacologic agents avail- NO produced similar vasorelaxation and were
able at the time (tolazoline). Its use was first inhibited by common antagonists. Ignarro et al.
described by Cotton in 1965 in newborns with also recognized that NO was inactivated by com-
HMD (Cotton 1965) and later in infants with bining with hemoproteins, and speculated that
PPHN by Goetzman et al. (1976), Korones and hemoglobin could trap endogenously produced
Eyal (1975), and Levin et al. (1976). However, its NO that diffused into the vascular lumen, thus
efficacy was limited by variable responsiveness preventing any “downstream” vasorelaxation by
and significant complications including systemic this paracrine mediator.
hypotension and gastrointestinal hemorrhage The recognition that the endogenous produc-
(Stevenson et al. 1979). tion of this EDRF/NO mediator could be com-
Multiple approaches to the treatment of PPHN petitively blocked by modified L-arginine
evolved since its first recognition as a disease analogs prompted early experiments into the
marked by severe pulmonary hypertension; how- effects of NO in the fetal and transitional pulmo-
ever, discovery of the elusive “selective pulmo- nary circulation. Abman et al. (1990) performed
nary vasodilator” would markedly change our the first experiments on the role of EDRF in the
60 Persistent Pulmonary Hypertension of the Newborn 937
ovine fetal circulation, demonstrating that signs of acute perinatal distress. Radiographic
endogenous EDRF/NO production modulates findings are variable, depending upon the primary
basal pulmonary vascular tone in the late- disease associated with PPHN. Classically, the
gestation fetus and that pharmacologic NO chest x-ray in idiopathic PPHN is oligemic, nor-
blockade inhibits endothelium-dependent pul- mally or slightly hyperinflated, and lacks paren-
monary vasodilation. These investigators also chymal infiltrates. In general, the degree of
showed that pharmacologic NO blockade atten- hypoxemia is disproportionate to the severity of
uates the rise in pulmonary blood flow at deliv- radiographic evidence of lung disease.
ery, thus implicating endogenous NO formation Not all term newborns with hypoxemic respi-
in postnatal adaptation after birth and linking this ratory failure have PPHN physiology (Abman and
laboratory observation to the life-threatening Kinsella 1995). Hypoxemia in the newborn can be
clinical condition of PPHN. In addition, experi- due to extrapulmonary shunt, as described above,
ments using this ovine model showed that in which high pulmonary artery pressure at sys-
increased fetal oxygen tension augments endog- temic levels leads to right-to-left shunting of
enous NO release (McQueston et al. 1993; blood flow across the PDA or PFO. However, in
Tiktinsky and Morin 1993) and the increase in many infants intrapulmonary shunt or ventilation-
pulmonary blood flow in response to rhythmic perfusion mismatch is the predominant abnormal-
distention of the lung and high inspired oxygen ity, in which hypoxemia results from the lack of
concentrations are mediated in part by endoge- mixing of blood with aerated lung regions due to
nous NO elaboration (Tiktinsky and Morin 1993; parenchymal lung disease, without the shunting of
Cornfield et al. 1992). blood flow across the PDA and PFO. In the latter
The observation that dilute NO gas could be setting, hypoxemia is related to the amount of
therapeutically delivered by inhalation was first pulmonary arterial blood that perfuses nonaerated
described by Higgenbottam et al. who reported lung regions. Although PVR is often elevated in
that brief (10 min) inhalational NO treatment hypoxemic newborns without PPHN, high PVR
caused potent and selective pulmonary vasodila- does not contribute significantly to hypoxemia in
tion in adults with severe pulmonary hypertension these cases.
(Higenbottam et al. 1988; Pepke-Zaba et al. Several factors can contribute to high pulmo-
1991). Frostell et al. demonstrated the selectivity nary artery pressure in neonates with PPHN-type
of inhaled NO in an adult animal model of hyp- physiology. Pulmonary hypertension can be due
oxic pulmonary vasoconstriction (Frostell et al. to vasoconstriction or structural vascular lesions
1991), and the first description of the potent, that directly increase PVR. Changes in lung vol-
sustained, and selective vasodilator effect of ume in neonates with parenchymal lung disease
inhaled NO in newborn lambs was reported by can also be an important determinant of PVR.
Kinsella et al. (1992a). PVR increases at low lung volumes due to dense
parenchymal infiltrate and poor lung recruitment,
or with high lung volumes due to hyperinflation
60.3 PPHN: Clinical Physiology associated with overdistension or gas-trapping.
and Evaluation Cardiac disease is also associated with PPHN.
High pulmonary venous pressure due to left ven-
Clinically, PPHN is most often recognized in term tricular dysfunction (e.g., asphyxia or sepsis) can
or near term neonates, but clearly can occur in also elevate PAP, causing right-to-left shunting,
premature neonates as well. PPHN typically pre- with little vasoconstriction. In this setting,
sents as respiratory distress and cyanosis within enhancing cardiac performance and systemic
6–12 h of birth. While PPHN is often associated hemodynamics may lower PAP more effectively
with perinatal distress, such as asphyxia, low than promoting pulmonary vasodilation. Thus,
APGAR scores, meconium staining, and other understanding the cardiopulmonary interactions
factors, idiopathic PPHN can present without is key to improving outcome in PPHN.
938 J. Gien et al.
PPHN is characterized by hypoxemia that is for the evaluation of left ventricular function and
poorly responsive to supplemental oxygen. In the diagnosis of anatomic heart disease, including
presence of right-to-left shunting across the PDA, such “PPHN mimics” as coarctation of the
“differential cyanosis” is often present, which is aorta, total anomalous pulmonary venous return,
difficult to detect by physical exam, and is defined hypoplastic left heart syndrome, and others.
by a difference in PaO2 between right radial artery Studies should carefully assess the predominant
versus descending aorta values >10 torr, or an O2 direction of shunting at the PFO as well as the
saturation gradient >5%. However, postductal PDA. Although right-to-left shunting at the PDA
desaturation can be found in ductus-dependent and PFO is typical for PPHN, predominant right-
cardiac diseases, including hypoplastic left heart to-left shunting at the PDA but left-to-right shunt
syndrome, coarctation of the aorta, or interrupted at the PFO may help to identify the important
aortic arch. The response to supplemental oxygen role of left ventricular dysfunction to the under-
can help to distinguish PPHN from primary lung lying pathophysiology. In the presence of severe
or cardiac disease. Although supplemental oxy- left ventricular dysfunction with pulmonary
gen traditionally increases PaO2 more readily in hypertension, pulmonary vasodilation alone
lung disease than cyanotic heart disease or PPHN, may be ineffective in improving oxygenation.
this may not be obvious with more advanced In this setting, efforts to reduce PVR should be
parenchymal lung disease. Marked improvement accompanied by targeted therapies to increase
in SaO2 (increase to 100%) with supplemental cardiac performance and decrease left ventricular
oxygen suggests the presence of V/Q mismatch afterload. In the setting of impaired LV perfor-
due to lung disease or highly reactive PPHN. Most mance, cardiotonic therapies that increase sys-
patients with PPHN have at least a transient temic vascular resistance may further worsen LV
improvement in oxygenation in response to inter- function and increase pulmonary artery pressure.
ventions such as high levels of inspired oxygen Thus, careful echocardiographic assessment pro-
and/or mechanical ventilation. Acute respiratory vides invaluable information about the underly-
alkalosis induced by hyperventilation to achieve ing pathophysiology and will help guide the
PaCO2 <30 torr and a pH >7.50 may increase course of treatment.
PaO2 >50 torr in PPHN, but rarely in cyanotic
heart disease.
The echocardiogram plays an important diag- 60.3.1 Insights into PPHN from
nostic role and is an essential tool for managing the Laboratory
newborns with PPHN. The initial echocardio-
graphic evaluation rules out structural heart dis- Diverse animal models have been used in order to
ease causing hypoxemia or ductal shunting (e.g., better understand the pathogenesis and patho-
coarctation of the aorta and total anomalous pul- physiology of PPHN. Such models have included
monary venous return). Further, as stated above, exposure to acute or chronic hypoxia after birth,
not all term newborns with hypoxemia have chronic hypoxia in utero, placement of meconium
PPHN physiology. Although high pulmonary into the airways of neonatal animals, sepsis, and
artery pressure is commonly found in association others. Each model demonstrates interesting
with neonatal lung disease, the diagnosis of physiologic changes that may be especially rele-
PPHN is uncertain without evidence of bidirec- vant to particular clinical settings, but most stud-
tional or predominantly right-to-left shunting ies examine only brief changes in the pulmonary
across the PFO or PDA. Echocardiographic circulation, and mechanisms underlying altered
signs suggestive of pulmonary hypertension lung vascular structure and function of PPHN
(e.g., increased right ventricular systolic time remain poorly understood. Neonates with severe
intervals and septal flattening) are less helpful. PPHN who die during the first days after birth
In addition to demonstrating the presence of already have pathologic signs of chronic pulmo-
PPHN physiology, the echocardiogram is critical nary vascular disease, suggesting that intrauterine
60 Persistent Pulmonary Hypertension of the Newborn 939
events may play an important role in this syn- hypertension is also associated with decreased
drome (Geggel and Reid 1984). Adverse intra- cGMP concentrations, associated with decreased
uterine stimuli during late gestation, such as soluble guanylate cyclase and upregulated cGMP-
abnormal hemodynamics, changes in substrate specific phosphodiesterase (PDE5) activities,
or hormone delivery to the lung, hypoxia, inflam- suggesting further impairments in downstream sig-
mation, or others, may potentially alter lung vas- naling (Hanson et al. 1996; Steinhorn et al. 1995;
cular function and structure, contributing to Tzao et al. 2001). Thus, multiple alterations in the
abnormalities of postnatal adaptation. Several NO-cGMP cascade appear to play an essential role
investigators have examined the effects of chronic in the pathogenesis and pathophysiology of exper-
intrauterine stresses, such as hypoxia or hyperten- imental PPHN, contributing to altered structure and
sion, in animal models in order to attempt to function of the developing lung circulation and
mimic the clinical problem of PPHN. Whether leading to failure of postnatal cardio-respiratory
chronic hypoxia alone can cause PPHN is contro- adaptation. Recent evidence indicates that exces-
versial. A past report that maternal hypoxia in rats sive production of reactive oxygen species (ROS),
increases pulmonary vascular smooth muscle such as superoxide in the pulmonary vasculature,
thickening in newborns, but this observation has may further contribute to the disruption in
not been reproduced in maternal rats or guinea NO-cGMP signaling in this model and may con-
pigs with more extensive studies (Murphy et al. tribute to poor responsiveness to inhaled NO ther-
1986). Acute hypoxia alone is insufficient to apy (Farrow et al. 2008a; Brennan et al. 2003;
account for PPHN, which is further reflected in Chester et al. 2009).
recent clinical observations that PPHN is rare in Upregulation of ET-1 may also contribute to
patients with severe asphyxia who were enrolled the pathophysiology of PPHN. Circulating levels
in hypothermia studies. of ET-1, a potent vasoconstrictor and co-mitogen
Pulmonary hypertension induced by early clo- for vascular smooth muscle cell hyperplasia, are
sure of the DA in fetal lambs alters lung vascular increased in human newborns with severe PPHN
reactivity and structure, causing the failure of (Rosenberg et al. 1993). In the experimental
postnatal adaptation at delivery and providing an model of PPHN due to compression of the DA
experimental model of PPHN (Levin et al. 1978; in fetal sheep, lung ET-1 mRNA and protein con-
Morin and Eagan 1989; Abman and Accurso tent is markedly increased, and the balance of ET
1989). Over days, pulmonary artery pressure and receptors is altered, favoring vasoconstriction (Ivy
PVR progressively increase, but flow remains low et al. 1996, 1998;). Chronic inhibition of the ET A
and PaO2 is unchanged (Abman and Accurso receptor attenuates the severity of pulmonary
1989). Marked right ventricular hypertrophy and hypertension, decreases pulmonary artery wall
structural remodeling of small pulmonary arteries thickening, and improves the fall in PVR at birth
develops after 8 days of hypertension. After deliv- in this model (Ivy et al. 1997). Thus, experimental
ery, these lambs have persistent elevation of PVR studies have shown the important role of the
despite mechanical ventilation with high oxygen NO-cGMP cascade and the ET-1 system in the
concentrations. Studies with this model show that regulation of vascular tone and reactivity of the
chronic hypertension without high flow can alter fetal and transitional pulmonary circulation.
fetal lung vascular structure and function. Oxidant stress plays an important role in the
This model is characterized by endothelial cell pathogenesis of PPHN. Increased ROS such as
dysfunction and abnormal smooth muscle cell superoxide (O2 ) and hydrogen peroxide
vasoreactivity and growth, including findings of (H2O2) have been demonstrated in pulmonary
impaired NO production and activity and down- arteries in the ovine ductal ligation model of per-
regulation of lung endothelial NO synthase mRNA sistent pulmonary hypertension (Brennan et al.
and protein expression (Storme et al. 1999; 2003; Fike et al. 2008). Mitochondrial dysfunc-
Villamor et al. 1997; Shaul et al. 1997; McQueston tion, increased expression and activity of NADPH
et al. 1995; Farrow et al. 2008a). Fetal pulmonary oxidase, and uncoupled eNOS activity can each
940 J. Gien et al.
generate ROS (Brennan et al. 2003; Konduri et al. sixfold increase in the prevalence of PPHN (Cham-
2003, 2007; Wedgwood et al. 2005). Increased bers et al. 2006), although it is not clear how many
ROS production promotes vasoconstriction infants developed severe disease. Newborn rats
directly and through multiple mechanisms that exposed in utero to fluoxetine develop pulmonary
may include increased endothelin levels (Wedg- vascular remodeling, abnormal oxygenation, and
wood and Black 2003) and oxidization of free higher mortality when compared with vehicle-
fatty acids to create vasoconstrictor metabolites, treated controls (Fornaro et al. 2007). However,
such as isoprostanes (Lakshminrusimha et al. these findings showed only mild changes in right
2006a). O2 rapidly combines and inactivates ventricular hypertrophy and pulmonary vascular
NO and forms peroxynitrite, a potent oxidant remodeling in the neonatal rat pups, with minimal
with the potential to produce vasoconstriction changes in vasoreactivity after maternal SSRI
and cytotoxicity. Increased ROS in the pulmonary exposure. Whether these effects were related to
vasculature of the ductal ligation model promotes direct impact on the fetal lung circulation or sec-
dysfunction of NO-cGMP signaling at multiple ondary to altered maternal or umbilical-placental
steps in the pathway, including blunted eNOS physiology remains unknown. As SSRIs have been
expression, uncoupled eNOS activity (thus further reported to reduce pulmonary vascular remodeling
promoting ROS production), and increased activ- in adult models of pulmonary hypertension, these
ity and expression of cGMP-specific phosphodi- findings also serve to highlight the unique vulner-
esterases, and impaired sGC activity (Farrow et al. ability of fetal pulmonary vascular development.
2008a, b; Chester et al. 2009). Superoxide
dismutases (SOD) catalyze the conversion of
superoxide anions to H2O2 and O2. Due to the 60.3.2 Treatment of PPHN
efficiency of the reaction between NO and super-
oxide, the local concentration of SOD is a key Several pathophysiologic disturbances contribute to
determinant of the biological half-life of endoge- hypoxemia in the newborn infant, including cardiac
nous NO (Faraci and Didion 2004). Evidence for a dysfunction, airway and pulmonary parenchymal
critical pathologic role for ROS in PPHN includes abnormalities, and pulmonary vascular disorders.
the recent observation that administration of a In some newborns with hypoxemic respiratory fail-
single intratracheal dose of rhSOD in neonatal ure, a single mechanism predominates (e.g., extra-
lambs with PPHN produced a sustained increase pulmonary right-to-left shunting without significant
in oxygenation over a 24-h period, reduced pro- parenchymal lung disease seen in patients with idi-
duction of isoprostanes and peroxynitrite, and opathic PPHN). These patients have systemic arte-
restored normal eNOS expression and function. rial hypoxemia despite high alveolar and pulmonary
In addition to vasoactive mediators, alterations venous oxygen tensions. More commonly, the clin-
of growth factors, such as VEGF and platelet- ical manifestations of severe PPHN and hypoxemic
derived growth factor (PDGF), likely play key respiratory failure are rarely attributable to a single
roles in PPHN. VEGF is markedly decreased in pathophysiologic disturbance. PPHN is often asso-
experimental PPHN, and treatment with recombi- ciated with severe parenchymal lung disease in con-
nant human VEGF restores endothelial function ditions such as meconium aspiration syndrome,
and lowers PVR in this model (Villamor et al. bacterial pneumonia, and surfactant deficiencies or
1997; Grover et al. 2003, 2005). In addition, inhi- dysfunction leading to both extrapulmonary and
bition of PDGF-B attenuates smooth muscle hyper- intrapulmonary shunting. Moreover, decreased car-
plasia in experimental pulmonary hypertension in diac performance and reduced left ventricular output
fetal lambs, suggesting a potential role in the path- can decrease systemic blood pressure, exacerbating
ogenesis of PPHN (Balasubramaniam et al. 2003). the right-to-left shunting of blood at the ductus
Additional new data suggest that maternal expo- arteriosus. Although severe PPHN is commonly
sure to selective serotonin reuptake inhibitors associated with near-term and term neonates, echo-
(SSRI) during late gestation is associated with a cardiographic studies in premature infants with
60 Persistent Pulmonary Hypertension of the Newborn 941
hyaline membrane disease (HMD) show that pul- sustain cardiac performance and systemic hemo-
monary hypertension may complicate the course of dynamic stability, and to reduce pulmonary vas-
severe HMD. cular resistance. In this section, management
The treatment of PPHN commonly focuses strategies for the patient with severe hypoxemic
only on pharmacologic therapy to reduce pulmo- respiratory failure and PPHN are described, but it
nary vascular resistance. For the relatively small is important to recognize that many therapies
subset of neonatal patients with idiopathic PPHN advocated for the management of PPHN have
who have pulmonary hypertension without con- not undergone rigorous evaluation with controlled
comitant lung disease, selective pulmonary vaso- clinical trials.
dilation alone can cause marked improvements in In general, therapy includes optimization of
oxygenation. However, PPHN often occurs with systemic hemodynamics with volume and cardio-
more common causes of neonatal respiratory dis- tonic therapy (dopamine, epinephrine, and
tress, including disorders characterized by moder- milrinone), in order to enhance cardiac output
ate to severe lung disease. Moreover, sepsis and systemic O2 transport. Beyond these agents,
neonatorum and perinatal asphyxia can severely another therapeutic option for stabilizing hemo-
compromise systemic vascular tone and cardiac dynamics is arginine vasopressin. In the systemic
performance, leading to systemic hypotension in circulation, vasopressin acts via V1a receptors of
addition to severe pulmonary hypertension. The the smooth muscle, leading to vasoconstriction of
pulmonary vasculature in many newborns with both arteries and veins (Share 1988). Work in
severe PPHN has marked structural changes, animal models has shown that despite the vaso-
which include endothelial swelling, smooth mus- constrictive effect systemically, vasopressin
cle hypertrophy, and increased adventitial thick- causes dilation of the pulmonary circulation,
ening. Moreover, functional abnormalities lead to likely mediated via nitric oxide release from the
altered responses to vasodilator and vasoconstric- endothelium (Evora et al. 1993; Russ and Walker
tor stimuli. Therefore, the therapeutic approach to 1992). Outside of the neonatal period, vasopressin
PPHN requires meticulous attention to all aspects is used in the setting of cardiac arrest, sepsis,
of the cardiopulmonary perturbations (pulmonary vasodilatory shock, and cardiac surgery with
hypertension, systemic vasodilation, decreased improved systemic blood pressure, a decrease in
cardiac performance, and parenchymal lung dis- catecholamine requirements, and increased urine
ease) that characterize this syndrome. output (Scheurer et al. 2005; Luccini et al. 2013;
PPHN is a dynamic syndrome characterized by Agrawal et al. 2012). In studies of patients with
progressive changes in pulmonary vasoreactivity, pulmonary hypertension, vasopressin improves
cardiac performance, and parenchymal lung dis- systemic hemodynamics without adverse effects
ease. In addition, the tendency for time-dependent on the pulmonary vasculature, making it an ideal
changes in the relative contribution of each mech- agent for treatment of infants who have pulmo-
anism to hypoxemia requires continued vigilance nary hypertension and systemic hypotension
as the disease progresses. Therefore, understand- (Radicioni et al. 2012; Filippi et al. 2011). Most
ing the relative contribution of these different recently in ten infants with severe PPHN, Moham-
causes of hypoxemia becomes critically important med et al. reported improvements in oxygenation
as the inventory of therapeutic options expands. index, peak effect, a reduction in iNO dose asso-
Therefore, management should be based on serial ciated with a concomitant improvement in blood
hemodynamic, echocardiographic, and radio- pressure and urine output after initiation of vaso-
graphic assessments. Because of the diverse pressin supporting the applicability of this agent
nature of diseases associated with PPHN, no sin- in this setting (Adel Mohamed et al. 2014). A
gle therapeutic approach is effective in all profound natriuresis is often accompanied by the
patients. In general, the goals of PPHN manage- increase in urine output and close monitoring of
ment are to optimize lung inflation and treat any urine and serum sodium advised with vasopressin
underlying pulmonary parenchymal disease, to administration (Luccini et al. 2013).
942 J. Gien et al.
Failure to respond to medical management, as disorders that are characterized by high PVR
evidenced by the failure to sustain improvement causing extrapulmonary right-to-left shunting of
in oxygenation with good hemodynamic function, blood across the arterial duct and/or oval foramen.
often leads to treatment with extracorporeal mem- The ability of inhaled NO therapy to selectively
brane oxygenation (ECMO). Although ECMO lower PVR and decrease extrapulmonary
can be a life-saving therapy, it is costly and labor venoarterial admixture accounts for the acute
intensive and can have severe side effects, such as improvement in oxygenation observed in new-
intracranial hemorrhage. Since arterio-venous borns with PPHN (Kinsella et al. 1993). However,
ECMO usually involves ligation of the carotid oxygenation can also improve during inhaled
artery, the potential for acute and long-term CNS NO therapy in critically ill patients who do not
injuries continues to be a major concern. Long- have extrapulmonary right-to-left shunting
term follow-up of 250 neonatal ECMO survivors (Abman et al. 1994; Gerlach et al. 1993). Hyp-
revealed significant abnormalities in motor per- oxemia in these cases is primarily due to
formance at 12 years of age (van der Cammen-van intrapulmonary shunting caused by continued
Zijp et al. 2014) with the presence of chronic lung perfusion of lung units that lack ventilation
disease correlating with adverse motor outcomes. (e.g., atelectasis), with variable contributions
In this study, abnormal motor development was form ventilation/perfusion (V/Q) inequality.
more subtle at 5 and 8 years of age, stressing the Distinct from its ability to decrease extra-
need for continued follow-up of neurodeve- pulmonary right-to-left shunting by reducing
lopmental outcomes in ECMO survivors (van PVR, low dose inhaled NO therapy can also
der Cammen-van Zijp et al. 2014). improve oxygenation by redirecting blood from
poorly aerated or diseased lung regions to better
aerated distal air spaces (“microselective
60.3.3 Nitric Oxide Therapy in PPHN effect”) (Rossaint et al. 1993).
Finally, the diagnostic value of inhaled NO ther-
60.3.3.1 Rationale for Inhaled NO apy is also important, in that failure to respond to
Therapy inhaled NO raises important questions about the
Early laboratory studies demonstrated that inhaled specific mechanism of hypoxemia. Poor responses
nitric oxide (NO) therapy caused marked and to inhaled NO should lead to further diagnostic
sustained reduction in pulmonary vascular resis- evaluation for “unsuspected” functional/structural
tance (PVR) in newborn animal models (Kinsella cardiovascular or pulmonary disease.
et al. 1992a; Roberts et al. 1993), and initial pilot
studies showed marked improvement in oxygen- 60.3.3.2 Inhaled NO for Treatment
ation in term newborns with PPHN (Roberts et al. of PPHN
1992; Kinsella et al. 1992b). Subsequent trials Due to its selective pulmonary vasodilator effects,
confirmed the safety and efficacy of inhaled NO inhaled NO therapy is an important adjunct to
in this population, and it is now an integral com- available treatments for term newborns with hyp-
ponent of PPHN therapy (Kinsella et al. 1997; oxemic respiratory failure. Inhaled nitric oxide
Roberts et al. 1997; Wessel et al. 1997; Davidson (iNO) therapy at low doses (5–20 ppm) improves
et al. 1998a; Neonatal Inhaled Nitric Oxide Study oxygenation and decreases the need for ECMO
Group 1997; Clark et al. 2000). therapy in patients with diverse causes of PPHN
As described above, the physiologic rationale (Clark et al. 2000; Davidson et al. 1998; Kinsella
for inhaled NO therapy in the treatment of PPHN et al. 1992b, 1997; Neonatal Inhaled Nitric Oxide
is based upon its ability to achieve potent and Study Group 1997; Roberts et al. 1997b). Multi-
sustained pulmonary vasodilation without center clinical trials support the use of iNO in
decreasing systemic vascular tone (Kinsella and near-term (>34 weeks gestation) and term new-
Abman 1995). As a syndrome, PPHN is associ- borns, although the use of iNO in infants less
ated with diverse neonatal cardiac and pulmonary than 34 weeks gestation remains largely
60 Persistent Pulmonary Hypertension of the Newborn 943
investigational. Studies support the use of iNO in from inhaled NO therapy. However, Davidson
infants who have hypoxemic respiratory failure et al. reported a controlled clinical trial in which
with evidence of PPHN, who require mechanical the average OI at study entry was 24 9 (David-
ventilation and high inspired oxygen concentra- son et al. 1998). It is important to note that inhaled
tions. The most common criterion employed has NO treatment did not reduce ECMO utilization in
been the oxygenation index (OI; mean airway this study. Although entry criteria for this trial
pressure times FiO2 times 100 divided by included echocardiographic evidence of pulmo-
PaO2). However, hypoxemic respiratory failure nary hypertension, only 9% of the patients had
in the term newborn represents a heterogeneous clinical evidence of right-to-left ductal shunting.
group of disorders, and disease-specific responses Because of the mechanism of action of inhaled
have clearly been described. For example, NO as a selective pulmonary vasodilator, it is
patients with extapulmonary right-to-left shunting likely that acute improvement in oxgyenation
(PPHN) show acute improvement in oxygenation caused by decreased pulmonary vascular resis-
when PVR becomes subsystemic during NO tance and reduced extrapulmonary right-to-left
therapy, and patients with predominantly shunting would be most predictive of clinical
intrapulmonary shunting (e.g., RDS) have less improvement. Therefore, current multicenter
dramatic responses. studies suggest that treatment with inhaled NO
Clinical trials of inhaled NO in the term new- may include an OI >25 with echocardiographic
born have incorporated ECMO treatment as an evidence of extrapulmonary right-to-left shunting.
endpoint. Therefore, most patients have been The first studies of inhaled NO treatment in
enrolled in the first few days of life. Although one term newborns reported initial doses that ranged
of the pivotal studies used to support the new drug from 80 ppm (Roberts et al. 1992) to 6–20 ppm
application for inhaled NO therapy included as an (Kinsella et al. 1992b). The rationale for doses
entry criterion a postnatal age up to 14 days, the used in these clinical trials was based on concen-
average age at enrollment in that study was trations which had previously been found to be
1.7 days (Neonatal Inhaled Nitric Oxide Study effective in animal experiments by the same
Group 1997). Currently, clinical trials support the investigators (Geggel and Reid 1984; Levin
use of inhaled NO before treatment with ECMO, or et al. 1978). Roberts et al. reported that brief
usually within the first week of life. However, (30 min) inhalation of NO at 80 ppm improved
clinical experience suggests that inhaled NO may oxygenation in patients with PPHN, but this
be of benefit as an adjuvant treatment after ECMO response was sustained in only one patient after
therapy in patients with sustained pulmonary NO was discontinued (Roberts et al. 1992b). In
hypertension (e.g., congenital diaphragmatic her- the second report, rapid improvement in oxygen-
nia). Thus, postnatal age alone should not define ation in neonates with severe PPHN was also
the duration of therapy in cases where prolonged demonstrated, but this was achieved at lower
treatment could be beneficial. doses (20 ppm) for 4 h (Kinsella et al. 1992b).
Studies support the use of inhaled NO in This study also reported that decreasing the
infants who have hypoxemic respiratory failure inhaled NO dose to 6 ppm for the duration of
with evidence of PPHN, who require mechanical treatment provided sustained improvement in
ventilation and high inspired oxygen concentra- oxygenation. The relative effectiveness of
tions. The most common criterion employed has low-dose inhaled NO in improving oxygenation
been the oxygenation index. Although clinical in patients with severe PPHN was corroborated in
trials commonly allowed for enrollment with OI a study by Finer et al. (1994). Acute improvement
levels >25, the mean OI at study entry for these in oxygenation during treatment was not different
studies approximated 40. Whether treatment at with doses of inhaled NO ranging from 5 to
lower OI levels reduces ECMO use is uncertain 80 ppm.
(Konduri et al. 2004). Thus, it is unclear whether These laboratory and clinical studies
infants with less severe hypoxemia would benefit established the boundaries of inhaled NO dosing
944 J. Gien et al.
protocols for subsequent randomized, clinical tri- safe, sustained treatment with 80 ppm NO
als in newborns (Morin and Eagan 1989; Abman increases the risk of methemoglobinemia. The
and Accurso 1989; Storme et al. 1999; Villamor lowest effective starting dose for inhaled NO in
et al. 1997; Shaul et al. 1997; McQueston et al. term newborns with PPHN has not been deter-
1995). Increasing the dose to 40 ppm does not mined. Cornfield et al. reported that initiating
generally improve oxygenation in patients who do treatment at 2 ppm does not acutely improve
not respond to the lower dose of 20 ppm. The oxygenation and may diminish the subsequent
initial dose in the NINOS trial was 20 ppm, but response to 20 ppm (Cornfield et al. 1999). How-
the dose was increased to 80 ppm if the improve- ever, this effect was refuted by Finer et al. who
ment in PaO2 was less than 20 torr (Neonatal found that initial exposure to low NO doses
Inhaled Nitric Oxide Study Group 1997). In this (1–2 ppm) did not compromise subsequent
study, only 3 of 53 infants (6%) who had little responses to higher doses (10–20 ppm), and
response to 20 ppm had an increase in PaO2 dose increases were required in 80% of the low
>20 torr when treated with 80 ppm inhaled dose group (Finer et al. 2001). Sustained improve-
NO. Whether a progressive increase in PaO2 ment in oxygenation (after >4 h of treatment with
would have occurred with continued exposure to 20 ppm) has been demonstrated for doses
20 ppm could not be determined with this study <10 ppm (Goldman et al. 1996).
design. Roberts et al. initiated treatment with Although clinical improvement during inhaled
80 ppm NO and subsequently weaned the inhaled NO therapy occurs with many disorders associ-
NO concentration if oxygenation improved; thus, ated with PPHN, not all neonates with acute hyp-
the effects of lower initial inhaled NO doses could oxemic respiratory failure and pulmonary
not be evaluated and the effects on ECMO utili- hypertension respond to iNO. Several mecha-
zation were not evaluated (Roberts et al. 1992b). nisms may explain the clinical variability in
These studies did not systematically evaluate responsiveness to iNO therapy (Goldman et al.
individual doses in an interpretable fashion. 1996). A major cause of poor responsiveness to
Davidson et al. reported the results of a random- iNO is an inability to deliver NO to the pulmonary
ized, controlled, dose-response trial in term new- circulation due to poor lung inflation. In addition,
borns with hypoxemic respiratory failure poor NO responsiveness may be related to myo-
(Davidson et al. 1998). In this study, patients cardial dysfunction or systemic hypotension,
were randomized to treatment with either 0 (pla- severe pulmonary vascular structural disease,
cebo), 5, 20, or 80 ppm NO. Each inhaled NO and unsuspected or missed anatomic cardiovascu-
dose improved oxygenation compared to placebo, lar lesions (such as total anomalous pulmonary
but there was no difference in responses between venous return, coarctation of the aorta, alveolar
groups. However, at 80 ppm, methemoglobinemia capillary dysplasia, pulmonary interstitial
(blood levels >7%) occurred in 13 of 37 patients glycogenosis, surfactant protein deficiency, and
(35%) and high inspired NO2 concentrations others). Since iNO is usually delivered with high
(>3 ppm) were reported in 7 of 37 patients concentrations of oxygen, there is also the poten-
(19%). Thus, 80 ppm inhaled NO was not more tial for enhanced production of reactive oxygen
effective in improving oxygenation than 5 or and reactive nitrogen metabolites, both of which
20 ppm, but was associated with adverse effects. may contribute to vasoconstriction and/or inade-
Unfortunately, this trial was limited by early ter- quate responses to iNO. While hyperoxic ventila-
mination due to slow enrollment and the exclusion tion is standard therapy for PPHN, high FiO2 may
of lung recruitment approaches to optimize be toxic to the developing lung through formation
inhaled NO efficacy. of ROS (Lakshminrusimha et al. 2006b). As noted
The available evidence, therefore, supports the above, iNO responsiveness may be blunted after
use of doses of inhaled NO beginning at 20 ppm in even brief (30 min) periods of ventilation with
term newborns with PPHN. Although brief expo- 100% O2, and that oxidant stress alters NO
sures to higher doses (40–80 ppm) appear to be responsiveness in part through increasing
60 Persistent Pulmonary Hypertension of the Newborn 945
expression and activity of cGMP-specific decrease over time after more prolonged therapy.
phosphodiesterases (Farrow et al. 2008b; However, inhaled NO withdrawal can be associ-
Lakshminrusimha et al. 2007). ated with life-threatening elevations of pulmonary
After improvement in oxygenation occurs with vascular resistance, profound desaturation, and
the onset of inhaled NO therapy, strategies for systemic hypotension due to decreased cardiac
weaning the inhaled NO dose become important. output. Mechanisms that contribute to these
Numerous approaches have been employed, and “rebound” effects are incompletely understood,
little differences have been noted until final discon- but may be related to downregulation of endoge-
tinuation of inhaled NO treatment. In one study, nous NO production during exogenous NO ther-
inhaled NO was reduced from 20 to 6 ppm after 4 h apy. Alternatively, the rise in pulmonary vascular
of treatment without acute changes in oxygenation resistance and drop in oxygenation after inhaled
(Kinsella et al. 1992b). In another trial, inhaled NO NO withdrawal may simply represent the pres-
was reduced in a stepwise fashion to as low as ence of more severe underlying pulmonary vas-
1 ppm without changes in oxygenation (Davidson cular disease with loss of treatment effect of
et al. 1998). It is important to recognize that inhaled NO. The sudden increase in pulmonary
weaning inhaled NO is a different process than artery pressure after rapid withdrawal of vasodi-
discontinuation of inhaled NO therapy. lator therapy is not unique to inhaled NO and has
In multicenter, clinical trials of inhaled NO been observed in other clinical settings, such as
therapy, the typical duration of inhaled NO treat- prostacyclin withdrawal in adults with primary
ment has been less than 5 days, which parallels the pulmonary hypertension and in postoperative car-
clinical resolution of PPHN. However, individual diac patients.
exceptions occur particularly in cases of pulmo-
nary hypoplasia (Goldman et al. 1996; Peliowski 60.3.3.3 Inhaled NO in the Premature
et al. 1995). If inhaled NO is required for longer Newborn
than 5 days, investigations into other causes of Early reports of iNO therapy in a premature new-
pulmonary hypertension should be considered born with pulmonary hypertension demonstrated
(e.g., alveolar capillary dysplasia), particularly if marked improvement in oxygenation caused by
discontinuation of inhaled NO results in supra- effective treatment of severe pulmonary hyperten-
sytemic elevations of pulmonary artery pressure sion and resolution of extra-pulmonary right-to-left
by echocardiography. In our practice, we discon- shunting (Peliowski et al. 1995), as well as other
tinue inhaled NO if the FiO2 is <0.60 and the preterm infants with severe respiratory failure
PaO2 is >60 without evidence of rebound pulmo- (Meurs et al. 1997). Subsequently, several ran-
nary hypertension or an increase in FiO2 >15% domized, controlled trials (RCTs) have confirmed
after inhaled NO withdrawal. the acute improvement in oxygenation caused by
Early clinical studies reported rapid and some- iNO treatment. However, in contrast to the direct
times dramatic decreases in oxygenation and pulmonary vasodilator effects of iNO, the focus of
increases in PVR after abrupt withdrawal of the most recently published studies has been on
inhaled NO during prolonged therapy. These the potential beneficial effects of prolonged iNO
responses are often mild and transient, and many administration on lung parenchymal and vascular
patients with decreased oxygenation after inhaled development (Abman 2001).
NO withdrawal will respond to brief elevations of In a small, unmasked, randomized trial of iNO
FiO2 and careful observation. In patients with a (20 ppm) and dexamethasone treatment, Subhedar
persistent need for treatment with higher inspired et al. reported no differences in survival, chronic
oxygen concentrations or with increased pulmo- lung disease, or ICH between iNO-treated infants
nary hypertension after inhaled NO withdrawal, and controls (Subhedar et al. 1997). In a random-
restarting inhaled NO treatment will generally ized, masked, multicenter clinical trial of low dose
cause rapid clinical improvement. In general, iNO therapy (5 ppm) in severely ill premature
this so-called “rebound” response appears to newborns with RDS who had marked hypoxemia
946 J. Gien et al.
despite surfactant therapy (a/A O2 ratio <0.10), The largest trials of iNO therapy in premature
iNO acutely improved PaO2, but did not reduce newborns reported to date include the single cen-
the incidence of mortality or BPD (Kinsella et al. ter study of Schreiber et al. (2003) and the multi-
1999). Notably, there was no increase in the inci- center trials of Van Meurs et al. (2005), Ballard
dence or severity of ICH in this trial, and the et al. (2006), and Kinsella et al. (2006) All of these
incidence of the most severe ICH (grade 4) was studies were randomized, controlled, and masked,
19% for the iNO group and 29% for the control but have key differences in patient population,
group. The Franco-Belgium study group reported disease severity, dose and duration of therapy,
the results of an acute iNO response study (2 h and other factors.
oxygenation endpoint); however, the brief dura- Schreiber et al. randomized 207 infants to
tion of therapy and a high rate of crossover before treatment with iNO or placebo. The main finding
the 2-h trial endpoint compromised the interpre- of the trial was a reduction in the incidence of
tation of late outcome measures (The Franco – BPD and death by 24% in the iNO group. These
Belgium Collaborative NO Trial Group 1999). benefits appeared to accrue predominantly from
Hascoet et al. reported the results of an unmasked, the subset of newborns with relatively mild respi-
randomized trial of iNO in 145 premature new- ratory failure (OI <6.94). However, in addition to
borns with hypoxemic respiratory failure apparent pulmonary benefit caused by low-dose
(Hascoet et al. 2005). They found no difference iNO, these authors also reported a 47% decrease
between the iNO and control groups in the pri- in the incidence of severe ICH and periventricular
mary outcome measure (intact survival at 28 days) leukomalacia (PVL). Moreover, in a subsequent
and no differences in adverse events. As noted by report, the same group showed that the early
Finer in an accompanying editorial, interpretation decrease in ICH/PVL associated with iNO treat-
of the findings is limited by a relatively high rate ment manifested in improved neurodeve-
of “open-label” iNO use and the lack of important lopmental outcome on follow-up examinations
outcomes such as death before discharge and BPD of this population (Mestan et al. 2005). In this
incidence at 36 weeks (Finer 2005). However, follow-up study, 138 children (82% of survivors
these investigators also studied the effect of of the RCT) were evaluated for neurodeve-
low-dose iNO on serum markers of oxidative lopmental outcome at 2 years of age. In the
stress and found that iNO treatment apparently group treated with iNO in the newborn period,
reduced signs of oxidative stress in these patients 24% had abnormal outcomes (defined as cerebral
(Hamon et al. 2005). Field et al. described the palsy, blindness, hearing loss, or one score of less
findings of the UK INNOVO trial. In this than 70 on the Bayley Scales of Infant Develop-
unblinded study, 108 premature infants with ment II), in contrast to 46% in the control group.
severe hypoxemic respiratory failure were ran- Van Meurs et al. enrolled 420 newborns
domized to receive or not receive iNO (Field (401–1500 g birthweight) in a multicenter RCT.
et al. 2005). There was no difference between Although the focus of this study was on premature
the iNO and control group in the main outcome newborns and the major outcome measure was
measure (death or severe disability at 1 year BPD, the design of the trial was similar to the
corrected age) and no difference in adverse previous NINOS trial in which term newborns
events. Limitations of the study included an 8% were enrolled and acute changes in oxygenation
crossover to iNO treatment and treatment with determined continued treatment with study gas.
other pulmonary vasodilators in 30% of the con- That is, an acute dose-response study was
trol group. Moreover, Field et al. describe a lack of performed and only patients who showed signifi-
equipoise among investigators demonstrated by cant improvement in PaO2 were continued on
the observation that 75 infants eligible for enroll- study gas. In striking contrast with other studies,
ment were treated with iNO outside of the trial, the average duration of iNO treatment was only
leaving only infants with very severe lung disease 76 h. Overall, they found no difference in the
enrolled in the study (Field 2005). incidence of death/BPD between the iNO and
60 Persistent Pulmonary Hypertension of the Newborn 947
control groups. However, in post hoc analyses, enrolled between 7 and 14 days, suggesting that
infants with birthweight >1000 g showed a reduc- early treatment is important to prevent BPD.
tion in death/BPD following treatment with iNO There were no differences between the iNO and
(50% iNO vs. 69% control). But a worrisome control groups in adverse events, including med-
outcome was suggested in a post hoc analysis of ical or surgical treatment of PDA. There also were
newborns weighing <1000 g. This analysis no differences between the groups in ICH inci-
showed an increased risk of ICH/PVL (43% iNO dence; however, infants were enrolled after the
vs. 33% control). However, as noted in an edito- first week of life. Thus, this trial does not help
rial by Martin and Walsh (2005), baseline ultra- inform the debate about iNO effects on brain
sound examinations were not performed, and it injury in the premature newborn.
cannot be determined whether these very severely In the second trial, 793 premature newborns
ill infants had ICH before iNO was initiated. with birth weights of 500–1250 g and requiring
Indeed, the severity of illness of infants in this mechanical ventilation in the first 48 h of life were
trial of Van Meurs et al. was also markedly differ- randomized to treatment with 5 ppm iNO or pla-
ent from the study of Schreiber et al. In the Van cebo gas and treated for 21 days or until extubated
Meurs trial, the mean oxygenation index (OI) at (Kinsella et al. 1992b). Overall, there was no
enrollment for the iNO group was 23, compared to difference in the incidence of death or BPD
the median OI of 7.3 in the Schreiber study. This between groups; however, iNO therapy reduced
suggests that the degree of illness based upon the the incidence of BPD for infants with birth weight
severity of respiratory failure may be related to >1000 g by 50% ( p = 0.001). Low-dose iNO
iNO safety and efficacy in this population; how- therapy reduced the incidence of PVL
ever, an increased risk of ICH/PVL was not ( p = 0.048), as well as the combined endpoints
observed in a previous trial of iNO in premature of ICH, PVL, and ventriculomegaly for the entire
newborns with severe hypoxemic respiratory fail- study population ( p = 0.032). INO therapy did
ure (OI = 30) Kinsella et al. 1992a. Other differ- not increase the incidence of adverse events,
ences between these two trials may offer insights including mortality, ICH, PVL, pulmonary hem-
into the disparate outcomes, including the dura- orrhage, and PDA treatment in any subgroup. In
tion of iNO treatment (3 days vs. 7 days), addition, this trial did not demonstrate a relation-
birthweight (839 g vs. 992 g), and gestational ship between OI and brain injury risk, in contrast
age (26 weeks vs. 27.4 weeks). Thus, Van Meurs to the findings of Van Meurs et al. Despite radio-
et al. enrolled smaller, more immature infants with graphic evidence of decreased brain injury with
severe respiratory failure who were treated rela- iNO treatment, long-term follow-up of infants
tively briefly with iNO, making direct compari- enrolled in these studies has failed to show
sons between these two trials problematic. improvement in neurologic outcomes with no dif-
The results of the two largest randomized, con- ference in outcomes between the iNO and placebo
trolled, and masked trials of iNO treatment in treated groups (Mestan et al. 2005; Martin and
premature newborns were recently reported. Bal- Walsh 2005; Walsh et al. 2010).
lard et al. randomized 582 premature newborns Interestingly, while neurologic outcomes were
with birth weights of 500–1250 g who required no different between groups, long-term respira-
ventilatory support between 7 and 21 days of age tory outcomes where significantly improved with
(Roberts et al. 1993). Infants were treated with iNO treatment decreasing the use of respiratory
study gas for a minimum of 24 days and had an medications in the first year of life (Hintz et al.
estimated OI of 7. They found that the incidence 2007). Subsequent studies however have failed to
of survival without BPD was increased in the iNO show any short- or long-term respiratory benefit
treatment group (43.9%) compared to controls with iNO treatment in mechanically ventilated
(36.8%) (P = 0.042). A major finding of this preterm infants (Hibbs et al. 2008).
trial was that the benefit of BPD reduction derived The effects of iNO in the premature newborn
almost entirely from the subset of patients may be dependent on the timing, dose, and
948 J. Gien et al.
duration of therapy, and the nature of the under- space disease (pneumonia, pulmonary edema)
lying disease. The available evidence from clini- may decrease the effective delivery of inhaled
cal trials suggests that routine use of iNO for the NO to its site of action in terminal lung units.
prevention and/or treatment of BPD is currently Second, in cases complicated by severe lung dis-
not recommended, other than for management of ease and underinflation, pulmonary hypertension
PPHN in preterm infants, such as in infants born may be exacerbated because of the adverse
preterm after prolonged rupture of membranes mechanical effects of underinflation on pulmo-
(Mercier et al. 2010). While a neuroprotective nary vascular resistance. Third, attention must be
effect of iNO has been demonstrated in large given to minimize overinflation to avoid inadver-
RCTs, long-term studies have failed to show a tent positive end expiratory pressure and gas trap-
difference in outcomes. In addition, the relation- ping that may elevate pulmonary vascular
ship of disease severity and ICH/PVL risk is resistance from vascular compression. This com-
uncertain. monly complicates the management of infants
with asymmetric lung disease or airways obstruc-
tion as observed in meconium aspiration
60.3.4 PPHN: Ventilator Management syndrome.
Treatment of the underlying lung disease is
Perhaps the most misunderstood aspect of severe essential (and sometimes sufficient) to resolve the
hypoxemic respiratory failure and PPHN is venti- accompanying pulmonary hypertension. Airway
latory management of these complex disorders. pressure is poorly transmitted to the pleural space
The patient with idiopathic PPHN (i.e., without in the underinflated and poorly compliant lung, but
significant lung disease) often requires only min- as lung volume and compliance improve, ventilator
imal ventilatory support. Applying inappropri- support must be reduced to avoid injury from the
ately high airway pressure to the normally adverse effects of overinflation on lung paren-
compliant lung can lead to air leak (e.g., pneumo- chyma and cardiac performance. Because of the
thorax) and adverse cardiopulmonary interactions diverse nature of diseases complicating PPHN,
(decreased cardiac output from reduced venous there is no single approach to mechanical ventila-
return and cardiac filling). tion in this syndrome. Ventilator adjustments must
However, in the more common setting of be made with attention to radiographic changes of
severe lung disease with PPHN, lung underinfla- the accompanying lung disease and hemodynamic
tion contributes to increased PVR. Considering status (including intravascular volume, systemic
the important role of parenchymal lung disease perfusion, and cardiac performance) (Gersony
in specific disorders included in the syndrome of 1984). Mechanical ventilation in PPHN should be
PPHN, pharmacologic pulmonary vasodilation initiated with conventional intermittent mandatory
alone should be expected to cause sustained clin- ventilation. Alkalosis induced by mechanical
ical improvement in many cases (Hibbs et al. hyperventilation decreases pulmonary arterial pres-
2008). Moreover, patients not responding to sure and improves oxygenation in some patients
inhaled NO can show marked improvement in with PPHN.
oxygenation with adequate lung inflation alone. The goal of mechanical ventilation in PPHN is
High success rates in early studies were achieved to improve oxygenation and achieve “optimal”
by withholding inhaled NO treatment until lung volume to minimize the adverse effects of
aggressive attempts were made to optimize venti- high or low lung volumes on PVR and the risk for
lation and lung inflation with mechanical ventila- lung injury (“volutrauma”). Mechanical ventila-
tion. These early studies demonstrated that the tion using inappropriate settings can produce
effects of inhaled NO may be suboptimal when acute lung injury (ventilator-induced lung injury;
lung volume is decreased in association with pul- VILI), causing pulmonary edema, decreased lung
monary parenchymal disease, for several reasons compliance, and promoting lung inflammation
(Mercier et al. 2010). First, atelectasis and air due to increased cytokine production and lung
60 Persistent Pulmonary Hypertension of the Newborn 949
neutrophil accumulation. The development of Past studies have shown that acute hyperventi-
VILI is an important determinant of clinical lation can improve PaO2 in neonates with PPHN,
course and eventual outcome of newborns with providing a diagnostic test and potential therapeu-
hypoxemic respiratory failure, and postnatal lung tic strategy. However, there are many issues with
injury worsens the degree of pulmonary hyperten- the use of hypocarbic alkalosis for prolonged
sion (Cole et al. 2011). On the other hand, failure therapy. Depending upon the ventilator strategy
to achieve adequate lung volumes (functional and underlying lung disease, hyperventilation is
residual capacity) contributes to hypoxemia and likely to increase VILI, and the ability to sustain
high PVR in newborns with PPHN. Some new- decreased PVR during prolonged hyperventila-
borns with parenchymal lung disease with PPHN tion is unproven. Experimental studies suggest
physiology improve oxygenation and decrease that the response to alkalosis is transient and that
right-to-left extrapulmonary shunting with alkalosis may paradoxically worsen pulmonary
aggressive lung recruitment during high fre- vascular tone, reactivity, and permeability edema
quency oscillatory ventilation (Davidson et al. (Acute Respiratory Distress Syndrome Network
1998) or with an “open lung approach” of higher 2000; Gordon et al. 1993). In addition, prolonged
positive end-expiratory pressure with low tidal hyperventilation reduces cerebral blood flow and
volumes, as more commonly utilized in older oxygen delivery to the brain, potentially worsen-
patients with ARDS (Kinsella and Abman 2000). ing neuro-developmental outcome. Overall,
In newborns with severe lung disease, HFOV hyperventilation is currently not recommended
is frequently used to optimize lung inflation and for prolonged treatment of PPHN.
minimize lung injury. The combination of HFOV
with iNO often enhances the improvement in
oxygenation in newborns with severe PPHN com- 60.3.5 PPHN: Alternate Therapies
plicated by diffuse parencyhmal lung disease and
underinflation (e.g., RDS, pneumonia). A ran- Additional therapies, including infusions of
domized, multicenter trial of infants with severe sodium bicarbonate, surfactant therapy and the
PPHN demonstrated that treatment with iNO in use of intravenous vasodilators, are also highly
combination with HFOV was successful in many variable between centers. Although surfactant
patients who failed to respond to HFOV or iNO improved oxygenation and reduced ECMO in
alone (Kinsella et al. 1997; Patterson et al. 1988). some lung diseases, such as meconium aspiration
For patients with PPHN complicated by severe and RDS, a multicenter trial showed benefit in
lung disease, response rates for HFOV+iNO were infants with relatively mild disease and failed to
better than HFOV alone or iNO with conventional show a reduction in ECMO utilization in the sub-
ventilation. In contrast, for patients without sig- set of newborns with idiopathic PPHN
nificant parenchymal lung disease, both iNO and (Lakshminrusimha et al. 2006b). The use of intra-
HFOV+iNO were more effective than HFOV venous vasodilator drug therapy, with agents such
alone. This response to combined treatment with as tolazoline, magnesium sulfate, and sodium
HFOV+iNO likely reflects both improvement in nitroprusside is also controversial due to the non-
intrapulmonary shunting in patients with severe selective effects of these agents on the systemic
lung disease and PPHN (using a strategy designed circulation and use of these agents is no longer
to recruit and sustain lung volume, rather than to recommended. Systemic hypotension may
hyperventilate) and augmented NO delivery to its worsen right-to-left shunting, impair oxygen
site of action. Although iNO may be an effective delivery, and worsen gas exchange in patients
treatment for PPHN, it should be considered only with parenchymal lung disease.
as part of an overall clinical strategy that simulta- The pulmonary vasodilator response to iNO is
neously addresses the role of parenchymal lung mediated primarily by the generation of cGMP
disease, cardiac performance, and systemic after activation of soluble guanylate cyclase
hemodynamics. (sGC). This effect is limited by high PDE5
950 J. Gien et al.
activity, which rapidly metabolizes cGMP, and PDE3 inhibitor, has been shown to decrease pul-
decreases the ability of iNO or other agonists to monary artery pressure and resistance and to act
sustain vasodilation (Walsh-Sukys et al. 2000; additively with iNO in animal studies. A recent
Laffey et al. 2000). Recently approved by the report indicates that the addition of intravenous
FDA for the treatment of adult chronic pulmonary milrinone to neonates with severe PPHN and poor
hypertension, sildenafil is a potent and highly iNO responsiveness was associated with improve-
specific PDE5 inhibitor that has been used in ments in oxygenation without compromising
several preclinical studies in animal models. For hemodynamic status (Steinhorn et al. 2007).
instance, in lambs with experimental pulmonary Milrinone is of additional benefit by lowering
hypertension, both enteric and aerosolized silden- systemic afterload in the setting of PPHN new-
afil dilate the pulmonary vasculature and augment borns with poor LV function.
the pulmonary vascular response to iNO (Ziegler Until recently, experience with bosentan, a
et al. 1998; Atz and Wessel 1999). Intravenous dual endothelin-1 receptor antagonist, was lim-
sildenafil was found to be a selective pulmonary ited to a few case reports in the management of
vasodilator with efficacy equivalent to inhaled PPHN. More recently a double-blind, placebo-
nitric oxide in a piglet model of meconium aspi- controlled, prospective study of bosentan for the
ration, although hypotension and worsening oxy- treatment of persistent pulmonary hypertension
genation resulted when sildenafil was used in of the newborn was performed with study end-
combination with iNO (Ichinose et al. 2001; points of oxygenation index <15, normal pulmo-
Weimann et al. 2000). In a recent open-label, nary artery pressure (<20 mm Hg), and no
dose- escalation trial in newborns with PPHN premature discontinuation of the drug because
and an oxygenation index (OI) >15. Sildenafil of drug-related toxicity or lack of efficacy
was delivered by continuous IV infusion to evalu- (Kelly et al. 2002). A favorable response to
ate the effect on OI. While the majority of infants bosentan was seen in 87.5% of patients as com-
were already receiving therapy with iNO, sildenafil pared with 20% of those who received placebo,
use was associated with a significant decrease on and no drug-related clinical or laboratory adverse
OI especially in the groups receiving higher dose events were reported. Use of bosentan is limited
infusion. In a smaller subset of infants, sildenafil by its availability only in an oral formulation, as
administration obviated the need for initiation of well as lack of experience with this agent; how-
iNO (Shekerdemian et al. 2002). In this study, ever, in severe cases of refractory pulmonary
hypotension was the most common adverse effect hypertension, use of this agent could be consid-
noted. The availability of IV sildenafil for clinical ered. Close monitoring of liver function testing is
use provides an alternate option for infants with recommended when therapy is initiated with this
pulmonary hypertension; unresponsive to inhaled agent (McNamara et al. 2006).
NO, however, should be administered with caution
in infants with hemodynamic instability.
Prostacyclin is a potent vasodilator that causes 60.4 Pulmonary Hypertension
pulmonary vasodilation through stimulation of in Congenital Diaphragmatic
adenylate cyclase to increase intracellular cAMP Hernia (CDH)
levels. Although iv prostacyclin may worsen gas
exchange in PPHN patients with lung disease and 60.4.1 Introduction
systemic vasodilation, inhaled PGI2 may enhance
oxygenation in infants that are poorly responsive Congenital diaphragmatic hernia (CDH) is a
to iNO (Shekerdemian et al. 2004). Another severe birth defect characterized by herniation of
potential approach taking advantage of cAMP abdominal contents into the thorax caused by a
signaling is inhibition of phosphodiesterase type defect in the diaphragm (Pierro and Thebaud
3 (PDE3) that metabolizes cAMP. Milrinone, a 2014). Recent insight into pathophysiologic
60 Persistent Pulmonary Hypertension of the Newborn 951
processes responsible for CDH suggests an early 60.4.2 Pulmonary Hypertension
role for environmental and/or genetic factors in CDH
before the development of the diaphragm, leading
to arrested development of both lungs. In addition, The classical histological findings of CDH show
incomplete closure of the diaphragm results in a pulmonary vascular remodeling superimposed on
diaphragm defect, herniation of the abdominal hypoplasia or pruning of the pulmonary vascular
contents into the chest, and compression of the bed (Pierro and Thebaud 2014). These changes in
intrathoracic structures. the pulmonary vasculature are responsible for
Solid organ herniation exacerbates the degree increased vascular tone and altered vasoreactivity
of lung hypoplasia, and the most severe cases are after birth (Pierro and Thebaud 2014). Manage-
associated with hypoplasia of the ipsilateral and ment of PH in the newborn with CDH is compli-
contralateral lung (low lung- to-head ratio [LHR] cated by the structural and functional changes in
(Lipshutz et al. 1997). Along with degree of lung the heart, pulmonary circulation, airways, and
hypoplasia, the severity of pulmonary hyperten- lung parenchyma. Moreover, the role and selec-
sion (PH) and presence of left ventricular tion of pulmonary vasodilator therapies for treat-
(LV) hypoplasia all contribute to the severity of ment of PH change as the underlying
the defect and adverse outcomes (Taira et al. 1998; pathophysiology evolves in the days and weeks
Wynn et al. 2013). Overall survival of infants with after birth. In response, management strategies
CDH has improved in experienced centers, but need to adjust as pulmonary vascular abnormali-
mortality and morbidity remain high. ties progress from the acute to subacute (late) and
Several individual prenatal prognostic factors finally chronic stages.
have been identified in CDH that can predict the
clinical course after birth as well as long-term out-
comes. These include liver position, severity of 60.4.3 Acute Pulmonary Hypertension
lung hypoplasia (as assessed by fetal lung volume in CDH
on MRI: percent predicted lung volume [PPLV]
and total lung volume [TLV]; LHR and observed After birth, infants with CDH typically present
to expected LHR by ultrasound), LV hypoplasia with severe hypoxemic respiratory failure (HRF)
(right ventricle [RV]:left ventricle disproportion on and shock. The etiology of hypoxemia is multi-
fetal echocardiogram [ECHO]), and development factorial and occurs secondary to intrapulmonary
and reactivity of the pulmonary vasculature (e.g., shunt as well as extrapulmonary right-to-left
McGoon Index, in utero hyperoxia test). In addi- shunting across fetal conduits (ductus arteriosus
tion, the presence of congenital heart disease or a [DA] and foramen ovale). Newborns with severe
genetic syndrome (Le et al. 2012) markedly CDH often present with left-to-right shunting at
impacts outcomes. The reliability of each individ- the atrial septum and right-to-left shunting at the
ual parameter to predict survival and long-term ductus arteriosus (Gien and Kinsella 2015). Dif-
outcome is low, and combining multiple parame- ferential shunting across these fetal conduits is
ters improves reliability. The CDH congenital responsible for postductal desaturation and differ-
prognostic index (CDH-CPI) is a useful tool that ences in pre- and postductal arterial blood gas
amalgamates ten prenatal parameters representing parameters (Gien and Kinsella 2015). The direc-
genetic, cardiac, hernia, and lung factors to com- tion of atrial level shunt is determined by the
prehensively capture the range of severity and relative right and left ventricular end diastolic
associated anomalies influencing prognosis pressures. Left-to-right shunting at the atrial sep-
(Le et al. 2012). The CDH-CPI score is correlated tum occurs when left ventricular end diastolic
with survival and extracorporeal membrane oxy- pressure (LVEDP) exceeds right ventricular end
genation (ECMO) support, with significantly lower diastolic pressures (RVEDP) with impaired LV
survival at scores below eight (Le et al. 2012). filling and elevated left atrial pressure (LAP).
952
Fig. 1 Left heart hypoplasia stratified by congenital diaphragmatic hernia (CDH) side ventricular volume) severity of hypoplasia increased with increasing severity of hernia,
and severity at fetal assessment. Left CDH: mild (n = 42), liver down; moderate (n = 41), while the effect in the fetus with right CDH was less pronounced. Adapted with permis-
lung-to-head ratio (LHR) 1-1.4; severe (n = 88), LHR 1; Right CDH: mild (n = 2), LHR sion from Byrne et al. Ultrasound Obstet Gynecol.8 CDH, congenital diaphragmatic
>1; severe (n = 15), LHR 1. For left heart measurements (mitral and aortic values, left hernia; L, left; R, right
J. Gien et al.
60 Persistent Pulmonary Hypertension of the Newborn 953
Structural and functional LV abnormalities are Overall, altered fetal hemodynamics leading to
responsible for impaired LV filling and contribute decreased LV output can occur in both right and
to the development of pulmonary venous hyper- left CDH, but an additional compressive effect on
tension. Baumgart et al. showed that ECMO- the left heart is seen in left-sided CDH (Byrne
treated CDH infants (survivors) had significantly et al. 2015).
smaller LV mass (P < 0.002) than infants requir- Echocardiographic findings may be valuable in
ing ECMO for other diagnoses and healthy term guiding the selective use of pulmonary vasodila-
infants (Baumgart et al. 1998). Moreover, ECMO- tors in management of early PH with CDH. For
treated CDH neonates who died had significantly example, ECHO findings in the presence of severe
smaller LV size than other groups (P < 0.0005) PH may show right-to-left shunting (caused by
including ECMO-treated CDH survivors suprasystemic pulmonary vascular resistance) at
(in addition to CDH and non-CDH ECMO-treated the atrial level and DA. This constellation of
infants and well infants) (Baumgart et al. 1998). echocardiographic findings suggests a favorable
Byrne et al. reported that fetuses with severe left response to pulmonary vasodilation. However, in
CDH were more likely to have smaller mitral the presence of LV dysfunction, right-to-left DA
valve (P < 0.001) and aortic valve sizes shunting is seen along with mitral insufficiency
(P < 0.001), and left ventricular end diastolic with left-to-right atrial shunting at the foramen
volume (P = 0.006) Z-scores than those with ovale (Kinsella and Abman 2000). This constel-
mild left CDH (Fig. 1) (Byrne et al. 2015). In lation of findings is again consistent with supra-
addition to the structural changes in the LV, their systemic right ventricular systolic pressure, but
percentage LV output was also lower. Those with left-to-right atrial shunting suggests the presence
severe left CDH trended towards higher risk of of pulmonary venous hypertension and a poor
neonatal death compared with those with mild left response to pulmonary vasodilator therapy. Dia-
CDH. Although mitral and aortic valve dimen- stolic dysfunction is difficult to assess, but can be
sions in fetuses with right CDH were larger than interpreted from a high LVEDP and manifests as
in left CDH, LV outputs were similarly left-to-right shunt at the atrial level. Pulmonary
diminished. vasodilator therapy in the setting of left-to-right
The etiology of LV hypoplasia in CDH is shunting at the atrial septum has the potential to
almost certainly multifactorial reflecting mechan- exacerbate LA and pulmonary venous hyperten-
ical compression by intra-abdominal contents as sion and contribute to pulmonary hemorrhage. In
well as alteration in LV filling hemodynamics addition, as preductal saturations are maintained
during fetal development due to changes in orien- in this setting, pulmonary vasodilator therapy is
tation of the inferior vena cava and venous return unlikely to improve preductal saturations and may
from the placenta. Left heart under-filling and result in only a modest increase in postductal
subsequent underdevelopment may result from saturations. Reserving iNO therapy for infants
abnormal hemodynamics due to leftward distor- with right-to-left atrial shunting and preductal
tion of the ductus venosus or reduced pulmonary desaturation is recommended early in the clinical
blood flow return to the left heart (Byrne et al. course and has the potential to prevent pulmonary
2015). In addition, after birth, compression of the hemorrhage in CDH. In addition, as right-to- left
LV by the RV in the presence of elevated RV shunting across the DA causes veno-arterial
pressure also impairs LV filling. The common admixture, it is common to see significant differ-
pathway for these mechanisms is decreased filling ences in pre- and postductal arterial blood gases
of the left ventricle. Altered hemodynamics and (ABG) measurements (Gien and Kinsella 2015).
compression of the heart by herniated abdominal Determining the need for ECMO, degree of respi-
viscera together can create strikingly abnormal ratory support and fraction of inspired oxygen
left ventricular structure and function with anom- (Fi02) should be based on measurement of pre-
alous relaxation and small chamber size, even ductal arterial gases in these infants (Gien and
with normal or near-normal systolic performance. Kinsella 2015).
954 J. Gien et al.
Overall, acute treatment of PH in CDH with CDH. Although speculative, the lack of response
pulmonary vasodilators is limited by the severity to pulmonary vasodilators is more likely due to
of LV hypoplasia, degree of impairment of LV left atrial/pulmonary vein hypertension than func-
filling, and LV systolic dysfunction. Because tional changes in the pulmonary arterial
infants with severe CDH and acute PH are poor vasculature.
responders, iNO should not be routinely adminis-
tered in this setting. However, careful ECHO
assessment can help identify limited clinical situ- 60.4.4 Subacute (Late) Pulmonary
ations that may benefit from PH therapies, includ- Hypertension in CDH
ing iNO, and guide the course of treatment
(Kinsella and Abman 2000; Kinsella et al. In addition to complicating the early course of
2005). In the acute management of CDH, iNO neonates with CDH, severe PH can be protracted
may have a selective role in stabilization for – persisting weeks to months after improvement
ECMO and treatment of marked preductal in respiratory failure and cardiac performance –
desaturation secondary to right-to-left atrial level leading to prolonged mechanical ventilation
shunt. Furthermore, the use of iNO for treatment (Kinsella and Abman 2000). In a multicenter pro-
of PH may be considered as LV performance spective ECHO study of neonates with CDH
improves. LV hypoplasia, and related LV output, (N = 220), mortality at discharge in newborns
also plays a role in the poor response to pulmo- with severe PH (right ventricular systolic pressure
nary vasodilators as diminished LV performance [RVSP]/systolic blood pressure [SBP] >2/3) was
results in RV-dependent systemic circulation 56.1% compared with 1.4% in infants with mild
(Kinsella and Abman 2000). Initiating pulmonary PH (RVSP/SBP <1/2) and 7.4% in those with
vasodilator therapy in the presence of an moderate PH (RVSP/SBP 1/2–2/3) (Wynn et al.
RV-dependent systemic circulation may adversely 2013). Recently, Lusk et al. reviewed ECHO
affect systemic hemodynamics. results for 140 newborns with CDH and found
The Neonatal Inhaled Nitric Oxide Study that although the majority of infants had resolu-
(NINOS) Group conducted the largest trial of tion of PH between 1 and 3 weeks of age, at
iNO in infants with CDH (N = 53) who were 2 weeks the severity of PH by echocardiogram
randomized to 20 ppm iNO or 100% oxygen predicted mortality and need for prolonged venti-
(control) (The Neonatal Inhaled Nitric Oxide lation (Lusk et al. 2015).
Study Group (NINOS) 1997). The oxygenation Treatment strategies for infants with late PH
index (OI) was approximately 45 in both have not been carefully studied. Inhaled NO is
groups indicating more severe disease. NINOS usually the first line therapy for treatment of PH
showed no difference in the combined endpoint in CDH. In a subset of newborns with CDH,
“death/ECMO utilization” between iNO-treated improvement in parenchymal lung disease may
patients and controls. However, ECMO utiliza- allow for the use of non invasive iNO by contin-
tion was higher in the iNO-treated group (80% uous positive airway pressure (CPAP) or nasal
vs. 54% control, P = 0.043) pointing to an cannula (Kinsella et al. 2003). There is limited
adverse effect of iNO early in the course of experience with other pharmacologic pulmonary
CDH. These results lend support to the hypoth- vasodilators (e.g., prostacyclin, endothelin antag-
esis that LV systolic and diastolic dysfunction onists, and phosphodiesterase inhibitors) in
contribute to morbidity in severe CDH and limit infants with CDH and late PH. Olson et al.
the efficacy of aggressive pharmacologic pul- recently described two infants with CDH and
monary vasodilator therapy early in the course severe PH at 6 weeks of age who responded
of CDH and severe PH. favorably to treatment with trepostinil (Olson
Indeed, a poor response to pulmonary vasodi- et al. 2015). Clearly, further investigation is
lation is not unexpected given the structural and needed to define an approach to the management
functional abnormalities that characterize acute of late PH in this population.
60 Persistent Pulmonary Hypertension of the Newborn 955
60.4.5 Chronic Pulmonary abnormal responses to injury that last far beyond
Hypertension in CDH the newborn period (Kinsella and Abman 2000).
Chronic PH may persist in CDH over months and
years, and enduring structural and functional 60.4.6 Improving Outcomes in CDH
abnormalities of pulmonary circulation in the ipsi-
lateral and contralateral lung can complicate the Treatment strategies for CDH continue to evolve
course of the disease. Cardiac catheterization of with increasing clinical experience and greater
seven patients with CDH who survived the neo- insight into the underlying nature of the condition.
natal period with protracted or recurrent PH These strategies include simultaneous postductal
revealed a range of pulmonary vascular abnormal- and preductal samples to measure blood gases
ities (Kinsella et al. 2005). These patients (age (adjusting ventilator support accordingly)
range, 3 months–12 years) had a history of severe (Table 1). Early ECHO is essential to define pul-
hypoxemic respiratory failure and PH as new- monary artery pressure (PAP) and assess LV size
borns. At catheterization, therapies included sup-
plemental oxygen (n = 7), iNO (n = 2), Table 1 Current approach to optimize management of
prostacyclin (n = 2), and bosentan (n = 1). CDH and related PH at Children’s Hospital Colorado
Three of the seven patients had significant pulmo- Adequate access with preductal arterial line, four central
nary vascular abnormalities in the lung contralat- venous ports
eral to the initial diaphragmatic defect. Major Importance of preductal ABG monitoring with R-L PDA
findings at cardiac catheterization included left Postductal ABG: 7.30/56/45
pulmonary artery hypoplasia or stenosis in three Preductal ABG: 7.35/44/136
patients and pulmonary vein stenosis or delayed Early ECHO
venous return in six patients. Two patients with Definition of PA pressure
right-sided diaphragmatic defect had striking left- Assessment of LV size and function
LV performance
sided pulmonary venous abnormalities. One
Atrial shunt
patient with right-sided CDH was discharged
Delayed iNO until ECHO evidence of adequate LV
home, but died at age 5 months with marked performance
pulmonary vascular changes on autopsy consis- Minimize volutrauma with low TV/PIP; early use of
tent with severe PH. After a median follow-up of HFOV
12 months from catheterization, five patients were LV afterload reduction with milrinone, consider
alive and discharged from hospital. The two maintenance of ductal patency with PGE1
patients with the most severe PH died from related Treat adrenal insufficiency
complications at ages 8 and 19 months. Avoid surfactant treatment
In some patients with CDH, significant PH, Delayed repair of defect
Achieve hemodynamic stability and decreased PVR
which may be subclinical, clearly continues
Consider NICU repair
beyond the neonatal period, contributing to mor-
Avoid interruption of ventilatory strategy
bidity and mortality. Understanding the patho-
ECMO if indicated
physiology underlying these long-term effects
Cardiac performance
will require a more sophisticated view of CDH Preductal desaturation with worsening acidemia
than that originating solely from in utero cardio- Nasal cannula NO postextubation for persistent PH
pulmonary compression. It is possible that the ABG arterial blood gas, ECHO echocardiogram, ECMO
injury associated with management of hypoxemic extracorporeal membrane oxygenation, HFOV high fre-
respiratory failure in newborns with CDH may quency oscillatory ventilation, iNO inhaled nitric oxide,
cause previously unrecognized long-term effects LV left ventricle, NICU neonatal intensive care unit, NO
nitric oxide, PA pulmonary artery, PGE1 prostaglandin E1,
in susceptible individuals, and/or the pulmonary PDA patent ductus arteriosus, PH pulmonary hypertension,
circulation in patients with severe CDH may be PVR pulmonary vascular resistance, TV/PIP tidal volume/
fundamentally altered in utero, leading to peak inspiratory pressure
956 J. Gien et al.
and function. It is reasonable to delay the use of limited by structural and functional changes of the
pulmonary vasodilator therapy until there is left ventricle. In a significant subset of newborns
ECHO evidence of adequate LV performance. with severe CDH, late or protracted PH occurs
Reducing LV afterload pharmacologically may and may persist weeks to months following
play an important role (e.g., milrinone), as well improvement in respiratory failure and cardiac
as maintaining ductal patency with prostaglandin performance. In contrast to early CDH, pulmo-
E1 (PGE1) if RV-dependent systemic circulation nary vasodilator therapy plays a critical role in
is demonstrated by ECHO. Adrenal insufficiency management of late PH in CDH and potentially
also complicates the course of newborns with improves survival.
severe CDH and decreases catecholamine drug Despite progress in CDH management,
responsiveness (Kamath et al. 2010). advances have been limited by the lack of ran-
Despite refinement of postnatal interventions, domized controlled trials to properly test new
limitations persist and treatment of CDH and pul- treatments. Major differences in clinical practice
monary hypertension remain suboptimal. Conse- regarding the ascertainment and treatment of PH
quently, new therapeutic options such as prenatal make it difficult to determine the most effective
intervention or cell-based therapy are the subject strategies to manage late PH in CDH infants.
of current investigation. The effects of LV dys- Moreover, institutional practices that lead to
function/hypoplasia on the neonatal course in “improved” outcomes are slowly adopted and
severe CDH provides a compelling reason to local changes are often guided only by experience
study fetal intervention. The efficacy of prenatal and conviction. To overcome these barriers, cen-
intervention with percutaneous fetoscopic endo- ters with the best outcomes for isolated CDH
luminal tracheal occlusion (FETO) therapy in should be identified from current databases and
CDH has been described in case series and con- their practices disseminated to the wider commu-
trolled studies (Jani et al. 2011; Ruano et al. nity. Improving outcomes in patients with CDH
2012). The potential role of FETO is being inves- will require continued vigilance, multidisciplinary
tigated in CDH in a European and North Ameri- collaboration, and widespread adoption of best
can collaboration called the Tracheal Occlusion practices.
To Accelerate Lung Growth (TOTAL) Trial
(Ruano et al. 2012).
Mesenchymal stem cells (MSCs) also repre-
References
sent an emerging therapeutic approach in CDH.
Several experimental studies in animal models Abman SH (2001) Bronchopulmonary dysplasia: a “vas-
have shown that treatment with MSCs can reduce cular hypothesis”. Am J Respir Crit Care Med
pulmonary injury and PH (Aslam et al. 2009; 164:1755–1756
Abman SH, Accurso FJ (1989) Acute effects of partial
Hoffman et al. 2011). A recent study in a rat
compression of ductus arteriosus on fetal pulmonary
model of experimental CDH found that MSC circulation. Am J Physiol Heart Circ Physiol 26:
transplantation promotes alveolar and pulmonary H626–H634
artery development, reducing the severity of pul- Abman SH, Kinsella JP (1995) Inhaled nitric oxide for
persistent pulmonary hypertension of the newborn:
monary hypoplasia (Yuniartha et al. 2014).
the physiology matters. Pediatrics 96:1153–1155
Abman SH, Chatfield BA, Hall SL, McMurtry IF (1990)
Role of endothelium-derived relaxing factor activity
during transition of pulmonary circulation at birth.
60.5 Conclusion Am J Physiol (Heart Circ Physiol 28) 259:
H1921–H1927
In summary, the early course of CDH is charac- Abman SH, Griebel JL, Parker DK et al (1994) Acute
effects of inhaled nitric oxide in severe hypoxemic
terized by severe PH, and cardiac, lung parenchy-
respiratory failure in pediatrics. J Pediatr 124:881–888
mal, and airway abnormalities. Acute treatment of Acute Respiratory Distress Syndrome Network (2000)
PH in CDH with pulmonary vasodilator therapy is Ventilation with lower tidal volumes as compared
60 Persistent Pulmonary Hypertension of the Newborn 957
with traditional tidal volumes for acute lung injury and activator, causes potent and sustained pulmonary vaso-
the ARDS. N Engl J Med 342:1301–1308 dilation in the ovine fetus. Am J Physiol 297:L318
Adel Mohamed MD, Nehad Nasef MD, Vibhuti Shah MD, Clark RH, Kueser TJ, Walker MW et al (2000) Low-dose
Patrick J, McNamara MD (2014) Vasopressin as a nitric oxide therapy for persistent pulmonary hyperten-
rescue therapy for refractory pulmonary hypertension sion of the newborn. Clinical inhaled nitric oxide
in neonates: case series. Pediatr Crit Care Med research group. N Engl J Med 342:469–474
15:148–154 Cole FS, Alleyne C, Barks JD, Boyle RJ, Carroll JL,
Agrawal A, Singh VK, Varma A, Sharma R (2012) Ther- Dokken D, Edwards WH, Georgieff M, Gregory K,
apeutic applications of vasopressin in pediatric Johnston MV, Kramer M, Mitchell C, Neu J, Pursley
patients. Indian Pediatr 49:297–305 DM, Robinson WM, Rowitch DH (2011) NIH consen-
Alano MA, Ngougmna E, Ostrea EM Jr, Konduri GG (2001) sus development conference statement: inhaled nitric-
Analysis of nonsteroidal antiinflammatory drugs in meco- oxide therapy for premature infants. Pediatrics 127
nium and its relation to persistent pulmonary hyperten- (2):363–369
sion of the newborn. Pediatrics 107(3):519–523 Cornfield DN, Chatfield BA, McQueston JA, McMurtry
Antunes MJ, Greenspan JS, Holt WJ, Vallieu DS, Spitzer IF, Abman SH (1992) Effects of birth related stimuli on
AR (1994) Assessment of lung function pre-nitric L-arginine-dependent vasodilation in the ovine fetus.
oxide therapy: a predictor of response? Pediatr Res Am J Physiol (Heart Circ Physiol 31) 262:
35:212A H1474–H1481
Aslam M, Baveja R, Liang OD, Fernandez-Gonzalez A, Cornfield DN, Maynard RC, deRegnier RO, Guaing SF,
Lee C, Mitsialis SA et al (2009) Bone marrow stromal Barbato JE, Milla CE (1999) Randomized, controlled
cells attenuate lung injury in a murine model of neona- trial of low-dose inhaled nitric oxide in the treatment of
tal chronic lung disease. Am J Respir Crit Care Med term and near-term infants with respiratory failure and
180:1122–1130 pulmonary hypertension. Pediatrics 104:1089–1094
Atz AM, Wessel DL (1999) Sildenafil ameliorates effects Cotton EK (1965) The use of priscoline in the treatment of
of inhaled nitric oxide withdrawal. Anesthesiology the hypoperfusion syndrome. Pediatrics 36:149
91:307–310 Davidson D, Barefield ES, Kattwinkel J et al (1998)
Balasubramaniam V, Le Cras TD, Ivy DD, Kinsella J, Inhaled nitric oxide for the early treatment of persistent
Grover TR, Abman SH (2003) Role of platelet-derived pulmonary hypertension of the term newborn: a ran-
growth factor in the pathogenesis of perinatal pulmo- domized, double-masked, placebo-controlled, dose –
nary hypertension. Am J Phys Lung Cell Mol Phys response, multicenter study. Pediatrics 101:325–334
284:L826–L833 Deprest J, De CP (2012) Antenatal management of isolated
Ballard RA, Truog WE, Cnaan A et al (2006) Inhaled nitric congenital diaphragmatic hernia today and tomorrow:
oxide in preterm infants undergoing mechanical venti- ongoing collaborative research and development. Jour-
lation. N Engl J Med 205:343–353 nal of pediatric surgery lecture. J Pediatr Surg
Baumgart S, Paul JJ, Huhta JC, Katz AL, Paul KE, Spettell 47:282–290
C et al (1998) Cardiac malposition, redistribution of Evora PR, Pearson PJ, Schaff HV (1993) Arginine vaso-
fetal cardiac output, and left heart hypoplasia reduce pressin induces endothelium-dependent vasodilation of
survival in neonates with congenital diaphragmatic the pulmonary artery. V1-receptor-mediated produc-
hernia requiring extracorporeal membrane oxygena- tion of nitric oxide. Chest 103:1241–1245
tion. J Pediatr 133:5762 Faraci F, Didion S (2004) Vascular protection: Superoxide
Behrman RE (1976) Persistence of the fetal circulation. dismutase isoforms in the vessel wall. Arterioscler
J Pediatr 89:636–637 Thromb Vasc Biol 24:1367–1373
Brennan LA, Steinhorn RH, Wedgwood S, Mata- Farrow KN, Lakshminrusimha S, Reda WJ, Wedgwood S,
Greenwood E, Roark EA, Russell JA, Black SM Czech L, Gugino SF, Davis JM, Russell JA, Steinhorn
(2003) Increased superoxide generation is associated RH (2008a) Superoxide dismutase restores eNOS
with pulmonary hypertension in fetal lambs. A role for expression and function in resistance pulmonary arter-
NADPH oxidase. Circ Res 92:683–691 ies from neonatal lambs with persistent pulmonary
Byrne FA, Keller RL, Meadows J, Miniati D, Brook MM, hypertension. Am J Phys Lung Cell Mol Phys 295(6):
Silverman NH et al (2015) Severe left diaphragmatic L979–L987
hernia limits size of fetal left heart more than right Farrow KN, Groh BS, Schumacker PT,
diaphragmatic hernia. Ultrasound Obstet Gynecol Lakshminrusimha S, Czech L, Gugino SF, Russell JA,
46(6):688–94 Steinhorn RH (2008b) Hyperoxia increases phospho-
Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler diesterase 5 expression and activity in ovine fetal pul-
MM, Louik C, Jones KL, Mitchell AA (2006) Selective monary artery smooth muscle cells. Circ Res 102
serotonin-reuptake inhibitors and risk of persistent pul- (2):226–233
monary hypertension of the newborn. N Engl J Med Field DJ (2005) Nitric oxide-still no consensus. Early Hum
354(6):579–587 Dev 81:1–4
Chester M, Tourneux P, Seedorf G, Grover TR, Abman SH Field D, Elbourne D, Truesdale A et al (2005) Neonatal
(2009) Cinaciguat, a soluble guanylate cyclase ventilation with inhaled nitric oxide versus ventilatory
958 J. Gien et al.
support without inhaled nitric oxide for preterm infants Goldman AP, Tasker RC, Haworth SG, Sigston PE,
with severe respiratory failure: the INNOVO multi- Macrae DJ (1996) Four patterns of response to inhaled
centre randomized controlled trial. Pediatrics nitric oxide for persistent pulmonary hypertension of
115:926–936 the newborn. Pediatrics 98:706–713
Fike CD, Slaughter JC, Kaplowitz MR, Zhang Y, Aschner Gordon JB, Martinez FR, Keller PA, Tod ML, Madden JA
JL (2008) Reactive oxygen species from NADPH oxi- (1993) Differing effects of actue and prolonged alkalo-
dase contribute to altered pulmonary vascular sis on hypoxic pulmonary vasoconstriction. Am Rev
responses in piglets with chronic hypoxia-induced pul- Respir Dis 148:1651–1656
monary hypertension. Am J Phys Lung Cell Mol Phys Grover TR, Parker TA, Zenge JP, Markham NE, Abman
295(5):L881–L888 SH (2003) Intrauterine pulmonary hypertension
Filippi L, Gozzini E, Daniotti M, Pagliai F, Catarzi S, decreases lung VEGF expression and VEGF inhibition
Fiorini P (2011) Rescue treatment with terlipressin in causes pulmonary hypertension in the ovine fetus. Am J
different scenarios of refractory hypotension in new- Phys 284:L508–L517
borns and infants. Pediatr Crit Care Med 12:e237–e241 Grover TR, Parker TA, Hunt-Peacock C, Markham NE,
Finer NN (2005) Inhaled nitric oxide for preterm infants: A Abman SH (2005) rhVEGF treatment improves pulmo-
therapy in search of an indication? The search con- nary vasoreactivity and structure in an experimental
tinues. J Pediatr 146:301–302 model of pulmonary hypertension in fetal sheep. Am
Finer NN, Etches PC, Kamstra B et al (1994) Inhaled nitric J Physiol LCMP 289:L529–L535
oxide in infants referred for extracorporeal membrane Hamon I, Fresson J, Nicolas MB et al (2005) Early inhaled
oxygenation: dose response. J Pediatr 124:302–308 nitric oxide improves oxidative balance in very preterm
Finer NN, Sun JW, Rich W, Knodel E, Barrington KJ infants. Pediatr Res 57:637–643
(2001) Randomized, prospective study of low-dose Hanson KA, Abman SH, Clarke WR (1996) Elevation of
versus high-dose inhaled nitric oxide in the neonate pulmonary PDE5-specific activity in an experimental
with hypoxic respiratory failure. Pediatrics fetal ovine perinatal pulmonary hypertension model.
108:949–955 Pediatr Res 39:334A
Fornaro E, Li D, Pan J, Belik J (2007) Prenatal exposure to Harrison MR, de Lorimier AA (1981) Congenital dia-
fluoxetine induces fetal pulmonary hypertension in the phragmatic hernia. Surg Clin North Am 61:1023–1035
rat. Am J Respir Crit Care Med 176(10):1035–1040 Hascoet JM, Fresson J, Claris O et al (2005) The safety and
Fox WW, Gewitz MH, Dinwiddie R, Drummond WH, efficacy of nitric oxide therapy in premature infants.
Peckham GJ (1977) Pulmonary hypertension in the J Pediatr 146:318–323
perinatal aspiration syndromes. Pediatrics 59:205–211 Haworth SG, Reid L (1976) Persistent fetal circulation:
Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM newly recognized structural features. J Pediatr
(1991) A selective pulmonary vasodilator reversing 88:614–620
hypoxic pulmonary vasoconstriction. Circulation Hibbs AM, Walsh MC, Martin RJ, Truog WE, Lorch SA,
83:2038–2047 Alessandrini E, Cnaan A, Palermo L, Wadlinger SR,
Furchgott RF, Zawadzki JV (1980) The obligatory role of Coburn CE, Ballard PL, Ballard RA (2008) One-year
endothelial cells in the relaxation of arterial smooth respiratory outcomes of preterm infants enrolled in the
muscle by acetylcholine. Nature 288:373–376 nitric oxide (to prevent) chronic lung disease trial.
Geggel RL, Reid LM (1984) The structural basis of PPHN. J Pediatr 153(4):525–529
Clin Perinatol 11:525–549 Higenbottam T, Pepke-Zaba J, Scott J, Woolman P,
Gerlach H, Rossaint R, Pappert D, Falke KJ (1993) Time- Coutts C, Wallwork J (1988) Inhaled “endothelium-
course and dose-response of nitric oxide inhalation for derived relaxing factor” (EDRF) in primary hyperten-
systemic oxygenation and pulmonary hypertension in sion (PPH). Am Rev Respir Dis 137:107S
patients with adult respiratory distress syndrome. Eur J Hintz SR, Van Meurs KP, Perritt R, Poole WK, Das A,
Clin Invest 23:499–502 Stevenson DK, Ehrenkranz RA, Lemons JA, Vohr BR,
Gersony WM (1984) Neonatal pulmonary hypertension: Heyne R, Childers DO, Peralta-Carcelen M,
pathophysiology, classification and etiology. Clin Peri- Dusick A, Johnson YR, Morris B, Dillard R,
natol 11:517–524 Vaucher Y, Steichen J, Adams-Chapman I,
Gersony WM, Duc GV, Sinclair JC (1969) “PFC” syn- Konduri G, Myers GJ, de Ungria M, Tyson JE,
drome (persistence of the fetal circulation). Circulation Higgins RD, NICHD Neonatal Research Network
40:111 (2007) Neurodevelopmental outcomes of premature
Gien J, Kinsella JP (2015) Differences in preductal and infants with severe respiratory failure enrolled in a
postductal arterial blood gas measurements in infants randomized controlled trial of inhaled nitric oxide. J
with severe congenital diaphragmatic hernia. Arch Dis Pediatr 151(1):16–22
Child Fetal Neonatal Ed 101:F314 Hoffman AM, Paxson JA, Mazan MR, Davis AM, Tyagi S,
Goetzman BW, Sunshine P, Johnson JD, Wennberg RP, Murthy S et al (2011) Lung-derived mesenchymal stro-
Hackel A, Merten DF et al (1976) Neonatal hypoxia mal cell post-transplantation survival, persistence,
and pulmonary vasospasm: response to tolazoline. paracrine expression, and repair of elastase-injured
J Pediatr 89:617–621 lung. Stem Cells Dev 20:1779–1792
60 Persistent Pulmonary Hypertension of the Newborn 959
Ichinose F, Erana-Garcia J, Hromi J, Raveh Y, Jones R, respiratory failure: a randomised controlled trial. Lan-
Krim L, Clark MWH, Winkler JD, Bloch KD, Zapol cet 354:1061–1065
WM (2001) Nebulized sildenafil is a selective pulmo- Kinsella JP, Parker TA, Ivy DD, Abman SH (2003) Non-
nary vasodilator in lambs with acute pulmonary hyper- invasive delivery of inhaled nitric oxide therapy for late
tension. Crit Care Med 29:1000–1005 pulmonary hypertension in newborn infants with con-
Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G genital diaphragmatic hernia. J Pediatr 142:397–401
(1987) Endothelium-derived relaxing factor produced Kinsella JP, Ivy DD, Abman SH (2005) Pulmonary vaso-
and released from artery and vein is nitric oxide. Proc dilator therapy in congenital diaphragmatic hernia:
Natl Acad Sci U S A 84:9265–9269 acute, late, and chronic pulmonary hypertension.
Ivy DD, Ziegler JW, Dubus MF, Fox JJ, Kinsella JP, Semin Perinatol 29:123–128
Abman SH (1996) Chronic intrauterine pulmonary Kinsella JP, Cutter GR, Walsh WF et al (2006) Early
hypertension alters endothelin receptor activity in the inhaled nitric oxide therapy in premature newborns
ovine fetal lung. Pediatr Res 39:435–442 with respiratory failure. N Engl J Med 205:354–364
Ivy DD, Parker TA, Ziegler JW, Galan HL, Kinsella JP, Konduri GG, Ou J, Shi Y, Pritchard KA Jr (2003)
Tuder RM, Abman SH (1997) Prolonged endothelin A Decreased association of HSP90 impairs endothelial
receptor blockade attenuates pulmonary hypertension nitric oxide synthase in fetal lambs with persistent
in the ovine fetus. J Clin Invest 99:1179–1186 pulmonary hypertension. Am J Physiol Heart Circ
Ivy DD, Le Cras TD, Horan MP, Abman SH (1998) Physiol 285(1):H204–H211
Increased lung preproET-1 and decreased Konduri GG, Solimani A, Sokol GM, Singer J, Ehrenkranz
ETB-receptor gene expression in fetal pulmonary RA, Singhal N, Wright LL, Van Meurs K, Stork E,
hypertension. Am J Phys 274(4 Pt 1):L535–L541 Kirpalani H, Peliowski A, Group NINOS (2004) A
Jani J, Valencia C, Cannie M, Vuckovic A, Sellars M, randomized trial of early versus standard inhaled nitric
Nicolaides KH (2011) Tracheal diameter at birth in oxide therapy in term and near-term newborn infants
severe congenital diaphragmatic hernia treated by with hypoxic respiratory failure. Pediatrics 113:
fetal endoscopic tracheal occlusion. Prenat Diagn 559–564
31:699–704 Konduri GG, Bakhutashvili I, Eis A, Pritchard KA (2007)
Kamath BD, Fashaw L, Kinsella JP (2010) Adrenal insuf- Oxidant stress from uncoupled nitric oxide synthase
ficiency in newborns with congenital diaphragmatic impairs vasodilation in fetal lambs with persistent pul-
hernia. J Pediatr 156:495–497 monary hypertension. Am J Physiol Heart Circ Physiol
Kelly LK, Porta NF, Goodman DM, Carroll CL, Steinhorn 292:H1812–H1820
RH (2002) Inhaled prostacyclin for term infants with Korones SB, Eyal FB (1975) Succesful treatment of “per-
persistent pulmonary hypertension refractory to inhaled sistent fetal circulation” with tolazoline. Pediatr Res
nitric oxide. J Pediatr 141:830–832 9:367
Kinsella JP, Abman SH (1995) Recent developments in the Laffey JG, Engelberts D, Kavanaugh BP (2000) Inurious
pathophysiology and treatment of persistent pulmonary effects of hypocapnic alkalosis in the isolated lung. Am
hypertension of the newborn. J Pediatr 126:853–864 J Respir Crit Care Med 162:399–405
Kinsella JP, Abman SH (2000) Clinical approach to Lakshminrusimha S, Russell JA, Wedgwood S, Gugino SF,
inhaled nitric oxide therapy in the newborn with hyp- Kazzaz JA, Davis JM, Steinhorn RH (2006a) Superox-
oxemia. J Pediatr 136:717–726 ide dismutase improves oxygenation and reduces oxi-
Kinsella JP, McQueston JA, Rosenberg AA, Abman SH dation in neonatal pulmonary hypertension. Am J
(1992a) Hemodynamic effects of exogenous nitric Respir Crit Care Med 174(12):1370–1377. Epub 2006
oxide in ovine transitional pulmonary circulation. Am Sep 1328
J Phys 262:H875–H880 Lakshminrusimha S, Russell JA, Steinhorn RH, Ryan RM,
Kinsella JP, Neish SR, Shaffer E, Abman SH (1992b) Gugino SF, Morin FC 3rd, Swartz DD, Kumar VH
Low-dose inhalational nitric oxide in persistent pulmo- (2006b) Pulmonary arterial contractility in neonatal
nary hypertension of the newborn. Lancet lambs increases with 100% oxygen resuscitation.
340:819–820 Pediatr Res 59(1):137–141. Epub 2005 Dec 2002
Kinsella JP, Neish SR, Ivy DD, Shaffer E, Abman SH Lakshminrusimha S, Russell JA, Steinhorn RH, Swartz DD,
(1993) Clinical responses to prolonged treatment of Ryan RM, Gugino SF, Wynn KA, Kumar VH,
persistent pulmonary hypertension of the newborn Mathew B, Kirmani K, Morin FC 3rd (2007) Pulmonary
with low doses of inhaled nitric oxide. J Pediatr hemodynamics in neonatal lambs resuscitated with 21%,
123:103–108 50%, and 100% oxygen. Pediatr Res 62:313–318
Kinsella JP, Truog WE, Walsh WF et al (1997) Random- Le LD, Keswani SG, Biesiada J, Lim FY, Kingma PS,
ized, multicenter trial of inhaled nitric oxide and high Haberman BE et al (2012) The congenital diaphrag-
frequency oscillatory ventilation in severe persistent matic hernia composite prognostic index correlates
pulmonary hypertension of the newborn. J Pediatr with survival in left-sided congenital diaphragmatic
131:55–62 hernia. J Pediatr Surg 47:57–62
Kinsella JP, Walsh WF, Bose CL et al (1999) Inhaled nitric Lees MH (1970) Cyanosis of the newborn. J Pediatr
oxide in premature neonates with severe hypoxaemic 77:484–498
960 J. Gien et al.
Levin DL, Heymann MA, Kitterman JA, Gregory GA, Murphy J, Aronovitz M, Reid L (1986) Effects of chronic
Phibbs RH, Rudolph AM (1976) Persistent pulmonary in utero hypoxia on the pulmonary vasculature of the
hypertension of the newborn infant. J Pediatr newborn guinea pig. Pediatr Res 20:292–295
89:626–630 Neonatal Inhaled Nitric Oxide Study Group (1997) Inhaled
Levin DL, Hyman AI, Heymann MA, Rudolph AM (1978) nitric oxide in full-term and nearly full-term infants
Fetal hypertension and the development of increased with hypoxic respiratory failure. N Engl J Med
pulmonary vascular smooth muscle: a possible mecha- 336:597–604
nism for persistent pulmonary hypertension of the new- Olson E, Lusk LA, Fineman JR, Robertson L, Keller RL
born infant. J Pediatr 92:265–269 (2015) Short-term treprostinil use in infants with con-
Lipshutz GS, Albanese CT, Feldstein VA, Jennings RW, genital diaphragmatic hernia following repair. J Pediatr
Housley HT, Beech R et al (1997) Prospective analysis 167:762–764
of lung-to-head ratio predicts survival for patients with Palmer RMJ, Ferrige AG, Moncada S (1987) Nitric
prenatally diagnosed congenital diaphragmatic hernia. oxide release accounts for the biological activity of
J Pediatr Surg 32:1634–1636 endothelium-derived relaxing factor. Nature 327:
Luccini B, Bimonetti GD, Ceschi A, Lava SA, Fare PB, 524–526
Bianchetti MG (2013) Severe signs of hyponatremia Parker TA, Ivy DD, Kinsella JP, Torielli F, Ruyle SZ, Thilo
secondary to desmopressin treatment for enuresis: a EH, Abman SH (1997) Combined therapy with inhaled
systematic review. J Pediatr Urol 9:1049–1053 nitric oxide and intravenous prostacyclin in an infant
Lusk LA, Wai KC, Moon-Grady AJ, Steurer MA, Keller with alveolar-capillary dysplasia. Am J Respir Crit
RL (2015) Persistence of pulmonary hypertension by Care Med 155:743–746
echocardiography predicts short-term outcomes in Patterson K, Kapur SP, Chandra RS (1988) PPHN: pulmo-
congenital diaphragmatic hernia. J Pediatr 166: nary pathologic effects. In: Rosenberg HS, Berstein J
251–256 (eds) Cardiovascular diseases, perspectives in pediatric
Martin RJ, Walsh MC (2005) Inhaled nitric oxide for pathology, vol 12. Karger, Basel, pp 139–154
preterm infants – who benefits? N Engl J Med Pearson DL, Dawling S, Walsh WF, Haines JL, Christman
353:82–84 BW, Bazyk A, Scott N, Summar ML (2001) Neonatal
McNamara PJ, Laique F, Muang-In S, Whyte HE (2006) pulmonary hypertension-urea-cycle intermediates,
Milrinone improves oxygenation in neonates with nitric oxide production, and carbamoyl-phosphate syn-
severe persistent pulmonary hypertension of the new- thetase function. N Engl J Med 344(24):1832–1838
born. J Crit Care 21(2):217–222 Peliowski A, Finer NN, Etches PC, Tierney AJ, Ryan CA
McQueston JA, Cornfield DN, McMurtry IF, Abman SH (1995) Inhaled nitric oxide for premature infants after
(1993) Effects of oxygen and exogenous L-arginine on prolonged rupture of the membranes. J Pediatr
EDRF activity in fetal pulmonary circulation. Am J 126:450–453
Physiol Heart Circ Physiol 264:865–871 Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D,
McQueston JA, Kinsella JP, Ivy DD, McMurtry IF, Abman Wallwork J (1991) Inhaled nitric oxide as a cause of
SH (1995) Chronic pulmonary hypertension in utero selective pulmonary vasodilation in pulmonary hyper-
impairs endothelium-dependent vasodilation. Am J tension. Lancet 338:1173–1174
Physiol Heart Circ Physiol 268:H288–H294 Pierro M, Thebaud B (2014) Understanding and treating
Mercier JC, Hummler H, Durrmeyer X, Sanchez-Luna M, pulmonary hypertension in congenital diaphragmatic
Carnielli V, Field D, Greenough A, Van Overmeire B, hernia. Semin Fetal Neonatal Med 19:357–363
Jonsson B, Hallman M, Baldassarre J, EUNO Study Radicioni M, Troiani S, Camerini PG (2012) Effects of
Group (2010) Inhaled nitric oxide for prevention of terlipressin on pulmonary artery pressure in a septic
bronchopulmonary dysplasia in premature babies cooled infant: an echocardiographic assessment. J Peri-
(EUNO): a randomised controlled trial. Lancet 376 natol 32:893–895
(9738):346–354 Roberton NRC, Hallidie-Smith DA, Davis JA (1967)
Mestan KK, Marks JD, Hecox K et al (2005) Neurodeve- Severe respiratory distress syndrome mimicking cya-
lopmental outcomes of premature infants treated with notic heart disease in term babies. Lancet 2:
inhaled nitric oxide. N Engl J Med 353:23–32 1108–1110
Meurs KP, Rhine WD, Asselin JM, Duran DJ (1997) Roberts JD, Polaner DM, Lang P et al (1992) Inhaled nitric
Response of premature infants with severe respiratory oxide in persistent pulmonary hypertension of the new-
failure to inhaled nitric oxide. Preemie NO collabora- born. Lancet 340:818–819
tive group. Pediatr Pulmonol 24:319–323 Roberts JD, Chen TY, Kawai N et al (1993) Inhaled nitric
Mohamed WA, Ismail M (2012) A randomized, double- oxide reverses pulmonary vasoconstriction in the hyp-
blind, placebo-controlled, prospective study of bosentan oxic and acidotic newborn lamb. Circ Res 72:246–254
for the treatment of persistent pulmonary hypertension Roberts JD, Fineman JR, Morin FC et al (1997) Inhaled
of the newborn. J Perinatol 32(8):608–613 nitric oxide and persistent pulmonary hypertension of
Morin FC III, Eagan EA (1989) The effect of closing the the newborn. N Engl J Med 336:605–610
ductus arteriosus on the pulmonary circulation of the Rosenberg AA, Kennaugh J, Koppenhafer SL, Loomis M,
fetal sheep. J Dev Physiol 11:245–250 Chatfield BA, Abman SH (1993) Elevated
60 Persistent Pulmonary Hypertension of the Newborn 961
immunoreactive endothelin-1 levels in newborn infants Stevenson DK, Kasting DS, Darnall RA et al (1979)
with persistent pulmonary hypertension. J Pediatr Refractory hypoxemia associated with neonatal pulmo-
123:109–114 nary disease: the use and limitations of tolazoline.
Rossaint R, Falke KJ, Lopez F et al (1993) Inhaled nitric J Pediatr 95:595–599
oxide for the adult respiratory distress syndrome. Storme L, Rairigh RL, Parker TA, Kinsella JP, Abman SH
NEJM 328:399–405 (1999) Acute intrauterine pulmonary hypertension
Ruano R, Yoshisaki CT, da Silva MM, Ceccon ME, Grasi impairs endothelium dependent vasodilation in the
MS, Tannuri U et al (2012) A randomized controlled trial ovine fetus. Pediatr Res 45:575–581
of fetal endoscopic tracheal occlusion versus postnatal Subhedar NV, Ryan SW, Shaw NJ (1997) Open
management of severe isolated congenital diaphragmatic randomised controlled trial of inhaled nitric oxide and
hernia. Ultrasound Obstet Gynecol 39:20–27 early dexamethasone in high risk preterm infants. Arch
Rudolph AM (1980) High pulmonary vascular resistance Dis Child 77:F185–F190
after birth: pathophysiologic considerations and etio- Taira Y, Yamataka T, Miyazaki E, Puri P (1998) Compar-
logic classification. Clin Pediatr 19:585–590 ison of the pulmonary vasculature in newborns and
Rudolph AM, Drorbraugh JE, Auld PAM, Rudolph AJ, stillborns with congenital diaphragmatic hernia. Pediatr
Nadas AS, Smith CA, Hubbell JP (1961) Studies in the Surg Int 14:30–35
circulation in the neonatal period. The circulation in the The Franco – Belgium Collaborative NO Trial Group (1999)
respiratory distress syndrome. Pediatrics 27:551–556 Early compared with delayed inhaled nitric oxide in mod-
Russ RD, Walker BR (1992) Role of nitric oxide in erately hypoxaemic neonates with respiratory failure: a
vasopressinergic pulmonary vasodilatation. Am J randomised controlled trial. Lancet 354:1066–1071
Phys 262:H743–H747 The Neonatal Inhaled Nitric Oxide Study Group (NINOS)
Scheurer MA, Scott MB, Atz AM (2005) Vasopressin to (1997) Inhaled nitric oxide and hypoxic respiratory
attenuate pulmonary hypertension and improve sys- failure in infants with congenital diaphragmatic hernia.
temic blood pressure after correction of obstructed Pediatrics 99:838–845
total anomalous pulmonary venous return. J Thorac Tiktinsky MH, Morin FC (1993) Increasing oxygen tension
Cardiovasc Surg 129:464–466 dilates fetal pulmonary circulation via endothelium-
Schreiber MD, Gin-Mestan K, Marks JD et al (2003) derived relaxing factor. Am J Phys 265:H376–H380
Inhaled nitric oxide in premature infants with the respi- Tzao C, Nickerson PA, Russell JA, Gugino SF, Steinhorn
ratory distress syndrome. N Engl J Med 349:2099–2107 RH (2001) Pulmonary hypertension alters soluble
Share L (1988) Role of vasopressin in cardiovascular reg- guanylate cyclase activity and expression in pulmonary
ulation. Physiol Rev 68:1248–1284 arteries isolated from fetal lambs. Pediatr Pulmonol
Shaul PW, Yuhanna IS, German Z, Chen Z, Steinhorn RH, 31:97–105
Morin FC III (1997) Pulmonary endothelial NO syn- van der Cammen-van Zijp MH, Janssen AJ, Raets MM,
thase gene expression is decreased in fetal lambs with van Rosmalen J, Govaert P, Steiner K, Gischler SJ,
pulmonary hypertension. Am J Phys Lung Cell Mol Tibboel D, van Heijst AF (2014) IJsselstijn H; Dutch
Phys 272:L1005–L1012 ECMO follow-up team. Motor performance after neo-
Shekerdemian L, Ravn H, Penny D (2002) Intravenous natal extracorporeal membrane oxygenation: a longitu-
sildenafil lowers pulmonary vascular resistance in a dinal evaluation. Pediatrics 134(2):e427–e435
model of neonatal pulmonary hypertension. Am J Van Marter LJ, Leviton A, Allred EN (1996) PPHN and
Respir Crit Care Med 165:1098–2002 smoking and aspirin and nonsteroidal antiinflammatory
Shekerdemian LS, Ravn HB, Penny DJ (2004) Interaction drug consumption during pregnancy. Pediatrics
between inhaled nitric oxide and intravenous sildenafil 97:658–663
in a porcine model of meconium aspiration syndrome. Van Meurs KP, Wright LL, Ehrenkranz RA et al (2005)
Pediatr Res 55(3):413–418. Epub 2004 Jan 2007 Inhaled nitric oxide for premature infants with severe
SIassi B, Goldberg SJ, Emmanouilides GC, Higashimo respiratory failure. N Engl J Med 353:13–22
SM, Lewis E (1971) Persistent pulmonary vascular Villamor E, LeCras TD, Horan MP, Halbower AC, Tuder
obstruction in newborn infants. J Pediatr 78:610–615 RM, Abman SH (1997) Chronic intrauterine pulmo-
Stahlman M (1964) Treatment of cardiovascular diseases nary hypertension impairs endothelial nitric oxide syn-
of the newborn. Pediatr Clin N Am 11:363–400 thase in the ovine fetus. Am J Phys Lung Cell Mol Phys
Steinhorn RH, Russell JA, Morin FC III (1995) Disrup- 272:L1013–L1020
tion of cyclic GMP production in pulmonary arteries Walsh MC, Hibbs AM, Martin CR, Cnaan A, Keller RL,
isolated from fetal lambs with pulmonary hyperten- Vittinghoff E, Martin RJ, Truog WE, Ballard PL,
sion. Am J Physiol Heart Circ Physiol 268: Zadell A, Wadlinger SR, Coburn CE, Ballard RA, NO
H1483–H1489 CLD Study Group (2010) Two-year neurodevelopmental
Steinhorn RH, Kinsella JP, Butrous G, Dilleen M, outcomes of ventilated preterm infants treated with
Oakes M, Wessel DL (2007) Open-label, multicentre, inhaled nitric oxide. J Pediatr 156(4):556–61.e1. https://
pharmacokinetic study of IV sildenafil in the treatment doi.org/10.1016/j.jpeds.2009.10.011. Epub 2010 Feb 6
of neonates with persistent pulmonary hypertension of Walsh-Sukys MC, Tyson JE, Wright LL, Bauer CR,
the newborn (PPHN). Circulation 116:II–614 Korones SB, Stevenson DK, Verter J, Stoll BJ, Lemons
962 J. Gien et al.
JA, Papile LA, Shankaran S, Donovan EF, Oh W, Wessel DL, Adatia I, Van Marter LJ et al (1997) Improved
Ehrenkranz RA, Fanaroff AA (2000) Persistent pulmo- oxygenation in a randomized trial of inhaled nitric
nary hypertension of the newborn in the era before oxice for persistent pulmonary hypertension of the
nitric oxide: practice variation and outcomes. Pediatrics newborn. Pediatrics 100:e7
105:14–20 Wynn J, Krishnan U, Aspelund G, Zhang Y, Duong J,
Wedgwood S, Black SM (2003) Role of reactive oxygen Stolar CJ et al (2013) Outcomes of congenital diaphrag-
species in vascular remodeling associated with pulmo- matic hernia in the modern era of management. J
nary hypertension. Antioxid Redox Signal 5(6):759–769 Pediatr 163:114–119
Wedgwood S, Steinhorn RH, Bunderson M, Wilham J, Yuniartha R, Alatas FS, Nagata K, Kuda M, Yanagi Y,
Lakshminrusimha S, Brennan LA, Black SM (2005) Esumi G et al (2014) Therapeutic potential of mesen-
Increased hydrogen peroxide downregulates soluble chymal stem cell transplantation in a nitrofen-induced
guanylate cyclase in the lungs of lambs with persistent congenital diaphragmatic hernia rat model. Pediatr
pulmonary hypertension of the newborn. Am J Phys Lung Surg Int 30:907–914
Cell Mol Phys 289(4):L660–L666. Epub 2005 Jun 2003 Ziegler JW, Ivy DD, Wiggins JW, Kinsella JP, Clarke
Weimann J, Ullrich R, Hromi J, Fujino Y, Clark MWH, WR, Abman SH (1998) Effects of dipyridamole and
Bloch KD, Zapol WM (2000) Sildenafil is a pulmonary inhaled nitric oxide in pediatric patients with pulmo-
vasodilator in awake lambs with acute pulmonary nary hypertension. Am J Respir Crit Care Med 158:
hypertension. Anesthesiology 92:1702–1712 1388–1395
Pulmonary Hypertension in
Congenital Diaphragmatic Hernia 61
Jason Gien, John P. Kinsella, and Steven H. Abman
Contents
61.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964
61.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964
61.3 Pulmonary Hypertension in CDH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964
61.4 Acute Pulmonary Hypertension in CDH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 965
61.5 Subacute (Late) Pulmonary Hypertension in CDH . . . . . . . . . . . . . . . . . . . . . . . . . . 967
61.6 Chronic Pulmonary Hypertension in CDH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 967
61.7 Improving Outcomes in CDH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 968
61.8 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 968
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 969
Abstract pulmonary hypoplasia and pulmonary hyper-
Congenital diaphragmatic hernia (CDH) is a tension after birth. Along with the degree of
severe congenital anomaly, where a defect in lung hypoplasia and pulmonary hypertension,
the diaphragm results in herniation of the underdevelopment of the left ventricle also
abdominal contents into the chest and com- determines severity in CDH and contributes
pression of the intrathoracic structures. In to adverse outcomes. After birth, CDH patients
utero compression of the lungs results in present with severe hypoxemic respiratory fail-
ure and shock, secondary to structural and
functional changes in the heart, pulmonary cir-
J. Gien (*) culation, airways, and lung parenchyma. The
University of Colorado Denver, Denver, CO, USA optimal approach to management of respira-
e-mail: [email protected] tory failure, pulmonary hypertension, and
J. P. Kinsella shock changes as the underlying pathophysiol-
University of Denver, Denver, CO, USA ogy evolves in the days and weeks after birth.
e-mail: [email protected] In this chapter, we describe the approach
S. H. Abman to CDH management as shock which predom-
University of Colorado Denver – Anschutz Medical inates early resolves and systemic hemody-
Campus, Denver, CO, USA
e-mail: [email protected] namics stabilize and pulmonary vascular
# Springer International Publishing AG, part of Springer Nature 2018 963
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_292
964 J. Gien et al.
abnormalities progress from acute to subacute experienced centers, but mortality and morbidity
(late) and finally chronic stages. remain high.
Several individual prenatal prognostic factors
have been identified in CDH that can predict the
61.1 Salient Points clinical course after birth as well as long-term
outcomes. These include liver position, severity
• Congenital diaphragmatic hernia (CDH) is a of lung hypoplasia (as assessed by fetal lung
severe birth defect characterized by herniation volume on MRI: percent predicted lung volume
of abdominal contents into the thorax and [PPLV] and total lung volume [TLV]; LHR and
arrested development of both lungs. observed to expected LHR by ultrasound), LV
• Presence of left ventricular hypoplasia contrib- hypoplasia (right ventricle [RV]:left ventricle dis-
utes to the severity of the defect and adverse proportion on fetal echocardiogram [ECHO]),
outcome. and development and reactivity of the pulmonary
• Pulmonary hypertension (PH) can persist vasculature (e.g., McGoon Index, in utero hyper-
months to years, and structural and functional oxia test). In addition, the presence of congenital
abnormalities of pulmonary circulation can heart disease, or a genetic syndrome (Le et al.
complicate the course of the disease. 2012), markedly impacts outcomes. The reliabil-
• Pulmonary vasodilator therapy can be used in ity of each individual parameter to predict sur-
acute treatment; it plays a critical role in man- vival and long-term outcome is low, and
agement of late PH in CDH and potentially combining multiple parameters improves reliabil-
improves survival. ity. The CDH congenital prognostic index (CDH-
CPI) is a useful tool that amalgamates 10 prenatal
parameters representing genetic, cardiac, hernia,
61.2 Introduction and lung factors to comprehensively capture the
range of severity and associated anomalies
Congenital diaphragmatic hernia (CDH) is a influencing prognosis (Le et al. 2012). The
severe birth defect characterized by herniation of CDH-CPI score is correlated with survival and
abdominal contents into the thorax caused by a extracorporeal membrane oxygenation (ECMO)
defect in the diaphragm (Lipshutz et al. 1997). support, with significantly lower survival at
Recent insight into pathophysiologic processes scores below 8 (Le et al. 2012).
responsible for CDH suggests an early role for
environmental and/or genetic factors before the
development of the diaphragm, leading to arrested 61.3 Pulmonary Hypertension in
development of both lungs. In addition, incom- CDH
plete closure of the diaphragm results in a dia-
phragm defect, herniation of the abdominal The classical histological findings of CDH show
contents into the chest, and compression of the pulmonary vascular remodeling superimposed on
intrathoracic structures. Solid organ herniation hypoplasia or pruning of the pulmonary vascular
exacerbates the degree of lung hypoplasia, and bed (Lipshutz et al. 1997). These changes in the
the most severe cases are associated with hypo- pulmonary vasculature are responsible for
plasia of the ipsilateral and contralateral lung (low increased vascular tone and altered vasoreactivity
lung to head ratio [LHR]) (Taira et al. 1998). after birth (Lipshutz et al. 1997). Management of
Along with degree of lung hypoplasia, the sever- PH in the newborn with CDH is complicated by
ity of pulmonary hypertension (PH) and presence the structural and functional changes in the heart,
of left ventricular (LV) hypoplasia all contribute pulmonary circulation, airways, and lung paren-
to the severity of the defect and adverse outcomes chyma. Moreover, the role and selection of pul-
(Wynn et al. 2013; Le et al. 2012). Overall sur- monary vasodilator therapies for treatment of PH
vival of infants with CDH has improved in change as the underlying pathophysiology
61 Pulmonary Hypertension in Congenital Diaphragmatic Hernia 965
evolves in the days and weeks after birth. In pressures (RVEDP) with impaired LV filling and
response, management strategies need to adjust elevated left atrial pressure (LAP).
as pulmonary vascular abnormalities progress Structural and functional LV abnormalities are
from the acute to subacute (late) and finally responsible for impaired LV filling and contribute
chronic stages. to the development of pulmonary venous hyper-
tension. Baumgart et al. showed that ECMO-
treated CDH infants (survivors) had significantly
61.4 Acute Pulmonary Hypertension smaller LV mass (P < 0.002) than infants requir-
in CDH ing ECMO for other diagnoses and healthy term
infants (Byrne et al. 2015). Moreover, ECMO-
After birth, infants with CDH typically present treated CDH neonates who died had significantly
with severe hypoxemic respiratory failure (HRF) smaller LV size than other groups (P < 0.0005)
and shock. The etiology of hypoxemia is multi- including ECMO-treated CDH survivors (in addi-
factorial and occurs secondary to intrapulmonary tion to CDH and non-CDH ECMO-treated infants
shunt as well as extrapulmonary right-to-left and well infants) (Byrne et al. 2015). Byrne et al.
shunting across fetal conduits (ductus arteriosus reported that fetuses with severe left CDH were
[DA] and foramen ovale). Newborns with severe more likely to have smaller mitral valve
CDH often present with left-to-right shunting at (P < 0.001) and aortic valve sizes (P < 0.001)
the atrial septum and right-to-left shunting at the and left ventricular end diastolic volume
ductus arteriosus (Baumgart et al. 1998). Differ- (P = 0.006) Z-scores than those with mild left
ential shunting across these fetal conduits is CDH (Fig. 1) (Kinsella and Abman 2000). In
responsible for postductal desaturation and differ- addition to the structural changes in the LV, their
ences in pre- and postductal arterial blood gas percentage LV output was also lower. Those with
parameters (Baumgart et al. 1998). The direction severe left CDH trended towards higher risk of
of atrial level shunt is determined by the relative neonatal death compared with those with mild left
right and left ventricular end diastolic pressures. CDH. Although mitral and aortic valve dimen-
Left-to-right shunting at the atrial septum occurs sions in fetuses with right CDH were larger than
when left ventricular end diastolic pressure in left CDH, LV outputs were similarly
(LVEDP) exceeds right ventricular end diastolic diminished.
Fig. 1 Left heart hypoplasia stratified by congenital dia- (mitral and aortic values, left ventricular volume) severity
phragmatic hernia (CDH) side and severity at fetal assess- of hypoplasia increased with increasing severity of hernia,
ment. Left CDH: mild (n = 42), liver down; moderate while the effect in the fetus with right CDH was less
(n = 41), lung-to-head ratio (LHR) 1 to 1.4; severe pronounced. Adapted with permission from Byrne et al.
(n = 88), LHR 1; Right CDH: mild (n = 2), LHR 41; L, left; R, right
severe (n = 15), LHR 1. For left heart measurements
966 J. Gien et al.
The etiology of LV hypoplasia in CDH is shunting at the atrial septum has the potential to
almost certainly multifactorial reflecting mechan- exacerbate LA and pulmonary venous hyperten-
ical compression by intra-abdominal contents as sion and contribute to pulmonary hemorrhage. In
well as alteration in LV filling hemodynamics addition, as preductal saturations are maintained
during fetal development due to changes in orien- in this setting, pulmonary vasodilator therapy is
tation of the inferior vena cava and venous return unlikely to improve preductal saturations and may
from the placenta. Left heart underfilling and sub- result in only a modest increase in postductal
sequent underdevelopment may result from saturations. Reserving iNO therapy for infants
abnormal hemodynamics due to leftward distor- with right-to-left atrial shunting and preductal
tion of the ductus venosus or reduced pulmonary desaturation is recommended early in the clinical
blood flow return to the left heart (Kinsella and course and has the potential to prevent pulmonary
Abman 2000). In addition, after birth, compres- hemorrhage in CDH. In addition, as right-to-left
sion of the LV by the RV in the presence of shunting across the DA causes veno-arterial
elevated RV pressure also impairs LV filling. admixture, it is common to see significant differ-
The common pathway for these mechanisms is ences in pre- and postductal arterial blood gases
decreased filling of the left ventricle. Altered (ABG) measurements (Baumgart et al. 1998).
hemodynamics and compression of the heart by Determining the need for ECMO, degree of respi-
herniated abdominal viscera together can create ratory support, and fraction of inspired oxygen
strikingly abnormal left ventricular structure and (Fi02) should be based on measurement of pre-
function with anomalous relaxation and small ductal arterial gases in these infants (Baumgart et
chamber size, even with normal or near-normal al. 1998).
systolic performance. Overall, altered fetal hemo- Overall, acute treatment of PH in CDH with
dynamics leading to decreased LV output can pulmonary vasodilators is limited by the severity
occur in both right and left CDH, but an additional of LV hypoplasia, degree of impairment of LV
compressive effect on the left heart is seen in left- filling, and LV systolic dysfunction. Because
sided CDH (Kinsella and Abman 2000). infants with severe CDH and acute PH are poor
Echocardiographic findings may be valuable in responders, iNO should not be routinely adminis-
guiding the selective use of pulmonary vasodila- tered in this setting. However, careful ECHO
tors in management of early PH with CDH. For assessment can help identify limited clinical situ-
example, ECHO findings in the presence of severe ations that may benefit from PH therapies, includ-
PH may show right-to-left shunting (caused by ing iNO, and guide the course of treatment
suprasystemic pulmonary vascular resistance) at (Kinsella et al. 2005; Pediatrics 1997). In the
the atrial level and DA. This constellation of acute management of CDH, iNO may have a
echocardiographic findings suggests a favorable selective role in stabilization for ECMO and treat-
response to pulmonary vasodilation. However, in ment of marked preductal desaturation secondary
the presence of LV dysfunction, right-to-left DA to right-to-left atrial level shunt. Furthermore, use
shunting is seen along with mitral insufficiency of iNO for treatment of PH may be considered as
with left-to-right atrial shunting at the foramen LV performance improves. LV hypoplasia, and
ovale (Kinsella and Abman 2000). This constel- related LV output, also play a role in the poor
lation of findings is again consistent with supra- response to pulmonary vasodilators as diminished
systemic right ventricular systolic pressure, but LV performance results in RV-dependent systemic
left-to-right atrial shunting suggests the presence circulation (Pediatrics 1997). Initiating pulmo-
of pulmonary venous hypertension and a poor nary vasodilator therapy in the presence of an
response to pulmonary vasodilator therapy. Dia- RV-dependent systemic circulation may adversely
stolic dysfunction is difficult to assess, but can be affect systemic hemodynamics.
interpreted from a high LVEDP and manifests as The Neonatal Inhaled Nitric Oxide Study
left-to-right shunt at the atrial level. Pulmonary (NINOS) Group conducted the largest trial of
vasodilator therapy in the setting of left-to-right iNO in infants with CDH (N = 53) who were
61 Pulmonary Hypertension in Congenital Diaphragmatic Hernia 967
randomized to 20 ppm iNO or 100% oxygen Treatment strategies for infants with late PH
(control) (Lusk et al. 2015). The oxygenation have not been carefully studied. Inhaled NO is
index (OI) was approximately 45 in both groups, usually the first-line therapy for treatment of PH
indicating more severe disease. NINOS showed in CDH. In a subset of newborns with CDH,
no difference in the combined endpoint “death/ improvement in parenchymal lung disease may
ECMO utilization” between iNO-treated patients allow for the use of noninvasive iNO by continuous
and controls. However, ECMO utilization was positive airway pressure (CPAP) or nasal cannula
higher in the iNO-treated group (80% vs 54% (Olson et al. 2015). There is limited experience
control, P = 0.043) pointing to an adverse effect with other pharmacologic pulmonary vasodilators
of iNO early in the course of CDH. These results (e.g., prostacyclin, endothelin antagonists, and
lend support to the hypothesis that LV systolic and phosphodiesterase inhibitors) in infants with CDH
diastolic dysfunction contribute to morbidity in and late PH. Olson et al. recently described two
severe CDH and limit the efficacy of aggressive infants with CDH and severe PH at 6 weeks of age
pharmacologic pulmonary vasodilator therapy who responded favorably to treatment with
early in the course of CDH and severe PH. treprostinil (Kamath et al. 2010). Clearly, further
Indeed, a poor response to pulmonary vasodi- investigation is needed to define an approach to the
lation is not unexpected given the structural and management of late PH in this population.
functional abnormalities that characterize acute
CDH. Although speculative, the lack of response
to pulmonary vasodilators is more likely due to 61.6 Chronic Pulmonary
left atrial/pulmonary vein hypertension than Hypertension in CDH
functional changes in the pulmonary arterial
vasculature. Chronic PH may persist in CDH over months and
years, and enduring structural and functional abnor-
malities of pulmonary circulation in the ipsilateral
61.5 Subacute (Late) Pulmonary and contralateral lung can complicate the course of
Hypertension in CDH the disease. Cardiac catheterization of seven patients
with CDH who survived the neonatal period with
In addition to complicating the early course of protracted or recurrent PH revealed a range of pul-
neonates with CDH, severe PH can be protracted monary vascular abnormalities (Pediatrics 1997).
– persisting weeks to months after improvement These patients (age range, 3 months–12 years) had
in respiratory failure and cardiac performance a history of severe hypoxemic respiratory failure and
–leading to prolonged mechanical ventilation PH as newborns. At catheterization, therapies
(Pediatrics 1997). In a multicenter prospective included supplemental oxygen (n = 7), iNO
ECHO study of neonates with CDH (N = 220), (n = 2), prostacyclin (n = 2), and bosentan
mortality at discharge in newborns with severe PH (n = 1). Three of the seven patients had significant
(right ventricular systolic pressure [RVSP]/sys- pulmonary vascular abnormalities in the lung con-
tolic blood pressure [SBP] >2/3) was 56.1% com- tralateral to the initial diaphragmatic defect. Major
pared with 1.4% in infants with mild PH (RVSP/ findings at cardiac catheterization included left pul-
SBP <1/2) and 7.4% in those with moderate PH monary artery hypoplasia or stenosis in three patients
(RVSP/SBP 1/2 to 2/3) (Le et al. 2012). Recently, and pulmonary vein stenosis or delayed venous
Lusk et al. reviewed ECHO results for 140 new- return in six patients. Two patients with right-sided
borns with CDH and found that although the diaphragmatic defect had striking left-sided pulmo-
majority of infants had resolution of PH between nary venous abnormalities. One patient with right-
1 and 3 weeks of age, at 2 weeks the severity of sided CDH was discharged home, but died at age 5
PH by echocardiogram predicted mortality and months with marked pulmonary vascular changes on
need for prolonged ventilation (Kinsella et al. autopsy consistent with severe PH. After a median
2003). follow-up of 12 months from catheterization, five
968 J. Gien et al.
patients were alive and discharged from hospital. such as prenatal intervention or cell-based ther-
The two patients with the most severe PH died apy are the subject of current investigation. The
from related complications at ages 8 and 19 months. effects of LV dysfunction/hypoplasia on the
In some patients with CDH, significant PH, neonatal course in severe CDH provide a com-
which may be subclinical, clearly continues pelling reason to study fetal intervention. The
beyond the neonatal period, contributing to mor- efficacy of prenatal intervention with percutane-
bidity and mortality. Understanding the patho- ous fetoscopic endoluminal tracheal occlusion
physiology underlying these long-term effects (FETO) therapy in CDH has been described in
will require a more sophisticated view of CDH case series and controlled studies (Ruano et al.
than that originating solely from in utero cardio- 2012; Deprest and De 2012). The potential role
pulmonary compression. It is possible that the of FETO is being investigated in CDH in a
injury associated with management of hypoxemic European and North American collaboration
respiratory failure in newborns with CDH may called the Tracheal Occlusion To Accelerate
cause previously unrecognized long-term effects Lung Growth (TOTAL) Trial (Hoffman et al.
in susceptible individuals, and/or the pulmonary 2011).
circulation in patients with severe CDH may be Mesenchymal stem cells (MSCs) also repre-
fundamentally altered in utero, leading to abnor- sent an emerging therapeutic approach in CDH.
mal responses to injury that last far beyond the Several experimental studies in animal models
newborn period (Pediatrics 1997). have shown that treatment with MSCs can
reduce pulmonary injury and PH (Aslam et al.
2009; Yuniartha et al. 2014). A recent study in
61.7 Improving Outcomes in CDH a rat model of experimental CDH found that
MSC transplantation promotes alveolar and
Treatment strategies for CDH continue to evolve pulmonary artery development, reducing the
with increasing clinical experience and greater severity of pulmonary hypoplasia (145).
insight into the underlying nature of the condi-
tion. These strategies include simultaneous post-
ductal and preductal samples to measure blood 61.8 Conclusion
gases (adjusting ventilator support accordingly)
(Gien and Kinsella 2015). Early ECHO is essen- In summary, the early course of CDH is charac-
tial to define pulmonary artery pressure (PAP) terized by severe PH, and cardiac, lung parenchy-
and assess LV size and function. It is reasonable mal and airway abnormalities. Acute treatment of
to delay the use of pulmonary vasodilator ther- PH in CDH with pulmonary vasodilator therapy is
apy until there is ECHO evidence of adequate LV limited by structural and functional changes of the
performance. Reducing LV afterload pharmaco- left ventricle. In a significant subset of newborns
logically may play an important role (e.g., with severe CDH, late or protracted PH occurs
milrinone), as well as maintaining ductal patency and may persist weeks to months following
with prostaglandin E1 (PGE1) if RV-dependent improvement in respiratory failure and cardiac
systemic circulation is demonstrated by ECHO. performance. In contrast to early CDH, pulmo-
Adrenal insufficiency also complicates the nary vasodilator therapy plays a critical role in
course of newborns with severe CDH and management of late PH in CDH and potentially
decreases catecholamine drug responsiveness improves survival.
(Jani et al. 2011). Despite progress in CDH management,
Despite refinement of postnatal interven- advances have been limited by the lack of ran-
tions, limitations persist and treatment of CDH domized controlled trials to properly test new
and pulmonary hypertension remains sub- treatments. Major differences in clinical practice
optimal. Consequently, new therapeutic options regarding the ascertainment and treatment of PH
61 Pulmonary Hypertension in Congenital Diaphragmatic Hernia 969
make it difficult to determine the most effective Kamath BD, Fashaw L, Kinsella JP (2010) Adrenal insuf-
strategies to manage late PH in CDH infants. ficiency in newborns with congenital diaphragmatic
hernia. J Pediatr 156:495–497
Moreover, institutional practices that lead to Kinsella JP, Abman SH (2000) Clinical approach to
“improved” outcomes are slowly adopted and inhaled nitric oxide therapy in the newborn with hyp-
local changes are often guided only by experience oxemia. J Pediatr 136:717–726
and conviction. To overcome these barriers, cen- Kinsella JP, Parker TA, Ivy DD, Abman SH (2003) Non-
invasive delivery of inhaled nitric oxide therapy for late
ters with the best outcomes for isolated CDH pulmonary hypertension in newborn infants with con-
should be identified from current databases and genital diaphragmatic hernia. J Pediatr 142:397–401
their practices disseminated to the wider commu- Kinsella JP, Ivy DD, Abman SH (2005) Pulmonary vaso-
nity. Improving outcomes in patients with CDH dilator therapy in congenital diaphragmatic hernia:
acute, late, and chronic pulmonary hypertension.
will require continued vigilance, multidisciplinary Semin Perinatol 29:123–128
collaboration, and widespread adoption of best Le LD, Keswani SG, Biesiada J, Lim FY, Kingma PS,
practices. Haberman BE et al (2012) The congenital diaphrag-
matic hernia composite prognostic index correlates
with survival in left – sided congenital diaphragmatic
hernia. J Pediatr Surg 47:57–62
References Lipshutz GS, Albanese CT, Feldstein VA, Jennings RW,
Housley HT, Beech R et al (1997) Prospective analysis
Aslam M, Baveja R, Liang OD, Fernandez-Gonzalez A, of lung – to – head ratio predicts survival for patients
Lee C, Mitsialis SA et al (2009) Bone marrow stromal with prenatally diagnosed congenital diaphragmatic
cells attenuate lung injury in a murine model of neona- hernia. J Pediatr Surg 32:1634–1636
tal chronic lung disease. Am J Respir Crit Care Med Lusk LA, Wai KC, MoonGrady AJ, Steurer MA, Keller RL
180:1122–1130 (2015) Persistence of pulmonary hypertension by echo-
Baumgart S, Paul JJ, Huhta JC, Katz AL, Paul KE, Spettell cardiography predicts short – term outcomes in con-
C et al (1998) Cardiac malposition, redistribution of genital diaphragmatic hernia. J Pediatr 166:251–256
fetal cardiac output, and left heart hypoplasia reduce Olson E, Lusk LA, Fineman JR, Robertson L, Keller RL
survival in neonates with congenital diaphragmatic (2015) Short – term Treprostinil use in infants with
hernia requiring extracorporeal membrane oxygena- congenital diaphragmatic hernia following repair. J
tion. J Pediatr 133:5762 Pediatr 167:762–764
Byrne FA, Keller RL, Meadows J, Miniati D, Brook MM, Ruano R, Yoshisaki CT, da Silva MM, Ceccon ME, Grasi
Silverman NH et al (2015) Severe left diaphragmatic MS, Tannuri U et al (2012) A randomized controlled
hernia limits size of fetal left heart more than right trial of fetal endoscopic tracheal occlusion versus post-
diaphragmatic hernia. Ultrasound Obstet Gynecol natal management of severe isolated congenital dia-
46(6):688–94 phragmatic hernia. Ultrasound Obstet Gynecol 39:
Deprest J, De CP (2012) Antenatal management of isolated 20–27
congenital diaphragmatic hernia today and tomorrow: Taira Y, Yamataka T, Miyazaki E, Puri P (1998) Compar-
ongoing collaborative research and development. J ison of the pulmonary vasculature in newborns and
Pediatr Surg 47:282–290 stillborns with congenital diaphragmatic hernia. Pediatr
Gien J, Kinsella JP (2015) Differences in preductal and Surg Int 14:30–35
postductal arterial blood gas measurements in infants The Neonatal Inhaled Nitric Oxide Study Group (NINOS)
with severe congenital diaphragmatic hernia. Arch Dis (1997) Inhaled nitric oxide and hypoxic respiratory
Child Fetal Neonatal Ed 101(4):F314 failure in infants with congenital diaphragmatic hernia.
Hoffman AM, Paxson JA, Mazan MR, Davis AM, Tyagi S, Pediatrics 99:838–845
Murthy S et al (2011) Lung – derived mesenchymal Wynn J, Krishnan U, Aspelund G, Zhang Y, Duong J,
stromal cell post – transplantation survival, persistence, Stolar CJ et al (2013) Outcomes of congenital diaphrag-
paracrine expression, and repair of elastase – injured matic hernia in the modern era of management. J
lung. Stem Cells Dev 20:1779–1792 Pediatr 163:114–119
Jani J, Valencia C, Cannie M, Vuckovic A, Sellars M, Yuniartha R, Alatas FS, Nagata K, Kuda M, Yanagi Y,
Nicolaides KH (2011) Tracheal diameter at birth in Esumi G et al (2014) Therapeutic potential of mesen-
severe congenital diaphragmatic hernia treated by chymal stem cell transplantation in a nitrofen – induced
fetal endoscopic tracheal occlusion. Prenat Diagn congenital diaphragmatic hernia rat model. Pediatr
31:699–704 Surg Int 30:907–914
Continuous Positive Airways Pressure
and Other Noninvasive Respiratory 62
Techniques in Newborns
Fabrizio Sandri, Gina Ancora, Gianluca Lista, and
Luc J. I. Zimmermann
Contents
62.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 972
62.2 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 972
62.3 Physiopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 973
62.3.1 Respiratory System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 973
62.3.2 Cardiocirculatory System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 976
62.3.3 Renal Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 977
62.3.4 Intracranial Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 977
62.4 Technical Aspect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 977
62.4.1 Continuous Flow Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 977
62.4.2 Variable Flow Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 977
62.5 Methods of Administering CPAP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 979
62.6 Clinical Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 980
62.6.1 Respiratory Distress Syndrome (RDS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 980
62.6.2 Neonatal Apnea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 983
F. Sandri (*)
Neonatology and Neonatal Intensive Care Unit, Ospedale
Maggiore, Bologna, Italy
e-mail: [email protected]
G. Ancora
Neonatology and Neonatal Intensive Care Unit, Ospedale
Infermi, Rimini, Italy
e-mail: [email protected]
G. Lista
Neonatology and Neonatal Intensive Care Unit, Ospedale
dei Bambini V. Buzzi, Milan, Italy
e-mail: [email protected]
L. J. I. Zimmermann
Department of Pediatrics and Neonatology, School for
Oncology and Developmental Biology (GROW),
Maastricht University Medical Center, Maastricht,
The Netherlands
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 971
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_209
972 F. Sandri et al.
62.6.3 Weaning the Patient from Mechanical Ventilation
(Post-extubation Phase) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984
62.6.4 Other Clinical Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985
62.7 Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985
62.8 Suggestions for N-CPAP Use in the Clinical Practice . . . . . . . . . . . . . . . . . . . . . 986
62.8.1 Pressure Level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 986
62.8.2 Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 986
62.8.3 How to Try to Prevent Failure of N-CPAP? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 987
62.8.4 Weaning from N-CPAP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 988
62.9 Nursing of the Neonate in N-CPAP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 988
62.9.1 Attachment (Headset and Nasal Prongs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 988
62.9.2 Positioning of the Circuit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 989
62.9.3 Positioning the Infant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 989
62.9.4 Humidification and Heating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 989
62.9.5 Airways Suction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 990
62.9.6 Feeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 990
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 990
Abstract • Nasal CPAP (N-CPAP), which is CPAP deliv-
Continuous positive airways pressure (CPAP) is ered with nasal prongs, is the most used and
a method of assisted respiration that consists of effective system for the administration of
the application of continuous positive pressure CPAP in the newborn.
to a spontaneously breathing patient’s airways • N-CPAP stabilizes airways, prevents alveoli
throughout the entire respiratory cycle. The first collapse, and allows spontaneously breathing
use of a CPAP was in the 1930s (Poulton EP, patient to achieve a functional residual capacity.
Oxon DM, Lancet 228:981–983, 1936; Bullowa • N-CPAP can be delivered by continuous or
JGH, The management of the Pneumonias. variable flow systems.
Oxford University Press, New York, 1937; • N-CPAP is considered a valid alternative to tra-
Barach AL, Martin J, Eckman M, Proc Am cheal intubation and mechanical ventilation in
Soc Clin Invest 16:664–680, 1937), but its first the acute phase of RDS by reducing occurrence
notable application in the neonatal field was in of bronchopulmonary dysplasia and death.
1971 when CPAP was used in the treatment of • Surfactant replacement and caffeine prophy-
RDS (respiratory distress syndrome) in sponta- laxis can reduce N-CPAP failure in preterm
neously breathing newborns undergoing tra- infants with RDS.
cheal intubation (Gregory GA, Kittermann JA, • N-CPAP after mechanical ventilation can pre-
Phibbs RH et al. N Engl J Med 284:1333–1340, vent extubation failure.
1971). Nowadays, nasal CPAP (N-CPAP) is • Nasal intermittent ventilation (NIV) especially if
considered a valid approach in the management synchronized could be a promising approach in
of respiratory failure of the preterm infant from case of N-CPAP failure before tracheal intubation.
birth reducing occurrence of bronchopulmonary • Nursing care is determinant to reduce N-CPAP
dysplasia (BPD) and death, without increasing failure.
risk of neurological damage.
62.2 Background
62.1 Salient Points
The premature lung is prone to collapse due to low
• CPAP is a valid approach in the management presence of endogenous surfactant and reduced
of respiratory failure of the newborn infant. capacity of the preterm baby to generate an
62 Continuous Positive Airways Pressure and Other Noninvasive Respiratory Techniques in Newborns 973
adequate positive pressure to maintain open the be capable of overcoming the elastic properties
alveoli. Therefore, many premature infants at birth and resistance of the respiratory system, thus
(especially when born before 32 weeks’ GA) show
signs of respiratory failure and need to be managed Ptot ¼ Pel þ Pres ¼ V=C þ FR
with respiratory support and surfactant therapy.
Continuous positive airways pressure (CPAP) where Ptot is the total pressure, Pel is the pres-
is a method of assisted respiration that consists of sure necessary to overcome the elastic forces, Pres
the application of continuous positive pressure to is the pressure required to overcome the resis-
a spontaneously breathing patient’s airways tance, C is compliance, R is resistance, V is vol-
throughout the entire respiratory cycle. The first ume, and F is flow (equation of motion of the
use of a CPAP dates back to1930s (Poulton and respiratory system).
Oxon 1936; Bullowa 1937; Barach et al. 1937), In the neonate, increased WOB is clinically
but its first notable application in the neonatal field manifested by the presence of tachypnea, inter-
was in 1971 when CPAP was used in the treatment costal/diaphragmatic retractions, and paradoxical
of RDS (respiratory distress syndrome) in sponta- breathing.
neously breathing newborns undergoing tracheal The amount of work expended in order to
intubation (Gregory et al. 1971). expand the rib cage depends principally on:
There is a distinction between CPAP and PEEP
(positive end expiratory pressure). CPAP main- The elasticity of the lungs (the work is inversely
tains a constant pressure of a level above ambient proportional to the compliance of the lungs)
air pressure, thus providing a continuous trans- The resistance to airflow imposed by the airways
pulmonary pressure gradient during the various The elastic and resistive properties of the rib cage
phases of the respiratory cycle. Another term for
CPAP is continuous distending pressure (Morley We will examine below the physiopathological
1999). Administered through the nose, (N-CPAP, characteristics of the neonatal respiratory system,
a technique first proposed by Italian authors in the with particular attention to aspects relating to pre-
early 1970s (Agostino et al. 1973; Caliumi- mature infants, and we will analyze the effects of
Pellegrini et al. 1974)) CPAP became a corner- CPAP application with respect to neonatal respi-
stone of respiratory support in the 1990s. When ratory physiology.
PEEP is used, positive pressure is applied to the The neonate, particularly if premature, has a
airways of a patient undergoing mechanical ven- double disadvantage in performing respiratory
tilation in the phases between artificial breaths. work:
There is increased pulmonary elastic resistance
62.3 Physiopathology The airways provide considerable resistance
The compliance of the rib cage is increased
62.3.1 Respiratory System
62.3.1.1 Increased Pulmonary Elastic
The main purpose of CPAP in the newborn is to Resistance
reduce the work of breathing (WOB). Work is The lungs are elastic in nature – elasticity
expressed as the function of force distance describes the tendency of a structure to return to
and specifically, in the case of respiratory work, its initial state after the application of a force
as pressure volume (P V ). It is necessary to causes it to depart from its initial conditions.
create a pressure gradient between the atmosphere Compliance (the change in volume created by
and the alveoli so that a volume of air comes into change in pressure, ΔV/ΔP) is the inverse of
contact with the alveolar-capillary membrane dur- elasticity and measures the distensibility of a
ing each inspiration. The pressure generated must structure.
974 F. Sandri et al.
Premature newborns present with reduced The structural composition of the lungs is insuffi-
compliance for various reasons: cient to keep the smaller airways open.
The reduction of FRC causes a reduction in diam-
Low surfactant production with consequent eter of the smaller airways.
increase in pulmonary surface tension and
reduction in pulmonary volume at the end of 62.3.1.3 Increased Compliance of the Rib
expiration (functional residual capacity, Cage
FRC). Compliance of the rib cage is inversely propor-
Excessive quantity of pulmonary fluid: the tional to gestational age. The compliance of the rib
clearance of the pulmonary fluid is slower cage is around five times greater than that of the
in the premature newborn, particularly lungs in premature newborns (for normal values
when delivered by elective cesarean sec- of pulmonary compliance) and around three times
tion. In fact, the premature infant is often greater in full-term newborns. In adults the ratio is
unable to generate an adequate delta pres- 1:1 (Gerhardt and Bancalari 1980). As such, the
sure to move the fluid throughout the air- newborn’s rib cage is much weaker and more
ways until the distal space of the lung flexible and is therefore incapable of maintaining
where it is reabsorbed by the interstitial adequate transpulmonary pressure at the end of
venous and lymphatic vessels. In addition, expiration. This brings a reduction in FRC, venti-
fluid and sodium absorption mechanisms lation at near-closing volumes, alveolar collapse,
are immature. Furthermore, the left-to-right imbalance in the ratio of ventilation to perfusion,
shunt that occurs when there is a patent hypoxemia, and hypercapnia with acidosis (see
ductus arteriosus (PDA), especially during ▶ Chap. 48, “Neonatal Pulmonary Physiology of
the recovery phase of RDS, can contribute Term and Preterm Newborns”).
to an increase in pulmonary fluid. The combined effect of reduced pulmonary
compliance and increased compliance of the rib
62.3.1.2 Greater Resistance of the cage results in a reduced FRC (Fig. 1) with a
Airways tendency toward atelectasis and a reduction in
The premature newborn presents increased resis- gaseous exchange.
tance above all due to the proximal airways for A mechanism enacted by the newborn to main-
various reasons: tain an adequate FRC is the partial closure of the
epiglottis during expiration (grunting): the prema-
Absence of the superficial layer of adipose tissue ture newborn often cannot maintain adequate
in the neck that helps to stabilize the airways, laryngeal tone and so may undergo a loss of
thus keeping them patent (Wilson et al. 1980; pulmonary volume. It has been shown that the
Cohen and Henderson-Smart 1986). suppression of grunt caused by endotracheal intu-
Reduced mobility of the genioglossus muscle that bation creates a reduction in paO2 (Harrison et al.
normally stabilizes the pharynx (Gauda et al. 1968).
1987). Aside from the cry, the newborn has two fur-
Reduced diameter of the airways. ther mechanisms to increase FRC: (1) maintaining
Increased compliance of the airways, which the contraction of the inspiratory muscles during
creates a tendency for them to collapse dur- the first phase of expiration and (2) commencing
ing inspiration; this increased compliance the inspiration before expiration has finished. This
also increases the ventilation of the dead strategy, which has the effect of increasing the
space. FRC (dynamic increase of FRC), can facilitate
gaseous exchange but is disadvantageous from
The premature newborn also presents the point of view of the amount of energy
increased resistance at the level of the peripheral expended (Schulze et al. 1990). Fatigue or the
airways. The reasons for this are: presence of apnea in the newborn with respiratory
62 Continuous Positive Airways Pressure and Other Noninvasive Respiratory Techniques in Newborns 975
a b
P P
FRC V FRC V
Fig. 1 Schematic representation of lung elastic (continu- expanding force of the chest wall. FRC is lower in the
ous line) and of chest wall (discontinuous line) forces in preterm (b) compared to the term newborn (a) due to
static conditions: the lung tends to a volume equal to zero, both an higher force of lung retraction (lower lung compli-
whereas the chest wall tends to a volume different from ance) and to a lower force of chest wall expansion. P
zero; the functional residual capacity (FRC) is achieved pressure, V volume
when the retraction force of the lung is equal to the
Fig. 2 Pressure/volume
curve of the lung
(compliance curve). ΔV,
Hyperdistension
change in volume; ΔP,
change in pressure; FRC
functional residual capacity. C ΔV3
Normal compliance in B; ΔP
low compliance in A and C
Volume
B ΔV2
FRC
ΔP
A
ΔV1
ΔP Critical opening pressure Residual
volume
Pressure
distress syndrome can defeat the abovementioned airways, followed by collapse of the alveoli.
mechanism and can encourage the development This necessitates greater pressures during inspira-
of atelectasis with consequent respiratory insuffi- tion in order to reopen the collapsed alveoli (crit-
ciency (Morley 1999). ical opening pressure). Pulmonary collapse also
The reduction in FRC means that the newborn causes epithelial damage with consequent protein
is working in the lower part of the compliance exudates and surfactant consumption (see
curve (Fig. 2, part A) and so is constrained to ▶ Chap. 63, “Lung Diseases: Surfactant Replace-
develop high pressures in order to gain small ment Therapy in Newborns”). This reduction in
increases in volume. A low volume at the end of pulmonary volume also brings a change in the
inspiration also induces closure of the small ratio of ventilation to perfusion with a consequent
976 F. Sandri et al.
increase in the alveolar-arterial gradient and CO2 through the elimination of the Hering-Breuer
concentration. deflation reflex which is activated by a distor-
tion in the inferior portion of the rib cage (Mar-
62.3.1.4 Respiratory Effects of CPAP tin et al. 1977). In this way, it also reduces the
The application of continuous positive pressure to incidence of obstructive apnea.
the airways amplifies the effect of the strategies by 6. Increasing the average pressure in the airways
the spontaneously breathing newborn that are (mean airways pressure, MAP) increasing the
aimed at maintaining an adequate volume at the ventilation-perfusion ratio.
end of expiration, minimizing the energy 7. Preserving the surfactant on the surface of the
expended to stabilize the respiratory system, and alveoli.
carrying out the mechanical work of respiration. 8. Reducing alveolar edema.
This prevents collapse of the airways and
improves many critical situations that bring Normalizing pulmonary volume, ventilations/
about an increase in the respiratory workload minute, and the ventilation-perfusion ratio, CPAP
required of the newborn. In summary, CPAP acts improves oxygenation, increases the elimination of
on the respiratory system by the following CO2, and reduces the WOB (Poulton and Oxon
mechanisms: 1936).
1. Increasing FRC (Fig. 2, Part B), eliminating
dynamic elevation of FRC reducing resistance 62.3.2 Cardiocirculatory System
in the airways. The reduction in airway resis-
tance is obtained by: CPAP results in a reduced preload in the right
Increasing the transverse section of the pharynx ventricle and consequently systolic output. The
(the oropharynx can account for 66% of extent of these effects depends on how much
supraglottidal resistance (Miller et al. 1990)). pressure is applied by the lungs to the vascular
Dilating the airways and making them more spaces: the lower the compliance, the lower the
rigid, stabilizing them, and preventing their applied pressure (Perlman and Thach 1988). In
collapse. In particular, an increase from the premature newborn, in the presence of a
12.5% to 47% of the ratio of the width to highly compliant rib cage and often low pulmo-
the length of the larynx at the moment of nary compliance, the pressure applied by the air-
maximum abduction of the vocal cords has ways to the pleural spaces is only 5–10%, with
been shown following CPAP application little effect on cardiac output. In full-term new-
(Gaon et al. 1999). borns with normal lungs, 25% of the pressure in
Increasing the FRC thus can favor caudal trac- the airways (Paw) can be transferred to the pleural
tion across the supraglottidal airways reduc- spaces, and therefore the use of high pressure in
ing their resistance (Van de Graaff 1988). these babies can have a significant effect on car-
2. Reducing the R-L shunt, thanks to the diac output. The increased thoracic compliance of
improved oxygenation and the consequent the premature newborn therefore protects the
vasodilation of the pulmonary circulation. intrathoracic vascular structure from a large
3. Stabilizing the thoracic wall, reducing its dis- increase in intrapleural pressure and from a con-
tortion and curbing paradoxical movement. sequent reduction in central venous return
Regularizing and slowing respiratory fre- (Gerhardt and Bancalari 1980). On the other
quency (Kurz 1999). hand, CPAP reduces pulmonary resistance in
4. Regularizing and slowing respiratory fre- babies with RDS because of the vasodilatation of
quency (Kurz 1999). the pulmonary circulation resulting from
5. Improving the capacity to generate a valid inspi- improved oxygenation; this is the most important
ratory force and thus to reopen collapsed alveoli effect in newborns with respiratory pathologies
following an obstructive event, probably treated with CPAP.
62 Continuous Positive Airways Pressure and Other Noninvasive Respiratory Techniques in Newborns 977
62.3.3 Renal Function 62.4.1 Continuous Flow Systems
Renal function depends largely on the hemody- These systems use a resistance to flow at the end
namic situation of the patient (Ahumada and of the respiratory circuit to produce pressure
Goldsmith 1996). In cases of low pulmonary com- above that of atmospheric pressure. These CPAP
pliance, the application of CPAP brings an systems include bubble CPAP. This device uses a
improvement in oxygenation, and renal function fixed gas flow, and the column of water in the
can only be positively affected. In the presence of expiratory limb generates CPAP equal to the
restricted water intake for the treatment or preven- length of the tube that is immersed under water,
tion of a PDA – a common situation in cases which creates chest vibrations through bubbling.
which require the application of CPAP – the All these devices are also fitted with systems to
administration of dopamine at renal doses may humidify and heat the air. Continuous-flow
be useful (approx. 3 μ/kg/min). mechanical ventilators can also be used to pro-
duce CPAP by the means of the PEEP valve to
maintain continuous positive pressure throughout
62.3.4 Intracranial Pressure the entire respiratory cycle.
A reduction in cerebral perfusion has been
reported in the course of the application of 62.4.2 Variable Flow Systems
PEEP. This is related to the level of the PEEP.
An increase in intracranial pressure was found 62.4.2.1 Benveniste System
during the application of CPAP by a box around The positive pressure is generated by a jet of gas
the head, due to compression of the veins in the directed toward an opening into a small chamber
neck. It does not appear that CPAP applied by from which the mixture for the newborn comes
endotracheal or nasal tube results in an increase out. Flow rates of 4–20 L/min serve to generate
of intracranial pressure (Ahumada and Goldsmith pressures in the chamber from 0 to 13 cmH2O.
1996). These pressures are comparable to those measured
at the oropharynx in the course of CPAP admin-
istered via one or two nasal prongs (this is indif-
62.4 Technical Aspect ferent, as long as the mouth is kept closed by the
use of a pacifier) (Pedersen and Nielsen 1994).
CPAP can be delivered by a variety of devices
and interfaces. There are two main types of 62.4.2.2 Infant Flow System
CPAP devices, categorized on the basis of the A generator is connected to a circuit composed of
flow characteristics: continuous and variable a three-channel tube (Figs. 3 and 4): one channel
flow systems. (inspiratory limb) provides gas flow and is
An important prerequisite for success in the connected to the nasal cavity via nasal prongs or
use of CPAP is a circuit that allows the pres- mask, one (expiratory limb) is open to ambient
sure to remain at the desired level throughout pressure, and one is used to measure the level of
the respiratory cycle. Excessive inspiratory pressure created at the generator level. The flow
or expiratory fluctuations directly increase provided by the infant flow driver is accelerated in
WOB and offset any benefits in pulmonary the twin injector nozzles of the N-CPAP genera-
mechanics produced by CPAP (Gherini et al. tor. When the patient makes a spontaneous inspi-
1979). ratory breathing effort, the generator provides
Substantial differences were found in the fluc- assistance by converting the kinetic energy of
tuations of Paw in different respiratory circuits the flow to pressure energy. When the infant
hooked up to a mechanical lung model (Rasanen makes a spontaneous expiratory effort, a pressure
and Leijala 1991). is applied at the nasal attachment of the N-CPAP
978 F. Sandri et al.
Fig. 3 Infant flow
generator
Fig. 4 Functioning of the Expiratory
infant flow generator tube
To the infant
Inspiration: flow towards the infrant
Expiratory
tube
From the infant
Expiration: flow deviated towards the expiratory tube
generator. This causes the flow to flip round and an inversion of the direction of the jet that helps
leave the generator via the expiratory limb. CPAP the expiration (Coanda effect). The kinetic energy
is maintained at the nasal connection throughout. of this high-velocity flow is transformed into pres-
When the expiratory breathing effort stops, the sure in the area of the nasal cavities, thus generat-
flow instantly flips back to the inspiratory posi- ing CPAP. Flow rates between 5 and 11 L/min
tion. The operating principle is that the high-pres- generate pressures between 2 and 10 cmH2O. As
sure jet flows in different directions in response to such, the system does not require an expiratory
the pressure generated at the level of the nasal valve. Tests on mechanical lung models have
cavities and the respiratory effort of the patient. demonstrated that a CPAP circuit achieves greater
During inspiration, the drop in pressure in the stability in Paw and a reduction in WOB of around
nasal cavities creates a pressure gradient that one quarter compared to traditional circuits (Moa
directs the flow toward the nasal cavities, thus et al. 1988; Moa and Nilsson 1993; Klausner et al.
assisting inspiration. During expiration, there is 1996). Available clinical studies have, on the
62 Continuous Positive Airways Pressure and Other Noninvasive Respiratory Techniques in Newborns 979
other hand, reported conflicting results. Two stud- times greater than in a full-term newborn. Cases of
ies did not show any difference between this sys- cerebral hemorrhaging have been reported in very
tem and traditional ones in terms of improving low birth weight newborns undergoing this ther-
pulmonary compliance, reducing oxygen require- apy due to the forces applied to the back of the
ments and improving respiratory frequency head by the mask’s attachments (Pape et al. 1976).
(Ahluwalia et al. 1998; Kavvadia et al. 2000). Facial Chamber The entire face protrudes into
A recent study comparing three circuits (infant a chamber held in place by a latex ring filled with
flow system, double nasal prongs, and single nasal styrene particles. This system too is now not used
prong fed by mechanical ventilators) for the appli- as it does not permit access to the newborn’s face
cation of NCPAP in newborns weighing less than for alimentation or aspiration.
1800 g with light respiratory distress or apnea Nasopharyngeal Tube (Mono-nasal CPAP)
demonstrated better pulmonary recruitment using The same type of tube used for tracheal intubation
the infant flow circuit (Courtney et al. 2001). is inserted through the nostril as far as the phar-
ynx. This is a simple technique, which is widely
used during the transport of the baby from the
62.5 Methods of Administering delivery room to the NICU or yet in the NICU,
CPAP in case of mild forms of respiratory distress or
apnea in the premature. The disadvantages lie in
Endotracheal Tube This method entails a notable the fact that this tube provides elevated resistance,
resistance (directly proportional to its length and particularly if it is of small diameter, and that the
inversely proportional to its radius) and as such tube also totally bypasses the humidifying-
involves a significant increase in WOB. At this heating action provided by the nasopharyngeal
time, it is no longer recommended as a system for mucous. In addition, it can give more nasal trauma
the administration of CPAP. Furthermore, by than nasal prongs.
bypassing the nasal and pharyngeal mucosa, it Nasal Prongs (Bi-nasal CPAP) Currently, this
creates an alteration in the humidification and is the most used and effective system for the
heating of the inhaled gases. Also the potential administration of CPAP in the newborn. The
trauma applied to the vocal cords and the respira- baby has to breathe through the nose; the nasal
tory mucosa makes its use inadvisable for new- prongs also allow the air to be humidified and
borns who do not need mechanical ventilation. heated by most of the nasopharyngeal mucous.
Head-Box (Helmet CPAP) This system is of The mouth in this case acts as a pop-off pressure
low efficacy below 1500 g bodyweight and valve. The nasal prongs are easily applied and less
extremely noisy and cumbersome and does not invasive than the endotracheal tube; first exam-
allow access to the newborn’s head. Furthermore, ples of nasal prongs were put into use in the early
it has been associated with an increased incidence 1970s (Agostino et al. 1973; Caliumi-Pellegrini et
of cerebral hemorrhage due to compression of the al. 1974; Kattwinkel et al. 1973). Particular atten-
neck (Vert et al. 1973). Aspiration pneumonia has tion has been paid to the work required of the
also been reported during feeding. newborn in order to overcome the resistance due
Face Mask This system too is rarely used, to the small diameter of the nasal prongs (the so-
particularly for premature infants. The mask called superimposed work of breathing). A study
should cover the nose and mouth and should reported an increase of 100% in WOB during
always be used with an orogastric feeding tube CPAP administered with nasal prongs compared
to avoid excessive abdominal distension. In the to CPAP with a face mask (Goldman et al. 1979).
premature newborn, apart from the problem of A closer evaluation of the study, however,
keeping the mask in place and the consequent revealed that this increase could, in part, be put
difficulty of generating a sufficient level of down to the increased resistance caused by the
CPAP with adequate flow, there are also problems catheter placed inside the prongs to relieve pres-
of excessive dead space that can be two or three sure. Recently, these prongs have been redesigned
980 F. Sandri et al.
with a precise angle and structure in order to This promotes the liberation of reserves of pulmo-
minimize resistance to the airflow (Klausner et nary surfactant, which in turn further stabilize the
al. 1996). Another problem with these prongs is air spaces preventing the formation of hyaline
related to the loss of flow (and hence of pressure) membranes and the following atelectasis that is
around the prongs themselves if they are not typical of surfactant deficiency. This should lead
secured properly. Nowadays, the prongs are to a decrease in the requirement for mechanical
made from a soft silicon material that expands ventilation with a reduction in its complications,
slightly in contact with the warmth and humidity in particular bronchopulmonary dysplasia.
of the nostrils, adapting to their dimensions and so The main reason for the interest in adopting
favoring a good fit. N-CPAP, especially in very low birth weight new-
Nasal Masks These devices, which consist of borns (VLBW, i.e., <1500 g), came from the
silicone masks that completely cover the nose, are publication of two multicenter retrospective stud-
sometimes a useful alternative to nasal prongs, in ies. They showed that the incidence of chronic
particular in extremely low birth weight infants. lung disease, assessed as the percentage of
VLBW survivors who were oxygen dependent at
28 days from birth, was significantly lower in
62.6 Clinical Applications centers that had been early adopters of N-CPAP,
despite having among the highest survival rates.
62.6.1 Respiratory Distress Syndrome The early adoption of N-CPAP at these centers
(RDS) was part of a low-invasiveness strategy consisting
of the tolerance of relatively high pCO2 values, up
The main physiopathological aspects of RDS, to 60 mmHg (permissive hypercapnia), before
whose principal cause is a deficit of surfactant proceeding to intubation and mechanical ventila-
(Avery and Mead 1959), are reduction in pulmo- tion, and the nonuse of paralyzing drugs (Avery et
nary compliance, reduction in FRC, and alteration al. 1987; Horbar et al. 1988).
in the ratio of ventilation to perfusion. The rigidity Early N-CPAP was largely used in VLBW
of the rib cage is also reduced with a paradoxical infants with recourse to intubation and mechani-
distortion during inspiration which is greater the cal ventilation only when it was held to be essen-
larger the reduction in pulmonary compliance, tial, based on well-established criteria (Jonsson et
with a consequent reduction in tidal volume (Mor- al. 1997; Kamper and Ringsted 1990; Kamper et
ley 1999; Greenough and Roberton 1996). These al. 1993; Lundstrom 1996). The common denom-
alterations lead to a profound alteration in gas inators of these clinical experiences are:
exchange and increase the respiratory workload;
the consequences of which are the presence of Intubation in the delivery room only if considered
hypoxemia, hypercapnia, and acidosis. essential for cardiopulmonary resuscitation
Early N-CPAP, i.e., application of N-CPAP to all
62.6.1.1 Clinical Evidence newborns within the first 30 min of life or at the
The first clinical experience of neonatal CPAP appearance of the first signs of respiratory
application came in 1971 with a case report of 20 distress
patients affected by RDS (Morley 1999). This was Intubation and, if necessary, mechanical ventila-
followed by others (Bancalari and Sinclair 1991; tion only if one or more of the following
Cordero et al. 1997; Tarnow-Mordi et al. 1986). criteria are met (criteria for failure of
The rationale behind the use of early N-CPAP N-CPAP): untreatable apnea, respiratory aci-
in the VLBW newborn lies in the facilitation of dosis (pCO2 > 65–70 mmHg and pH <7.20),
the acquisition and maintenance of an adequate and requirement of exogenous surfactant
pulmonary volume (FRC). As well as improved
gas exchange, a normal air-liquid interface is In Scandinavia, where the N-CPAP is wide-
maintained at the level of the terminal alveoli. spread and long-term used, the success of
62 Continuous Positive Airways Pressure and Other Noninvasive Respiratory Techniques in Newborns 981
N-CPAP in treating VLBW infants avoiding 25 and 28 weeks and an ability to breathe at 5 min
mechanical ventilation, was proportional to the after birth but needing respiratory support. Infants
gestational age (76% of newborns 26 weeks’ were ineligible if they had been intubated before
GA require ventilation compared to 43% of new- randomization or if they required no respiratory
borns >26 weeks) regardless the use of prenatal support or oxygen. At 5 min after birth, the allo-
prophylaxis with steroids (Jonsson et al. 1997). cated treatment was started. In infants who were
There is a general tendency to tolerate higher assigned to receive N-CPAP, this was started at a
pCO2 values than in the past (Avery et al. 1987; pressure of 8 cm of water with nasal prongs. They
Kamper and Ringsted 1990; Kamper et al. 1993), were intubated and underwent ventilation only if
and this has reduced the need for intubation. Even they had any of the following clinical signs: apnea
when mechanical ventilation is undertaken, it unresponsive to stimulation and methylxanthine
does not require the use of aggressive ventilation treatment, an arterial pH of less than 7.25 with a
strategies in search of blood gas values that are partial pressure of arterial carbon dioxide (paCO2)
obtained at the cost of high baro-volutrauma of more than 60 mmHg (8.0 kPa), a metabolic
(Jonsson et al. 1997). acidosis not responsive to treatment, or treatment
A study carried out on 67 newborns of with more than a 60% concentration of oxygen.
<1000 g birthweight (extremely low birth weight, Infants receiving N-CPAP were treated with sur-
ELBW) who underwent early N-CPAP, if they factant only after intubation. Surfactant treatment,
were not intubated in the delivery room for pri- ventilation settings, and extubation and
mary resuscitation, demonstrated that it was not reintubation criteria were not mandated in either
necessary to intubate and start mechanical venti- group and followed local protocols. Half the
lation in 73% of the newborns >28 weeks and in infants in the N-CPAP group were subsequently
32% of the newborns 28 weeks (Lindner et al. intubated. Infants in the N-CPAP group had a
1999). In another study, Finer et al. (Finer et al. better outcome at 28 days than those in the intu-
2004) found that all infants of 23 weeks’ gestation bation group. The two groups had similar out-
required intubation in the delivery room, whereas comes at 36 weeks’ gestational age, but there
only 3 of 21 (14%) infants of 27 weeks’ GA was an increased incidence of pneumothorax in
required such intubation. the N-CPAP group.
The reduction in the percentage of mechani- In 2010, Finer et al. published the SUPPORT
cally ventilated newborns did not cause an trial (Finer et al. 2010).In this randomized multi-
increase in mortality or negative side effects center trial, inborn infants of 24.0–27.6 weeks’
such as cerebral hemorrhage (Jonsson et al. GA were randomly assigned to intubation and
1997; Kamper et al. 1993; Lindner et al. 1999; surfactant treatment (within 1 h after birth) or to
Gittermann et al. 1997; Jacobsen et al. 1993; N-CPAP treatment initiated in the delivery room.
Sandri et al. 1999). The primary outcome was death or BPD at
However, despite uncontrolled and cohort 36 weeks’ postmenstrual age. A total of 1318
studies suggesting the efficacy of N-CPAP in infants were enrolled in the study. The rates of
avoiding MV and ventilatory-induced lung injury, primary outcome did not differ significantly
there were few randomized clinical trials between the two groups (47.8% and 51.0%,
confirming the benefit of N-CPAP as the primary respectively) without any other differences in
type of respiratory support in preterm newborns. terms of adverse neonatal outcomes. The authors
Morley et al. published the COIN trial in 2008 concluded that CPAP has to be considered as an
(Morley et al. 2008). In this trial, N-CPAP was alternative to intubation and surfactant in preterm
compared with intubation and ventilation on the infants.
hypothesis that the use of N-CPAP shortly after There are studies of great interest that have
birth would reduce the rates of death and demonstrated the efficacy of an approach that pre-
bronchopulmonary dysplasia. The main eligibility scribes the use of early N-CPAP together with the
criteria were a gestational age at delivery between administration of surfactant in the treatment of
982 F. Sandri et al.
RDS. This approach, known as the INSURE >40% showed no difference in requirements for
approach (intubation-surfactant-extubation), is surfactant and mechanical ventilation comparing
based upon the adoption of the following proce- two groups to which N-CPAP had been applied: in
dure. In a newborn undergoing N-CPAP, when- the first group, N-CPAP was applied within 300 of
ever administration of surfactant is indicated, the birth, regardless of the clinical picture; in the
patient is intubated, surfactant is administered in second group, N-CPAP was applied only in the
the usual doses, and the patient is then placed presence of respiratory distress with oxygen
again in N-CPAP after extubation (assuming that requirements >40% (Sandri et al. 2004).
the patient is breathing spontaneously). Mechan- A systematic review of the INSURE approach
ical ventilation is only applied when indicated by reported a reduced need for MV in the first week
well-defined criteria of failure (Blennow et al. of life, when used early in respiratory distress
1999). syndrome (Stevens et al. 2007).
A multicenter study carried out in Sweden Either prophylactic surfactant or delivery room
compared the incidence of mechanical ventilation N-CPAP to maintain functional residual volume
in two groups of newborns affected by moderate- was identified as potentially beneficial practice
to-severe RDS to whom early CPAP was applied which, if adopted in extremely preterm infants,
(e.g., application at the first clinical signs of respi- could reduce lung injury (Burch et al. 2003).
ratory distress). The treatment group received the Recently, the CURPAP study compared the
INSURE approach if their oxygen requirement administration of prophylactic surfactant
exceeded 60%. The control group received treat- followed by N-CPAP (prophylactic INSURE)
ment only with N-CPAP and surfactant was with early N-CPAP followed by early selective
reserved for cases where mechanical ventilation surfactant given through a brief course of endo-
was required. The criteria for application of tracheal intubation (early rescue INSURE) to pre-
mechanical ventilation (apnea and or oxygen term newborns of GA 25–28 weeks not intubated
requirement gt, 80%) were the same for both at birth (Sandri et al. 2010). In both groups, MV
groups. Recourse to mechanical ventilation was was started after surfactant in the absence of good
reduced from 85% in the control group to 43% in respiratory drive. Infants who were extubated to
the treatment group (Verder et al. 1994). N-CPAP after surfactant were eligible for MV if
The same authors later carried out a multicen- the following N-CPAP failure criteria occurred:
ter study on newborns with RDS below 30 weeks’ FiO2 > 0.40 on N-CPAP to maintain oxygen
gestational age and who were undergoing early saturation of 85–92% for at least 30 min unless
N-CPAP. They demonstrated that when the rapid clinical deterioration occurred, intractable
INSURE approach was adopted early in RDS, i. apnea, respiratory acidosis defined as
e., at an oxygen requirement between 40% and pCO2 > 65 mmHg (8.5 kPa), and pH <7.20.
60%, there was a reduction in the need for This study showed that, in spontaneously breath-
mechanical ventilation and of death in the first 7 ing preterm newborns treated with N-CPAP, pro-
days postpartum from 63% to 21% compared to a phylactic surfactant given within 30 min from
later approach (oxygen requirement >60%) birth is not superior to early selective surfactant
(Verder et al. 1999). in terms of requirement of MV in the first 5 days of
This last work, aside from demonstrating the life.
efficacy of the INSURE approach, permitted the The main implication for clinical practice of
establishment of a limit to the oxygen requirement the CURPAP study is that N-CPAP should be
in patients with RDS undergoing N-CPAP (FiO2 started soon after birth in spontaneously breathing
about 40%) above which the administration of infants of 25–28 weeks’ gestation, and early selec-
surfactant is indicated. tive surfactant should be given once signs of
A study conducted in Italy on 155 newborns of respiratory distress have developed. Extubation
gestational age 28 and <32 weeks treated by after surfactant administration should be
the INSURE approach at oxygen requirements attempted as soon as possible. With this strategy,
62 Continuous Positive Airways Pressure and Other Noninvasive Respiratory Techniques in Newborns 983
more than 50% of infants will need only N-CPAP, (Schmölzer et al. 2013; Fischer and Bührer 2013).
49% intubation and surfactant, and nearly one This concept is reinforced in the current neonatal
third also mechanical ventilation in the first resuscitation guidelines (Wylie et al. 2015).
5 days of life. Overall, the respiratory approach In conclusion, the available published data
used in this study resulted in a very good respira- suggests that:
tory outcome: 78–79% of infants, in both arms,
survived without any supplementary oxygen or VLBW infants, not intubated at birth for cardio-
respiratory support at 36 weeks’ postmenstrual pulmonary resuscitation, can be treated conser-
age. The incidences of moderate/severe BPD vatively using NCPAP, with the administration
were 14.3 and 11.7%, respectively, in the prophy- of surfactant and mechanical ventilation only
lactic surfactant and N-CPAP groups, which is being used if precise clinical, laboratory test
lower than the 30% incidence reported in other and instrumental criteria are met.
studies (Walsh et al. 2003; Payne et al. 2006). Prenatal steroids, higher GA, and female sex are
Finally, Dunn MS et al. published the VON associated with higher chances of being treated
trial (Dunn et al. 2011). In this multicenter ran- noninvasively.
domized trial, three approaches were compared A precise limit of gestational age or birth weight
for the initial respiratory management of preterm below which N-CPAP cannot be used with
infants (26.0–28.6 weeks’ GA): prophylactic sur- success has not yet been established.
factant (PS) and mechanical ventilation, prophy- Using NCPAP together with early selective sur-
lactic surfactant given as INSURE procedure factant to avoid more invasive strategies does
(ISX) followed by N-CPAP (bubble CPAP), or not entail an increase in mortality rates or neg-
N-CPAP (bubble CPAP) and selective surfactant ative side effects.
treatment. Primary outcome was the incidence of
death and BPD at 36 weeks’ postmenstrual age.
Six hundred forty eight infants were enrolled in 27 62.6.2 Neonatal Apnea
centers. Preterm infants initially managed with
INSURE approach or N-CPAP plus selective sur- Apnea is traditionally classified into three catego-
factant therapy showed similar outcomes to those ries based on the presence or absence of obstruc-
treated with PS and mechanical ventilation. tion of the upper airways: central, obstructive, and
Therefore, the authors concluded that early N- mixed (see ▶ Chap. 66, “Apnea of Prematurity
CPAP approach may be recommended as a less and Sudden Infant Death Syndrome”)
invasive and potentially less expensive method of (Kattwinkel 1977; Miller et al. 1985).
management in this category of patients. Because most apneic episodes have an obstruc-
In the past, doubts have been cast on the pos- tive component, CPAP appears to be one of the
sibility of generalizing low-invasiveness treat- most effective strategies. It splints the upper air-
ment strategies in VLBW infants (Roberton way with positive pressure and decreases the risk
1993). Currently, similar doubts may be raised of pharyngeal or laryngeal obstruction. CPAP
for ELBW infants, in whom the application of probably also improves apnea by increasing func-
results from studies (Finer et al. 2004; Morley et tional residual capacity (FRC) and so improving
al. 2008; Sandri et al. 2010) should take into oxygenation status (Kattwinkel 1977; Miller et al.
account the rate of prenatal steroid use and the 1985). The positive effect of CPAP is also due to
type of antenatal healthcare program. the stabilization of the rib cage, (Miller et al. 1990;
Nevertheless, two meta-analysis that analyzed Van de Graaff 1988; Kattwinkel 1977) that con-
the results of the most recent RCTs (e.g., CURPAP, tributes to the airways opening and to the reduc-
COIN, SUPPORT, etc.) demonstrated that using a tion of the Hering-Breuer reflex (Martin et al.
non-invasive respiratory approach in the DR and 1977).
beyond can lead to a small but significant reduction Given that N-CPAP does not have a direct
in the rate of BPD in very premature infants effect on apnea of central origin, its use in
984 F. Sandri et al.
association with stimulants of the respiratory cen- confirmed the efficacy of N-CPAP in weaning
ters such as methylxanthine below 32 weeks of of patients from mechanical ventilation and thus
gestational age is generally accepted (AARC recommended its adoption as an elective method
(American Association for Respiratory Care) for use after extubation, if necessary in combi-
1994; Aranda and Turmen 1979; Schmidt et al. nation with a methylxanthine (Davis and
2006). Henderson-Smart 2000). To achieve successful
In case of persistent and severe apnea of pre- extubation to N-CPAP, it is also important to
maturity, before deciding to intubate the baby, it choose the most appropriate moment in terms
could be useful to switch the infant from N- of parameters of mechanical ventilation. This
CPAP to other form of noninvasive respiratory should be at a point where the respiratory prob-
approach (e.g., bi-level CPAP or NIPPV), even lem can be considered overcome by ventilation
better if synchronized with the patient effort, as (FiO2 < 0.35, mean airways pressure [MAP]
suggested from a recent randomized crossover <7 cmH2O, ventilatory frequency 20/min)
trial (Gizzi et al. 2015). (So et al. 1995; Higgins et al. 1991; Davis and
Henderson-Smart 2000). A recent study com-
paring a continuous flow with a variable flow
62.6.3 Weaning the Patient from CPAP device (bubble CPAP vs. infant flow sys-
Mechanical Ventilation (Post- tem) concluded that both devices were effective
extubation Phase) in the post-extubation management of infants
with RDS. However, in infants ventilated
It is well known that after a period (long or for 14 days, bubble CPAP is associated with
short) of intubation and mechanical ventila- a significantly higher rate of successful
tion, extubation can fail, leading to the re- extubation and with a significantly reduced
intubation of the newborn (Fox et al. 1981). duration of CPAP support (Gupta et al. 2009).
The reasons for this failure are substantially as Even if previous RCTs have shown that N-
follows: CPAP is a useful method for providing respira-
tory support after extubation, nevertheless this
Apnea approach sometimes fails and physicians use as
An increase in oxygen requirements (this can be alternative nasal intermittent positive pressure
correlated to a loss of volume from a malfunc- ventilation (NIPPV). A recent meta-analysis
tion of the glottis after intubation or to (Lemyre et al. 2017) has compared effects of
atelectasis) management with N-CPAP versus NIPPV in
Respiratory acidosis preterm infants after extubation. The Cochrane
review concluded that NIPPV reduces the inci-
Various contributors have demonstrated the dence of extubation failure and the need for re-
efficacy of N-CPAP application in the post-- intubation within 48 h to 1 week more effec-
extubation phase following mechanical ventila- tively than N-CPAP. However, nasal ventilation
tion. N-CPAP compared to direct extubation has no effect on BPD nor on mortality. The
reduces the need of re-intubation, both in new- authors suggested that synchronization may be
borns weighing <1500 g (16% failure rate vs. important in increasing the efficacy of NIPPV.
52%) (So et al. 1995) and in those weighing Last but not least, a recent meta-analysis (Wil-
<1000 g (24% failure rate vs. 79%) (Higgins kinson et al. 2016) demonstrated that high-flow
et al. 1991). The factors that necessitate re- nasal cannulae (HFNC) have similar rates of
intubation, principally apnea but also an efficacy than other forms of noninvasive respi-
increase in oxygen requirement due to loss of ratory support in preterm infants to prevent fail-
pulmonary volume and respiratory acidosis, are ure of extubation. Therefore, HFNC could be
counteracted by N-CPAP. A meta-analysis considered a valid alternative to N-CPAP in this
62 Continuous Positive Airways Pressure and Other Noninvasive Respiratory Techniques in Newborns 985
phase of the management of preterm infants atelectasis, CPAP may be used electively
with respiratory distress. (AARC (American Association for Respiratory
Care) 1994).
Bronchiolitis Early CPAP (predominantly
62.6.4 Other Clinical Applications nasal) can rapidly aid respiratory muscles and
improve respiratory distress symptoms (retrac-
Transient Tachypnea of the Newborn (TTN) Some tions, tachypnea, agitation) and blood gas mea-
doubts have been raised regarding the safety of surements (pO2, pH, pCO2). These effects have
N-CPAP in TTN (see ▶ Chap. 55, “Pulmonary been attributed to widening of the bronchioli by
Hemorrhage, Transient Tachypnea, and Neonatal positive pressure, followed by emptying of the
Pneumonia”) due to the theoretical risk of air lung and restoration of a normal FRC. This leads
trapping and pneumothorax. There are, however, to a reduction in the use of mechanical ventilation
no relevant published data (Greenough 1996). (Beasley and Jones 1981; Soong et al. 1993).
Authoritative guidelines include TTN in indica- N-CPAP has also demonstrated its efficacy in the
tions for N-CPAP application (AARC (American treatment of apnea associated with RSV infection
Association for Respiratory Care) 1994; Jonzon (McNamara and Sullivan 1997).
1991), and our personal experience is that the Paralysis of the Phrenic Nerve Cases have
early application of N-CPAP for TTN brings been published in which paralysis of the phrenic
about a reduction in the clinical signs of respira- nerve was successfully treated with N-CPAP
tory distress without a significant increase in the application, which corrects the deficit in trans-
incidence of pneumothorax. mural pressure caused by paralysis of the dia-
Meconium Aspiration Syndrome (MAS) The phragm (Bucci et al. 1974).
application of a continuous distending pressure Nebulization of Pharmaceuticals N-CPAP has
could be beneficial, resolving the areas of atelec- recently been used for the respiratory administra-
tasis and reopening and stabilizing the airways tion of pharmaceuticals (beta-blockers, steroids,
(Ahumada and Goldsmith 1996; Fox et al. acetylcysteine, and adrenaline), although this
1975). However, it should be reserved for the does not currently seem to be of great clinical
less severe forms of MAS (see ▶ Chap. 50, interest (Smedsaas-Lofvemberg et al. 1999).
“Meconium Aspiration Syndrome”). More seri-
ous cases will require intubation (bronchoalveolar
lavage with) surfactant, and mechanical ventila- 62.7 Side Effects
tion (Lam 1999; Mosca et al. 1996).
Congenital Cardiopathies with Hyperafflux System Malfunctions The obstruction of the nasal
Pulmonary hyperafflux can lead to a reduction in prongs or the tube by mucous (like the obstruction
pulmonary compliance and to a change in the of the nasal passages) is common during N-CPAP,
ventilation-perfusion ratio, with consequent hyp- with potentially serious consequences (sudden
oxemia, which is potentially correctable with decrease in oxygenation) due to the lack of airflow
CPAP (Ahumada and Goldsmith 1996). delivered to the patient (AARC (American Asso-
Tracheobronchomalacia CPAP resolves the ciation for Respiratory Care) 1994).
collapse of the airways present in this condition, Pulmonary Overdistention Pulmonary hyper-
considerably relieving the respiratory distress cor- distension is the most serious complication that
related with it (AARC (American Association for can occur during N-CPAP. This condition can
Respiratory Care) 1994; Miller et al. 1986). occur whenever the positive pressure applied is
Atelectasis The onset of atelectasis can be due excessive with respect to the patient’s pulmonary
to different factors but its resolution will require compliance.
the removal of the root cause in each case. How- The presence of a hyperdistended lung leads to
ever, in many situations, e.g., post-extubation an increased risk of pneumothorax, a worsening
986 F. Sandri et al.
Fig. 5 Effects of different 120 8 80
CPAP levels on the central 7
100
venous pressure (CVP (■),
PaCO2 (mmHg)
6
PaO2(mmHg)
CPV(mmhg)
PaO2 (~), and PaCO2 (◆) 80 5
(Modified from Gregory 40
60 4
(1986))
40 3
2
20 1
0 0 0
3 5 8 11 13
CPAP (mbar)
of the ventilation-perfusion ratio, and an increase
in CO2 retention and WOB. It is also known that 62.8 Suggestions for N-CPAP Use in
the higher the pulmonary compliance, the greater the Clinical Practice
the transmission of positive pressure to the poste-
rior mediastinum, followed by an increase in cen- 62.8.1 Pressure Level
tral venous pressure with a decrease in venous
return and cardiac output. Figure 5 shows the There have been few data published to evaluate a
effects of rising CPAP values on central venous method that would allow the establishment of an
pressure, on paO2, and on paCO2, the onset of optimum pressure for CPAP, and its clinical appli-
which correlates directly with hemodynamic and cability in practice is very limited (Tanswell et al.
respiratory interferences (Fig. 2, part C) (Gregory 1980; Elgellab et al. 2001).
1986). These hemodynamic effects can have seri- It is advisable to:
ous consequences on gastrointestinal, renal, and
cerebral perfusion and can cause an increase in Start with a level of CPAP between 5 and 7 cmH2O.
intracranial pressure due to the decrease in venous Individualize the CPAP level on the basis of respi-
drainage (Ahumada and Goldsmith 1996; AARC ratory dynamics, respiratory frequency,
(American Association for Respiratory Care) grunting, and thoracic retraction. The level of
1994). CPAP can be increased up to 8–10 cmH2O.
Gastric Distension It can cause reduced venti- Choose higher values if there is reduced pulmo-
latory excursion due to compression of the dia- nary volume.
phragm or even gastric perforation (CPAP belly Once an improvement in the respiratory dynamics
syndrome) (Ahumada and Goldsmith 1996; has been reached, adjust the FiO2 so as to
AARC (American Association for Respiratory maintain PaO2 between 60 and 80 mmHg or
Care) 1994; Leone and Krasna 2000). It can be tcO2 saturation (measured by pulse oximetry,
prevented by properly affixing the nasal prongs, SpO2) at target range (e.g., 90–95% in preterm
by positioning a permanent orogastric tube, and infants as suggested by the recent European
by periodically checking the degree of abdominal RDS guidelines) (Sweet et al. 2017).
distension. Reduce the level of CPAP as long as lung compli-
Nasal Lesions Nasal-cutaneous lesions have ance, lung volume, and oxygenation improve
been described during N-CPAP with possible in order to avoid hyperdistension and transmis-
permanent deformities (Loftus et al. 1994; Rob- sion of positive pressure to the mediastinum.
ertson et al. 1996). These lesions can be pre-
vented by choosing silicone nasal prongs 62.8.2 Monitoring
(which permit good contact without being
harmful), nasal prongs of the correct dimensions The use of N-CPAP therapy requires accurate
with relation to the newborn’s nostrils and monitoring to both evaluate the evolution of the
ensuring their correct positioning. illness and to identify negative side effects:
62 Continuous Positive Airways Pressure and Other Noninvasive Respiratory Techniques in Newborns 987
Blood gas analysis from arterial or an arterialized the lymphatic and vein vessels in the hours fol-
capillary blood represents the gold standard for lowing birth (Hooper et al. 2015). The term infant
blood gas measurement. It should be carried is able to generate this delta pressure with the first
out within 15–30 min of starting therapy and three to five initial prolonged inspiration to clear
whenever clinically indicated (Ahumada and the lung fluid (Karlberg 1960). On the contrary,
Goldsmith 1996). the preterm infants are often unable to do it. In
Pulse oximetry. Despite its universally known animal experiment, it has been demonstrated that
limitations, this is the method of choice for the use of sustained inflation (SI) (a deep and
the continuous monitoring of oxygena- prolonged inflation), especially when followed
tion level, particularly when the situation has by an adequate PEEP, is an intriguing approach
stabilized, . It is advisable to target O2 satura- to allow the preterm animal to create the FRC (Te
tion values according to the recent guidelines Pas et al. 2009). Also in humans, the use of SI
(e.g., 90–95%) (Sweet et al. 2017). (e.g., a peak pressure of 20–25 cmH20 maintained
Transcutaneous PO2 and PCO2. This type of mon- for 10–15 sec) seems to facilitate the respiratory
itoring, though potentially very useful, has in transition at birth. In fact, a recent meta-analysis
reality many limitations that require great cau- that compared SI versus positive pressure ventila-
tion in interpreting the values it obtains, which tion at birth in preterm infants at risk for RDS or
should be verified and checked frequently with signs of respiratory failure concluded that SI
against the blood gas values. improved short respiratory outcomes (reduced the
ECG and systemic arterial pressure. The potential need of mechanical ventilation in the first 72 h of
side effects of CPAP on circulation require life), even if death and BPD occurrence were not
continuous monitoring of heart rate and peri- improved (Schmolzer et al. 2014). For this reason,
odic measurement of systemic blood pressure. the recent neonatal resuscitation guidelines sug-
Chest X-ray provides valuable information in gest against the routine use of SI in the resuscita-
evaluating the effect of CPAP on the evolution tion of infants with signs of respiratory failure, but
of the disease, such as improvement of the suggest the use only in individual clinical circum-
radiological picture or the development of stances or in research settings (Wylie et al. 2015).
complications such as hyperdistension or Some authors suggest to use two ancillary thera-
pneumothorax. pies in the delivery room to reduce the N-CPAP
failure: early surfactant administration and caf-
feine (Kribs and Hummler 2016). Surfactant in
62.8.3 How to Try to Prevent Failure of fact allows to achieve an early FRC by improving
N-CPAP? lung compliance (Davis et al. 1998), and caffeine
is a determinant in promoting spontaneous breath-
Since the incidence of N-CPAP failure in large ing in premature infants that are at risk for apnea
RCTs evaluating CPAP versus routine intubation (Henderson-Smart and Steer 2001). Surfactant is
is close to 50% (Wright et al. 2016) and CPAP delivered by less invasive surfactant application
failure occurs early (at about 8 h of life) above all (LISA) by inserting a small catheter in the tra-
because of increasing of oxygen requirements, it chea and delivering the surfactant through this
seems to be reasonable that early interventions catheter without intubation (Kribs and Hummler
used to establish an effective FRC may help N- 2016). The authors concluded that these two
CPAP a success. After delivery, the lung is fluid- approaches can be considered a “bridge”
filled and the reabsorption of the liquid from the between the delivery room and the NICU in
lung, in the past attributed to the epithelial sodium order to facilitate the initial success of the N-
channel, is initially related to the delta pressure CPAP. Future research is needed to identify
generated by the first breaths that move the lung which preterm infants can have benefits from
fluid in the airway until the alveoli, where the fluid this early approach yet in the delivery suite
is pumped into the interstitium and reabsorbed by instead of in the NICU. Further studies will also
988 F. Sandri et al.
make clear whether the LISA procedure, or sim- are fixed to. The bonnet must be large enough to
ilar procedures, can replace INSURE (see section reach the level of the eyebrows and to cover the
“Clinical Evidence”) or what the place of both ears completely. If it is too small, it will tend to
LISA and INSURE are in the treatment of infants ride up, forcing the circuit toward the neonate’s
with RDS on N-CPAP. Indeed, both procedures nose. The prongs generally come in three sizes
have advantages and disadvantages. (small, medium, and large): the size that is most
compatible with the patient’s nostrils must be
chosen. It is wrong to assume that the smallest
62.8.4 Weaning from N-CPAP prongs are for the most delicate neonate. If the
prongs are too small, they do not give an adequate
Once clinical improvement has been obtained as hold, which is necessary to maintain a constant
previously described, the improved situation is level of CPAP and to avoid an increase in airways
shown by the ability to progressively reduce resistance. This does not allow a reduction in
FiO2 (in 2–5% steps down to 21%) and the WOB and may cause it to increase.
level of positive pressure (1 cmH2O at a time The silicone nasal prongs warm up when
down to 2–3 cmH2O). Once minimal values inserted into the nostrils, and in doing so, they
have been reached for both parameters, the N- become softer and expand slightly, improving
CPAP therapy can be stopped more or less grad- their hold. The use of creams or plasters around
ually, taking into account the weight and gesta- the nose is not recommended. Once the circuit has
tional age of the baby monitoring an eventual been positioned, care must be taken that the edge
increase of WOB (clinically manifested, e.g., by of the prongs does not adhere to the nasal septum:
tachypnea and or intercostal and diaphragmatic the base of the prongs must always be visible
retractions) and depending on the presence or (Fig. 6) (see also section “Positioning of the
lack of other indications for therapy, e.g., apnea Circuit”).
of prematurity. The prongs can increase the production of
nasal secretions, and for this reason, the system
for humidifying and heating the administered gas
62.9 Nursing of the Neonate in N-
CPAP
The importance of nursing is particularly impor-
tant when CPAP is administered via nasal prongs.
The following require particular attention (Sahni
et al. 2016):
Correct attachment (headset and nasal prongs)
Correct positioning (circuit and infant)
Correct temperature setting on the humidifier
Correct aspiration of the airways and feeding
62.9.1 Attachment (Headset and Nasal
Prongs)
The attachments for the nasal prongs always
include a bonnet, which the prongs themselves Fig. 6 Correct positioning of the nasal prongs
62 Continuous Positive Airways Pressure and Other Noninvasive Respiratory Techniques in Newborns 989
outside the incubator in order to minimize noise:
if necessary use the extension tube.
62.9.3 Positioning the Infant
The infant can be placed in a prone, supine (with
support), or lateral position. The neck, however,
must always be slightly extended. The prone
position has been shown to be better for the
premature neonate with respiratory distress
(Sahni et al. 2016).
Kangaroo care is possible during N-CPAP. It is
important to keep the infant’s mouth closed. This
Fig. 7 Nasal mask for the application of nasal CPAP confers at least three benefits:
It avoids loss of pressure and consequent instabil-
ity of CPAP, therefore reducing WOB.
is very important (see section “Humidification It avoids drying of the mucous and the formation
and Heating”). When the infant cries, there may of dense, whitish secretions because it favours
be a loss of pressure: therefore, correct nursing is the deglutition of saliva.
extremely important during the administration of It keeps the jaw in the forward position,
CPAP (see also section “Positioning the Infant”). thus avoiding the tongue falling backward
Silicone masks are available as an alternative and guaranteeing the patency of the airways.
to nasal prongs for very small or large infants
(Fig. 7). The infant can be helped to keep their mouth
closed. Initially, it can be of use to place a
support (e.g., roll of gauze) under the neonate’s
62.9.2 Positioning of the Circuit chin. The use of a pacifier favors deglutition and
reduces the formation of saliva in the infant’s
The tubes should be positioned so as not to pull on mouth. It also helps keep the jaw in the forward
the flow generator or put pressure on the neonate’s position.
nose.
The flow generator is connected to the nasal
mask by ribbons, which must not be too tight. 62.9.4 Humidification and Heating
Once the ribbons have been fixed, they should be
directed downward, that is, toward the base of Adequate humidification is important in order to
the ears and away from the eyes in order to avoid avoid drying of the mucous and the accumulation
swelling at this level. Plasters or knots between of dense secretions, which can block the airways.
the ribbons and the nasal mask should be The recommended gas temperature is 37 C: this
avoided to facilitate the rapid adjustment of the is obtained by setting the resistance temperature of
prongs. Only the gas arrival tube should be the circuit at 39 C and that of the gas at 2 C less.
attached to the bonnet while the others should It is always important to ensure that the tempera-
be left free. ture sensor is placed outside the incubator. If the
In the case of the infant flow generator, it is neonate is positioned under an infant warmer, the
important that the outlet tube be positioned sensor should be thermally isolated.
990 F. Sandri et al.
62.9.5 Airways Suction Bancalari E, Sinclair JC (1991) Mechanical ventilation. In:
Sinclair JC, Brachen MB (eds) Effective care of the
newborn infant. Oxford University Press, Oxford, pp
It is not necessary to regularly suction the infant in 200–220
N-CPAP and this maneuver should be performed Barach AL, Martin J, Eckman M (1937) Positive pressure
only when necessary. To reduce the formation of respiration and its application to the treatment of acute
oral and nasal secretions, the following measures pulmonary edema and respiratory obstruction. Proc
Am Soc Clin Invest 16:664–680
can be used: Beasley JM, Jones SEF (1981) Continuous positive airway
pressure in bronchiolitis. Br Med J 283:1506–1508
Set the humidifier to a suitable temperature (see Blennow M, Jonsson B, Dahlstrom A et al (1999) Lung
previous paragraph): if the temperature is too function in premature infants can be improved. Surfac-
tant therapy and CPAP reduce the need of respiratory
low, it can favor the formation of dry support. Lakartidningen 96:1571–1576
secretions. Bucci G, Marzetti G, Picece-Bucci S et al (1974) Phrenic
Keep the infant’s mouth closed (see section “Posi- nerve palsy treated by continuous positive pressure
tioning the Infant”). breathing by nasal cannula. Arch Dis Child 49:230–232
Bullowa JGH (1937) The management of the pneumonias.
Oxford University Press, New York
Burch K, Rhine W, Baker R et al (2003) Implementing
62.9.6 Feeding potentially better practices to reduce lung injury in
neonates. Pediatrics 111:e432–e436
Caliumi-Pellegrini G, Agostino R, Orzalesi M et al (1974)
The use of N-CPAP does not prevent feeding. Twin nasal cannula for administration of continuous
Food intake should be encouraged (via orogastric positive airway pressure to newborn infants. Arch Dis
feeding tube or bottle and also nipple feeding). Child 49:228–230
Additionally, fed newborns will avoid swallowing Cohen G, Henderson-Smart D (1986) Upper airway stabil-
ity and apnoea during nasal occlusion in newborn
air, thus reducing abdominal distension. An infants. J Appl Physiol 60:1511–1517
orogastric tube is not always necessary. Cordero L, Ayers LW, Davis K (1997) Neonatal airway
colonization with gram-negative bacilli: association
with severity of bronchopulmonary dysplasia. Pediatr
Infect Dis J 16:18–23
References Courtney SE, Pyon KH, Saslow JG et al (2001) Lung
recruitment and breathing pattern during variable ver-
AARC (American Association for Respiratory Care) sus continuous positive airway pressure in premature
(1994) Application of continuous positive airway pres- infants. An evaluation of three devices. Pediatrics
sure to neonates via nasal prongs or nasopharyngeal 197:304–308
tube. Respir Care 39:817–823 Davis PG, Henderson-Smart DJ (2000) Nasal CPAP imme-
Agostino R, Orzalesi M, Nodari S et al (1973) Continuous diately after extubation for preventing morbidity in
positive airway pressure (CPAP) by nasal cannula in preterm infants. Cochrane Database Syst Rev 3:
the respiratory distress syndrome (RDS) of the new- CD000143
born. Pediatr Res 7:50 Davis AJ, Jobe AH, Häfner D et al (1998) Lung function in
Ahluwalia JS, White DK, Morley CJ (1998) Infant flow premature lambs and rabbits treated with a recombinant
driver or single prong nasal continuous positive airway SP-C surfactant. Am J Respir Crit Care Med 157(2):
pressure: short term physiological effects. Acta Pediatr 553–559
87:325–327 Dunn MS, Kaempf J, de Klerk A et al (2011) Randomized
Ahumada CA, Goldsmith JP (1996) Continuous distending trial comparing 3 approaches to the initial respiratory
pressure. In: Goldsmith JP, Karotkin EH (eds) Assisted management of preterm neonates. Pediatrics 128(5):
ventilation of the neonate. WB Saunders, Philadelphia, e1069–e1076
pp 151–165 Elgellab A, Riou Y, Abbazine A et al (2001) Effects
Aranda JV, Turmen T (1979) Methylxanthines in apnoea of of nasal continuous airway positive pressure (NCPAP)
prematurity. Clin Perinatol 6:87–108 on breathing pattern in spontaneously breathing prema-
Avery ME, Mead J (1959) Surface properties in relation to ture newborn infants. Intensive Care Med 27:
atelectasis and hyaline membrane disease. Am J Dis 1782–1787
Child 97:517–523 Finer NN, Waldemar AC, Duara S et al (2004) Delivery
Avery ME, Tooley WH, Keller JB et al (1987) Is chronic room continuous positive airway pressure/positive end-
lung disease in low birth weight infants preventable? A expiratory pressure in extremely low birth weight
survey of eight centers. Pediatrics 79:26–30 infants: a feasibility trial. Pediatrics 114:651–657
62 Continuous Positive Airways Pressure and Other Noninvasive Respiratory Techniques in Newborns 991
Finer NN, Carlo WA, Walsh MC et al (2010) Early CPAP Harrison VC, de Heese Hde V, Klein M (1968) The signif-
versus surfactant in extremely preterm infants. N Engl J icance of grunting in hyaline membrane disease. Pedi-
Med 362(21):1970–1979 atrics 41:549–559
Fischer HS, Bührer C (2013) Avoiding endotracheal ven- Henderson-Smart DJ, Steer P (2001) Methyl-xanthine
tilation to prevent bronchopulmonary dysplasia: a treatment for apnea in preterm infants. Cochrane Data-
meta-analysis. Pediatrics 132(5):e1351–e1360 base Syst Rev 3:CD000140
Fox WW, Berman LS, Downes JJ Jr, Peckham GJ (1975) Higgins RD, Richter SE, Davis JM (1991) Nasal continuous
The therapeutic application of end-expiratory pressure positive airway pressure facilitates extubation of very
in the meconium aspiration syndrome. Pediatrics 56: low birth weight neonates. Pediatrics 88:999–1003
214–217 Hooper SB, Siew ML, Kitchen MJ (2015) Respiratory
Fox WW, Schwartz JG, Shaffer TH (1981) Successful transition in the newborn: a three phase process. Arch
extubation of neonates: clinical and physiological fac- Dis Child Fetal Neonatal Ed 101(3):F266–F271
tors. Crit Care Med 9:823–826 Horbar JD, McAuliffe TL, Adler SM et al (1988) Variabil-
Gaon P, Lee S, Hannan S et al (1999) Assessment of effect ity in 28- day outcomes for very low birth weight
of nasal continuous positive pressure on laryngeal infants: an analysis of 11 neonatal intensive care
opening using fibre optic laryngoscopy. Arch Dis units. Pediatrics 82:554–559
Child Fetal Neonatal Ed 80:F230–F232 Jacobsen T, Gronvall J, Petersen S et al (1993) “Mini-
Gauda EB, Miller MJ, Carlo W et al (1987) Genioglossus touch” treatment of very low birth weight infants.
response to airway occlusion in apneic versus non- Acta Pediatr 82:934–938
apneic infants. Pediatr Res 22:683–687 Jonsson B, Katz-Salamon M, Faxelius G et al (1997)
Gerhardt T, Bancalari E (1980) Chestwall compliance in Neonatal care of very low birth weight infants in special
full-term and premature infants. Acta Pediatr Scand care units and neonatal intensive care units in Stock-
69:359–364 holm. Early nasal continuous positive airway pressure
Gherini S, Peters RM, Virgilio RW (1979) Mechanical versus mechanical ventilation: gains and losses. Acta
work on the lungs and work of breathing with positive Pediatr Suppl 419:4–10
end expiratory pressure and continuous positive airway Jonzon A (1991) Indications for continuous positive air-
pressure. Chest 76:251–256 way pressure and respiratory therapy. Int J Technol
Gittermann MK, Fusch C, Gittermann AR et al (1997) Assess Health Care 7(Suppl 1):26–30
Early nasal continuous positive airway pressure treat- Kamper J, Ringsted C (1990) Early treatment of idiopathic
ment reduces the need for intubation in very low birth respiratory distress syndrome using binasal continuous
weight infants. Eur J Pediatr 156:384–388 positive airway pressure. Acta Pediatr Scand 79:
Gizzi C, Montecchia F, Panetta V et al (2015) Is syn- 581–586
chronised NIPPV more effective than NIPPV and Kamper J, Wulff K, Larsen C et al (1993) Early treatment
NCPAP in treating apnoea of prematurity (AOP)? A with nasal continuous positive airway pressure in very
randomised cross-over trial. Arch Dis Child Fetal Neo- low birth weight infants. Acta Pediatr 82:193–197
natal 100(1):F17–F23 Karlberg P (1960) The adaptive changes in the immediate
Goldman SL, Brady JP, Bchir MB et al (1979) Increased postnatal period, with particular reference to respira-
work of breathing associated with nasal prongs. Pedi- tion. J Pediatr 56:585–604
atrics 64:160–164 Kattwinkel J (1977) Neonatal apnoea: pathogenesis and
Greenough A (1996) Transient tachypnoea of the newborn. therapy. J Pediatr 90:342–347
In: Greenough A, Roberton NRC, Milner AD (eds) Kattwinkel J, Fanaroff A, Cha C et al (1973) Controlled
Neonatal respiratory disorders. Arnold, London, pp trial of continuous positive airway pressure (CPAP) in
280–285 RDS and a simplified application by the nasal route.
Greenough A, Roberton NRC (1996) Respiratory distress Pediatr Res 7:396
syndrome. In: Greenough A, Roberton NRC, Milner Kavvadia V, Greenough A, Dimitriou G (2000) Effect on
AD (eds) Neonatal respiratory disorders. Arnold, Lon- lung function of continuous positive airway pressure
don, pp 238–279 administered either by infant flow driver or a single
Gregory GA (1986) Continuous positive airways pressure. nasal prong. Eur J Pediatr 159:289–292
In: Thibeault DW, Gregory GA (eds) Neonatal pulmo- Klausner JF, Lee AY, Hutchinson AA (1996) Decreased
nary care, 2nd edn. Appleton & Lange, Norwalk, p 355 imposed work with a new nasal continuous positive
Gregory GA, Kittermann JA, Phibbs RH et al (1971) airway pressure device. Pediatr Pulmonol 22:188–194
Treatment of the idiopathic respiratory distress syn- Kribs A, Hummler H (2016) Ancillary therapies to
drome with continuous positive airway pressure. N enhance success of non-invasive modes of respiratory
Engl J Med 284:1333–1340 support – approaches to delivery room use of surfac-
Gupta S, Sinha SK, Tin W, Donn SM (2009) A randomized tant and caffeine? Semin Fetal Neonatal Med 21(3):
controlled trial of post-extubation bubble continuous 212–218
positive airway pressure versus infant flow driver con- Kurz H (1999) Influence of nasopharyngeal CPAP on
tinuous positive airway pressure in preterm infants with breathing pattern and incidence of apnoeas in preterm
respiratory distress syndrome. J Pediatr 154:645–650 infants. Biol Neonate 76:129–133
992 F. Sandri et al.
Lam BC (1999) Surfactant lavage for the management of severe meconium aspiration syndrome. Intensive Care
severe meconium aspiration syndrome. Biol Neonate Med 22:1412–1413
76(Suppl 1):10–14 Pape KE, Armstrong DL, Fitzhardinge PM (1976) Central
Lemyre B, Davis PG, De Paoli AG et al (2017) Nasal nervous system pathology associated with mask venti-
intermittent positive pressure ventilation (NIPPV) ver- lation in the very low birth weight infant: a new etiol-
sus nasal continuous positive airway pressure (NCPAP) ogy for intracerebellar hemorrhages. Pediatrics
for preterm neonates after extubation. Cochrane Data- 58:473–483
base Syst Rev 2:CD003212. https://doi.org/10.1002/ Payne NR, LaCorte M, Karna P et al (2006) Reduction of
14651858.CD003212.pb3) bronchopulmonary dysplasia after participation in the
Leone RJ, Krasna IH (2000) “Spontaneous” neonatal gas- Breathsavers Group of the Vermont Oxford Network
tric perforation: is it really spontaneous? J Pediatr Surg Neonatal Intensive Care Quality Improvement Collab-
35:1066–1069 orative. Pediatrics 118:S73–S77
Levy J, Habib RH, Liptsen E et al (2006) Prone versus Pedersen JE, Nielsen K (1994) Oropharyngeal and
supine positioning in the well preterm infant: effects on esophaegeal pressure during mono-and binasal CPAP
work of breathing and breathing patterns. Pediatr in neonates. Acta Pediatr 83:143–149
Pulmonol 41:754–758 Perlman J, Thach B (1988) Respiratory origin of fluctuations
Lindner W, Vossbeck S, Hummler H et al (1999) Delivery in arterial blood pressure in premature infants with respi-
room management of extremely low birth weight ratory distress syndrome. Pediatrics 81:399–403
infants: spontaneous breathing or intubation? Pediat- Poulton EP, Oxon DM (1936) Left-sided heart failure with
rics 103:961–967 pulmonary edema: its treatment with the “pulmonary
Loftus BC, Ahn J, Haddad J (1994) Neonatal nasal defor- plus pressure machine”. Lancet 228:981–983
mities secondary to nasal continuous positive airway Rasanen J, Leijala M (1991) Breathing circuit respiratory
pressure. Laryngoscope 104:1019–1022 work in infants recovering from respiratory failure. Crit
Lundstrom KE (1996) Initial treatment of preterm Care Med 19:31–35
infants–continuous positive airway pressure or ventila- Roberton NRC (1993) Does CPAP work when it really
tion? Eur J Pediatr 155(Suppl 2):S25–S29 matters? Acta Pediatr 82:206–207
Martin RJ, Nearman HS, Katona PG et al (1977) The effect Robertson NJ, McCarthy LS, Hamilton PA, Moss ALH
of a low continuous positive airway pressure on the (1996) Nasal deformities resulting from flow driver
reflex control of respiration in the preterm infant. J continuous positive airway pressure. Arch Dis Child
Pediatr 90:976–981 Fetal Neonatal Ed 75:F209–F212
McNamara F, Sullivan CE (1997) Nasal CPAP treatment in Sahni R, Schiaratura M, Polin RA (2016) Strategies for the
an infant with respiratory syncitial virus-associated prevention of continuous positive airway pressure fail-
apnoea. Pediatr Pulmonol 24:218–221 ure. Semin Fetal Neonatal Med 21(3):196–203
Miller MJ, Carlo WA, Martin RJ (1985) Continuous pos- Sandri F, Ancora G, Rinaldi M et al (1999) Incidence of
itive airway pressure selectively reduces obstructive intact survival in a group of ELBWI and permissive
apnoea in preterm infants. J Pediatr 106:91–94 hypercapnia. Pediatr Res 45:223A
Miller RW, Pollack MM, Murphy TM et al (1986) Effec- Sandri F, Ancora G, Lanzoni A et al (2004) Prophylactic
tiveness of continuous positive airway pressure in the nasal continuous positive airways pressure in newborns
treatment of bronchomalacia in infants: a broncho- of 28–31 weeks gestation: multicentre randomised con-
scopic documentation. Crit Care Med 14:125–127 trolled clinical trial. Arch Dis Child Fetal Neonatal Ed
Miller MJ, DiFiore JM, Strohl KP et al (1990) Effects of 89:F394–F398
nasal CPAP on supraglottic and total pulmonary resis- Sandri F, Plavka R, Ancora G et al (2010) Prophylactic or
tance in preterm infants. J Appl Physiol 68:141–146 early selective surfactant combined with nCPAP in very
Moa G, Nilsson K (1993) Nasal continuous positive airway preterm infants. Pediatrics 125:e1402–e1409
pressure: experiences with a new technical approach. Schmidt B, Roberts RS, Davis P et al (2006) Caffeine
Acta Pediatr 82:210–211 therapy for apnea of prematurity. N Engl J Med
Moa G, Nilsson K, Zetterstrom H et al (1988) A new 355:958–959
device for administration of nasal continuous positive Schmölzer GM, Kumar M, Pichler G et al (2013) Non-
airway pressure in the newborn: an experimental study. invasive versus invasive respiratory support in preterm
Crit Care Med 16:1238–1242 infants at birth: systematic review and meta-analysis.
Morley C (1999) Continuous distending pressure. Arch BMJ 347:f5980
Dis Child Fetal Neonatal Ed 81:F152–F156 Schmolzer GM, Kumar M, Aziz K et al (2014) Sustained
Morley CJ, Davis PG, Doyle LW et al (2008) Nasal CPAP inflation versus positive pressure ventilation at birth: a
or intubation at birth for very preterm infants. N Engl J systematic review and meta-analysis. Arch Dis Child
Med 358:700–708 Fetal Neonatal Ed 100(4):F361–F368
Mosca F, Colnaghi M, Castoldi F (1996) Lung lavage with Schulze A, Madler HJ, Gehrhardt B et al (1990) Titration of
a saline volume similar to functional residual capacity continuous positive airway pressure by the pattern of
followed by surfactant administration in newborns with breathing: analysis of flow-volume-time relationships
62 Continuous Positive Airways Pressure and Other Noninvasive Respiratory Techniques in Newborns 993
by a non-invasive computerized system. Pediatr Van de Graaff WB (1988) Thoracic influence on upper
Pulmonol 8:96–103 airway patency. J Appl Physiol 65:2124–2131
Smedsaas-Lofvemberg A, Nilsson K, Moa G et al (1999) Verder H, Robertson B, Greisen G et al (1994) Surfactant
Nebulization of drugs in a nasal CPAP system. Acta therapy and nasal continuous positive airway pressure
Paediatr 88:89–92 for newborns with respiratory distress syndrome. N
So BH, Tamura M, Mishina J et al (1995) Application of Engl J Med 331:1051–1055
nasal continuous positive airway pressure to early Verder H, Albertsen P, Ebbesen F et al (1999) Nasal con-
extubation in very low birth weight infants. Arch Dis tinuous positive airway pressure and early surfactant
Child Fetal Neonatal Ed 72:F191–F193 therapy for respiratory distress syndrome in newborns
Soong WJ, Hwang B, Tang RB (1993) Continuous positive of less than 30 weeks’ gestation. Pediatrics 103:e24
airway pressure by nasal prongs in bronchiolitis. Vert P, Andre M, Silbout M (1973) Continuous positive
Pediatr Pulmonol 16:163–166 airway pressure and hydrocephalus. Lancet 302:319
Stevens TP, Blennow M, Myers EH, Soll R (2007) Early Walsh MC, Wilson-Costello D, Zadell A et al (2003)
surfactant administration with brief ventilation vs. Safety, reliability, and validity of a physiologic defini-
selective surfactant and continued mechanical ventila- tion of bronchopulmonary dysplasia. J Perinatol
tion for preterm infants with or at risk for respiratory 23:451–456
distress syndrome. Cochrane Database Syst Rev 3: Wilkinson D, Andersen C, O’Donnell CP et al (2016) High
CD003063 flow nasal cannula for respiratory support in preterm
Sweet DG, Carnielli V, Greisen G et al (2017) European infants. Cochrane Database Syst Rev 2:CD006405.
consensus guidelines on the management of respiratory https://doi.org/10.1002/14651858.CD006405.pub3.
distress syndrome – 2016 update. Neonatology Review
111:107–125 Wilson SL, Thach BT, Brouillette RT et al (1980) Upper
Tanswell AK, Clubb RA, Smith BT et al (1980) Individu- airway patency in the human infant: influence of airway
alized continuous distending pressure applied within 6 pressure and posture. J Appl Physiol Respir Environ
hours of delivery in infants with respiratory distress Exerc Physiol 48:500–504
syndrome. Arch Dis Child 55:33–39 Wright CJ, Polin RA, Kirpalani H (2016) Continuous
Tarnow-Mordi WO, Sutton P, Wilkinson AR (1986) Inad- positive airway pressure to prevent neonatal lung
equate humidification of respiratory gases during injury: how did we get here, and how do we improve?
mechanical ventilation of the newborn. Arch Dis J Pediatr 173:17–24.e2
Child 61:698–700 Wylie J, Perlman JM, Kattwinkel J et al (2015) Part 7:
Te Pas AB, Siew M, Wallace MJ et al (2009) Establishing neonatal resuscitation:2015 international consensus on
functional residual capacity at birth: the effect of cardiopulmonary resuscitation and emergency. Cardio-
sustained inflation and positive end-expiratory pressure vascular care science with treatment recommendations.
in a rabbit model. Pediatr Res 65(5):537–541 Resuscitation 95:e171–e203
Lung Diseases: Surfactant
Replacement Therapy in Newborns 63
Henry L. Halliday
Contents
63.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 996
63.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 996
63.3 Respiratory Distress Syndrome and Rationale for Surfactant
Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 997
63.4 Results from Randomized Trials and Systematic Reviews . . . . . . . . . . . . . . 997
63.4.1 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 997
63.4.2 Timing of First Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 998
63.4.3 Size of First Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 998
63.4.4 Method of Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 999
63.4.5 Need for Redosing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1000
63.4.6 Type of Surfactant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1000
63.4.7 Concomitant Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1001
63.4.8 Other Indications for Surfactant Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1002
63.5 Future Developments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1003
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1004
Abstract survival is directly related to more effective
In the past three decades, introduction of pre- prevention or treatment of the disease. RDS is
natal steroid treatment, postnatal surfactant caused by surfactant insufficiency leading to
therapy, and assisted ventilation has contrib- alveolar collapse and increased work of breath-
uted to better outcomes for neonates with respi- ing with consequent hypoxia, respiratory fail-
ratory distress syndrome (RDS). Improved ure, and mixed respiratory and metabolic
acidosis. Following unsuccessful clinical trials
in the 1960s with nebulized synthetic surfac-
tants, comprised of phospholipids without sur-
H. L. Halliday (*) factant proteins, a number of randomized
Formerly Regional Neonatal Unit, Royal Maternity
Hospital, Belfast, UK controlled trials in the 1980s demonstrated
benefits of surfactant instilled directly into the
Formerly Department of Child Health, Queen’s University
Belfast, Belfast, UK lungs of preterm infants. Currently, because of
e-mail: [email protected] increased use of prenatal steroids and early
# Springer International Publishing AG, part of Springer Nature 2018 995
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_210
996 H. L. Halliday
CPAP, it is clear that early selective use of 63.2 Introduction
surfactant is superior to routine prophylactic
treatment. However, there are still some occa- In the past three decades, introduction of prenatal
sions when surfactant should be administered steroid treatment, postnatal surfactant therapy, and
in the delivery room including cases when assisted ventilation has contributed to improved
intubation of very preterm infants is needed neonatal outcomes (Speer et al. 2013). Improved
for stabilization. survival is directly related to more effective pre-
vention or treatment of respiratory distress syn-
drome (RDS), which prior to the 1990s had a
63.1 Salient Points high mortality. Following unsuccessful clinical tri-
als with nebulized synthetic surfactants, comprised
• Respiratory distress syndrome is caused by of phospholipids without surfactant proteins, in the
surfactant insufficiency which leads to pro- 1960s (Soll 2000a) a number of randomized con-
gressive hypoxia, respiratory failure, and trolled trials in the 1980s demonstrated benefits of
mixed respiratory and metabolic acidosis as a surfactants instilled directly into the lungs of pre-
result of alveolar collapse and increased work term infants (Soll 2000a, b; Seger and Soll 2009;
of breathing. Soll and Ozek 2010). These surfactants were of two
• The use of prenatal steroids and early CPAP main types: natural (derived from animal lungs or
make early selective use of surfactant superior human amniotic fluid) (Soll 2000a; Seger and Soll
to routine prophylactic treatment. There are 2009) containing surfactant proteins B and C
still some occasions when surfactant should (SP-B and SP-C) and synthetic (Soll and Ozek
be administered in the delivery room including 2010; Soll 2000b) (containing phospholipids and
cases when intubation of very preterm infants other agents to facilitate spreading and adsorption).
is needed for stabilization. Both types of surfactant, given either prophylacti-
• The dose of surfactant required for optimal cally (in the delivery room within 15 min of birth)
effects is not known. It is possible that 100 (Soll 2000a; Soll and Ozek 2010) or for treatment
mg/kg is sufficient for prophylactic treatment, of RDS (Seger and Soll 2009; Soll 2000b),
but 200 mg/kg may give better outcomes for increased neonatal survival and reduced pulmo-
the later treatment of RDS. nary air leaks such as pneumothorax and pulmo-
• The INSURE (INtubateSURfactant Extubate nary interstitial emphysema.
to CPAP) technique minimizes the duration of More recently, further randomized clinical tri-
ventilation and is useful for babies initially als helped determine the best surfactant (Pfister
treated with CPAP who may avoid mechanical et al. 2007, 2009; Ardell et al. 2015), the optimal
ventilation altogether. timing for initial treatment (Singh et al. 2015;
• Less invasive surfactant administration (LISA) Rojas-Reyes et al. 2012; Bahadue and Soll 2012;
and nebulization are techniques that show Stevens et al. 2007), the need for redosing (Soll
promise and help to avoid endotracheal and Ozek 2009), and the dose of phospholipids
intubation. needed for best outcomes (Speer et al. 2013).
• Other indications for surfactant include meco- Results from these trials have provided guidelines
nium aspiration syndrome (reducing the need for best practice, and these are now available in
for ECMO) and pneumonia, but in other cases Europe (Sweet et al. 2013), the USA (Polin
the treatment is experimental. et al. 2014), and Canada (Davis et al. 2005). The
• Surfactant may be used as a vehicle to deliver aim of this chapter is to summarize the recommen-
drugs to the lungs, and trials with budesonide dations for surfactant treatment based on evidence
show promise as a means of reducing from clinical trials and systematic reviews and to
bronchopulmonary dysplasia. point out areas where controversy still exists.
63 Lung Diseases: Surfactant Replacement Therapy in Newborns 997
63.3 Respiratory Distress Syndrome with evidence pointing to earlier therapy being
and Rationale for Surfactant superior to later treatment (Rojas-Reyes
Therapy et al. 2012; Bahadue and Soll 2012). However,
with increased use of prenatal steroids and early
Respiratory distress syndrome (RDS) is caused by CPAP, prophylactic surfactant treatment may not
surfactant insufficiency (Avery and Mead 1959) be superior to delayed selective treatment (Rojas-
which leads to progressive hypoxia, respiratory Reyes et al. 2012). The incidence of RDS varies
failure, and mixed respiratory and metabolic aci- from about 80% at 28 weeks’ gestation or below
dosis as a result of alveolar collapse and increased to about 50% at 30 weeks, 30% at 32 weeks, and
work of breathing (Halliday 2003). Surfactant 10% at 34 weeks (Halliday 2003).
deficiency is strongly associated with prematurity,
and progressive acidosis further reduces surfac-
tant production. The normal surfactant phospho- 63.4 Results from Randomized Trials
lipid pool size at birth is about 100 mg/kg, but in and Systematic Reviews
preterm infants this is often reduced to below
25 mg/kg, and if severe RDS is present, less than These are discussed under the following subhead-
5 mg/kg (Halliday 2003). Surfactant may also be ings: efficacy, timing of first dose, size of first dose,
inactivated by leaking of inhibitory proteins from method of administration, need for redosing, type
the plasma into the alveoli. Prior to introduction of of surfactant, concomitant interventions, and other
surfactant therapy, infants with RDS who sur- indications for surfactant therapy.
vived began to produce their own endogenous
surfactant after 2–3 days, and this heralded their
recovery (Halliday 2003). Those infants who did 63.4.1 Efficacy
not survive either developed progressive respira-
tory failure with irreversible hypoxic injury to the Randomized clinical trials of synthetic (protein-
cardiovascular and central nervous systems or free) and natural (containing SP-B and SP-C)
acute deterioration associated with pulmonary air surfactants, given both prophylactically (within
leaks or intraventricular hemorrhage. 10–15 min of birth in the delivery room) or as
Surfactant therapy prevents or overcomes alve- treatment for established RDS in the neonatal unit,
olar collapse, especially at end expiration, reduce neonatal mortality and pulmonary air leaks
increases lung volumes and pulmonary compli- such as pneumothorax and pulmonary interstitial
ance, and reverses respiratory failure (Halliday emphysema (Speer et al. 2013; Soll 2000a, b;
2003). The result is improved survival and signif- Seger and Soll 2009; Soll and Ozek 2010).
icant reduction in pulmonary air leaks following Although most of these trials took place in the
surfactant treatment (Soll 2000a, b; Seger and Soll 1980s and 1990s, when prenatal corticosteroid
2009; Soll and Ozek 2010). There is evidence treatment was less frequent than today, there is
from both animal studies and clinical trials that no reason to believe that surfactant treatment does
natural surfactants, containing SP-B and SP-C, act not continue to have a positive impact on the
more rapidly than synthetic preparations outcome of preterm infants (Speer et al. 2013).
containing mainly phospholipids, leading to Indeed prenatal corticosteroids and postnatal sur-
improved outcomes with regard to survival and factant have synergistic effects (Jobe et al. 1993),
pulmonary air leaks (Pfister et al. 2007; Ardell and both should be considered when preterm birth
et al. 2015). There may also be differences when is likely. The sizes of the effects of prophylactic
natural (animal-derived) surfactants are compared surfactant administration on neonatal mortality,
(Singh et al. 2015). Timing of surfactant therapy pneumothorax, and other selected outcomes are
may also be important in determining outcome shown in Table 1.
998 H. L. Halliday
Table 1 Meta-analyses of prophylactic surfactant treatment of preterm infants
Natural surfactant Synthetic surfactant
95%
Outcome RR 95% CI NNT CI RR 95% CI NNT/H 95% CI
Neonatal mortality 0.60 0.44–0.83 14 9–35 0.70 0.58–0.85 15 10–31
Pneumothorax 0.35 0.26–0.49 7 5–9 0.67 0.50–0.90 20 12–67
Pulmonary interstitial 0.46 0.35–0.60 6 4–8 0.68 0.50–0.93 16 9–77
emphysema
Pulmonary hemorrhage – – – – 3.28 1.50–7.16 33 20–100
Intraventricular hemorrhage 0.89 0.84–1.15 – – 0.96 0.81–1.14 – –
Severe IVH 1.22 0.90–1.66 – – 1.01 0.75–1.38 – –
Persistent ductus arteriosus 1.08 0.94–1.24 – – 1.11 1.00–1.22 21 11–500
Retinopathy of prematurity 1.37 0.63–2.98 – – 0.96 0.86–1.07 – –
Severe ROP 0.58 0.27–1.24 – – 0.89 0.58–1.36 – –
Bronchopulmonary dysplasia 0.93 0.80–1.07 – – 1.06 0.83–1.36 – –
Data obtained from Cochrane Library (Soll 2000a; Soll and Ozek 2010). RR relative risk, CI confidence interval, NNT/H
number needed to treat or harm; IVH intraventricular hemorrhage, ROP retinopathy of prematurity, BPD
bronchopulmonary dysplasia
63.4.2 Timing of First Dose in the delivery room including cases when intu-
bation of very preterm infants is needed for stabi-
It is clear that the earlier surfactant is given in the lization (Sweet et al. 2013).
course of RDS, the better the outcomes with
reduction in pulmonary air leaks, neonatal mor-
tality, and CLD (Bahadue and Soll 2012). In early 63.4.3 Size of First Dose
trials of prophylactic surfactant in infants
<31 weeks’ gestation, neonatal mortality and Clinical trials used surfactant doses ranging from
pneumothorax were reduced compared to later 25 to 200 mg phospholipids/kg (Morley 1991).
treatment of established RDS (Rojas-Reyes These doses are all much larger by at least tenfold
et al. 2012). However, recent large trials that than the amount of lipids needed to form a
reflect current practice (including greater use of monolayer on the alveolar surface of the lungs
prenatal steroids and early stabilization with (Robertson and Halliday 1998). For licensed sur-
CPAP) do not support these benefits and show factant preparations, the recommended doses vary
reduced risk of CLD or death when using early from 50 to 200 mg/kg with dose volumes of
CPAP with selective surfactant administration for 1.2–5 mL/kg (Table 2) (Sweet et al. 2013; Polin
infants needing intubation (Rojas-Reyes et al. 2014; Walsh et al. 2013). Larger doses of
et al. 2012). Administration of surfactant gener- surfactant are superior to smaller ones (Konishi
ally requires endotracheal intubation, and routine et al. 1988; Gortner et al. 1994). Surfactant TA in a
prophylaxis of infants <31 weeks’ gestation dose of 120 mg/kg (100 mg phospholipids/kg)
might lead to unnecessary treatment in up to improved oxygenation and reduced BPD
50% of cases (Speer et al. 2013). This will compared to 60 mg/kg (Konishi et al. 1988).
increase costs of care and could cause unwanted When 100 mg/kg of bovactant was compared
lung injury leading to BPD. Currently, because of with 50 mg/kg, the larger dose was associated
increased use of prenatal steroids and early CPAP, with better improvement in oxygenation (Gortner
it is clear that early selective use of surfactant is et al. 1994). For poractant alfa 200 mg/kg gives a
superior to routine prophylactic treatment (Rojas- better acute response than 100 mg/kg (Halliday
Reyes et al. 2012). However, there are still some et al. 1993; Ramanathan et al. 2004) and probably
occasions when surfactant should be administered improved survival (Ramanathan et al. 2004). The
63 Lung Diseases: Surfactant Replacement Therapy in Newborns 999
Table 2 Some surfactant preparations in clinical use
Generic Trade Phospholipids Dose Volume
name name Source (mg/mL) (mg/kg) (mL/kg) Manufacturer (country)
Beractant Survanta Bovine 25 (50% 100 4 Abbott Labs (USA)
mince DPPC)
BLES bLES Bovine 27 135 5 BLES Biochemicals (Canada)
lavage
Bovactant Alveofact Bovine 42 50 1.2 Lyomark Pharma (Germany)
lavage
Calfactant Infasurf Bovine 35 (74% 105 3 ONY and Forest Labs (USA)
lavage DPPC)
Poractant Curosurf Porcine 80 (70% 100–200 1.25–2.5 Chiesi Farmaceutici (Italy)
alfa mince DPPC)
Surfactant Surfacten Bovine 30 (48% 120 4 Tokyo Tanabe and Mitsubishi
TA mince DPPC) Pharma (Japan)
All preparations contain SP-B and SP-C in varying amounts. BLES bovine lipid extract surfactant
dose of surfactant required for optimal effects is with infusion over 30 min in an animal model
not known but is probably at least 100 mg phos- with the former giving more uniform distribution
pholipids/kg which is close to the 100–250 mg/kg (Ueda et al. 1994). However, a small clinical trial
estimated to form the total pulmonary surfactant with beractant found no differences in outcome
pool in a full-term neonate (Robertson and when three dosing procedures were compared
Halliday 1998; Hallman 1989). It is possible that (Zola et al. 1993), and this was supported by a
100 mg/kg is sufficient for prophylactic treatment study with poractant alfa, which compared a bolus
(Speer et al. 2013), but 200 mg/kg may give better dose with a 1 min infusion through a dual lumen
outcomes for later treatment of RDS (Ramanathan tube (Valls-i-Soler et al. 1998). It is important to
et al. 2004). minimize duration of mechanical ventilation after
surfactant administration as this is an independent
risk factor for development of BPD (Vento
63.4.4 Method of Administration et al. 2009). The INSURE (INtubate SURfactant
Extubate to CPAP) technique minimizes duration
Surfactants usually need to be administered of ventilation and is useful for babies initially
directly into the lungs during at least a brief period treated with CPAP who may avoid mechanical
of endotracheal intubation (Speer et al. 2013). ventilation altogether (Bohlin et al. 2008).
Preterm infants at high risk of developing RDS Although more surfactant is used with INSURE
should be born in centers where personnel and (RR 1.62, 95%CI 1.41–1.86), the benefits of
equipment are readily available to allow appropri- reduced air leak (RR 0.52, 95%CI 0.28–0.96),
ate care to begin from birth (Sweet et al. 2013). In BPD (RR 0.51, 95%CI 0.26–0.99), and need for
some of the earlier clinical trials, surfactant was mechanical ventilation (RR 0.67, 95%CI
administered as a bolus into each main bronchus 0.57–0.79) (Stevens et al. 2007) mean that this
or as a single bolus into the lower trachea, whereas technique is recommended (Sweet et al. 2013).
in other trials it was given as divided doses The benefits appear to be even greater when
directed into each lung lobe by positioning the infants are treated at a lower threshold oxygen
baby (Morley 1991). After instillation the baby requirement of less than 45% (Stevens
is either manually ventilated for a short time or et al. 2007).
reconnected to the ventilator to distribute the sur- Other methods to forgo the need for endotra-
factant. A sterile feeding tube is often used to cheal intubation include nebulization (Berggren
deliver the surfactant through the endotracheal et al. 2000), direct tracheal instillation at laryn-
tube. Bolus administration has been compared goscopy using a fine feeding catheter (Kribs
1000 H. L. Halliday
et al. 2008), intrapartum pharyngeal deposition Specific recommendations by surfactant man-
(Kattwinkel et al. 2004), and use of a laryngeal ufacturers differ slightly: for beractant retreatment
mask (Trevisanuto et al. 2005). Of these, less may be given at intervals of at least 6 h for up to
invasive surfactant administration (LISA) is the four doses; for poractant alfa treatment may be
most widely accepted (Kribs et al. 2008, 2015), repeated 12 hourly for two further doses if still
but the technique needs considerable expertise intubated and after prophylaxis may be repeated
and may not prove to be widely applicable 6–12 h later and after a further 12 h (Speer
(Speer et al. 2013). Studies with nebulization of et al. 2013). However, the Canadian Paediatric
surfactant are ongoing, and this technique shows Society recommends retreatment of infants need-
promise (Pillow and Minocchieri 2012). ing more than 30% oxygen as early as 2 h after the
first dose (Davis et al. 2005), and the European
Association of Perinatal Medicine recommends
63.4.5 Need for Redosing retreatment if there is ongoing RDS indicated by
need for mechanical ventilation and supplemental
At least two studies demonstrated that multiple oxygen (Sweet et al. 2013). The latter also recom-
doses (up to three) are superior to a single dose mends that babies extubated to CPAP should be
(Dunn et al. 1990; Speer et al. 1992), and this is retreated (with the INSURE technique) when
confirmed in a systematic review showing they need more than 50% oxygen or if they are
reduced pneumothorax (RR 0.51, 95%CI likely to need mechanical ventilation (Sweet
0.30–0.88) and a trend toward reduced mortality et al. 2013).
(RR 0.63, 95%CI 0.39–1.02) (Soll and Ozek
2009). Multiple dose treatment with poractant
alfa reduced both neonatal mortality and pneumo- 63.4.6 Type of Surfactant
thorax in preterm infants with severe RDS (Speer
et al. 1992). This study used retreatment criteria Surfactant preparations studied in the 1990s were
based on continued need for mechanical ventila- either synthetic (containing phospholipids with-
tion and oxygen supplementation at 12 and 24 h out surfactant proteins) or natural (derived from
after the first dose, and about two-thirds of babies animal lungs and containing both phospholipids
needed retreatment. Currently, babies with RDS and SP-B and SP-C) (Speer et al. 2013). Of these,
are being treated with surfactant earlier or even the best known synthetic surfactants were
prophylactically, and the need for retreatment is colfosceril palmitate and pumactant, but they
much less than before. Poractant alfa in an initial are no longer available for clinical use. The best
dose of 200 mg/kg compared to 100 mg/kg leads known natural surfactants are beractant,
to reduced need for second and third doses calfactant, surfactant TA, and bovactant (all of
(Halliday et al. 1993; Ramanathan et al. 2004). bovine origin) and poractant alfa (of porcine ori-
Although criteria for redosing in the past were gin) (Table 2). Recently, other surfactants have
fixed, it is best to adopt a more flexible approach been produced in Cuba (Surfacen), Korea
(Speer et al. 2013; Sweet et al. 2013). Redosing of (Newfacten), Brazil, and India, but there is little
infants needing more than 30% oxygen has been information about them (Speer et al. 2013;
compared with more than 40% in a randomized Halliday 2006). Also, more recently studied
trial using calfactant (Kattwinkel et al. 2000). are the so-called new-generation synthetic sur-
Babies with uncomplicated RDS did equally factant preparations (Pfister et al. 2007, 2009)
well with the higher threshold retreatment crite- which contain phospholipids and surfactant
rion, but about one-quarter of those enrolled had peptide analogues such as lucinactant
complicated RDS (associated with birth asphyxia (Moya et al. 2005; Sinha et al. 2005) and recom-
or sepsis), and they had a lower mortality when binant SP-C surfactant (Curstedt and Johansson
retreated earlier (Kattwinkel et al. 2000). 2006).
63 Lung Diseases: Surfactant Replacement Therapy in Newborns 1001
As noted earlier, studies comparing synthetic 63.4.7 Concomitant Interventions
and natural surfactants provide evidence that the
latter act more rapidly to improve pulmonary sta- Prenatal steroids, methods of respiratory support
tus, and in the longer term they show improved including CPAP, and caffeine treatment will be
survival with fewer pulmonary air leaks (Ardell considered in this section. There have been at
et al. 2015). As a result, the older synthetic sur- least 21 randomized trials of prenatal steroids
factants, colfosceril palmitate and pumactant, are involving over 4,000 infants at risk of RDS
no longer available as commercial products. (Roberts and Dalziel 2006). Treatment with pre-
There have been 16 trials comparing various nat- natal steroids is associated with an overall reduc-
ural surfactant preparations (Singh et al. 2015), tion in neonatal mortality (RR 0.69, 95%CI
and the largest of these compared beractant with 0.58–0.81), RDS (RR 0.66, 95%CI 0.59–0.73),
calfactant for both prevention and treatment of intraventricular hemorrhage (RR 0.54, 95%CI
RDS (Bloom and Clark 2005). Unfortunately, 0.43–0.69), necrotizing enterocolitis (RR 0.46,
the planned sample size was not reached, although 95%CI 0.29–0.74), respiratory support and
more than 2,000 infants had been recruited to the intensive care admissions (RR 0.80, 95%CI
two arms of the study, due to slow recruitment, but 0.65–0.99), and systemic infections in the first
in those studied there was no trend to suggest 48 h of life (RR 0.96, 95%CI 0.38–0.85) (Roberts
different outcomes including survival without and Dalziel 2006). As prenatal steroids are also
BPD (Bloom and Clark 2005). Studies comparing effective in women with premature rupture of
beractant and poractant alfa are smaller but show membranes and pregnancy-related hypertension,
that the latter produces a more rapid onset of they should be given in most cases where preterm
action in preterm infants with RDS (Ramanathan birth is anticipated before 35 weeks’ gestation.
et al. 2004). This US trial of 293 preterm infants Furthermore, there is evidence of synergistic
with moderately severe RDS compared two doses effects of prenatal steroids and postnatal surfac-
of poractant alfa (200 mg/kg and 100 mg/kg) with tant (Jobe et al. 1993), and therefore both are
a 100 mg/kg dose of beractant and found that there indicated in cases with high risk of RDS.
was a reduced need for redosing with the higher The combination of early surfactant treatment
dose of poractant alfa (Ramanathan et al. 2004). and CPAP was assessed in many studies (Dani
Furthermore, there was improved survival for et al. 2004; Sandri et al. 2010; Verder
infants of less than 32 weeks’ gestation treated et al. 1999; Morley et al. 2008; Finer et al. 2010)
with the 200 mg/kg dose of poractant alfa com- with two studies comparing nasal CPAP with
pared with those treated with beractant. A meta- intubation at birth in very preterm infants (Morley
analysis of nine randomized trials comparing et al. 2008; Finer et al. 2010). It is clear that the
beractant with poractant alfa confirmed an combination of CPAP and early surfactant admin-
increased mortality prior to discharge with the for- istration reduces the need for mechanical ventila-
mer (RR 1.44, 95%CI 1.04–2.00; NNH 20, 95%CI tion particularly in infants of greater than
10–100), although the benefit seemed to be limited 27 weeks’ gestation (Bohlin et al. 2008; Sandri
to those infants treated with the higher dose et al. 2010; Verder et al. 1999) although the reduc-
(200 mg/kg) of poractant alfa (Singh et al. 2015). tion in BPD is rather modest (Bohlin et al. 2008).
Despite the numbers of infants studied in these CPAP started in the delivery room without pro-
comparisons being modest and the American phylactic surfactant in infants of 25–28 weeks’
Academy of Pediatrics stating that it is still gestation does not significantly reduce the rate of
“unclear whether significant differences in clinical death or BPD compared to intubation and is asso-
outcomes exist among the available animal-derived ciated with a threefold increased risk of pneumo-
surfactant products” (Polin et al. 2014), poractant thorax (Morley et al. 2008). However,
alfa is now the most widely used surfactant prepa- prophylactic surfactant is not superior to CPAP
ration worldwide (Curstedt et al. 2015). and early selective surfactant in infants of
1002 H. L. Halliday
25–28 weeks’ gestation (Sandri et al. 2010). To surfactant replacement therapy in these conditions,
facilitate extubation after early surfactant admin- and the evidence base is much weaker than for
istration by the INSURE technique, the use of RDS (Speer et al. 2013; Polin et al. 2014). Four
respiratory stimulants such as caffeine has been randomized trials (326 infants) of surfactant treat-
recommended (Bohlin et al. 2008). ment in meconium aspiration syndrome are
There are other reasons for recommending caf- included in a systematic review that found
feine administration for treatment of apnea of improved oxygenation and a reduced need for
prematurity as this has been shown to reduce extracorporeal membrane oxygenation (ECMO)
risks of BPD, persistent ductus arteriosus (PDA), in treated infants (RR 0.64, 95%CI 0.46–0.91;
and need for ductus ligation (Schmidt et al. 2006). NNT 6, 95%CI 3–25) (El Shahed et al. 2014).
The reduced incidence of BPD in infants less than However, there were no differences in risk of pneu-
1,250 g may be due to shortening the duration of mothorax, CLD, or mortality (RR 0.98, 95%CI
mechanical ventilation by about 1 week, and at 0.41–2.39). These studies used a six-hourly dosing
18–20 months the surviving caffeine-treated regimen with up to 150 mg/kg of bovine surfactant
infants had better neurodevelopmental outcomes for up to four doses, and in general the improve-
with less cerebral palsy (Schmidt et al. 2007). ment in oxygenation was not seen until after the
Follow-up studies at 5 years of age suggest that third dose of surfactant (El Shahed et al. 2014).
these improved neurodevelopmental outcomes More recently dilute surfactant lavage has been
may be limited to a reduction in developmental used to try to remove meconium particles from
coordination disorder (Doyle et al. 2014). There the lungs (Dargaville et al. 2008), and studies
are clear benefits from treatment of very preterm have shown a reduced composite outcome of
infants with caffeine for apnea of prematurity and death or need for ECMO (RR 0.33, 95%CI
to facilitate extubation following surfactant ther- 0.11–0.96; NNT 5, 95%CI 3–33), but further con-
apy. There is no clear evidence that early inhaled trolled clinical trials are needed to confirm treat-
nitric oxide will prevent BPD in these very imma- ment effect, refine the method of lavage, and
ture babies. compare this technique with standard bolus dosing
Management of PDA in surfactant-treated (Hahn et al. 2013; Choi et al. 2012).
infants is discussed below with treatment of pul- Surfactant inactivation is also present in neo-
monary hemorrhage. It is good practice to monitor natal pneumonia, and a subgroup of term infants
surfactant-treated infants for PDA and to use pros- with this condition showed improved oxygena-
taglandin synthetase inhibitors (indomethacin or tion and reduced need for ECMO in a small,
ibuprofen) early to prevent relapse of respiratory randomized trial of beractant (Lotze et al. 1998).
status and/or pulmonary hemorrhage. A larger observational study of poractant alfa in
infants with group B streptococcal pneumonia
showed similar short-term improvements in oxy-
63.4.8 Other Indications for Surfactant genation, but these were less impressive than
Therapy those in preterm infants with RDS (Herting
et al. 2000). Although the number of infants with
Secondary surfactant dysfunction may occur in pneumonia and respiratory failure treated with
neonatal respiratory disorders other than RDS surfactant is relatively small, improved oxygena-
where the deficiency is primary. Surfactant inacti- tion warrants further study and continued use of
vation and secondary dysfunction probably occur surfactant for this indication.
in meconium aspiration syndrome, congenital Pulmonary hemorrhage is now relatively uncom-
pneumonia, pulmonary hemorrhage, acute lung mon but may still occur in very preterm infants
injury or acute respiratory distress syndrome following surfactant therapy, and it has been postu-
(ARDS), and early stages of BPD (Polin lated that this is due to rapidly improving pulmonary
et al. 2014; Robertson and Halliday 1998). There vascular resistance and large left-to-right shunt
are varying degrees of evidence of effectiveness of through a PDA (Halliday and Speer 1995). It is
63 Lung Diseases: Surfactant Replacement Therapy in Newborns 1003
advisable to monitor preterm infants after surfactant there was an unexpectedly large reduction in the
therapy for PDA clinically, echographically, and by combined outcome of death and BPD in infants
blood pressure assessment and to use either indo- treated with beractant plus budesonide compared
methacin or ibuprofen at an early stage to prevent to those treated with beractant alone (32% versus
pulmonary hemorrhage. Surfactant has been used to 61%; p = 0.003) (Yeh et al. 2008). Recently a
treat massive pulmonary hemorrhage and the ratio- larger trial (n = 265) of this approach to preventing
nale is that blood inhibits surfactant function. There BPD reported a reduction of the composite out-
is evidence of modest improvement in oxygenation come, BPD or death, from 66% to 42%
after surfactant treatment, but this comes from ( p < 0.001; RR 0.58, 95%CI 0.44–0.77; NNT
observational studies rather than randomized trials, 4, 95%CI 3–8) (Yeh et al. 2016).
which clearly would be difficult to perform (Aziz Congenital diaphragmatic hernia is also asso-
and Ohlsson 2012). A small randomized trial com- ciated with surfactant insufficiency (Cogo
paring poractant alfa and beractant to treat preterm et al. 2013), but surfactant treatment in a large
infants with pulmonary hemorrhage showed series of infants did not improve outcomes
improvements in oxygenation index with both sur- (Polin et al. 2014). On the contrary, there were
factants but no differences in BPD or mortality increased rates of CLD, mortality, and need
(Bozdag et al. 2015). for ECMO in surfactant-treated infants (Keiser
In acute lung injury or ARDS, surfactant is and Bhandari 2016). Until more evidence is forth-
inactivated by proteins and other substances leaking coming, surfactant replacement cannot be
into the alveolar spaces. Pneumonia and sepsis are recommended for infants with congenital dia-
frequently underlying causes, and surfactant is at phragmatic hernia although a recent survey
least partially effective in reversing signs of respi- found that 45% of pediatric surgeons administer
ratory failure in these term infants (Robertson and surfactant (Zani et al. 2016).
Halliday 1998; Lotze et al. 1998; Herting
et al. 2000). In some preterm infants born to
mothers with severe preeclampsia, there may be 63.5 Future Developments
delayed onset of respiratory distress which could
be due to surfactant inactivation, a form of ARDS, Further research is needed to more precisely deter-
and in these infants surfactant may be only partly mine if there any infants who benefit more from
effective with multiple doses being needed. Acute prophylactic surfactant as opposed to early selec-
lung injury may be a prelude to the development of tive treatment after CPAP failure. Efforts should
BPD, and surfactant has been used to treat infants continue to reduce rates of BPD while maximizing
with early CLD in a small observational study, survival, and this will mean limiting the duration of
which showed transient improvement in oxygena- mechanical ventilation with judicious use of CPAP
tion (Pandit et al. 1995). Late booster doses of and perhaps caffeine. There will be further studies
calfactant given to preterm infants still ventilated aimed to widen indications for surfactant use
at 7–10 days transiently improved the respiratory beyond RDS (Speer et al. 2013; Keiser and
severity score without long-term benefits (Merrill Bhandari 2016). Alternative means of administer-
et al. 2011). In a large (n = 511) randomized trial, ing surfactant without the need for endotracheal
similar infants were treated with inhaled nitric oxide intubation will be pursued and tested in large ran-
and either calfactant or sham instillation every domized trials. LISA is showing promise but needs
1–3 days to a maximum of five doses (Ballard special expertise, whereas aerosolization, if
et al. 2016). The primary endpoint, survival without perfected and shown to be efficacious, should be
BPD, was almost identical in both groups. Recently easier to administer (Speer et al. 2013).
beractant has been used as a vehicle to deliver New-generation synthetic surfactants are likely to
budesonide to the airways of preterm infants with eventually replace natural surfactants especially if
severe RDS with a view to preventing BPD (Yeh they can be produced more cheaply and in greater
et al. 2008). In this relatively small randomized trial, quantities (Speer et al. 2013; Polin et al. 2014). In
1004 H. L. Halliday
particular it is likely that surfactants will be used in Dargaville PA, Copnell B, Tingay DG et al (2008) Refining
the future to deliver other drugs, such as the method of therapeutic lung lavage in meconium
aspiration syndrome. Neonatology 94:160–163
budesonide (Yeh et al. 2008, 2016) or other anti- Davis DJ, Barrington KJ, Fetus and Newborn Committee,
inflammatory agents, directly to the airways to Canadian Paediatric Society (2005) Recommendations
ameliorate acute lung injury and prevent BPD. for neonatal surfactant therapy. Paediatr Child Health
10:109–116 [updated Jan 2015]
Doyle LW, Schmidt B, Anderson PJ et al (2014) Reduction
in developmental coordination disorder with neonatal
References caffeine therapy. J Pediatr 165:356–359
Dunn MS, Shennan AT, Possmayer F (1990) Single versus
Ardell S, Pfister RH, Soll R (2015) Animal derived surfac- multiple- dose surfactant replacement therapy in neo-
tant extract versus protein free synthetic surfactant for nates of 30 to 36 weeks’ gestation with respiratory
the prevention and treatment of respiratory distress distress syndrome. Pediatrics 86:567–571
syndrome. Cochrane Database Syst Rev 8:000144 El Shahed AI, Dargaville P, Ohlsson A et al (2014) Surfac-
Avery ME, Mead J (1959) Surface properties in relation to tant for meconium aspiration syndrome in full term and
atelectasis and hyaline membrane disease. Am J Dis late preterm infants. Cochrane Database Syst Rev
Child 97:517–523 12, CD002054
Aziz A, Ohlsson A (2012) Surfactant for pulmonary hem- Finer NN, Carlo WA, Walsh MC et al (2010) Early CPAP
orrhage in neonates. Cochrane Database Syst Rev versus surfactant in extremely preterm infants. N Engl J
7, CD005254 Med 362:1970–1979
Bahadue FL, Soll R (2012) Early versus delayed selective Gortner L, Pohlandt F, Bartmann P et al (1994) High-dose
surfactant treatment for neonatal respiratory distress versus low-dose bovine surfactant treatment in very
syndrome. Cochrane Database Syst Rev 11, CD001456 premature infants. Acta Paediatr 83:135–141
Ballard RA, Keller RL, Black DM et al (2016) Random- Hahn S, Choi HJ, Soll R et al (2013) Lung lavage for
ized trial of late surfactant treatment in ventilated pre- meconium aspiration in newborn infants. Cochrane
term infants receiving inhaled nitric oxide. J Pediatr Database Syst Rev 4, CD003486
168:23–29.e4 Halliday HL (2003) Respiratory distress syndrome. In:
Berggren P, Liljedahl M, Winbladh B et al (2000) Pilot Greenough A, Milner AD (eds) Neonatal respiratory
study of nebulized surfactant therapy for neonatal disorders, 2nd edn. Arnold, London, pp 247–271
respiratory distress syndrome. Acta Paediatr Halliday HL (2006) Recent clinical trials of surfactant
89:460–464 treatment for neonates. Biol Neonate 89:323–329
Bloom BT, Clark RH (2005) Comparison of Infasurf Halliday HL, Speer CP (1995) Strategies for surfactant
(calfactant) and Survanta (beractant) in the prevention therapy in established neonatal respiratory distress syn-
and treatment of respiratory distress syndrome. Pediat- drome. In: Robertson B, Taeusch HW (eds) Surfactant
rics 116:392–399 therapy for lung disease. Marcell Dekker, New York,
Bohlin K, Jonsson B, Gustafsson AS et al (2008) Contin- pp 443–459
uous positive airway pressure and surfactant. Neona- Halliday HL, Tarnow-Mordi WO, Corcoran JD et al (1993)
tology 93:309–315 Multicentre randomised trial comparing high and low
Bozdag S, Dilli D, Gokmen T et al (2015) Comparison of dose surfactant regimens for the treatment of respira-
two natural surfactants for pulmonary hemorrhage in tory distress syndrome (the Curosurf 4 trial). Arch Dis
very low-birth-weight infants: a randomized controlled Child 69:276–280
trial. Am J Perinatol 32:211–218 Hallman M (1989) Recycling of surfactant: a review of
Choi HJ, Hahn S, Lee J et al (2012) Surfactant lavage human amniotic fluid as a source of surfactant for
therapy for meconium aspiration syndrome: a systematic treatment of respiratory distress syndrome. Rev Perinat
review and meta-analysis. Neonatology 101:183–191 Med 6:197–226
Cogo PE, Simonato M, Danhaive O et al (2013) Impaired Herting E, Gefeller O, Land M et al (2000) Surfactant
surfactant protein B synthesis in infants with congenital treatment of neonates with respiratory failure and
diaphragmatic hernia. Eur Respir J 41:677–682 group B streptococcal infection. Pediatrics
Curstedt T, Johansson J (2006) New synthetic 106:957–964
surfactants–how and when? Biol Neonate 89:336–339 Jobe AH, Michell BR, Gunkel JH (1993) Beneficial effects
Curstedt T, Halliday HL, Speer CP (2015) A unique story of the combined use of prenatal corticosteroids and
in neonatal research: the development of a porcine postnatal surfactant on preterm infants. Am J Obstet
surfactant. Neonatology 107:321–329 Gynecol 168:508–513
Dani C, Bertini G, Pezzati M et al (2004) Early extubation Kattwinkel J, Bloom BT, Delmore P et al (2000) High-
and nasal continuous positive airway pressure after versus low threshold surfactant retreatment for neonatal
surfactant treatment for respiratory distress syndrome respiratory distress syndrome. Pediatrics 106:282–288
among preterm infants 30 weeks’ gestation. Pediatrics Kattwinkel J, Robinson M, Bloom BT et al (2004) Tech-
113:e560–e563 nique for intrapartum administration of surfactant
63 Lung Diseases: Surfactant Replacement Therapy in Newborns 1005
without requirement for an endotracheal tube. J beractant (Survanta) in the treatment of respiratory
Perinatol 24:360–365 distress syndrome in preterm infants. Am J Perinatol
Keiser A, Bhandari V (2016) Surfactant therapy in 21:109–119
nonrespiratory distress syndrome conditions in neo- Roberts D, Dalziel S (2006) Antenatal corticosteroids for
nates. Am J Perinatol 33:1–8 accelerating fetal lung maturation for women at risk
Konishi M, Fujiwara T, Naito T et al (1988) Surfactant of preterm birth. Cochrane Database Syst Rev 3,
replacement therapy in neonatal respiratory distress CD004454
syndrome. A multicenter randomised clinical trial: Robertson B, Halliday H (1998) Principles of surfactant
comparison of high versus low-dose of Surfactant replacement. Biochim Biophys Acta 1408:346–361
TA. Eur J Pediatr 147:20–25 Rojas-Reyes MX, Morley CJ, Soll R (2012) Prophylactic
Kribs A, Vierzig A, Hunseler C et al (2008) Early surfac- versus selective use of surfactant in preventing morbid-
tant in spontaneously breathing with nCPAP in ELBW ity and mortality in preterm infants. Cochrane Database
infants – a single center four year experience. Acta Syst Rev 3, CD000510
Paediatr 97:293–298 Sandri F, Plavka R, Ancora G et al (2010) Prophylactic or
Kribs A, Roll C, Gopel W et al (2015) Nonintubated early selective surfactant combined with nCPAP in very
surfactant application vs conventional therapy in preterm infants. Pediatrics 125:e1402–e1409
extremely preterm infants: a randomized clinical trial. Schmidt B, Roberts R, Davis P et al (2006) Caffeine
JAMA Pediatr 169:723–730 therapy for apnea of prematurity. N Engl J Med
Lotze A, Mitchell BR, Bulas DJ et al (1998) Multicenter 354:2112–2121
study of surfactant (beractant) use in the treatment of Schmidt B, Roberts RS, Davis P et al (2007) Long-term
term infants with severe respiratory failure. J Pediatr effects of caffeine therapy for apnea of prematurity. N
132:40–47 Engl J Med 357:1893–1902
Merrill JD, Ballard PL, Courtney SE et al (2011) Pilot trial Seger N, Soll R (2009) Animal derived surfactant extract
of late booster doses of surfactant for ventilated prema- for treatment of respiratory distress syndrome.
ture infants. J Perinatol 31:599–606 Cochrane Database Syst Rev 2, CD007836
Morley CJ (1991) Surfactant treatment of premature Singh N, Halliday HL, Stevens TP et al (2015) Compar-
babies: a review of clinical trials. Arch Dis Child ison of animal-derived surfactants for the prevention
66:445–450 and treatment of respiratory distress syndrome in pre-
Morley CJ, Davis PG, Doyle LW et al (2008) Nasal CPAP term infants. Cochrane Database Syst Rev
or intubation at birth for very preterm infants. N Engl J 12, CD010249
Med 358:700–708 Sinha S, Lacaze-Masmoneil T, Valls-i-Soler A et al (2005)
Moya F, Gadzinowski J, Bancalari E et al (2005) A multi- A randomized, controlled trial of lucinactant versus
center, randomized, masked, comparison trial of poractant alfa in very premature infants at high risk
lucinactant, colfosceril palmitate, and beractant for the for respiratory distress syndrome. Pediatrics
prevention of respiratory distress syndrome in very 115:1030–1038
preterm infants. Pediatrics 115:1018–1029 Soll RF (2000a) Prophylactic natural surfactant extract for
Pandit PB, Dunn MS, Kelly EN et al (1995) Surfactant preventing morbidity and mortality in preterm infants.
replacement in neonates with early chronic lung dis- Cochrane Database Syst Rev 2, CD000511
ease. Pediatrics 95:851–854 Soll RF (2000b) Synthetic surfactant for respiratory dis-
Pfister RH, Soll RF, Wiswell T (2007) Protein containing tress syndrome in preterm infants. Cochrane Database
synthetic surfactant versus animal derived surfactant Syst Rev 2, CD001149
extract for the prevention and treatment of respiratory Soll R, Ozek E (2009) Multiple versus single doses of
distress syndrome. Cochrane Database Syst Rev exogenous surfactant for the prevention or treatment
4, CD006069 of neonatal respiratory distress syndrome. Cochrane
Pfister RH, Soll R, Wiswell TE (2009) Protein-containing Database Syst Rev 1, CD000141
synthetic surfactant versus protein-free synthetic sur- Soll R, Ozek E (2010) Prophylactic protein free synthetic
factant for the prevention and treatment of respiratory surfactant for preventing morbidity and mortality in
distress syndrome. Cochrane Database Syst Rev preterm infants. Cochrane Database Syst Rev
4, CD006180 1, CD001079
Pillow JJ, Minocchieri S (2012) Innovation in surfactant Speer CP, Robertson B, Curstedt T et al (1992) Random-
therapy II: surfactant administration by aerosolization. ized European multicenter trial of surfactant replace-
Neonatology 101:337–344 ment therapy for severe neonatal respiratory distress
Polin RA, Carlo WA, Committee on Fetus and Newborn syndrome: single versus multiple doses of Curosurf.
(2014) Surfactant-replacement therapy for preterm and Pediatrics 89:13–20
term neonates with respiratory distress. Pediatrics Speer CP, Sweet DG, Halliday HL (2013) Surfactant ther-
133:156–163 apy: past, present and future. Early Hum Devel 89
Ramanathan R, Rasmussen MR, Gerstmann DR (Suppl 1):S22–S24
et al (2004) A randomized, multicenter masked com- Stevens TP, Harrington EW, Blennow M, Soll R (2007)
parison trial of poractant alfa (Curosurf) versus Early surfactant administration with brief ventilation
1006 H. L. Halliday
vs. selective surfactant and continued mechanical ven- Verder H, Albertsen P, Ebbesen F et al (1999) Nasal con-
tilation for preterm infants with or at risk for respiratory tinuous positive airway pressure and early surfactant
distress syndrome. Cochrane Database Syst Rev therapy for respiratory distress syndrome in newborns
4, CD003063 of less than 30 weeks’ gestation. Pediatrics 103, e24
Sweet DG, Carnielli V, Greisen G et al (2013) European Walsh BK, Daigle B, DiBlasi RM et al (2013) AARC
consensus guidelines on the management of neonatal clinical practice guideline. Surfactant replacement ther-
respiratory distress syndrome in preterm infants – 2013 apy: 2013. Respir Care 58:367–375
update. Neonatology 103:353–368 Yeh TF, Lin HC, Chang CH et al (2008) Early intratracheal
Trevisanuto D, Grazzina N, Ferrasse P et al (2005) Laryn- instillation of budesonide using surfactant as a vehicle
geal mask airway used as a delivery conduit for the to prevent chronic lung disease in preterm infants: a
administration of surfactant to preterm infants with respi- pilot study. Pediatrics 121:e1310–e1318
ratory distress syndrome. Biol Neonate 87:217–220 Yeh TF, Chen CM, Wu SY et al (2016) Intratracheal
Ueda T, Ikegami M, Rider ED et al (1994) Distribution of administration of budesonide/surfactant to prevent
surfactant and ventilation in surfactant-treated preterm bronchopulmonary dysplasia. Am J Respir Crit Care
lambs. J Appl Physiol 76:45–55 Med 193:86–95
Valls-i-Soler A, Fernandez-Ruanova B, Lopez-Heredia J Zani A, Eaton S, Puri P et al (2016) International survey on
et al (1998) A randomized comparison of surfactant the management of congenital diaphragmatic hernia.
dosing via a dual-lumen endotracheal tube in respira- Eur J Pediatr Surg 26:38–46
tory distress syndrome. Pediatrics 101, E4 Zola EM, Gunkel JH, Chan RK et al (1993) Comparison of
Vento M, Cheung P-Y, Aguar M (2009) The first golden three dosing procedures for administration of bovine
minutes of the extremely-low-gestational-age neonate: surfactant to neonates with respiratory distress syn-
a gentle approach. Neonatology 95:286–298 drome. J Pediatr 122:453–459
Extracorporeal Membrane
Oxygenation for Neonates 64
Anne Greenough, Niovi Papalexopoulou, Munir Ahmed, and
Adam P. R. Smith
Contents
64.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1008
64.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1008
64.3 Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1008
64.3.1 ECMO Circuit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1009
64.3.2 Management During ECMO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1009
64.3.3 Eligibility for ECMO (ELSO 2015) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1009
64.3.4 Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1010
64.3.5 Morbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1011
64.3.6 Cost-Effectiveness of ECMO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012
64.3.7 Changes in ECMO Requirements with Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012
Abstract
Extracorporeal membrane oxygenation
(ECMO) is a modified form of cardiopulmo-
nary bypass such that patients can be supported
for a prolonged period, even up to weeks, until
A. Greenough (*) the patient’s respiratory and/or cardiac function
Division of Asthma, Allergy and Lung Biology, MRC recovers or definitive treatment is adminis-
Centre for Allergic Mechanisms of Asthma, King’s
College London, London, UK tered. A systematic review of results of
244 infants entered into randomized trials dem-
NIHR Biomedical Centre at Guy’s and St Thomas NHS
Foundation Trust and King’s College London, London, onstrated that ECMO was associated with a
UK reduction in mortality (relative risk 0.44, 95%
NICU, King’s College Hospital, London, UK
CI 0.31–0.61) and the number needed to treat
e-mail: [email protected] was three. Survival is best in neonates with
N. Papalexopoulou · M. Ahmed · A. P. R. Smith meconium aspiration syndrome and worse in
Division of Asthma, Allergy and Lung Biology, MRC those with congenital diaphragmatic hernia.
Centre for Allergic Mechanisms of Asthma, King’s Chronic respiratory, neurological, and growth
College London, London, UK problems have been reported following
e-mail: [email protected]; Munir.
[email protected]; [email protected] ECMO. Overall, follow-up of infants into the
# Springer International Publishing AG, part of Springer Nature 2018 1007
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_211
1008 A. Greenough et al.
largest randomized trial, the UK ECMO trial, 64.2 Introduction
showed at 7 years of age a continuing benefit of
ECMO for the primary outcome of death or Extracorporeal membrane oxygenation (ECMO)
severe disability (relative risk 0.64, 95% CI is a modified form of cardiopulmonary bypass
0.47–0.86; p = 0.004). While treatment was such that patients can be supported for a
cost-effective in most diagnostic groups, the prolonged period, even up to weeks, until the
cost ratio for infants with CDH was far poorer. patient’s respiratory and/or cardiac function
Subsequent advances in other respiratory sup- recovers or definitive treatment is administered,
port techniques for term and near-term infants, for example, in cardiac anomalies. Gibbon
including high-frequency oscillation and nitric designed and used a heart-lung machine during
oxide, and, however, have reduced the number the first successful open-heart surgery in 1953
of cases referred for ECMO and altered the (Gibbon 1954). In the following decades, mem-
profile of such patients. brane oxygenators began to be used for infants
with respiratory failure and congenital cardiac
defects and in 1975 Bartlett and colleagues dem-
64.1 Salient Points onstrated the potential of ECMO for neonates
(Bartlett et al. 1976). Since 1989, the Extracorpo-
• Extracorporeal membrane oxygenation real Life Support Organization (ELSO) has
(ECMO) is a form of cardiopulmonary bypass maintained a registry of ECMO use in over
that supports neonates until their pulmonary 200 centers (Rais-Bahrami and Van Meurs
and/or cardiac function recovers. 2014). Approximately 35,500 “neonatal ECMO
• There are two methods of ECMO: venoarterial patients” have been recorded, comprising approx-
(VA ECMO) providing support for both pul- imately half (51.4%) of all ECMO cases. ECMO
monary and cardiac function and venovenous in adults was almost abandoned as initial trials
(VV ECMO) in which the artificial lung is in failed to show better survival than that achieved
series with the patient’s lung and pulmonary by conventional respiratory support (Zapol
and systemic perfusion relies on the patient’s et al. 1979; Morris et al. 1994). There has, how-
ventricular function. ever, been a resurgence of ECMO use in adults
• VA ECMO has disadvantages which include following the positive outcomes during the 2009
possible systemic emboli and lower myocar- influenza A (H1N1) pandemic (Peek et al. 2009;
dial oxygen delivery, and the carotid artery is Noah et al. 2011). Conversely, survival rates and
cannulated, and arterial reconstruction may be the use of ECMO in neonates reached a peak in
difficult, particularly in small infants. the early 1990s and have thereafter been declining
• The overall survival to hospital discharge is (Frenckner and Radell 2008). In this chapter, the
greatest in infants with a primary diagnosis of techniques used, the management of a neonate on
meconium aspiration syndrome and lowest in ECMO, and the indications for ECMO are
those with a congenital diaphragmatic hernia. described. In addition, the results achieved and
• Advances in other respiratory support tech- the impact of the advent of new respiratory sup-
niques for term and near-term infants, includ- port techniques and therapies on the use of ECMO
ing high-frequency oscillation and nitric oxide, are discussed.
have reduced the number of cases referred for
ECMO and altered the profile of such patients.
• A potential concern with the institution of 64.3 Techniques
newer methods of respiratory support is that it
may delay ECMO treatment, which in There are two methods of providing ECMO:
non-randomized studies has been associated venoarterial (VA) and venovenous (VV). In VA
with prolongation of both ECMO and conven- ECMO, blood is drained from the right jugular
tional treatment, as well as increased mortality. vein and returned via the right carotid artery. The
64 Extracorporeal Membrane Oxygenation for Neonates 1009
major advantage of VA ECMO is that it provides surface area of the oxygenator; hence, a heat
support for both lung and heart functions, as 80% exchanger warms the blood before it is returned
cardiopulmonary bypass is achieved. VA ECMO, to the infant.
however, has disadvantages which include possi-
ble systemic emboli, lower myocardial oxygen
delivery, and potentially worse organ perfusion 64.3.2 Management During ECMO
from loss of pulsatile flow (Rais-Bahrami and
Van Meurs 2014). In addition, the carotid artery Prior to cannulation, infants are heparinized and
is cannulated and arterial reconstruction may be remain on a heparin continuous infusion (20–50
difficult, particularly in small infants. In VV units/kg/h) while on ECMO to maintain an acti-
ECMO, the artificial lung is in series with the vated clotting time of 180–200 s. Systemic
patient’s lung, and pulmonary and systemic per- anticoagulation is administered in the circuit to
fusion relies on the patient’s ventricular function. prevent thromboembolic events resulting from
A double lumen catheter may be sited in the right activation of the clotting cascade from blood
atrium via the right jugular vein: venous blood is coming into contact with the tubing. As a result
drained from one lumen into the ECMO circuit of anticoagulation, bleeding complications do
and oxygenated blood is returned through the occur, most commonly during cannulation and
other lumen into the right atrium (Rais-Bahrami at surgical wounds. This is exacerbated as plate-
and Van Meurs 2014). Alternatively the blood is lets become sequestered in the oxygenator.
drained from the internal jugular vein and Bleeding complications can be minimized
returned to the inferior vena cava via the femoral by maintaining adequate platelet counts
or, less commonly, the umbilical vein. VV ECMO (>100,000 cells/mm3), a normal international
obviates the need for carotid artery cannulation, normalized ratio of prothrombin time (INR),
but leg edema can occur following femoral vein and adequate levels of fibrinogen. Additional
ligation after decannulation. Advantages of VV respiratory support is required during ECMO,
ECMO include perfusion of myocardium with but it is important to use settings that minimize
oxygenated blood, risk of pulmonary emboli further lung injury while avoiding atelectasis.
rather than systemic, and maintenance of pulsatile Typical “lung rest” settings are peak pressures
flow. There is, however, recirculation of blood less than 30 cmH2O, PEEP levels of
with overall lower oxygen delivery. Both tech- 8–10 cmH2O, rates of 10–25 breaths per minute,
niques share similar hemorrhagic and mechanical and an inspired oxygen concentrations of
risks. 0.21–0.40. Medications and fluids can be
added into the circuit; the pharmacokinetics of
certain drugs during ECMO, however, are not
64.3.1 ECMO Circuit entirely clear, with unknown dosing implica-
tions (Rehder et al. 2013). Weaning is achieved
Venous blood is pumped through an oxygenator, by gradually reducing the pump flow rate. Serial
which has blood and gas compartments separated cranial ultrasound examinations should be
by semipermeable membranes, through which the undertaken during ECMO.
diffusion of oxygen and carbon dioxide occurs.
The circuit contains a “bladder” – a reservoir
which stops the pump from working if venous 64.3.3 Eligibility for ECMO (ELSO 2015)
drainage becomes too low, preventing air bubbles
and clots. Oxygen transfer is dependent on the ECMO is used in term or near-term infants with
surface area of the membrane, pump flow, and reversible respiratory or cardiac failure
the degree of saturation of the venous blood. Car- unresponsive to maximal conventional therapy.
bon dioxide elimination is affected by the flow Furthermore, the underlying pathology should
rate. Heat is lost, particularly due to the large have short-term reversibility.
1010 A. Greenough et al.
The oxygenation index (OI) is usually used to preductal saturation >85% and a PaCO2
determine the need for ECMO. <65 mmHg is strongly associated with a
worse prognosis attributable to pulmonary
Mean airway pressure FiO2 100 hypoplasia and constitutes exclusion criteria
OI ¼
Postductal PaO2 for ECMO in some centers.
ECMO has most commonly been used for
meconium aspiration syndrome, persistent pul-
FiO2 = fraction of the inspired oxygen monary hypertension, and congenital diaphrag-
matic hernia. Newer uses include intractable
An OI > 40 has been used, as it had predicted a primary arrhythmias (Dyamenahalli et al. 2012)
mortality of > 80%, but in the UK ECMO trial, an and congenital hypertrophic cardiomyopathy
OI > 40 on conventional ventilation was only caused by maternal diabetes (Arzuaga and Groner
associated with a mortality of 41% 2013).
(UK Collaborative ECMO Trial Group 1996).
ELSO indicates ECMO in neonatal respiratory
failure in the following cases (ELSO 2015): 64.3.4 Mortality
1. OI > 40 for >4 h There are four randomized control trials compar-
2. OI > 20 with lack of improvement despite ing neonatal ECMO with conventional therapy for
prolonged (>24 h) maximal medical therapy respiratory failure (UK Collaborative ECMO
or persistent episodes of decompensation Trial Group 1996; O’Rourke et al. 1989; Bartlett
3. Severe hypoxic respiratory failure with acute et al. 1985; Gross et al. 1994). The largest ran-
decompensation (PaO2< 40 mmHg) domized neonatal ECMO trial recruited 185 neo-
unresponsive to intervention nates with severe respiratory failure from
4. Progressive respiratory failure and/or pulmo- 55 neonatal intensive care units in the UK
nary hypertension with evidence of right ven- (UK Collaborative ECMO Trial Group 1996).
tricular dysfunction or continued high Parental consent to entry into the trial was
inotropic requirement requested if the OI was greater than 40 or the
arterial partial pressure of CO2 was >12 kPa for
Contraindications include: 3 h. Infants were then randomized to either remain
on conventional therapy at their neonatal unit or
• Lethal chromosomal (includes trisomy 13 and be transferred for ECMO at one of five UK cen-
18 but not 21) or congenital disorder ters. Overall, there was a significant reduction in
• Irreversible brain damage mortality for the ECMO group (relative risk
• Uncontrolled bleeding (RR) 0.55, 95% CI 0.39–0.77; p = 0.0005).
• Grade III intraventricular hemorrhage There was a benefit for ECMO in all diagnoses,
although the effect in CDH infants was marginal;
Relative contraindications include: 17 CDH infants supported conventionally died
before discharge and 14 of 18 supported with
1. Irreversible organ damage, unless candidate ECMO died before 1 year of age (ELSO 2015).
for transplantation. A systematic review of results of 244 infants
2. Weight less than 2 kg and/or gestation less than entered into randomized trials demonstrated that
34 weeks as such infants are at increased risk of ECMO was associated with a reduction in mortal-
intracranial hemorrhage. ity (RR 0.44, 95% CI 0.31–0.61) and the number
3. Mechanical ventilation greater than 10–14 days. needed to treat was three (Mugford et al. 2008).
4. In infants with congenital diaphragmatic her- Up to July 2015, over 35,500 cases of neonatal
nia, the absence of an initial period with a ECMO have been reported to the ELSO registry;
64 Extracorporeal Membrane Oxygenation for Neonates 1011
the majority (28,271) received ECMO for respi- death, cerebral infarction, intracranial hemorrhage,
ratory causes. The cumulative survival to hospital or seizures) during ECMO support. Mortality was
discharge or transfer is currently 74%. In 2015 higher in patients with neurological complications
survival of neonatal respiratory cases was 63% (62% vs. 36%, p < 0.001) (Polito et al. 2013). The
compared to 81% in 1990, while the average only long-term data on outcome following ran-
“run” time has increased to 203 h from 144 h in domization to ECMO or conventional manage-
1990 (Vasavada et al. 2011). Those data ment, however, comes from the UK ECMO trial.
(Vasavada et al. 2011) reflect the change in the Follow-up at 1 year revealed that ECMO was
nature of the population now undergoing ECMO associated with a reduction in mortality without
(see later). Survival remains best in neonates with an increase in severe disability (defined as having a
MAS (94%) and worst in those with CDH (51%). Griffiths quotient less than 50 or being unable to
VA ECMO was used in approximately 72% of participate in quantitative developmental assess-
cases with a cumulative survival of 71% and VV ment due to severity of disability). At 4 years of
ECMO in 28% of cases with 82% survival (Rais age, more of the ECMO surviving infants had no
and Van Meurs 2014). Late mortality (>90 days disability (50% vs. 37%) (Bennett et al. 2001).
post ECMO) has been reported to occur in 5.5% Ninety of the infants (56 ECMO; 34 conventional)
of patients, those with CDH being at the most risk were seen at 7 years, and there were no significant
(Ijsselstijn and van Heijst 2014). differences in overall cognitive ability between the
Approximately 17% of cases reported to the two groups; 76% of infants had an overall perfor-
ELSO Registry had a primary cardiac problem, mance within the normal range (McNally
with an overall survival of 41%. ECMO is also et al. 2006). Overall, the study showed a continu-
used during cardiopulmonary resuscitation ing benefit of ECMO for the primary outcome of
(n = 1,188) with 41% survival (Organization death or severe disability (relative risk 0.64, 95%
ELS 2015). Overall survival to hospital discharge CI 0.47–0.86; p = 0.004). Longitudinal assess-
of 641 infants who received extracorporeal car- ment of motor performance at 5, 8, and/or
diopulmonary resuscitation was 39% (McMullan 12 years after neonatal ECMO of a Dutch cohort
et al. 2014). Lower birth weight and of 254 survivors demonstrated that motor prob-
pre-extracorporeal cardiopulmonary resuscitation lems persist throughout childhood and become
oxygenation, as well as complications including more obvious with time (Van der Cammen-van
CNS hemorrhage, increased the odds of death Zijp et al. 2014).
(McMullan et al. 2014). Analysis of data from Beardsmore et al. showed that ECMO-
the ELSO registry has demonstrated that neonates supported infants from the UK RCT had better
requiring prolonged ECMO support (>20 days) lung function at 1 year of age than those
have only a 24% survival to hospital discharge; who remained on conventional ventilation
many had CDH (Prodhan et al. 2014). Complica- (Beardsmore et al. 2000). At 7 years of age,
tions were common with prolonged ECMO, but more children from the “conventional” group
only receipt of inotropes was shown to be inde- had evidence of respiratory morbidity, 32%
pendently associated with mortality (Prodhan had intermittent wheeze during the 12 months
et al. 2014). prior to questioning, and 41% regularly used
inhalers, compared to 11% and 25%, respec-
tively, of the ECMO group (McNally
64.3.5 Morbidity et al. 2006). Spoel et al. undertook a prospective
longitudinal study evaluating outcomes of
Chronic respiratory, neurological, and growth 121 infants supported by ECMO at 5, 8, and/or
problems have been reported following ECMO. 12 years. They demonstrated long-term pulmo-
Review of 7,910 neonates supported by ECMO nary sequelae in the CDH patients with a ten-
between 2005 and 2010 demonstrated that 1,412 dency for lung function to deteriorate with time
(20%) had neurological complications (brain (Spoel et al. 2012).
1012 A. Greenough et al.
64.3.6 Cost-Effectiveness of ECMO that it may delay ECMO treatment, which in
non-randomized studies has been associated with
The costs of ECMO at 1 year are dominated by the prolongation of both ECMO and conventional
expense of initial hospital care, reflecting partly treatment, as well as increased mortality (Prodhan
the cost of ECMO provision itself, but also that et al. 2014; Coppola et al. 2008).
the reduced mortality results in an increased aver-
age duration of stay in conventional neonatal Acknowledgments We thank Dr Nicholas Barrett (Con-
intensive care. Cost-effectiveness improves over sultant in Critical Care at Guy’s and St Thomas’s Hospital
NHS Foundation Trust) for providing data on the current
time, with the 7-year follow-up analysis from the
mortality and Mrs Deirdre Gibbons for secretarial
UK ECMO trial estimating that the incremental assistance.
cost per life year gained was £13,385 (2002–2003 The research was supported by the National Institute for
prices) (Petrou et al. 2006). While treatment of Health Research (NIHR) Clinical Research Facility at
Guy’s and St Thomas’ NHS Foundation Trust and NIHR
infants was cost-effective in most diagnostic
Biomedical Research Centre based at Guy’s and St
groups, the cost ratio for infants with CDH was Thomas’ NHS Foundation Trust and King’s College
far poorer. London. The views expressed are those of the authors
and not necessarily those of the NHS, the NIHR, or the
Department of Health.
64.3.7 Changes in ECMO Requirements
with Time
References
Advances in other respiratory support techniques
for term and near-term infants, including high- Arzuaga BH, Groner A (2013) Utilization of extracorpo-
frequency oscillation and nitric oxide, have real membrane oxygenation in congenital hypertrophic
reduced the number of cases referred for ECMO cardiomyopathy caused by maternal diabetes. J Neona-
and altered the profile of such patients. Data from tal Perinatal Med 6:345–348
Bartlett RH, Gazzaniga AB, Jefferies MR et al (1976)
the ELSO registry highlight that neonatal respira- Extracorporeal membrane oxygenation (ECMO) car-
tory cases fell from a peak of 1,516 in 1992 to diopulmonary support in infancy. Trans Am Soc Artif
627 in 2015 and that the proportion of cases with Int Organs 22:80–93
MAS fell from 35% to 25%, while CDH cases Bartlett RH, Roloff DW, Cornell RG et al (1985) Extracor-
poreal circulation in neonatal respiratory failure: a pro-
rose from 18% to 28% (Qureshi et al. 2013). Con- spective randomized study. Pediatrics 76:479–487
versely the number of neonatal cardiac cases has Beardsmore C, Dundas I, Poole K et al (2000) Respiratory
been increasing with improved survival. Infants function in survivors of the United Kingdom Extracor-
with CDH are now the commonest patient popu- poreal Membrane Oxygenation Trial. Am J Respir Crit
Care Med 161:1129–1135
lation requiring ECMO (Rais and Van Meurs Bennett CC, Johnson A, Field DJ et al (2001) UK collab-
2014). A retrospective review of 18,130 all neo- orative randomised trial of neonatal extracorporeal
nates undergoing noncardiac ECMO between membrane oxygenation: follow-up to age 4 years. Lan-
1990 and 2010 demonstrated that neonates of cet 357:1094–1096
Coppola CP, Tyree M, Larry K et al (2008) A 22-year
ethnic minorities have continued to dispropor- experience in global transport extracorporeal mem-
tionally require ECMO support compared to brane oxygenation. J Pediatr Surg 43:46–52
their birth rates (Qureshi et al. 2013). A compar- Dyamenahalli U, Tuzcu V, Fontenot E et al (2012) Extra-
ison of infants with severe respiratory failure corporeal membrane oxygenation support for intracta-
ble primary arrhythmias and complete congenital heart
treated at a single center during two time periods block in newborns and infants: short- term and
showed a decrease in ECMO utilization from medium-term outcomes. Pediatr Crit Care Med
42.8% to 27.7% (Hintz et al. 2000). There were 13:47–52
concomitant increases in the use of HFOV ELSO (2015) Guidelines for neonatal respiratory failure
2013. [Cited 18 Dec 2015]. Available from: https://
(36.7–87.2%), surfactant (26.5–89.3%), and iNO www.elso.org/Portals/0/IGD/Archive/FileManager/
(0–44.7%). One potential concern with the insti- 8588d1a580cusersshyerdocumentselsoguidelinesforneo
tution of newer methods of respiratory support is natalrespiratoryfailure13.pdf
64 Extracorporeal Membrane Oxygenation for Neonates 1013
Frenckner B, Radell P (2008) Respiratory failure and extra- support versus extracorporeal membrane oxygenation
corporeal membrane oxygenation. Semin Pediatr Surg for severe adult respiratory failure (CESAR): a
17:34–41 multicentre randomised controlled trial. Lancet 374:
Gibbon JH Jr (1954) Application of a mechanical heart and 1351–1363
lung apparatus to cardiac surgery. Minn Med 37: Petrou S, Bischof M, Bennett C et al (2006) Cost-
171–185 effectiveness of neonatal extracorporeal membrane
Gross SJ, Bifano EM, D’Euqenio DB et al (1994) 86 pro- oxygenation based on 7-year results from the United
spective randomized controlled trial of conventional Kingdom Collaborative ECMO Trial. Pediatrics
treatment or transport for ecmo in infants with severe 117:1640–1649
persistent pulmonary hypertension (PPHN): two year Polito A, Barrett CS, Wypij D et al (2013) Neurologic
follow up. Pediatr Res 36:17A-A complications in neonates supported with extracorpo-
Hintz SR, Suttner DM, Sheehan AM et al (2000) real membrane oxygenation. An analysis of ELSO
Decreased use of neonatal extracorporeal membrane registry data. Intensive Care Med 39:1594–1601
oxygenation (ECMO): how new treatment modalities Prodhan P, Stroud M, El-Hassan N et al (2014) Prolonged
have affected ECMO utilization. Pediatrics 106: extracorporeal membrane oxygenator support among
1339–1343 neonates with acute respiratory failure: a review of the
Ijsselstijn H, van Heijst AF (2014) Long-term outcome of extracorporeal life support organization registry.
children treated with neonatal extracorporeal mem- ASAIO J 60:63–69
brane oxygenation: increasing problems with increas- Qureshi FG, Jackson HI, Brown J et al (2013) The chang-
ing age. Semin Perinatol 38:114–121 ing population of the United States and use of extracor-
McMullan DM, Thiagarajan RR, Smith KM et al (2014) poreal membrane oxygenation. J Surg Res 184:
Extracorporeal cardiopulmonary resuscitation out- 572–576
comes in term and premature neonates. Pediatr Crit Rais BK, Van Meurs KP (2014) Venoarterial versus
Care Med 15:e9–e16 venovenous ECMO for neonatal respiratory failure.
McNally H, Bennett CC, Elbourne D et al (2006) United Semin Perinatol 38:71–77
Kingdom collaborative randomized trial of neonatal Rais-Bahrami K, Van Meurs KP (2014) Venoarterial versus
extracorporeal membrane oxygenation: follow-up to venovenous ECMO for neonatal respiratory failure.
age 7 years. Pediatrics 117:e845–e854 Semin Perinatol 38:71–77
Morris AH, Wallace CJ, Menlove RL et al (1994) Ran- Rehder KJ, Turner DA, Cheifetz IM (2013) Extracorporeal
domized clinical trial of pressure-controlled inverse membrane oxygenation for neonatal and pediatric
ratio ventilation and extracorporeal CO2 removal for respiratory failure: an evidence-based review of the
adult respiratory distress syndrome. Am J Respir Crit past decade (2002–2012). Pediatr Crit Care Med 14:
Care Med 149:295–305 851–861
Mugford M, Elbourne D, Field D (2008) Extracorporeal Spoel M, Laas R, Gischler SJ et al (2012) Diagnosis-
membrane oxygenation for severe respiratory failure in related deterioration of lung function after extracorpo-
newborn infants. Cochrane Database Syst Rev real membrane oxygenation. Eur Respir J 40:
3, CD001340 1531–1537
Noah MA, Peek GJ, Finney SJ et al (2011) Referral to an UK Collaborative ECMO Trial Group (1996) UK collabo-
extracorporeal membrane oxygenation center and mor- rative randomised trial of neonatal extracorporeal
tality among patients with severe 2009 influenza A membrane oxygenation. Lancet 348:75–82
(H1N1). JAMA 306:1659–1668 Van der Cammen-van Zijp M, Janssen A, Raets M
O’Rourke PP, Crone RK, Vacanti JP et al (1989) Extracor- et al (2014) Motor performance after neonatal extracor-
poreal membrane oxygenation and conventional medi- poreal membrane oxygenation: a longitudinal evalua-
cal therapy in neonates with persistent pulmonary tion. Pediatrics 134:e427–e435
hypertension of the newborn: a prospective randomized Vasavada R, Feng Q, Undar A (2011) Current status of
study. Pediatrics 84:957–963 pediatric/neonatal extracorporeal life support: clinical
Organization ELS (2015) ECLS registry report – interna- outcomes, circuit evolution, and translational research.
tional summary 2015 July. Available from: https:// Perfusion 26:294–301
www.elso.org/Registry/Statistics/InternationalSummary. Zapol WM, Snider MT, Hill JD et al (1979) Extracorporeal
aspx membrane oxygenation in severe acute respiratory fail-
Peek GJ, Mugford M, Tiruvoipati R et al (2009) Efficacy ure. A randomized prospective study. JAMA 242:
and economic assessment of conventional ventilatory 2193–2196
Lung Diseases: Problems of Steroid
Treatment of Fetus and Newborn 65
Henry L. Halliday
Contents
65.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015
65.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1016
65.3 Results from Randomized Trials of Prenatal Corticosteroids . . . . . . . . . . . . . 1017
65.4 Results from Randomized Trials of Postnatal Steroids . . . . . . . . . . . . . . . . . . . . 1018
65.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1019
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1020
Abstract first week of life, do not seem to outweigh the
Corticosteroids given in the perinatal period adverse effects on neurodevelopment. However,
have a multitude of biologic effects on the devel- late postnatal steroid therapy, after the first week
oping lung. Clearly, some of these will be ben- of life, seems to be associated with similar ben-
eficial to the immature fetus or neonate, while eficial pulmonary effects without significant
others will be detrimental. For the fetus at risk of increase in neurodevelopmental sequelae. Late
preterm birth, a single course of betamethasone steroid therapy with dexamethasone is probably
or dexamethasone leads to lung maturity and still indicated for preterm infants with CLD who
reduces the risk of RDS and other important cannot be weaned from ventilation. Thus,
complications of prematurity. Consensus administration of corticosteroids in the perinatal
seems to support repeat courses of prenatal ste- period must be based upon clinical judgment of
roids when there is a high risk of preterm birth the balance of benefits and risks. Further evalu-
before 29 weeks’ gestation even if there are ation should be done considering long-term fol-
some controversies. The beneficial pulmonary low-up in order to confirm their safety before
effects of early postnatal dexamethasone, in the they can be recommended for routine use.
H. L. Halliday (*) 65.1 Salient Points
Formerly Regional Neonatal Unit, Royal Maternity
Hospital, Belfast, UK
• Corticosteroids given in the perinatal period
Formerly Department of Child Health, Queen’s University
Belfast, Belfast, UK
have a multitude of biological effects on the
e-mail: [email protected] developing lung and other organs.
# Springer International Publishing AG, part of Springer Nature 2018 1015
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_212
1016 H. L. Halliday
• Prenatal steroids accelerate fetal lung maturity alveolarization, increased production of surfactant
reducing neonatal mortality, respiratory dis- lipids and proteins, increased absorption of lung
tress syndrome, intraventricular hemorrhage, fluid, and increased antioxidant activity. Clearly,
and necrotizing enterocolitis without affecting some of these will be beneficial to the immature
maternal health. fetus or neonate, while others will be detrimental.
• Betamethasone and dexamethasone have been Thus administration of corticosteroids in the peri-
used to enhance fetal lung maturity. natal period must be based upon clinical judgment
• Repeat doses improve neonatal outcomes of the balance of benefits and risks.
except for a reduction in some measures of The first randomized trials of corticosteroids in
weight at birth. the perinatal period were published in 1972 in the
• Early (first week) postnatal steroids lead to ear- same issue of a pediatric journal (Liggins and
lier extubation and decreased bronchopulmonary Howie 1972; Baden et al. 1972). They were
dysplasia (BPD), patent ductus arteriosus, and aimed at either preventing or treating respiratory
retinopathy of prematurity (ROP) but increased distress syndrome (RDS), a condition of predom-
gastrointestinal (GI) bleeding and perforation, inantly preterm infants, which then had a high
hyperglycemia, hypertension, hypertrophic car- mortality rate. RDS is due to primary deficiency
diomyopathy (HOCM), growth failure, and cere- of pulmonary surfactant (Avery and Mead 1959),
bral palsy (CP), although an outcome combining and Mont Liggins, an obstetrician in
death and CP is not increased. New Zealand, had shown that an infusion of cor-
• Hydrocortisone (low dose) and dexamethasone tisol into fetal lambs seemed to prevent RDS
were used in these trials, and benefits and adverse (Liggins 1968). He and a colleague from pediat-
effects were limited to treatment with the latter. rics, Ross Howie, performed a large randomized
• The recent PREMILOC trial of early low dose trial of prenatal betamethasone that showed this
hydrocortisone suggests an increase in survival not only decreased the risk of RDS in neonates but
without BPD although there was increased also reduced mortality (Liggins and Howie 1972).
sepsis in infants of 24–25 weeks’ gestation. Since 1972, many randomized trials have con-
• Inhaled budesonide (first 12 h) reduced BPD in firmed the benefits of prenatal corticosteroids
one large trial, but there was a trend toward (Roberts and Dalziel 2006), and long-term fol-
increased neonatal mortality. low-up of the original cohort at age 31 years has
• Late (after first week) postnatal steroids lead to been published (Dalziel et al. 2005). Detrimental
earlier extubation and reduced neonatal mor- effects of prenatal corticosteroids and the contro-
tality, BPD, death, or BPD, while there is versy over any additional benefit of repeat courses
increased GI bleeding, hyperglycemia, hyper- will be discussed in this chapter.
tension, HOCM, and severe ROP, but no sig- The trial of Baden et al. recruited only
nificant increase in CP. 44 infants with RDS to test the effects of hydro-
• It is prudent to reserve late postnatal steroids for cortisone on blood gases, need for assisted venti-
infants who cannot be weaned from ventilation. lation and survival (Baden et al. 1972).
• Early low dose hydrocortisone improves sur- Unfortunately, there were no beneficial effects of
vival without BPD (OR 1.48; 95%CI hydrocortisone, and the authors also concluded
1.02–2.16; p = 0.04) with higher sepsis rate in that there were no immediate detrimental effects
infants of 24–25 weeks’ gestation. of the therapy. However, two subsequent follow-
up publications raised concerns about an excess of
severe intraventricular hemorrhage (IVH) and
65.2 Introduction neurosensory and electroencephalographic abnor-
malities (Fitzhardinge et al. 1974; Taeusch
Corticosteroids given in the perinatal period have et al. 1973) in hydrocortisone-treated infants.
many biologic effects on the developing lung Despite these early concerns, dexamethasone
(Grier and Halliday 2004). These include reduced was used to treat infants with bronchopulmonary
65 Lung Diseases: Problems of Steroid Treatment of Fetus and Newborn 1017
dysplasia (BPD) and ventilator dependence less maturity and concluded that no clear advantages
than a decade later (Mammel et al. 1983; Avery were found, although dexamethasone may have
et al. 1985). The rationale for dexamethasone some benefits compared to betamethasone with
therapy was to reduce inflammation in the lung, less IVH and a shorter length of NICU stay
an important precursor to the development of (Brownfoot et al. 2013). An Australasian trial is
BPD. However, the doses of dexamethasone currently underway to address this question
used in these trials were very large (about (Crowther et al. 2013). In 2015 a systematic
0.5 mg/kg/day as a starting dose) giving pharma- review concluded that a single course of prenatal
cologic rather than physiologic effects. It was not steroids in women at high risk for preterm birth
surprising that the acute beneficial effects on lung appears to improve most neurodevelopmental
function (Mammel et al. 1983; Avery et al. 1985) outcomes in offspring born before 34 weeks of
would later be shown to have had adverse long- gestation (Sotiriadis et al. 2015).
term effects on the developing central nervous Recently, however, there has been concern
system when dexamethasone was given in the about the ineffectiveness of prenatal steroids in
first week of life (Yeh et al. 1998). low-income and middle-income countries (Azad
and Costello 2014; Dalziel et al. 2014). This con-
cern is based on the findings of the WHO
65.3 Results from Randomized Trials Multicountry Survey on Maternal and Newborn
of Prenatal Corticosteroids Health involving more than 300,000 births in
359 hospitals in 29 countries (Vogel et al. 2014).
The most recent Cochrane Review of a single The results have been criticized because of poor
course of prenatal steroids for accelerating fetal treatment coverage and underreporting of preterm
lung maturation includes 21 studies and 4,269 birth, but it is agreed that prenatal steroids are not
infants (Roberts and Dalziel 2006). The authors a panacea for preterm mortality in low-income
conclude that prenatal steroid treatment does not and middle-income countries, and drugs should
increase risk of death to the mother, chorioam- be included in a package of simple efficacious
nionitis, or puerperal sepsis. However, treatment measures (Dalziel et al. 2014).
was associated with an overall reduction in neo- The most recent systematic review of repeat
natal death (RR 0.69, 95%CI 0.58–0.81), RDS doses of prenatal steroids for women at risk
(RR 0.66, 95%CI 0.59–0.73), IVH (RR 0.54, of preterm birth for preventing RDS included
95%CI 0.43–0.69), necrotizing enterocolitis ten trials and involved 4,733 women and 5,700
(NEC) (RR 0.46, 95%CI 0.29–0.74), respiratory babies (Crowther et al. 2015). Treatment with
support and intensive care admissions (RR 0.80; repeat dose(s) of steroids was associated with a
95%CI 0.65–0.99), and systemic infections in reduction in RDS (RR 0.83, 95%CI 0.75–0.91)
the first 48 h of life (RR 0.56, 95%CI and serious infant outcome (RR 0.84, 95%CI
0.38–0.85). Prenatal steroid use is also effective 0.75–0.94). Mean birth weight was reduced by
in women with premature rupture of membranes 75.9 g (95%CI 34.0–117.6 g) with repeat doses,
and pregnancy-related hypertension syndromes but after adjustment of birth weight for gestational
(Roberts and Dalziel 2006). The authors con- age, these differences disappeared. The authors
cluded that a single course of prenatal steroids concluded that repeat dose(s) of prenatal steroids
should be considered routinely for preterm deliv- reduces the occurrence of RDS and serious health
ery with few exceptions. Further information is problems in the first few weeks of life. The short-
needed concerning optimal dose to delivery inter- term benefits for babies support the use of repeat
val, optimal steroid to use, effects in multiple dose(s) of prenatal steroids for women at risk of
pregnancies, and confirm long-term effects into preterm birth. However, these benefits are associ-
adulthood (Roberts and Dalziel 2006; Wapner ated with a reduction in some measures of weight at
and Jobe 2011). A recent review assessed differ- birth, and more research is needed on the longer-
ent steroid regimens for accelerating lung term benefits and risks (Crowther et al. 2015).
1018 H. L. Halliday
65.4 Results from Randomized Trials 0.04) in preterm infants (<28 weeks’ gestation)
of Postnatal Steroids treated with low dose hydrocortisone for 10 days
starting before 24 h after birth (Baud et al. 2016). In a
The most recent systematic reviews of postnatal subgroup of infants of 24–25 weeks’ gestation there
steroids for preventing (Doyle et al. 2014a) and was an increase in sepsis (sub-hazard ratio 1.87; 95
treating chronic lung disease (CLD) (Doyle %CI 1.09–3.21; p = 0.02). A recent follow-up study
et al. 2014b) in preterm infants were published in from Finland reported neurodevelopmental impair-
the Cochrane Library in 2014. Twenty-nine trials ment in 61% of children at 5–7 years who had been
enrolling 3,750 infants were included in the system- treated with early hydrocortisone to prevent BPD
atic review of postnatal steroids given in the first compared to 39% of placebo-treated infants
week of life to try to prevent CLD in preterm infants (Peltoniemi et al. 2016). The authors of the
(Doyle et al. 2014a). There were significant benefits Cochrane Review concluded that the benefits of
of early postnatal steroids as regards earlier early postnatal steroid treatment (<8 days), partic-
extubation and decreased risks of CLD at both ularly with dexamethasone, may not outweigh the
28 days (RR 0.87, 95%CI 0.81–0.93) and known or potential adverse effects of this treatment.
36 weeks’ postmenstrual age (PMA) (RR 0.79, Although early steroid treatment facilitates
95%CI 0.71–0.88). There were also decreases in extubation and reduces risk of CLD and PDA, it
persistent ductus arteriosus (PDA) (RR 0.79, 95% causes short-term adverse effects including GI
CI 0.72–0.85), retinopathy of prematurity (ROP) bleeding, intestinal perforation, hyperglycemia,
(RR 0.88, 95%CI 0.80–0.97), and severe ROP hypertension, hypertrophic cardiomyopathy, and
(RR 0.79, 95%CI 0.64–0.94). There were no signif- growth failure. Long-term follow-up studies report
icant differences in rates of mortality, infection, increased risks of abnormal neurological examina-
severe IVH, periventricular leukomalacia, NEC, or tion and cerebral palsy. There is a compelling need
pulmonary hemorrhage. Important adverse effects for more long-term follow-up and reporting of late
included gastrointestinal (GI) bleeding (RR 1.86, outcomes, especially neurological and develop-
95%CI 1.35–2.55), intestinal perforation (RR 1.81, mental outcomes, among surviving infants who
95%CI 1.33–2.48), hyperglycemia (RR 1.33, 95% participated in all randomized trials of early post-
CI 1.20–1.47), hypertension (RR 1.85, 95%CI natal steroids. Hydrocortisone in the doses and
1.54–2.22), hypertrophic cardiomyopathy (RR regimens used in these trials had few beneficial or
4.33, 95%CI 1.40–13.4), and growth failure harmful effects and cannot be recommended for
(RR 6.67, 95%CI 2.27–19.6). Twelve of 29 trials prevention of CLD (Doyle et al. 2010, 2014a).
reported late outcomes, and several adverse effects Inhaled steroids have been used to try to prevent
were found including cerebral palsy (RR 1.45, 95% CLD in the hope that they would have fewer adverse
CI 1.06–1.98) and abnormal neurological examina- effects. A recent large randomized trial of high-dose
tion (RR 1.81, 95%CI 1.33–2.47). However, the inhaled budesonide reported a reduction in BPD
rates of the combined outcomes of death or cerebral (RR 0.74, 95%CI 0.60–0.91) in preterm infants
palsy and death or major neurosensory disability treated within 12 h of birth (Bassler et al. 2015).
were not significantly increased (Doyle et al. 2014a). Although there was also a reduction in the combined
Dexamethasone was used in 20 studies and outcome of death or BPD (RR 0.86, 95%CI
hydrocortisone in nine. In a subgroup analysis, 0.75–1.00), the authors were concerned that the
most of the beneficial and harmful effects were advantage of reduced BPD may have come at the
attributable to dexamethasone although with hydro- expense of increased neonatal mortality (Bassler
cortisone there was an increase in intestinal perfora- et al. 2015). Further studies of inhaled steroids
tion (RR 2.02, 95%CI 1.13–3.59) and a borderline with long-term follow-up are needed before this
reduction in PDA (RR 0.85, 95%CI 0.73–0.99) treatment can be recommended as a routine.
(Doyle et al. 2010, 2014a). A French randomized Twenty-one trials enrolling a total of 1,424
clinical trial recently reported an increase in survival infants were included in the systematic review of
without BPD (OR 1.48; 95 %CI 1.02–2.16; p = late (>7 days) postnatal steroids for CLD in
65 Lung Diseases: Problems of Steroid Treatment of Fetus and Newborn 1019
preterm infants (Doyle et al. 2014b). Late steroid powered to detect increased rates of important
treatment was associated with a reduction in neo- long-term outcomes. Given the evidence of both
natal mortality (RR 0.49, 95%CI 0.28–0.85) but benefits and harms of treatment and the limitations
not at discharge (RR 0.86, 95%CI 0.66–1.13). of the evidence at present, it appears prudent to
Other beneficial effects included earlier extubation reserve the use of late postnatal steroids to infants
and reductions in CLD at both 28 days (RR 0.87, who cannot be weaned from mechanical ventilation
95%CI 0.81–0.94) and 36 weeks’ PMA (RR 0.82, and to minimize the dose and duration of any
95%CI 0.70–0.96), need for late treatment with course of treatment (Doyle et al. 2014b).
dexamethasone (RR 0.47, 95%CI 0.38–0.59), dis-
charge on home oxygen therapy (RR 0.71, 95%CI
0.54–0.94), and death or CLD at both 28 days 65.5 Conclusions
(RR 0.84, 95%CI 0.78–0.89) and 36 weeks’ PMA
(RR 0.76, 95%CI 0.68–0.85). There was a trend There are some problems with steroid treatment of
toward an increased risk of GI bleeding but not the fetus and newborn, but on the whole if used
NEC. Short-term adverse effects included hyper- according to accepted guidelines, the benefits out-
glycemia (RR 1.50, 95%CI 1.25–1.80), glycosuria weigh the risks. For the fetus at risk of preterm birth,
(RR 8.03, 95%CI 2.43–26.5), and hypertension a single course of betamethasone or dexamethasone
(RR 2.12, 95%CI 1.45–3.10). There was an leads to lung maturity and reduces the risk of RDS,
increase in hypertrophic cardiomyopathy neonatal mortality, and other important complica-
(RR 2.76, 95%CI 1.33–5.74) and severe ROP tions of prematurity (Roberts and Dalziel 2006). The
(RR 1.38, 95%CI 1.07–1.79), but no significant current recommendation is to give two doses of
increase in blindness. There was a trend toward 12 mg betamethasone, 24 h apart, to women who
reduction in severe IVH (RR 0.44, 95%CI may deliver within 7 days and are less than
0.19–1.02), and trends toward an increase in cere- 35 weeks pregnant (Sweet et al. 2013). There
bral palsy (RR 1.12, 95%CI 0.79–1.60) and abnor- remains some controversy about repeat courses of
mal neurological examination were partly offset by prenatal steroids, as they are associated with reduced
a trend in the opposite direction in death before late fetal growth, but consensus seems to support their
follow-up. The combined rate of death or cerebral use when there is a high risk of preterm birth before
palsy was not significantly different between ste- 29 weeks’ gestation (Wapner and Jobe 2011).
roid and control groups. Major neurosensory dis- The beneficial pulmonary effects of early post-
ability and the combined rate of death or major natal dexamethasone, in the first week of life, do not
neurosensory disability were not significantly dif- outweigh the adverse effects on neurodevelopment
ferent between groups. There were no substantial (Doyle et al. 2014a). However, late postnatal steroid
differences between groups for other outcomes in therapy, after the first week of life, seems to be
later childhood, including respiratory health or associated with similar beneficial pulmonary
function, blood pressure, or growth (Doyle effects without significant increase in neurodeve-
et al. 2014b). The authors concluded that the ben- lopmental sequelae (Doyle et al. 2014b). Infants at
efits of late steroid therapy (>7 days) may not higher risk of BPD have increased rates of survival
outweigh actual or potential adverse effects. free of cerebral palsy after postnatal steroid treat-
Although there continues to be concern about an ment (Doyle et al. 2014c). Late steroid therapy,
increase in adverse neurological outcomes in with low-dose, short duration dexamethasone, is
infants treated with early postnatal steroids, this probably still indicated for preterm infants with
review of late steroids suggests that this may reduce CLD who remain ventilator dependent and have
neonatal mortality without significantly increasing severe respiratory disease (Halliday 2011).
the risk of adverse long-term neurodevelopmental Inhaled steroids may be a promising method of
outcomes. However, the methodological quality of reducing BPD with reduced adverse effects, but
the studies determining long-term outcomes is lim- further evaluation in randomized clinical trials with
ited in some cases, and no study was sufficiently long-term follow-up is needed to confirm their
1020 H. L. Halliday
safety before they can be recommended for routine Doyle LW, Ehrenkranz RA, Halliday HL (2014b) Late (>7
use (Bassler et al. 2015; Halliday 2011). days) postnatal corticosteroids for chronic lung disease
in preterm infants. Cochrane Database Syst Rev
5, CD001145
Doyle LW, Halliday HL, Ehrenkranz RA et al (2014c) An
update on the impact of postnatal systemic corticoste-
References roids on mortality and cerebral palsy in preterm infants:
effect modification by risk of bronchopulmonary dys-
Avery ME, Mead J (1959) Surface properties in relation to plasia. J Pediatr 165:1258–1260
atelectasis and hyaline membrane disease. Am J Dis Fitzhardinge PM, Eisen A, Lejtenyi C (1974) Sequelae of
Child 97:517–523 early steroid administration to the newborn infant.
Avery GB, Fletcher AB, Kaplan M et al (1985) Controlled Pediatrics 53:877–883
trial of dexamethasone in respirator-dependent infants Grier DG, Halliday HL (2004) Effects of glucocorticoids
with bronchopulmonary dysplasia. Pediatrics 75:106–111 on fetal and neonatal lung development. Treat Respir
Azad C, Costello A (2014) Extreme caution is needed Med 3:295–306
before scale-up of antenatal corticosteroids to reduce Halliday HL (2011) Postnatal steroids: the way forward.
preterm deaths in low-income settings. Lancet Glob Arch Dis Child Fetal Neonatal Ed 96:F158–F159
Health 2:e191–e192 Liggins GC (1968) Premature parturition after infusion of
Baden M, Bauer CR, Colle E et al (1972) A controlled trial corticotrophin or cortisol into foetal lambs. J
of hydrocortisone therapy in infants with respiratory Endocrinol 42:323–329
distress syndrome. Pediatrics 50:526–534 Liggins GC, Howie RN (1972) A controlled trial of
Bassler D, Plavka R, Shinwell ES et al (2015) Early inhaled antepartum glucocorticoid treatment for prevention of
budesonide for the prevention of bronchopulmonary the respiratory distress syndrome in preterm infants.
dysplasia. N Engl J Med 373:1497–1506 Pediatrics 50:515–525
Baud O, Maury L, Lebail F et al (2016) Effect of early Mammel MC, Green TP, Johnson DE et al (1983) Con-
low-dose hydrocortisone on survival without trolled trial of dexamethasone therapy in infants with
bronchopulmonary dysplasia in extremely preterm infants bronchopulmonary dysplasia. Lancet 1:1356–1358
(PREMILOC): a double-blind, placebo-controlled, Peltoniemi OM, Lano A, Yliherva A, Kari MA, Hallman M,
multicentre, randomised trial. Lancet 387: 1827–1836 Neonatal Hydrocortisone Working Group (2016)
Brownfoot FC, Gagliardi DI, Bain E et al (2013) Different Randomised trial of early neonatal hydrocortisone dem-
corticosteroids and regimens for accelerating fetal lung onstrates potential undesired effects on neurodevelopment
maturation for women at risk of preterm birth. at preschool age. Acta Paediatr 105:159–164
Cochrane Database Syst Rev 8, CD006764 Roberts D, Dalziel S (2006) Antenatal corticosteroids for
Crowther CA, Harding JE, Middleton PF et al (2013) Aus- accelerating fetal lung maturation for women at risk of
tralasian randomized trial to evaluate the role of mater- preterm birth. Cochrane Database Syst Rev 3, CD004454
nal intramuscular dexamethasone versus Sotiriadis A, Tsiami A, Papatheodoros S et al (2015)
betamethasone prior to preterm birth to increase sur- Neurodevelopmental outcome after a single course of
vival free of childhood neurosensory disability. BMC antenatal steroids in children born preterm: a systematic
Pregnancy Childbirth 13:104 review and meta-analysis. Obstet Gynecol 125:
Crowther CA, McKinlay CJ, Middleton et al (2015) Repeat 1385–1396
doses of prenatal corticosteroids for women at risk of Sweet DG, Carnielli V, Greisen G et al (2013) European
preterm birth for improving health outcomes. Cochrane consensus guidelines on the management of neonatal
Database Syst Rev 7, CD003935 respiratory distress syndrome in preterm infants – 2013
Dalziel SR, Lim VK, Lambert A et al (2005) Antenatal update. Neonatology 103:353–368
exposure to betamethasone: psychological functioning Taeusch HW Jr, Wang NS, Baden M et al (1973) A con-
and health related quality of life 31 years after inclusion trolled trial of hydrocortisone therapy in infants with
in randomised controlled trial. BMJ 331:665–668 respiratory distress syndrome: II. Pathol Pediatr
Dalziel SR, Crowther CA, Harding JE (2014) Antenatal 52:850–854
steroids 40 years on: we can do better. Lancet Vogel JP, Souza JP, Gulmezoglu AM et al (2014) Use of
384:1829–1831 antenatal corticosteroids and tocolytic drugs in preterm
Doyle LW, Ehrenkranz RA, Halliday HL (2010) Postnatal births in 29 countries: an analysis of the WHO
hydrocortisone for preventing or treating Multicountry Survey on Maternal and Newborn
bronchopulmonary dysplasia in preterm infants: a sys- Health. Lancet 384:1869–1877
tematic review. Neonatology 98:111–117 Wapner R, Jobe AH (2011) Controversy: antenatal ste-
Doyle LW, Ehrenkranz RA, Halliday HL (2014a) Early roids. Clin Perinatol 38:529–545
(<8 days) postnatal corticosteroids for preventing Yeh TF, Lin YJ, Huang CC et al (1998) Early dexametha-
chronic lung disease in preterm infants. Cochrane Data- sone therapy in preterm infants: a follow-up study.
base Syst Rev 5, CD001146 Pediatrics 101, e7
Apnea of Prematurity and Sudden
Infant Death Syndrome 66
Christian F. Poets
Contents
66.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1022
66.2 Apnea of Prematurity (AOP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1022
66.2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1022
66.2.2 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1023
66.3 Sudden Infant Death Syndrome (SIDS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1027
66.3.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1028
66.3.2 Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1029
66.3.3 Genetic Studies in SIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1030
66.3.4 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1030
66.3.5 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1030
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1032
Abstract primary prevention campaigns in many coun-
Apnea of prematurity is a self-resolving, yet tries, yet continues to be a leading cause of
very common condition in preterm infants. death beyond the neonatal period. Although
Recent observational data suggest that the still incompletely understood, it seems that
intermittent hypoxemia often occurring with death is the result of an external trigger (e.g.,
it may be associated with an increased risk of prone sleep position) occurring in a vulnerable
adverse outcome, including cerebral palsy, ret- infant (e.g., born to a mother who smoked
inopathy of prematurity, and death. Treatment during pregnancy) during a critical develop-
should follow an incremental approach, mental period (e.g., 2–4 months of age). Mem-
starting with head elevated positioning, ory monitor recordings obtained during SIDS
followed by caffeine administration and nasal suggest that bradycardia, probably resulting
respiratory support. from severe hypoxemia, is the primary abnor-
Sudden infant death syndrome has mality in the sequence of events ultimately
decreased markedly in incidence following resulting in these deaths. Prevention should
focus on a safe sleep environment, i.e., supine
sleep position, a smoke-free environment,
C. F. Poets (*) avoidance of overheating, use of a sleeping
Department of Neonatology, Tübingen University
Hospital, Tübingen, Germany bag, and room but not bed sharing.
e-mail: [email protected]
# Springer International Publishing AG, part of Springer Nature 2018 1021
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_213
1022 C. F. Poets
infant during a critical developmental
List of Abbreviations
period.
AAP American Academy of Pediatrics
• Prevention should focus on a safe sleep envi-
ALTE Apparent life-threatening event
ronment (supine positioning), a smoke-free
AOP Apnea of prematurity
environment, and avoidance of overheating.
BPD Bronchopulmonary dysplasia
CDC Centers for Disease Control
CI Confidence interval
CO2 Carbon dioxide
66.2 Apnea of Prematurity (AOP)
IH Intermittent hypoxemia
LQTS Long-QT-syndrome
66.2.1 Introduction
MCAD Medium-chain acyl-CoA
Apnea of prematurity (AOP) is a developmental
dehydrogenase
and thus self-resolving disorder, which nonethe-
N-CPAP Nasal continuous positive airway
less may cause serious long-term sequelae
pressure
through accompanying hypoxemia. Almost
N-IPPV Nasal intermittent positive pressure
every infant born at less than 29 weeks gestation
ventilation
exhibits AOP, but little was known when it
NNT Number needed to treat
became potentially harmful. Recently, a second-
OR Odds ratio
ary analysis of pulse oximeter saturation (SpO2)
PaO2 Partial pressure of oxygen in arte-
and pulse rate data recorded for a mean duration
rial blood
of 68 days in 1035 participants in the Canadian
PAR Population-attributable risk
Oxygen Trial (COT), who were born at 23–27
RCT Randomized controlled trial
weeks GA and survived to 36 weeks post-
ROP Retinopathy of prematurity
menstrual age (PMA), showed the following
RR Relative risk
(Poets et al. 2015):
SIDS Sudden infant death syndrome
SpO2 Arterial oxygen saturation mea-
– Mean percentages of recorded time with hyp-
sured by pulse oximetry
oxemia (pulse oximeter saturation (SpO2)
TPN Total parenteral nutrition
<80% for at least 10 s) for the least and most
VLBW Very low birth weight
affected 10% of infants was at 0.4 and 13.5%,
respectively, while bradycardia (pulse rate
<80/min.) was rarer at 0.1 and 0.3%.
66.1 Salient Points – Being in the highest decile for % time with
intermittent hypoxemia (IH) was associated
• Apnea of prematurity is a self-resolving and with three to fivefold increased odds of devel-
very common condition in preterm infants. oping the primary outcome of death beyond
• The intermittent hypoxemia accompanying it 36 weeks or disability at 18 months, with
may be associated with an increased risk of these associations being significant only for
adverse outcome (cerebral palsy, retinopathy of events lasting at least 1 min.
prematurity, and death). – Odds ratios for secondary outcomes (motor
• Treatment consists of head elevated position- impairment, cognitive, or language delay
ing, followed by caffeine administration and and severe retinopathy of prematurity)
nasal up to nasal respiratory support. were similarly increased after prolonged
• The incidence of sudden infant death syn- hypoxemia.
drome (SIDS) has markedly decreased even if – Bradycardia, in the absence of concomitant
it remains a leading cause of death in the post- hypoxemia, did not significantly add to the
neonatal period. risk of adverse outcome.
• It seems that death is the result of an external – The severity of IH, expressed as the area-
trigger (position) occurring in a vulnerable under-the-curve (AUC), and the rate with
66 Apnea of Prematurity and Sudden Infant Death Syndrome 1023
which desaturation occurred, added little prog- threshold used with it has ever been validated.
nostic value. However, the low rates of retinopathy of prema-
– Associations between hypoxemic exposure turity (ROP; <2% for stage 3 or higher in infants
and adverse outcomes were stronger at later <1500 g birth weight in 2010–2015) and high
postnatal ages (i.e., at 8–10 week) and for Bayley scores (Moll et al. 2011) associated with
infants assigned to a target range of 91–95% implementation of this apnea scoring paradigm
compared to a target range of 85–89% SpO2. suggest its potential as a protocol that warrants
further study. In any case, such a severity score
Thus, of the three components contributing to may only serve as an example for how apnea
AOP (apnea, bradycardia, hypoxemia), it seems severity may be assessed more objectively with-
prudent to focus on the avoidance of IH, particu- out documentation via continuous recordings,
larly episodes lasting for 1 min, or longer, if we which would be preferable but is yet impractical
want to avoid adverse effects of AOP in extremely in most units.
preterm infants. Up to now, however, most studies
on interventions for AOP focussed on apnea.
Although not fully in line with the above data, 66.2.2 Treatment
the approach taken in the author’s institution for
the last 10 years has been to grade the intensity of In the following, interventions to improve AOP
the treatment provided for AOP based on a sever- will be grouped into those that have been shown
ity score that relies largely on the nurses’ acute to be beneficial and those where the effect is
intervention to events (e.g. stimulation, bagging; questionable and/or needs further study
Fig. 1). Neither the score nor any treatment (Table 1).
Heart rate ≤ 80/min.
or
SpO2 ≤ 80%
Intervention: Intervention: Intervention: Intervention:
none, tactile stimulation increased FiO2
spontan. recovery manual inspiration infant turned over bagging
Score Score Score Score
1 2 3 8
Start/increase treatment if score ≥ 20 in 8 h and PCA <34 wk,
or if score ≥ 10 and PCA ≥34 wk/score 10 reached within 2 h
Reduce treatment if score ≤ 8 in ≥3 consecutive 8 interavals.
Fig. 1 A proposed apnea severity score to standardize vulnerable to the detrimental effects of intermittent hypox-
assessment across different raters/infants. The values in emia (Modified based on Poets CF (2010). Interventions
the lower row of boxes indicate the respective score. The for apnoea of prematurity: a personal view. Acta Paediatr
threshold for an increase in treatment severity is lower in 99; 2172–2177, with permission)
more mature infants as these are considered more
1024 C. F. Poets
Table 1 Suggested incremental treatment plan for AOP nasopharyngeal tube or (bi-)nasal prongs.
First Step: 15 head-up tilt position Reintubation rates are 40% lower with the latter
Second Step: Caffeinea (relative risk (RR) 0.59 [95%-confidence interval
Third Step: Variable flow CPAP or synchronized N-IPPV (CI) 0.41; 0.85], number needed to treat (NNT) 5)
Fourth Step: Intubation and mechanical ventilationb (De Paoli et al. 2008), suggesting nasal prongs as
a
Consider caffeine as first-line treatment in infants the preferred patient interface when applying
<29 weeks GA CPAP. An extension of CPAP is nasal intermittent
b
High-dose caffeine or doxapram may be considered as
positive pressure ventilation (N-IPPV), with bet-
alternatives in infants who continue to exhibit recurrent
hypoxemia despite mechanical ventilation ter effectiveness than CPAP in preventing
extubation failure if used in synchrony with the
infant’s own breathing efforts. Typically, an inspi-
66.2.2.1 Interventions with Proven ratory pressure of 15–20 cm H2O, applied at a rate
Benefit of 10–20/min, is combined with a CPAP level of
5–6 cm H2O. A recent meta-analysis investigating
Head-Elevated Positioning the effects of synchronised and nonsynchronized
While a recent Cochrane analysis demonstrated no nasal ventilation versus CPAP on respiratory fail-
advantage of the prone position in reducing apnea ure rates found a significant effect only for the
rates in preterm infants (data on intermittent hyp- former, making this the preferred mode of nasal
oxia were not reported), a head-elevated 15 tilt ventilatory support if a trial of CPAP fails
position was associated with a 49% reduction in (Lemyre et al. 2014). Interestingly, gastric disten-
desaturations to <85% in a study involving 12 pre- sion, a theoretical concern with nasal ventilation,
term infants. A reinvestigation of the effectiveness was not an issue in the studies contributing to this
of this position, however, triggered by the obser- meta-analysis (Lemyre et al. 2014).
vation that infants appear more comfortable when An even more recent study investigated differ-
only the chest and head rather than the entire body ent synchronized nasal ventilation system in
are being tilted showed only a modest ( 6%) and 19 infants at a mean PMA of 30 week and reported
nonsignificant reduction in hypoxemia rates in the a decrease in bradycardia (<80/min) and
head elevated tilt compared to the horizontal posi- desaturation (<80%) from 6.1/h with CPAP to
tion (Reher et al. 2008), and also no significant 2.9/h with S-NIPPV. With nonsynchronized
advantage ( 22%) for the head-and-chest elevated NIPPV, this rate was similar to that with CPAP
position. This much less clear advantage of the (5.9 events/h) (Gizzi et al. 2014). An earlier study
head-up tilt position may be due to the fact that comparing nonsynchronized N-IPPV with nasal
several infants in the earlier study had received no CPAP, delivered via a variable flow CPAP device
other treatment for AOP, whereas in the more that reduces work of breathing (InfantFlow,
recent one, all had received methylxanthines CareFusion, San Diego, CA), showed a decrease
and/or continuous positive airway pressure in bradycardia and desaturation rate by approxi-
(CPAP) in addition to positioning (Reher et al. mately 50% compared to both, nonsynchronized
2008). Thus, a head-up tilt position may be con- N-IPPV or CPAP (Pantalitschka et al. 2009).
sidered a first step in an incremental treatment plan Thus, a reduced work of breathing and/or effec-
for AOP, while this intervention may be less effec- tive synchronization with the infant’s own breath-
tive in infants already receiving other treatments ing efforts may be key to success for nasal
for AOP, such as caffeine or CPAP (see below). respiratory support applied to ameliorate AOP.
Continuous Positive Airway Pressure (CPAP) Caffeine
and Synchronized Nasal Ventilation Methylxanthines increase chemoreceptor sensitiv-
(S-NIPPV) ity as well as respiratory drive and can also improve
CPAP has been shown to reduce extubation fail- diaphragmatic function. Of the substances avail-
ure in preterm infants and can be applied via a able, caffeine has a wider therapeutic range and
66 Apnea of Prematurity and Sudden Infant Death Syndrome 1025
fewer side effects than theophylline. Its effective- Interestingly, the reduced duration of the need for
ness in improving patient outcome was proven in a ventilatory support was only evident in those who
large placebo-controlled RCT enrolling over 2000 were randomized within the first 3 postnatal days,
infants (the CAP study (Schmidt et al. 2007)). and the effect on death or disability was only
Caffeine (or placebo) was started during the first significant for infants receiving at least 3.5 mg/
10 postnatal days in infants of 500–1250 g birth kg/day of caffeine base (7 mg/kg/day caffeine cit-
weight at a dose of 5 10 mg/kg caffeine citrate in rate). Also in secondary data analysis, a significant
infants considered eligible for caffeine treatment difference in the rate of cerebral palsy between
and given until no longer considered necessary caffeine- and placebo-group infants was only
for AOP treatment. Mechanical ventilation, found in those receiving caffeine for at least
CPAP, and oxygen could all be discontinued 45 days. Thus, caffeine administration should be
approximately 1 week earlier in infants treated started within the first 3 days of age in infants
with caffeine. Somewhat unexpected, and not a <1250 g requiring respiratory support and being
primary outcome, was the finding of a 40% lower likely to develop AOP.
risk of bronchopulmonary dysplasia (BPD; 36% It is important also to consider when to discon-
vs. 47%; OR 0.6; 95% CI 0.5; 0.8), a 30% lower tinue caffeine treatment. In the CAP study, caffeine
risk of developing a symptomatic patent ductus was given until a mean PMA of 34.4 weeks
arteriosus (OR 0.7; [0.5; 0.8]), and a 40% reduction (Schmidt et al. 2007). However, caffeine continues
in the risk of developing stage 4 or 5 retinopathy of to be effective in reducing intermittent hypoxia
prematurity (ROP) or requiring treatment for ROP rates until 35 weeks PMA (Rhein et al. 2014).
in the caffeine group (OR 0.61 [0.42; 0.89]) With no current standards for discontinuing caf-
(Schmidt et al. 2007). Most important, however, feine therapy, the use of an apnea severity score
are the data on the primary outcome, showing a such as that proposed in Fig. 1 may provide a
23% reduction in death or disability at 18 months treatment guideline in the clinical setting.
corrected age in addition to a reduction in cerebral At what dose should caffeine be given? First, it
palsy in infants in the caffeine group (Schmidt et al. has to be remembered that caffeine is usually avail-
2007). able as caffeine citrate, in which the active compo-
Results from the 5-year follow-up of this study nent (caffeine) comprises only 50% of the total
still showed an effect of caffeine on death or dose. In this chapter, all data will be on this active
disability, but this was no longer significant. Neo- component. In the CAP study, a loading dose of
natal caffeine therapy, however, reduced motor 10 mg/kg (iv or orally) and a maintenance dose of
impairment (OR 0.66; 0.48; 0.91) (Schmidt et al. 2.5–5 mg/kg once daily were used. Another recent
2012). Motor dysfunction not associated with randomized controlled trial compared a loading
cerebral palsy or cognitive impairments is referred dose of 40 mg/kg caffeine (maintenance dose
to as developmental coordination disorder. At 10 mg/kg/day) with a “conventional” 10/2.5 mg/
5 years of age, this condition was found in 11% kg regimen in 234 infants born at a mean GA of
of caffeine-group infants compared to 15% of 27 weeks. Infants in the high dose group had only
placebo-group infants. Regarding other long- half the risk of failing extubation within 48 h of
term (side)effects, sleep studies, performed in caffeine loading or to require reintubation and
201 former CAP participants at age 5–12 years, mechanical ventilation or doxapram within 7 days
showed no difference in sleep disorders in sub- of caffeine loading (15.0% vs. 29.8%, RR 0.51
jects treated with neonatal caffeine compared to [0.31; 0.85]) (Steer et al. 2004). They received
placebo (Marcus et al. 2014). mechanical ventilation for 14.4 days (SD 11.1),
In subgroup analysis, the effect of caffeine on compared to 22.1 (17.1) days for infants in the
the primary outcome was found to be restricted to lower dose group. This better efficacy was not at
those requiring ventilatory support at randomiza- the expense of an increased risk of side effects,
tion, i.e. caffeine had no effect on death or disabil- including no difference in Griffith’s mental devel-
ity in infants not requiring CPAP or IPPV. opment scales at age 12 months. Given the
1026 C. F. Poets
extremely sparse data on doxapram (see below), This is particularly worrisome given that in a
clinicians may consider starting caffeine at the study on factors associated with poor develop-
standard dose of 10 mg/kg loading, 5 mg/kg/day ment in extremely low birth weight infants, the
maintenance, but to switch to a higher dose if only difference found was that infants with
AOP persists in an occasional infant. It has to be developmental delay (defined as a Mental Devel-
kept in mind, however, that the follow-up study opment Index <70) had received a mean cumu-
on high dose caffeine was underpowered to lative doxapram dose of 2233 mg, compared to
detect a difference in neurodevelopmental out- 615 mg in matched controls without delay
come between the low- and the high-dose group ( p < 0.01) (Sreenan et al. 2001). Although
that at this dose the serum level should occasion- such a retrospective analysis cannot distinguish
ally be checked to identify those approaching whether this reflects sequelae of severe AOP (for
toxic levels (>50 mg/l), and that a recent RCT which doxapram had been given) or a direct drug
testing the same dose as used by Steer et al. effect, it clearly raises concern. In the CAP study
(2004) was stopped prematurely because of an (Schmidt et al. 2007), placebo group infants not
unexpectedly high rate of cerebellar hemor- only had been more likely to develop cerebral
rhages (36% vs. 10%) in infants receiving high- palsy but were also three times more likely to
dose caffeine (McPherson et al. 2015). There are have received doxapram. Given these data
no indications that tachyphylaxis occurs with (or lack thereof), doxapram cannot be
caffeine, but higher doses and a 12-h dosing recommended as a standard treatment for AOP,
interval may be necessary in infants approaching although it seems to be rather widely used in
term-equivalent age because of a more rapid some countries.
caffeine metabolism in this age group.
Oxygen Administration
66.2.2.2 Interventions That Are That oxygen stabilizes neonatal respiration was
Potentially Effective but first observed in 1923 and responsible for an epi-
Require Further Study demic in ROP in the following years. Several
crossover trials in infants with and without BPD
Doxapram have since shown that the application of low-flow
Doxapram stimulates peripheral chemoreceptors oxygen results in a reduced rate of apnea and
at low and central ones at high doses. It shows a IH. Application of this therapy, however, has to
clear dose–response curve, with a 50% reduction be weighed against side effects potentially
in apnea rate occurring in 47%, 65%, 82%, and resulting from oxygen toxicity. The issue has
89% of infants at doses of 0.5, 1.5, 2.0, and resurfaced with the recent data from RCTs com-
2.5 mg/kg/h, respectively. In an own longitudinal paring an SpO2 target range of 85–89% with
study, desaturation rates to 80% SpO2 were 91–95%. As perhaps to be expected, there was a
reduced from a median of 8/h to 2/h, with this higher rate of ROP in infants randomized to the
effect continuing for the follow-up period of higher range, but – unexpectedly – also a lower
6 days (Poets et al. 1999a). Most studies used a mortality in two of these studies, which was con-
continuous intravenous infusion, although some firmed in meta-analysis (Saugstad and Aune
suggest that the iv solution may also be given 2014). Interestingly, however, the study achieving
orally at twice the dose with good effect (enteral the widest separation in SpO2 between study
absorption is approximately 50%) (Poets et al. groups was also that where no difference was
1999a). Short-term side effects become quite found for either ROP or mortality (Schmidt et al.
common at doses above 1.5 mg/kg/h and include 2013). Infants randomized to the lower target
irritability, myoclonus, elevated blood pressure, range indeed also had more episodes of IH (SpO2
and gastric residuals. Of concern is the fact that < 80%) (Poets et al. 2015). Whether these data
the long-term effects of doxapram are unknown. are sufficient to recommend keeping the SpO2 at a
66 Apnea of Prematurity and Sudden Infant Death Syndrome 1027
target range of 91–95% to prevent some episodes Oscillating Waterbed/Mechanosensory
of IH is yet open to debate. Stimulation
The theory behind this intervention is that entrain-
Increased Inspiratory CO2 Concentration ment can be achieved between an infant’s own
One determinant of respiratory drive is CO2. If breathing rhythm and an external rhythm genera-
CO2 levels fall below the eupneic baseline value, tor, e.g., an inflatable mattress connected to a
apnea occurs. A Canadian group performed an respirator. A meta-analysis of 3 RCTs testing this
RCT in 87 infants of 27–32 weeks GA to test intervention, involving a total of 165 infants,
whether adding 0.5 l/min. of CO2 to the inspired showed no effect on apnea or bradycardia. This
air (corresponding to a CO2 concentration of 1%) may be explained by the observation that synchro-
was as effective as theophylline in reducing apnea nization with an external rhythm generator is sig-
duration and rate (Alvaro et al. 2012). They found nificantly better beyond than before 35 weeks GA,
that apnea time indeed decreased with CO2 inha- but at that age AOP is no longer a major issue. As
lation from 183 44 to 101 26, 105 29, a result, this intervention has largely been aban-
and 94 26 s/h during the 3 days of intervention, doned. More recently, however, it has resurfaced
but this was still twice as high as the apnea time in the form of a stochastic mechanosensory stim-
seen in infants randomized to theophylline. No ulation, where actuators are embedded in a spe-
data on oxygenation were provided. cially designed mattress (Bloch-Salisbury et al.
2009) trying to simulate the cutaneous stimulation
Red Blood Cell Transfusions given by maternal licking of the newborn as
An increase in respiratory drive resulting from an observed in many animal species after birth.
increased tissue oxygenation is also one of the Using such a device in a crossover design in
proposed mechanisms for red cell transfusions 10 preterm infants with a mean PMA of
potentially to ameliorate AOP, and anemia has 33 weeks and a study duration of 2 1.5 h, a
indeed been implicated in the pathophysiology 65% reduction in time with SpO2 < 85% was
of AOP. It would thus seem only logical to found. Confirmation of the effectiveness of this
hypothesize that giving a blood transfusion is an approach in a larger sample and longer study
effective treatment modality in infants with AOP duration is necessary.
who are anemic. Data on the effect of blood trans- In summary, treatment for AOP may follow an
fusions on the frequency of these episodes, how- incremental approach, starting with infant care
ever, are conflicting. In two crossover studies procedures such as prone head-up tilt position-
from the author’s group, no effect of transfusion ing, followed by methylxanthines and CPAP/
was found on bradycardia and IH. In contrast, N-IPPV.
others found an age-dependent improvement in
frequency and severity of IH after transfusion
beyond the first week of life when IH events 66.3 Sudden Infant Death Syndrome
begin to increase. A meta-analysis of 4 RCTs (SIDS)
comparing the effects of a liberal with a more
restrictive transfusion policy found no statistically Sudden deaths in infants are known since biblical
significant differences in the combined outcomes times, but it was only in 1970 that Bergman et al.
of death or serious morbidity at first hospital dis- coined the term SIDS. More recently, it was
charge (Whyte and Kirpalani 2011). While this redefined by an expert panel as “the sudden unex-
result doesn’t exclude some minor effects on pected death of an infant <1 year of age, with
apnea rate, it clearly suggests that such effects, if onset of the fatal episode apparently occurring
they exist, do not improve clinical outcomes and during sleep, that remains unexplained after a
make it therefore difficult to justify blood trans- thorough investigation, including performance of
fusions as a means to treat AOP. a complete autopsy and review of the
1028 C. F. Poets
circumstances of death and the clinical history.” classified as SIDS, but now as suffocation (Malloy
To facilitate research, this definition was stratified and MacDorman 2005).
into cases with the “classic” features of SIDS
present and completely documented (so-called
Category 1A SIDS), those with these features 66.3.1 Epidemiology
present but incompletely documented (IB), and
those meeting Category I criteria except for one 66.3.1.1 Incidence
or more of the following: age <3 weeks or >270 Despite a recent decline in incidence, SIDS con-
days, similar deaths in siblings, close relatives or tinues to be the leading cause of postneonatal
infants in the custody of the same caregiver, peri- mortality in developed countries after excluding
natal conditions such as a history of premature perinatal event-related deaths (Table 2). Because
birth, suspected mechanical suffocation, or of the misclassification problem mentioned
marked inflammatory changes not sufficient to above, it is important always to report changes in
be assigned a cause of death (i.e., Category II) both SIDS and postneonatal mortality rates and to
(Krous et al. 2004). According to this definition, uniformly use a classification system that includes
all cases not meeting criteria for category I or II SIDS and deaths ascribed to accidental suffoca-
SIDS, including those for which an autopsy has tion, such as that introduced by the CDC (see
not been performed, are now called “Unclassified above).
Sudden Infant Death” (Krous et al. 2004). To also
include cases of sudden unexpected death attrib- 66.3.1.2 Age and Time of Death
uted to positional suffocation (previously often One of the most striking epidemiological features
classified as SIDS), in 2010 the Centers for Dis- in SIDS is its characteristic age distribution. Some
ease Control (CDC) introduced the term “sudden 75% of deaths occur between 2 and 4 months of
unexpected infant death (SUID),” which includes age, and 95% before 9 months of age (Poets 2008).
SIDS, ill-defined and unknown causes of death, Early beliefs that SIDS is extremely rare in the
and accidental sleep-related suffocation (Shapiro- neonatal period cannot be maintained: 6–7% of
Mendoza et al. 2014). In an initial evaluation of SIDS victims are younger than 1 month of age,
this classification system, 88% of 436 SUID were and 11% of all neonatal deaths are due to SIDS
classified as unexplained, with 73% occurring in (Poets 2008). There is also the recent recognition
an unsafe sleep environment, while 12% were that sudden deaths or near-death events may occur
assigned to suffocation, and 22% to possible suf- in apparantly healthy neonates only a few hours
focation with unsafe sleep factors. With the after delivery. Here, many risk factors otherwise
increased recognition of positional suffocation as largely abandoned in recent years (see below), such
a potential cause of death, it seems important from as prone position, overheating, or maternal fatigue,
an epidemiological and preventive point of view continue to be highly prevalent. Caregivers need to
not to dismiss cases that previously had been be alerted to the possibility of these events to occur
Table 2 SIDS and postneonatal mortality (PNM) rates in Death Syndrome: Stabilization of rates requires further
different countries, 1990 vs. 2003 (Data taken from Hauck action. Pediatrics 2007; 122:660–666)
FR, Tanabe KW: International Trends in Sudden Infant
Country PNM1990 PNM2003 Change(%) SIDS1990 SIDS2003 Change(%)
Netherlands 2.3 1.2 48 0.56 0.10 82
Sweden 2.4 0.96 60 1.0 0.23 77
Germany 3.3 1.4 58 1.42 0.43 70
USA 3.38 2.67 31 1.30 0.54 58
New Zealand 4.21 1.90 55 2.90 0.80 72
66 Apnea of Prematurity and Sudden Infant Death Syndrome 1029
and infants closely monitored already in the deliv- been identified. These include head covering,
ery room (Poets et al. 2012). which has a pooled adjusted OR of 16.9 (95%
Throughout the year, there used to be a prepon- CI 13.6; 22.7) and a population-attributable risk
derance of the cold season, but this has almost (PAR) of 27% (Blair et al. 2008), and prone
disappeared following the back-to-sleep campaigns. sleeping in preterm and low birth weight infants.
Parents of the latter infants may get confused by
66.3.1.3 Risk Factors the common use of the prone position in hospital;
A large number of factors associated with an it is thus particularly important to place these
increased risk of SIDS have been identified infants on their back before hospital discharge
(Poets 2008) (Table 3). Many underscore the and to explain the importance of supine sleeping
importance of social factors in the pathogenesis to their parents. Bed-sharing is also a relatively
of SIDS; others, such as maternal smoking or “new” risk factor. This practice seems particu-
anemia during pregnancy, suggest that there larly dangerous if taking place on a sofa or with a
must already be a disturbance during intrauterine parent who drank alcohol or who smokes and
life that poses an infant at risk. Factors that are cosleeps with an infant <3 months of age (Blair
potentially amenable to modification include et al. 2014).
maternal smoking, not breast feeding, not using
a pacifier, overheating, and a nonsupine sleep
position, and these are the factors targeted by 66.3.2 Pathology
most intervention campaigns. Subsequently,
however, additional modifiable risk factors have 66.3.2.1 Intrathoracic Petechial
Hemorrhages
As implied by its definition, there is no morpho-
Table 3 Risk factors for SIDS (Derived from Poets (2008) logical finding in SIDS that sufficiently explains
with permission)
death. There are, however, a number of charac-
Maternal factors Infantile factors teristic findings in these infants, such as serosal
Young age Male gender petechiae, which are so consistent that they
Multiparity Low birth weight appear to support the concept that SIDS may
Smoking during pregnancy Low birth length
indeed form a specific disease entity. Other char-
Maternal drug abuse Premature birth
acteristic findings in SIDS include the occur-
Previous fetal deaths Blood type B
rence of (often bloody) froth around the nose
Anemia during pregnancy Low Apgar scores
and mouth. Both may result from high trans-
Placenta praevia Low hematocrit at 48 h
Premature rupture of Not using a pacifier
pulmonary pressure swings, such as occurring
membranes during breathing against an obstructed upper air-
Low social class Prone or side sleeping way (Poets 2008).
position
Low family income Bed-sharing 66.3.2.2 Abnormalities in Brainstem
Short interpregnancy Overheating Serotonergic System
interval
Serotonin is a neurotransmitter involved in regu-
Unmarried mother Not breastfed
lating various processes potentially related to
Partner unemployed Siblings in family
SIDS, e.g., sleep and arousal, control of breathing,
Late attendance of antenatal Sleeping in own room
clinic airway reflexes, and autonomic function (Paterson
Postnatal depression Previous SIDS in family et al. 2007). Endogenously released serotonin is
Attendance to psychiatrist Previous cyanotic also required for gasping. Comparative studies on
episode the binding properties of neurotransmitter recep-
Urinary tract infection in tors found multiple brainstem abnormalities in
pregnancy SIDS compared to control infants, suggesting
1030 C. F. Poets
that such abnormalities may be involved in some and gasping. The underlying causes of both the
SIDS deaths (Paterson et al. 2007). hypoxemia and the failure of these infants to
resuscitate themselves from this hypoxemia
remain to be determined.
66.3.3 Genetic Studies in SIDS
Some infants who die suddenly and unexpectedly
66.3.5 Prevention
do so because they have an inherited disease such as
the A984G mutation in the medium-chain acyl-CoA
66.3.5.1 Primary Prevention
dehydrogenase (MCAD) gene or in genes encoding
Dissemination of advice on safe sleeping has been
cardiac ion channels resulting in long-QT syndrome.
one of the most effective health interventions ever
These well-defined diseases, however, contribute
performed. Recommendations are reviewed in reg-
only a few percent to all cases of SIDS (and, by
ular intervals to incorporate new data. The current
definition, prohibit defining SIDS as the cause of
advice given by the American Academy of Pediat-
death). More relevant to SIDS may be recent data on
rics (AAP) includes the following (abbreviated)
gene polymorphisms that may predispose infants to
(American Academy of Pediatrics 2011):
SIDS under certain circumstances, such as those
found in the serotonin transporter gene, although
– Infants should be placed for sleep in a supine
there are also strong arguments to question this
position for every sleep.
proposed link (Paterson et al. 2007; Weese-Mayer
– Use a firm sleep surface. Pillows or sheepskins
et al. 2007; Paterson 2013).
should not be placed under a sleeping infant.
– Room-sharing without bed-sharing is
66.3.4 Pathophysiology recommended.
– Keep soft objects and loose bedding out of
There are now a number of recordings from car- the crib.
diorespiratory monitors that were obtained during – Pregnant women should receive regular
SIDS. Despite some limitations, these recordings prenatal care.
have for the first time provided us with objective – Avoid smoke exposure during pregnancy and
data on the pathophysiological mechanisms after birth.
immediately preceding SIDS. In an analysis of – Avoid alcohol and illicit drug use during preg-
nine recordings of chest wall impedance and nancy and after birth.
heart rate from infants who had an autopsy diag- – Breastfeeding is recommended.
nosis of SIDS or mild BPD, gasping was the – Consider offering a pacifier at nap time and
predominant pattern, being already present at the bedtime.
time of the monitor alarm in three infants and – Avoid overheating. Bedroom temperature
occurring within 3 min after it in a further four should be comfortable for a lightly closed
(Fig. 2) (Poets et al. 1999b). Primary trigger for adult.
the monitor alarm had been bradycardia in all but – Do not use home cardiorespiratory monitors as
two infants, but there was no indication of heart a strategy for reducing the risk of SIDS.
block or ventricular tachycardia. These observa- – Infants should be immunized in accordance
tions, confirmed by a similar, more recent study with recommendations of the AAP and CDC.
(Sridhar et al. 2003), suggest that prolonged apnea – Avoid commercial devices marketed to reduce
is unlikely to be a primary mechanism in the the risk of SIDS.
sequence of events leading to most cases of – Supervised, awake tummy time is
SIDS, while the “primary” bradycardia is most recommended to facilitate development and
likely caused by hypoxemia. In addition, there to minimize development of positional
seems to be a failure or depression of arousal plagiocephaly.
66 Apnea of Prematurity and Sudden Infant Death Syndrome 1031
Fig. 2 Section from a memory monitor printout of a recording, followed by several smaller increases in heart
1-month old infant born at 34 weeks gestation and with rate that appear to occur in response to the gasps and are
an autopsy diagnosis of SIDS. There are 11 gasps which also decreasing in amplitude over time (From Poets et al.
progressively decrease in amplitude. There is an increase in (1999b), with permission). G, gasp
heart rate from 72 to 140 bpm during the first 20 s of
66.3.5.2 Secondary Prevention reader is referred to a recent Clinical Practice
For many years, the use of home monitors in Guideline (Tieder et al. 2016). The second group
specific risk groups, i.e., secondary prevention, involves technology-dependent infants (e.g., with
has been the only method to prevent SIDS, but a tracheostomy), infants with respiratory control
its effectiveness in reducing its incidence has disorders, and preterm infants with persistent
never been proven, and the AAP now clearly AOP. AOP is not associated with an increased
discourages its use to prevent SIDS. Nonetheless, risk of SIDS, but monitoring may be indicated to
home monitoring may be prescribed as a diagnos- prevent potential sequelae of IH (see above).
tic tool or as an early warning of potentially dan- Whatever the indication, a pulse oximeter with
gerous pathophysiology. The first indication motion-resistant technology to reduce the fre-
comprises infants after an apparent life- quency of false alarms is currently the preferred
threatening event (ALTE) and infants from fami- monitoring device. Although there are no con-
lies who had two or more sudden unexpected trolled trials on this issue, there is evidence to
infant deaths. Here, documented monitoring may suggest that apnea and hypoxemia may occur
help to reach a diagnosis. A detailed description of too late during the events leading to death always
the diagnostic work-up of infants with ALTE to allow for successful resuscitation. Monitoring
would go beyond the scope of this chapter; the should continue for 4 weeks after the last (true)
1032 C. F. Poets
monitor alarm except for siblings from families weeks in a German perinatal center. Klin Paediatr
with multiple deaths who should be monitored 223:251–254
Pantalitschka T, Sievers J, Urschitz MS et al (2009)
until the age of the oldest infant who died. Randomised crossover trial of four nasal respiratory
support systems for apnoea of prematurity in very low
birthweight infants. Arch Dis Child Fetal Neonatal Ed
94:F245–F248
References Paterson DS (2013) Serotonin gene variants are unlikely to
play a significant role in the pathogenesis of the sudden
Alvaro RE, Khalil M, Qurashi M et al (2012) CO2 inhala- infant death syndrome. Respir Physiol Neurobiol
tion as a treatment for apnea of prematurity: a random- 189:301–314
ized double-blind controlled trial. J Pediatr 60:252–257 Paterson DS, Trachgenberg FL, Thompson EG et al (2007)
American Academy of Pediatrics (2011) Policy Statement: Multiple serotonergic brainstem abnormalities in sudden
SIDS and other sleep-related infant deaths: expansion infant death syndrome. J Am Med Ass 296:2124–2132
of recommendations for a safe infant sleeping environ- Poets CF (2008) Apnea of prematurity, sudden infant death
ment. Pediatrics 128:1030–1039 syndrome, and apparent life-threatening events. In:
Blair PS, Mitchell EA, Heckstall-Smith EMA, Fleming PJ Taussig LM, Landau LI (eds) Pediatric respiratory
(2008) Head covering – a major modifiable risk factor medicine, 2nd edn. Mosby, Philadelphia, pp 413–434
for sudden infant death syndrome: a systematic review. Poets CF, Darraj S, Bohnhorst B (1999a) Effect of doxapram
Arch Dis Child 93:778–783 on episodes of apnoea, bradycardia and hypoxaemia in
Blair PS, Sidebotham P, Pease A, Fleming PJ (2014). preterm infants. Biol Neonate 76:207–213
Bed-sharing in the absence of hazardous circum- Poets CF, Meny RG, Chobanian MR et al (1999b) Gasping
stances: is there a risk of sudden infant death syn- and other cardiorespiratory patterns during sudden
drome? An analysis from two case-control studies infant deaths. Pediatr Res 45:350–354
conducted in the UK. PLoS One 9:e1077999 Poets A, Urschitz MS, Steinfeldt R, Poets CF (2012) Risk
Bloch-Salisbury E, Indic PP, Bednarek F, Paydarfar D factors for early sudden deaths and severe apparent life-
(2009) Stabilizing immature breathing patterns of pre- threatening events. Arch Dis Child Fetal Neonatal Ed
term infants using stochastic mechanosensory stimula- 97:F395–F397
tion. J Appl Physiol 107:1017–1027 Poets CF, Roberts RS, Schmidt B, Canadian Oxygen Trial
De Paoli AG, Davis PG, Faber B et al (2008) Devices and Investigators et al (2015) Association between inter-
pressure sources for administration of nasal continuous mittent hypoxemia or bradycardia and late death or
positive airway pressure (NCPAP) in preterm neonates. disability in extremely preterm infants. JAMA
Cochrane Database Syst Rev: CD002977 314:595–603
Gizzi C, Montecchia F, Panetta V et al (2014) Is syn- Reher C, Kuny KD, Pantalitschka T et al (2008)
chronised NIPPV more effective than NIPPV and Randomised crossover trial of different postural inter-
NCPAP in treating apnoea of prematurity (AOP)? A ventions on bradycardia and intermittent hypoxia in
randomised cross-over trial. Arch Dis Child Fetal Neo- preterm infants. Arch Dis Child Fetal Neonatal Ed
natal Ed 100:F17–F23 2016;93(4):F289–91
Krous HF, Beckwith JB, Byard RW et al (2004) Sudden Rhein LM, Dobson NR, Darnall RA, Caffeine Pilot Study
infant death syndrome and unclassified sudden infant Group et al (2014) Effects of caffeine on intermittent
deaths: a definitional and diagnostic approach. Pediat- hypoxia in infants born prematurely: a randomized
rics 114:234–238 clinical trial. JAMA Pediatr 168:250–257
Lemyre B, Davis PG, De Paoli A, Kirpalani H (2014) Saugstad OD, Aune D (2014) Optimal oxygenation of
Nasal intermittent positive pressure ventilation extremely low birth weight infants: a meta-analysis
(NIPPV) versus nasal continuous pressure (NCPAP) and systematic review of the oxygen saturation target
for preterm neonates after extubation. Cochrane Data- studies. Neonatology 105:55–63
base Syst Rev 9:CD003212 Schmidt B, Roberts RS, Davis P, Caffeine for Apnea of
Malloy MH, MacDorman M (2005) Changes in the classi- Prematurity Trial Group et al (2007) Long-term effects
fication of sudden unexpected infant deaths: United of caffeine therapy for apnea of prematurity. N Engl J
States, 1992–2001. Pediatrics 115:1247–1253 Med 357:1893–1902
Marcus CL, Meltzer LJ, Roberts RS, Caffeine for Apnea of Schmidt B, Anderson PJ, Doyle LW et al (2012) Survival
Prematurity-Trial group et al (2014) Long-term effects without disability to age 5 years after neonatal caffeine
of caffeine therapy for apnea of prematurity on sleep at therapy for apnea of prematurity. JAMA 307:275–282
school age. Am J Respir Crit Care Med 190:791–799 Schmidt B, Whyte RK, Asztalos EV et al (2013) Effects of
McPherson C, Neil JJ, Tjoeng TH, Pineda R, Inder TE targeting higher vs lower arterial oxygen saturations on
(2015) A pilot randomized trial of high-dose caffeine death or disability in extremely preterm infants: a ran-
therapy in preterm infant. Pediatr Res 78:198–204 domized clinical trial. JAMA 309:2111–2120
Moll M, Schöning M, Goelz R et al (2011) 2-year follow- Shapiro-Mendoza CK, Camperlengo L, Ludvigsen R
up examinations (Bayley II) in infants born at <32 (2014) Classification system for the Sudden
66 Apnea of Prematurity and Sudden Infant Death Syndrome 1033
Unexpected Infant Death Case Registry and its appli- Tieder JS, Bonkowsky JL, Etzel RA et al (2016) Brief
cation. Pediatrics 134:e210–e219 resolved unexplained events (formerly apparent life-
Sreenan CEP, Demianczuk N, Robertson CMT (2001) threatening events) and evaluation of lower-risk
Isolated mental developmental delay in very low birth infants. Pediatrics 137:e20160590
weight infants: association with prolonged doxapram Weese-Mayer DE, Ackerman MJ, Marazita ML, Berry-
therapy for apnea. J Pediatr 139:832–837 Kravis EM (2007) Sudden infant death syndrome:
Sridhar RTB, Kelly DH, Henslee JA (2003) Characterization review of implicated genetic factors. Am J Med Gen
of successful and railed autoresuscitation in human 143A:771–788
infants, including those dying of SIDS. Pediatr Pulmonol Whyte R, Kirpalani H (2011) Low versus high haemoglobin
36:113–122 concentration threshold for blood transfusion for pre-
Steer P, Flenady V, Shearman A et al (2004) High dose venting morbidity and mortality in very low birth weight
caffeine citrate for extubation of preterm infants: a infants. Cochrane Database Syst Rev: CD000512.
randomised controlled trial. Arch Dis Child Fetal Neo- https://doi.org/10.1002/14651858.CD000512.pub2
natal Ed 89:F499–F503
Part VI
Cardiovascular System
Cardiovascular Physiology, Pathology,
and Clinical Investigation in Neonatal 67
Medicine
Luciane Piazza, Angelo Micheletti, Javier Fernandez Sarabia,
Diana Negura, Carmelo Arcidiacono, Antonio Saracino,
Mario Carminati, and Francesca R. Pluchinotta
Contents
67.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1038
67.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1038
67.3 The Fetal and Neonatal Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1038
67.4 Pulmonary and Hemodynamic Transition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1040
67.5 Regulation of Pulmonary Vascular Resistance and Pulmonary
Blood Flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1040
67.6 Closure of the Ductus Arteriosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1040
67.7 Measurements for Evaluating Transition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1041
67.8 Clinical Presentation of the Congenital Heart Disease . . . . . . . . . . . . . . . . . . . 1041
67.8.1 Cyanosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1042
67.8.2 Heart Failure in the Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1043
67.8.3 Initial Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1044
67.8.4 Confirming the Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1047
67.9 CHD in the Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1048
67.9.1 Duct-Dependent Pulmonary Blood Flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1048
67.9.2 Duct-Dependent Systemic Blood Flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1053
67.9.3 Parallel Circulation/Transposition of the Great Arteries . . . . . . . . . . . . . . . . . . . . . 1058
67.9.4 Lesions with Complete Intracardiac Mixing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1059
67.9.5 Left-to-Right Shunt Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1061
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063
Abstract
A thorough understanding of cardiovascular
physiology is essential for proper management
L. Piazza (*) · A. Micheletti · J. F. Sarabia · D. Negura · C.
Arcidiacono · A. Saracino · M. Carminati · F. R. of congenital heart disease. The clinical evalu-
Pluchinotta ation and treatment of neonates with a
Department of Pediatric Cardiology, IRCCS Policlinico suspected congenital heart disease is challeng-
San Donato, San Siro, Milan, Italy
ing given the unique nature and complexity of
e-mail: [email protected];
[email protected]; neonatal cardiac physiology. The transition
[email protected] from fetal to neonatal circulation is
# Springer International Publishing AG, part of Springer Nature 2018 1037
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_214
1038 L. Piazza et al.
characterized by physiologic changes that start 67.2 Introduction
when the newborn takes its first breaths. After
birth a careful clinical examination may seem Congenital heart defects (CHD) are a heteroge-
normal, and the affected neonate may be neous entity, representing the most common
discharged home undiagnosed. Signs and malformations in the fetal and neonatal period.
symptoms of severe heart disease in the new- The incidence of moderate to critical structural
born period include cyanosis, irritability, CHD that will require expert cardiologic care
sweating, crying with feeding, and respiratory is 2.5–3 per 1,000 live births. It is the most
difficulties; these symptoms may be also pre- common form of the birth defect. Specialized
sent in metabolic disease and sepsis. To con- cardiologic care is not needed for most minor
firm the diagnosis, two-dimensional and color forms of CHD, such as tiny ventricular septal
Doppler echocardiography should be used to defect (VSD) or atrial septal defect (ASD) (Hoff-
define the anatomy, physiology, and myocar- man and Kaplan 2002). Most infants with con-
dial function. Cardiac catheterization is genital heart disease are identified by the end of
reserved for special cases where echocardiog- neonatal period. Critical congenital heart disease
raphy is not diagnostic. (CCHD) has been defined as a structural malfor-
mation of the heart that is present at birth and
requires intervention in the first year of life
67.1 Salient Points (Olney Richard et al. 2015). CCHD is responsi-
ble for 20% of deaths in the neonatal period (Lee
• The transition from fetal to neonatal circulation et al. 2001). Congenital heart disease has a public
is characterized by physiologic changes that health importance because the early diagnosis
start when the newborn takes its first breaths. can help to prevent complications and decrease
• In the fetal circulation, the right and left ven- the mortality. For this reason, all over the world,
tricles work in a parallel circuit. the screening on the newborn is implemented.
• At birth the pulmonary circulation is The pulse oximetry screening and a prenatal
established due to a rapid increase in systemic ultrasound detection have become a significant
vascular resistance, removal of the very-low- contributor to early identification CHD.
resistance placenta circulation, and closure of
the ductus venosus.
• Physical aeration of the lungs results in 67.3 The Fetal and Neonatal
decreased pulmonary vascular resistance, fall Circulation
in pulmonary pressure, and increased pulmo-
nary blood flow. Fetal circulation is shown in Fig. 1.
• The most common presentation of critical In the fetal circulation, the right and left ven-
CHD is the presence of a murmur, cyanosis, tricles work in a parallel circuit. Three cardiovas-
respiratory distress, heart failure, and shock. cular structures, unique to the fetus, are
• A hyperoxia test should be considered to make important for maintaining this circulation: ductus
the differential diagnosis between oxygen venosus, foramen ovale, and ductus arteriosus.
desaturation due to heart disease and that due The umbilical vein carries oxygenated blood
to pulmonary disease. (PO2 about 30–35 mmHg) from the placenta to
• Diagnosis relays on two-dimensional and color the inferior vena cava (IVC) through the ductus
Doppler echocardiography. venosus, where it partially mixes with poorly
• Cardiac catheterization is reserved for special oxygenated IVC blood derived from the lower
cases where echocardiography is not part of the fetal body. When it reaches the right
diagnostic. atrium (RA), oxygenated blood preferentially
67 Cardiovascular Physiology, Pathology, and Clinical Investigation in Neonatal Medicine 1039
Fig. 1 Diagram of fetal
circulation showing the four
sites of shunt: placenta,
ductus venosus, foramen
Aorta
ovale, and ductus arteriosus Aorta Ductus
(Modified with permission arteriosus
from Fesslova Pulmonary artery
V. Ecocardiografia fetale. Left
Raffaello Cortina Editore, Foramen ovale atrium
Milano 2008, p. 39)
Right atrium
Right Left
lung lung
Right ventricle
Hepatic vein
Ductus venosus
Liver
Inferior vena cava
Portal vein Aorta
Umbilical
artery
Umbilical vein
Placenta
streams across the foramen ovale (FO) and enters output is ejected into the pulmonary arteries
the left atrium (LA), where it mixes with the (PA) because the fetal lungs are still not expanded
pulmonary venous return before entering the and ventilated, and pulmonary vascular resis-
left ventricle (LV). From the LV, the ascending tances is therefore very high. Most RV output
aorta supplies fully oxygenated blood (PO2 bypasses the lungs and flows through the ductus
about 28 mmHg) flows to the coronary arteries, arteriosus into the descending aorta and the infe-
the head, and the upper extremities. Only a small rior part of the fetal body, after which it returns to
portion of the LV output flows through the aortic the placenta via the two umbilical arteries.
arch and supplies the thoracic aorta. Superior A distinctive feature of fetal circulation is the
caval vein blood, which is considerably less oxy- role of the placenta, low-resistance vascular bed,
genated (PO2 12–14 mmHg), enters the RA where where oxygenation and metabolite exchange
it is directed to the RV. Just about 10% of RV occur. The placenta is not only an organ for a
1040 L. Piazza et al.
gas exchange, and the fetus adapts itself produc- Fetal respiratory movements are controlled by
ing fetal hemoglobin which has a higher affinity hypoxia and hypercapnia, and they are discontin-
for oxygen, at about 70–80% of fetal hemoglobin uous, occurring <50% of the time. The mecha-
compared to adult hemoglobin. nisms controlling the switch to continuous
The dimensions of fetal cardiac chambers breathing after birth are currently unknown (van
reflect the differences between right- and left- Vonderen et al. 2014), although the activation of
sided blood volume, with the RV and pulmonary chemoreceptors such as an increase in arterial,
artery being larger than the LV and ascending PCo2, and physical stimulants such as light, tem-
aorta, although the pressure in both circuits is perature, and handling are considered stimuli for
equal due to the patency of the ductus arteriosus. large inspiratory movements.
At birth, as gas exchange occurs in the lungs,
PVR promptly decreases and simultaneously pul-
67.4 Pulmonary and Hemodynamic monary blood flow increases. Those events are
Transition associated with thinning of the medial layer of
the pulmonary arterioles as well as hyperplasia
The transition from fetal to neonatal circulation is of alveolar units and their own circulatory vessels.
characterized by physiologic changes that start After the initial sudden decrease in PVR and pres-
when the newborn takes the first breaths. The sure, there is a slow progressive decrease within
main circulatory and respiratory changes are as 2–6 weeks. Several factors may interfere with the
follows: first, the placental circulation disappears pulmonary flow or pulmonary vascular resistance,
(clamping the umbilical cord), and the pulmonary causing conditions such as persistent pulmonary
circulation is established due to (i) a rapid increase hypertension or delay in PVR normalization
in systemic vascular resistance (SVR) as a result of process:
very-low-resistance placenta circulation removal
and (ii) closure of the ductus venosus. Second, • Hypoxia and/or altitude
physical aeration of the lungs results in: • Acidosis
(i) decreases of the pulmonary vascular resistance • Severe hyaline membrane disease or other pul-
(PVR), fall in PA pressure, and increment of pul- monary diseases
monary blood flow; (ii) mechanical and passive • Congenital heart defects such as large VSD or
closure of the FO due to a difference between left PDA, which are characterized by high PA pres-
and right atrial pressure; pressure in the left sure, secondary to direct transmission of the
exceeds that in the right because of increased pul- systemic pressure to the PA through the large
monary venous return to the LA and decreased defect
venous return to the RA after ductus venosus clo- • Increased pressure in the LA or pulmonary
sure; and (iii) closure of patent ductus arteriosus veins
(PDA) secondary to increased arterial oxygen sat-
uration. The ductus venosus will remain patent
days after birth and mostly does not influence the 67.6 Closure of the Ductus
cardiovascular system. Arteriosus
During fetal life, the ductus arteriosus is fully patent
67.5 Regulation of Pulmonary and pulmonary and aortic pressures are therefore
Vascular Resistance equal. The immediate consequence of the neonatal
and Pulmonary Blood Flow transition is the reversal of vascular shunts through
the foramen ovale and ductus arteriosus. Once the
In fetal life, the PVR is high and the oxygen ductus arteriosus closes, pulmonary artery pressure
concentration, at the level of smooth muscle decreases as the resistance in the pulmonary vascu-
cells in the pulmonary arteriolar walls, is low. lar bed falls. The functional closure of the PDA
67 Cardiovascular Physiology, Pathology, and Clinical Investigation in Neonatal Medicine 1041
occurs because of constriction of medial, smooth SO2 should preferably be measured
muscle cells within 10–15 h after birth. The follow- preductally using pulse oximetry.
ing factors are relevant to ductal closure: • Cardiac output (CO) and stroke volume
(SV) (CO = HR.SV). Echocardiography has
• Oxygen. A postnatal increase in systemic cir- been used to monitor CO during the neonatal
culatory oxygen saturation is the strongest transition.
stimulus for smooth muscle cell constriction. • Blood pressure (BP) is considered an important
• Gestational age of the newborn. The ductus value for hemodynamic monitoring of criti-
arteriosus is more likely to remain open in cally ill infants. It is useful to measure BP
preterm infants because of immaturity of the preductally (right arm) to evaluate the hemo-
constrictor response to oxygen by ductal dynamic transition and assess the cardiac out-
smooth muscle cells. put. The BP is influenced by crying, gestational
• Prostaglandin E (PGE). An acute decrease in age, and administration of fluids.
PGE levels results in constriction of the ductus • Gas exchange measurements, i.e., parameters
arteriosus. This event is determined by pla- such as tidal volume, respiratory rate, inspira-
centa removal, since the placenta is a signifi- tory time, and expiratory time.
cant source of PGE. Drugs like indomethacin, • Tissue Perfusion:
a prostaglandin synthetase inhibitor, can be Two methods can be used: perfusion index and
used to effect closure of PDA. infrared spectroscopy (NIRS), which may
• Hypoxia and acidosis relax the ductus be used to monitor the perfusion of the brain
arteriosus but constrict pulmonary arterioles tissue
which are also constricted by sympathetic The accurate recognition of cardiovascular
stimulation and α-adrenergic stimulation. instability and the perinatal complications
• Oxygen constricts the ductus arteriosus but can prevent the failure of compensatory
relaxes pulmonary arterioles. mechanism and may potentially improve
both short- and long-term outcomes.
67.7 Measurements for Evaluating
Transition 67.8 Clinical Presentation
of the Congenital Heart Disease
The hemodynamic and general status of the
patient is determined by the interpretation of the In spite of a wide spectrum of CHD, clinical pre-
data obtained through the monitoring of the sentation does not vary much. The first approach to
patient and with an understanding of the fetal the newborn with suspected CHD is crucial in
circulation and mechanisms of transition. Nowa- improving the mortality and morbidity associated
days, noninvasive physiological measurements with these malformations. Prenatal diagnosis by
are made during extrauterine life: echocardiography has also been associated with
improved morbidity and mortality. However, a
• Heart rate (HR) – A cutoff value of HR of large number of cases are not identified in utero,
100 beats per minute by Virginia Apgar is and some defects can be challenging to identify
characterized as adequate transition. At the using the fetal cardiac ultrasonography. After
same time in some newborns, we can observe birth, a careful clinical examination may seem nor-
short moments of bradycardia followed by a mal, and the affected neonate is discharged home
rapid increase of the HR. undiagnosed. Table 7 summarizes the most com-
• Oxygen saturation (SO2) is measured periph- mon presenting CHD after discharge.
erally. The pink color described by the clini-
cians is very subjective and variable compared • Coarctation of the aorta
to the objective measurement of saturation. • Interruption of the aortic arch
1042 L. Piazza et al.
• Aortic valve stenosis The level of hemoglobin influences the
• Total anomalous pulmonary return appearance of cyanosis. In patients with polycy-
• Hypoplastic left heart syndrome themia, cyanosis is detectable at a higher level of
oxygen saturation; conversely in patients with
Signs and symptoms of severe heart disease in anemia, cyanosis appears at a lower level of
the newborn period include cyanosis, irritability, oxygen saturation. In the polycythemic neonate
sweating, crying with feeding, and respiratory dif- (Hb 22 g/dL), cyanosis becomes evident when
ficulties. For this reason, it is very difficult to O2 saturation approaches 85–92%. In a normal
differentiate in the newborn between an error of neonate, the usual level of Hb is about 17 g/dL,
metabolism, sepsis, and congenital heart disease. and cyanosis becomes evident when O2 satura-
The most common presentation of critical CHD is tion approaches 82% and PaO2 38–39 mmHg.
the presence of a murmur, cyanosis, respiratory Often preterm babies have a reduced Hb concen-
distress, heart failure, and shock. In this last sce- tration, about 12 g/dL or less, in which case
nario, the treatment of shock and clinical stabiliza- cyanosis appears at an O2 saturation level of
tion should precede definitive anatomic diagnosis. about 75%.
Cyanosis may be either peripheral or central.
Peripheral cyanosis is a bluish discoloration lim-
67.8.1 Cyanosis ited to the extremities, associated with normal
arterial O2 saturation and pink color of mucous
Cyanosis is a blue discoloration of the skin membranes; it can be seen with acrocyanosis or
caused by deoxygenated blood within the capil- exposure to cold. The blue color may reflect inter-
lary network. Detection of cyanosis depends on mittent vasomotor changes in the skin. A patho-
the skill and experience of the physician and logical cause of acrocyanosis is cutaneous arterial
environmental light (it is more evident in natural constriction resulting from low cardiac output
than in artificial light). Cyanosis does not always state with sluggish peripheral blood flow. Central
indicate hypoxemia: a neonate may be severely cyanosis is cyanosis associated with arterial oxy-
hypoxemic but not clinically cyanosed. Cyano- gen desaturation.
sis can be detected on many parts of the body: Unlike cyanosis secondary to lung disease,
lips, fingernails, toenails, tip of the nose, oral cyanosis related to CHD is generally not associ-
mucous membranes, conjunctivae, and tip of ated with respiratory distress. Exceptions to this
the tongue. rule are:
By definition cyanosis is determined by a
deoxygenated hemoglobin (Hb) concentration • Central cyanosis with low PaO2 in the 20s or
exceeding 3 g/dL in arterial blood or 5 g/dL in a less associated with tachypnea.
capillary bed. • Cyanosis associated with low cardiac output.
Fetal and adult hemoglobin are different in This is commonly seen with left heart obstruc-
terms of oxygen affinity, which is indicated by tive lesions if the ductus arteriosus becomes
the P50 value. P50 is the level of partial pressure restrictive. The pulse volume will be poor and
of oxygen (PaO2) at which 50% of hemoglobin is the extremities cool.
bound to O2. It is about 27 mmHg in adults. • Cyanosis associated with obstruction of pulmo-
The P50 of fetal hemoglobin is about nary venous drainage resulting in pulmonary
20 mmHg; the venous oxygen saturation (O2 sat) edema, such as what is seen in obstructed total
is therefore higher in the neonate (about 80%) anomalous pulmonary venous return:
than in the adult (about 70% or less). As a conse- – Differential cyanosis. This occurs when
quence, cyanosis in neonates becomes clinically cyanosis is more evident in the lower
evident at a lower level of PaO2 than in adults or extremities than the upper or vice versa.
children, about 38–39 mmHg and 52–54 mmHg, • Upper limb saturation higher than the lower
respectively. limb: deoxygenated blood coming from RV
67 Cardiovascular Physiology, Pathology, and Clinical Investigation in Neonatal Medicine 1043
shunts from pulmonary artery to distal aorta 1. Clinical evaluation of cyanosis: central or
through the ductus arteriosus because of either peripheral, extension, and localization.
elevated PVR or aortic obstruction proximal to The heart rate, arterial pulses, blood pressure,
the ductus, such as in critical aortic coarctation respiratory rate, and presence of respiratory
or interrupted aortic arch. distress.
• Lower limb saturation higher than upper 2. Chest X-ray: may reveal a pulmonary or car-
limb: typical of this condition is a reversed diac cause and the severity of the problem.
flow into the ascending aorta and the aortic 3. Arterial blood gas analysis in room air: con-
arch from the pulmonary artery through a firms or excludes central cyanosis.
large ductus arteriosus, such as in transposi- 4. Hyperoxia test: helps in differentiating pulmo-
tion of great arteries, large PDA, and pulmo- nary or central nervous system causes from
nary hypertension. cardiac causes.
5. Umbilical arterial line: PaO2 in a preductal
Differential cyanosis is fairly uncommon and artery (e.g., a radial artery) 10–15 mmHg
is of little practical diagnostic use. higher than the PaO2 in a postductal artery
(e.g., from an umbilical arterial line) suggests
67.8.1.1 Differential Diagnosis a right-to-left ductal shunt.
Cyanosis is one of the most common clinical pre- 6. Prostaglandin E1: to be commenced if a cyanotic
sentations of diverse disease processes, including defect is suspected as a result of investigations.
cardiac, lung, and central nervous system abnor-
malities. Table 1 summarizes the differential diag- Table 2 summarize the differential diagnoses
nosis of cyanosis. of CHF in the neonate.
A suggested plan for investigation of the cya-
notic newborn baby includes:
67.8.2 Heart Failure in the Newborn
Table 1 Differential diagnosis of cyanosis
Congestive heart failure (CHF) as clinical presen-
Newborns with CHD tation accounts for about 30% of infants and chil-
CHD with increased CHD with decreased dren with CHD (Olney Richard et al. 2015). CHF
pulmonary vascularity pulmonary vascularity
is a clinical syndrome in which cardiac output is
D-Transposition of Tetralogy of Fallot
great arteries
insufficient to meet the metabolic demands of the
Total anomalous Double outlet right tissues, including oxygen and nutrient delivery
pulmonary venous return ventricle with PS and waste removal. In the early stages, infants
Taussig-Bing anomaly Ebstein’s anomaly may be tachypneic and tachycardic with increased
PPHN Pulmonary atresia respiratory effort, and there may be hepatomegaly
Truncus arteriosus Tricuspid atresia and delayed capillary refill. In worsening CHF,
Single ventricle without Single ventricle with PS dyspnea with grunting and intercostal and
PS subcostal recession may appear. Feeding difficul-
TGA and VSD TGA and PS
ties, failure to thrive, and sweating may occur
Pulmonary disease
later. The challenge for the clinicians is an early
Pneumothorax or pleural effusion
identification of the patients with the potential
Diaphragmatic hernia
rapid decompensation. An acute form with pul-
Persistent fetal circulation syndrome
Perinatal asphyxia
monary edema and circulatory collapse may occur
Central nervous system with “left-sided” lesions. Left obstructive lesions
Cyanosis with normal PaO2 have the highest postdischarge mortality rate.
PS pulmonary stenosis, PPHN persistent pulmonary Almost all infants (68%) with this form of CHD
hypertension of the newborn, TGA transposition of the discovered within 3 weeks of age present in heart
great arteries, VSD ventricular septal defect failure (Ashley and Lu Le 2015) .
1044 L. Piazza et al.
Table 2 Causes of heart failure in newborns 67.8.3.2 Physical Examination
1. Structural heart disease Physical examination of the neonate can provide
Anomalies of coronary At birth important clues to the anatomic diagnosis.
circulation Inspection: Look for the presence of cyanosis
Ebstein’s anomaly of tricuspid with or without respiratory distress and respira-
valve
tory pattern including the effort of breathing and
Hypoplastic left heart
syndrome
use of accessory muscles, a general appearance
typical of a syndrome, chromosomal abnormali-
Transposition of the great First week
arteries ties, or malformations that may be associated
Premature infants with large with CHD.
patent ductus arteriosus Palpation: Reduced or absent distal pulses are
Total anomalous pulmonary highly suggestive of obstruction of the aortic arch.
venous return Weak arterial pulses are characteristic of critical
Critical aortic or pulmonary 1–4 weeks aortic valve stenosis, hypoplastic left heart syn-
stenosis drome, or cardiogenic shock. Palpation of the
Coarctation of the aorta precordium may detect the presence of a thrill
Structural cardiac disease with that usually indicates at least moderate outflow
left-to-right shunt at level of
ventricles tract obstruction or a restrictive VSD with low
Tetralogy of Fallot or right ventricular pressure. A hyperdynamic
pulmonary atresia with precordium suggests heart disease with high vol-
aortopulmonary collaterals ume overload such as left-to-right shunt lesions
2. Myocardial disease and/or severe valvular regurgitation. A cool neo-
A) Primary nate with prolonged capillary refill time should
Myocarditis always raise the possibility of severe CHD.
Transient myocardial ischemia (with or without birth
Auscultation: Rarely conclusive for CHD diag-
asphyxia)
Cardiomyopathy (as seen in infants of diabetic
nosis. More than 50% of full-term newborn
mothers) infants have an innocent murmur at some time
B) Secondary during the first week of life. Most pathological
Sustained tachyarrhythmias (atrial flutter or murmurs should be audible during the first month
fibrillation) of life. Heart murmurs audible immediately after
Congenital heart block birth are due to stenotic lesions (e.g., aortic steno-
Birth asphyxia resulting in transient myocardial sis, pulmonary stenosis, and coarctation of aorta)
ischemia
or left-to-right shunt lesions (e.g., a small VSD).
Severe anemia (as seen in hydrops fetalis)
The onset of a murmur due to a large VSD may be
Overtransfusion or fluid overload
Metabolic causes: hypoglycemia, hypocalcemia
delayed until the first or second week of life. The
Neonatal sepsis
continuous murmur of a PDA may not appear for
2–3 weeks. Diastolic murmurs are always indica-
tive of cardiovascular disease. During ausculta-
67.8.3 Initial Evaluation tion, the physician must pay attention to the
heart rate, noting its regularity and/or variability.
67.8.3.1 History
The history can provide useful information lead- 67.8.3.3 Four-Limb Blood Pressure
ing to the suspicion of CHD: (1) maternal disease Blood pressure should be measured in the upper
during first trimester of gestation due to viral and lower limbs. A difference between arms and
infections, X-ray exposure, drug intake, alcohol legs of more than 10 mmHg is suggestive of
abuse, and diabetes and (2) problems in the peri- coarctation of the aorta, aortic arch hypoplasia,
natal period (low Apgar score and/or the need of or interrupted aortic arch. Blood pressure mea-
cardiopulmonary resuscitation). surements are highly specific but not sensitive
67 Cardiovascular Physiology, Pathology, and Clinical Investigation in Neonatal Medicine 1045
for the diagnosis. Moreover, coarctation cannot be In neonates with infracardiac total anomalous
ruled out even in the absence of significant blood pulmonary venous drainage (which is almost
pressure gradient as it may occur when a large always “obstructed”), the chest X-ray shows a
ductus arteriosus is still patent. small heart, upper lobe blood diversion, and
fluid in the fissures (signs of pulmonary edema).
67.8.3.4 Chest X-Ray Differentiating between primary pulmonary dis-
Chest X-ray can give important clues leading to ease and respiratory distress syndrome is some-
the diagnosis of CHD and/or associated lung dis- times difficult.
ease. The cardiothoracic ratio of normal newborn
infants is > 0.5; the normal value in older children 67.8.3.5 Electrocardiogram (ECG)
and adults is < 0.5. Therefore, the evaluation of The normal ECG of a newborn is different from
heart size should take into consideration the that of an older child because it reflects the hemo-
degree of inspiration, judged by the level of the dynamic relations existing in utero. Usually it
diaphragm. Particularly in newborns, the heart shows: (1) tachycardia with a rate as high as
size may be difficult to determine due to an over- 160 beats/min; (2) right-sided deviation of the
lying thymus. In addition to the size of the heart, QRS axis with a mean of +125 and a maximum
its position within the chest should be considered of +180 ; (3) relatively small QRS complex volt-
to assess visceral and cardiac situs (e.g., ages and T wave; (4) right ventricular dominance
dextrocardia, right or left isomerism, is frequently with tall R waves in V4R, V1, and V2; and
associated with CHD). (5) occasional Q waves in V1. The diagnostic
Cardiac silhouette may be typical in some value of an ECG during the newborn period is
CHD as the “egg shape” in transposition of the highly nonspecific and the precise diagnosis of
great arteries (Fig. 2). Evaluation of pulmonary CHD is generally obtained by other diagnostic
vascular markings in neonates can be difficult. It is tools, in particular echocardiography.
often hard to distinguish between increased pul-
monary blood flow and pulmonary venous con- 67.8.3.6 Hyperoxia Test
gestion. A poorly perfused lung field suggests In newborns with suspected CHD, a hyperoxia
decreased pulmonary blood flow and indicates test should be considered to make the differential
serious cyanotic congenital heart defects or sig- diagnosis between oxygen desaturation due to
nificant left atrial hypertension. heart disease and that due to pulmonary disease.
Although this test does not give a complete diag-
nosis, it remains useful, especially when an echo-
cardiogram is not easily or quickly available. The
hyperoxia test is obtained by measuring the oxy-
gen tension in room air (if tolerated), followed by
repeated measurements with the patients receiv-
ing 100% inspired oxygen for 5 min. If possible,
the arterial partial pressure of oxygen (PO2)
should be measured directly by arterial puncture,
although PO2 values obtained from a properly
applied transcutaneous oxygen monitor are also
acceptable. The measurements should be taken at
both “preductal” and “postductal” sites.
• When a baby breathes 100% oxygen, an arte-
rial PO2 of 250 mmHg in both upper and lower
Fig. 2 Transposition of the great vessels. The heart is limbs virtually eliminates critical structural
enlarged and has an egg-shaped configuration cyanotic heart disease (positive test).
1046 L. Piazza et al.
• Patients with pulmonary disease only will 67.8.3.8 Stabilization and Transport
show a significant increase in PO2. After the initial evaluation, attention should con-
• Stable intracardiac right-to-left shunting (failed tinue to be focused on the basic neonatal life
or negative test). An arterial PO2 of support. Airways should be stabilized, vascular
<100 mmHg in the absence of lung disease is access secured, volume status and inotropic sup-
most likely due to intracardiac right-to-left port maintained, and systemic and pulmonary cir-
shunting. There is only a mild increase of oxy- culation kept in balance. The neonate may need to
gen saturation, but it is usually below basal be transferred to a medical center with full pedi-
levels. atric cardiological facilities.
• Patients with large left-to-right shunting and Each CHD has multiple anatomic variations and
systemic hypoxemia. In this situation, there is these anatomical details may change the physiol-
a high level of oxygenation, because the ogy. On the basis of this assumption, it might
inspired oxygen normalizes the saturation of be easier to consider the physiology and analyze
pulmonary venous blood, which can be low an assessment between the systemic vascular resis-
due to pulmonary edema and oxygen diffusion tance (SVR) and pulmonary vascular resistance.
gradient (an example of this situation is For example, (i) if PVR is decreased or SRV is
represented by obstructed total anomalous pul- increased, blood will flow to the lungs and
monary venous return). become oxygenated. (ii) If SVR is decreased or
• Patients with PO2 between 100 and 250 mmHg PVR in increased, blood flows to the systemic
may be affected by a structural cardiac lesion vasculature but receives inadequate oxygenation
with intracardiac mixing and greatly increased in the lungs.
pulmonary blood flow as seen when there is a The equation to guide this balance is based on
single ventricle. Fick’s principle:
• Markedly higher oxygen content in the upper
versus the lower part of the body. This is an Qp : Qs ¼ ðSaO2 SvO2 Þ : ðSpvo2 SpaO2 Þ
important diagnostic clue to lesions that include – SaO2 is the oxygen saturation.
all forms of critical aortic arch obstruction or left – SvO2 is the mixed venous oxygen
ventricular outflow tract obstruction. saturation.
• Reverse differential cyanosis. This occurs in – SpvO2 is the pulmonary venous
neonates with transposition of the great desaturation.
arteries and those with abnormal pulmonary to – SpaO2 is the pulmonary arterial oxygen
aortic shunting due to coarctation, interruption saturation.
of the aortic arch, or suprasystemic pulmonary
vascular resistance (persistent fetal circulation). The PVR and SRV may be manipulated to
obtain the Qp:Qs ratio 1:1.
Patients with a positive hyperoxia test are It is crucial to define or identify those
likely to have a duct-dependent CHD, and prosta- who can take advantage from prostaglandin E1
glandin E1 should be given, until the anatomic administration.
abnormality can be defined.
67.8.3.9 Prostaglandin E1
67.8.3.7 Laboratory Analysis When systemic perfusion depends on patency of
Initial investigations should include: complete the ductus arteriosus, a continuous infusion of
blood count for anemia, electrolyte, methemoglo- PGE1 may be lifesaving. PGE is indicated for
bin level, lactic acid, pH, ammonia, blood culture, the treatment of duct-dependent lesions. Indica-
urine culture, uric organic acids, thyroid- tions and treatment recommendations are shown
stimulating hormone, and free thyroxine. Brain in Tables 3 and 4.
natriuretic peptide (BNP)/N-terminal pro-BNP The mechanism of action of PGE1 action
(NT-pro-BNP) can be used. consists of the relaxation of the smooth muscle
67 Cardiovascular Physiology, Pathology, and Clinical Investigation in Neonatal Medicine 1047
Table 3 Indications for prostaglandin E1 vital signs, including pulse oximetry, and arterial
Cyanotic heart disease with severely limited or no blood gas analysis.
pulmonary blood flow Following the initial diagnosis and medical
Tricuspid atresia stabilization, the neonate should be transferred to
Pulmonary atresia and critical pulmonary stenosis a tertiary pediatric cardiac center that is fully
Children with obstructed systemic blood flow may equipped for any required additional treatment.
depend on ductal patency, e.g., in the following
conditions
Aortic atresia
Critical aortic stenosis 67.8.4 Confirming the Diagnosis
Critical coarctation of the aorta
Interrupted aortic arch To confirm the diagnosis, two-dimensional and
Hypoplastic left heart syndrome color Doppler echocardiography is used to define
Patients with transposition of great arteries benefit from the anatomy, physiology, and myocardial
patency of the ductus arteriosus because the pulmonary and function.
systemic circulation is in parallel Echocardiography is the most commonly used
noninvasive diagnostic tool. It is harmless, but
some precautions have to be taken if the patient
Table 4 Recommendations for treatment with prostaglan- is very sick: for example, temperature stability
din E1 should be maintained, and extension of the neck
The usual starting dose is 0,05 mcg/kg/min for suprasternal views of the arch may be prob-
When the desired effect is achieved, reduce to 0.025 mcg/ lematic, particularly in a neonate with respiratory
kg/min distress. Careful specialized nursing assistance is
Secure vascular access recommended.
67.8.4.1 Cardiac Catheterization
fibers forming the ductal tissue. In other tissues, Cardiac catheterization is reserved for special
PGE1 has been shown to result in increased cases where echocardiography is not diagnostic,
levels of nitric oxide and nitric oxide synthetase as in the definition of the anatomy of peripheral
(Bichell et al. 2006). When ductal dilatation pulmonary branches, aortopulmonary collaterals,
occurs, systemic perfusion increases (peripheral some complex pulmonary venous anomalies, or in
vasodilatation) and pulmonary congestion may other situations where the decision making pro-
decrease. This change is accompanied by a rise cess can be hampered by an incomplete or incor-
in PH and a decrease in lactate accumulation rect diagnosis. Echocardiography is fully
because of improved tissue perfusion. diagnostic for intracardiac anatomy, in virtually
Adverse effects include respiratory depres- all the cases.
sion; PGE can cause apnea in 10–12% of the Interventional catheterization: nowadays, a
neonates and a stable airway must be maintained. wide range of interventional procedures can be
Generally all neonates receiving PGE1 infusion carried out in very small babies (Table 5). These
should be intubated for transport. Systemic procedures include a preoperative palliation, for
hypotension and bradycardia have also been instance, by balloon atrial septostomy, or as an
seen. Sometimes additional side effects are alternative to surgery, e.g., by balloon dilatation of
observed, e.g., bradycardia (7%), tachycardia a pulmonary or aortic stenosis. PDA stent implan-
(3%), and edema and cardiac arrest (1%) (Mitch- tation in newborn with hypoplastic left heart syn-
ell et al. 1971). PGE1 inhibits platelet aggrega- drome. Interventional catheterization can also
tion and may impair clotting. Prolonged use of play a role in a wide spectrum of postoperative
PGE1 has been associated with gastric obstruc- sequelae, such as residual pulmonary branch ste-
tion and cortical hyperostosis of the long bones. nosis. See the following text for further details on
Patients receiving PGE1 need to be monitored for catheter interventional procedures.
1048 L. Piazza et al.
Table 5 Indications for neonatal interventional Table 6 Duct-dependent pulmonary blood flow
catheterization
Critical pulmonary valve stenosis
Atrial septostomy (Rashkind) Pulmonary atresia with intact ventricular septum
Balloon Pulmonary valvular stenosis Severe tetralogy of Fallot
valvuloplasty Aortic valvular stenosis Complex congenital heart disease with severe pulmonary
stenosis or pulmonary atresia
Balloon angioplasty of native coarctation of the aorta
Transcatheter radiofrequency perforation and Table 7 Lesion specific: ductus arteriosus dependent sys-
valvuloplasty ! atretic pulmonary valve temic blood flow
Miscellaneous Coil embolization of abnormal Aortic stenosis
vascular communications Coarctation of the aorta
Stenting of a PDA Interrupted aortic arch
Stenting of the right ventricle Hypoplastic left heart syndrome
outflow
Cardiac catheterization of newborns, either 67.9 CHD in the Newborn
interventional or diagnostic, carries more risks
than when performed on older patients. Basic The types of CHD that may present during the
medical stabilization, airway management, seda- newborn period differ from those recognized later
tion and body temperature control are crucial. in infancy. During the neonatal period, CHD can be
The baby’s hemodynamic condition should be classified according to anatomy, physiopathology,
as stable as possible. Intravenous lines should or timing of presentation. In each of the following
be secured and intravenous infusion pumps sections, specific lesions will be discussed focusing
adequately prepared. For example, a prostaglan- on pathophysiology and clinical presentation.
din infusion should be given by a dedicated
intravenous line.
67.9.1 Duct-Dependent Pulmonary
67.8.4.2 Computed Tomography Blood Flow
and Magnetic Resonance
Neonatal cardiovascular tomographic angiogra- This group of CHD is characterized by obstruc-
phy (CTA) and magnetic resonance imaging tion of pulmonary blood flow due to severe pul-
(MRI) require the immobilization of the neonate monary stenosis or pulmonary atresia. In this
and breath holding and contrast injection may be situation, pulmonary blood flow depends mainly
necessary. Neonatal MRI is technically difficult at on the patency of the duct (Tables 6 and 7).
this age because the required imaging time to
complete a study is longer and the patients is 67.9.1.1 Critical Pulmonary Valve
less accessible for monitoring and (or) interven- Stenosis
tion than CTA. The choice of modality should be Congenital obstruction to RV outflow can be clas-
based on evaluation of the risks and benefits: sified as valvar, subvalvar, or involving pulmonary
radiation dose, efficacy, and image quality. During trunk and peripheral pulmonary artery branches.
the neonatal period, echocardiography is the bet- This pathology (pulmonary stenosis, PS) is rela-
ter imaging tool for the evaluation congenital tively common; the frequency approaches 8–10%
heart disease. CTA and MRI can be used to offer of all cardiac defects. There are many anatomical
additional anatomical information that could not descriptions of the pulmonary valve: dome-shaped
be obtained through echocardiography, e.g., valve; dysplastic hypertrophy of the pulmonary
anomalous coronary arteries and anomalous pul- valve leaflets; uni-commissural, bicuspid, and tri-
monary venous connection. cuspid valve; and hypoplastic annulus with
67 Cardiovascular Physiology, Pathology, and Clinical Investigation in Neonatal Medicine 1049
dysplastic valve (Gikonyo et al. 1987; Bichell et al. pulmonary valve with a well- developed RV to a
2006). The main cardiac consequence of PS is an severely hypoplastic-rudimentary RV with RV cor-
elevated RV pressure because of obstruction to onary fistulae and absent infundibulum. Focusing
right ventricular cardiac output. The rise in pressure on pathophysiology, in the case of rudimentary RV,
causes RV hypertrophy that is proportional to the systemic venous blood, brought to the right atrium
degree of obstruction. This hypertrophy is particu- from caval veins and coronary sinus, passes mainly
larly evident in the infundibular region, producing into the left side of the heart across the foramen
dynamic narrowing of the outflow tract. Because ovale without passing the lungs. Anatomically, the
the ventricular septum is intact, the systolic pres- pulmonary valve is often well formed with definable
sure generated in the RV may exceed the LV sys- fused commissures. There is also a form when the
tolic pressure. Moreover, the higher diastolic valve is more dysmorphic with unicuspid or
pressure in the RV caused by muscular hypertrophy quadricuspid configurations, as well as complete
results in a noncompliant RV and increased right absence of some valvular architecture with a fibrous
atrial filling pressure. When the right atrial pressure ventriculoarterial junction (Kutsche and Van
exceeds the left atrial pressure, a right-to-left shunt Mierop 1983). Typically, the tricuspid valve
at the foramen ovale appears, resulting in central (TV) is smaller than normal. The TV is commonly
cyanosis or hypoxemia. There may be associated dysplastic and variably regurgitant. The size of the
RV dysfunction and/or tricuspid regurgitation. TV correlates with the RV cavity size, and this is
In critical pulmonary stenosis or pulmonary important in the prognosis of PA-IVS. The RV is
atresia, the pulmonary flow is duct dependent, as hypertrophied with a small cavity in 90% of cases
previously explained. and severely hypoplastic in more than 50%. RV
Newborns with critical PS present within the may be unipartite (inlet only), bipartite (inlet and
first week of life with cyanosis and hypoxemia outlet), or tripartite (inlet, outlet, and trabecular por-
and signs of CHF with peripheral vasoconstriction. tions). Coronary artery abnormalities are common,
Cardiac auscultation reveals a single second heart including areas of stenosis or complete atresia. Ret-
sound. The systolic murmur of PS may be soft or rograde blood flow from the hypertensive RV into
even absent, reflecting diminished flow across the coronary circulation through ventriculo-coronary
right ventricle outflow tract. More often, a systolic connections (sinusoids) may be necessary for myo-
regurgitant murmur due to tricuspid insufficiency is cardial perfusion (Fig. 5). Ventriculo-coronary fis-
heard at the left mid-sternal border. tulae are not present in cases of significant tricuspid
ECG reveals RV hypertrophy and right axis regurgitation, presumably because RV hypertension
deviation. Chest X-ray reveals reduction of pul- does not develop. After birth, with ductal runoff,
monary blood flow. diastolic pressure is relatively low and in competi-
Normal or severe cardiomegaly is present, as in tion with the suprasystemic RV pressure for coro-
case with severe tricuspid regurgitation. nary artery perfusion. The pulmonary arteries are
Differential diagnosis during the neonatal usually confluent, supplied by a left-sided ductus
period: TGA, pulmonary atresia with intact ventric- arteriosus. Usually, because of the obligatory right-
ular septum, Ebstein’s anomaly. The definitive diag- to-left shunt at the atrial level, these patients have a
nosis is made by echocardiography (Figs. 3 and 4) foramen ovale or an atrial septal defect (ASD).
Newborns with this malformation become cya-
67.9.1.2 Pulmonary Atresia with Intact notic and hypoxemic immediately after functional
Ventricular Septum closure of the PDA. When the ASD is restrictive,
Pulmonary atresia with intact ventricular septum the cardiac output may be affected. Cyanosis is
(PA-IVS) is a rare lesion occurring in an estimated usually apparent within hours of birth, worsening
8 of 1,000 live births (Bichell et al. 2006). PA-IVS is progressively. In the absence of significant acido-
characterized by abnormalities proximal to the sis and reduced cardiac output, tachypnea may be
RV-PA junction. This pathology includes a spec- evident. Cardiac examination reveals single first
trum of disease ranging from imperforate and second heart sounds. A soft pansystolic
1050 L. Piazza et al.
Fig. 3 Two-dimensional
echocardiogram in newborn
with severe pulmonary
valve stenosis. (a) A
parasternal right ventricular
outflow tract view
demonstrating a systolic
doming of the pulmonary
valve leaflets. (b)
Two-dimensional color
Doppler echocardiogram
(parasternal long axis)
demonstrating a central jet
(asterisks) across the
pulmonary valve. The
pulmonary trunk is dilated.
Ao aortic valve, RV right
ventricle. (c) Thickened
pulmonary valve cusps
(arrow)
Fig. 4 Two-dimensional
echocardiogram (apical
four-chamber view,
anatomical orientation)
demonstrating a significant
right ventricle hypertrophy.
RV right ventricle, RA right
atrium, LA left atrium, LV
left ventricle
67 Cardiovascular Physiology, Pathology, and Clinical Investigation in Neonatal Medicine 1051
Fig. 5 Angiogram of a
newborn with pulmonary
atresia with intact
ventricular septum. The
right outflow tract (asterisk)
ends blindly at the level of
the atretic pulmonary valve
(circle). Coronary
sinusoids. RV right ventricle
murmur is often audible at the left lower sternal 22q11 chromosome microdeletion (Bailliard and
border. Sometimes the murmur of TR is Anderson 2008). This deletion, manifested by
prominent. varying degrees of palatal abnormalities, dysmor-
Chest X-ray reveals a variable degree of phic facies, learning difficulties, immune deficien-
cardiomegaly. Pulmonary vascular markings are cies, and hypocalcemia, is typical of DiGeorge
decreased. syndrome.
ECG reveals LV dominance or significant LV Anatomically, TOF results from anterior and
hypertrophy. There are right atrial enlargement cephalad deviation of the infundibular portion of
and ST-T abnormalities, consistent with some the ventricular septum. This deviation causes:
degree of subendocardial ischemia. (1) aortic overriding over the crest of interven-
Echocardiography is effective in making the tricular septum, (2) a malaligned subaortic ven-
diagnosis. Catheterization is indicated for the pre- tricular septal defect, (3) obstruction of right
cise assessment of the possible presence of sinu- ventricular outflow tract (RVOTO) (the level of
soids, RV to coronary fistulae, and stenosis of the the obstruction can be subvalvular, valvular, and
coronary vessels when there is a severely hypo- supravalvular, in the pulmonary artery or its
plastic RV (“RV-dependent coronary circula- branches, and either isolated or in combination),
tion”). However, when there is a tripartite RV, and (4) systemic pressure in the RV with second-
perforation of the atretic pulmonary valve ary hypertrophy (Fig. 6).
followed by balloon dilation can be performed as In case of TOF with pulmonary atresia
an alternative to surgical valvulotomy. (PAVSD), the right and left pulmonary arteries
are confluent in approximately 50%, with blood
67.9.1.3 Tetralogy of Fallot to the pulmonary arteries flowing through the
Tetralogy of Fallot (TOF) occurs in 3–6 infants PDA. In the other 50%, pulmonary supply is
per 10,000 live births (Mitchell et al. 1971). The multifocal. In these patients, the pulmonary
etiology is multifactorial but reported associations blood supply may originate partly from the
include untreated maternal diabetes, phenylketon- “true” pulmonary arteries and partly from
uria and an increased intake of retinoic acid. Some aortopulmonary collateral arteries (MAPCAS). If
associated chromosomal anomalies have been the pulmonary arteries are discontinuous or
described: trisomies of chromosomes 21, 18, and absent, pulmonary supply is only from MAPCAS
13; however, the most frequent association is with or from a combination of MAPCAS and PDA.
1052 L. Piazza et al.
Fig. 6 Schematic diagram
of oxygen saturation (%)
and pressures in anatomy of
Tetralogy of Fallot. The
findings include: equal right
and left ventricular
pressures, a right-to-left
(R-L) shunt at ventricular
level, an anteriorly
displaced infundibular
septum resulting in
subpulmonary stenosis
Other associated lesions include atrial septal phenomenon produces RV overload which is
defects, additional ventricular septal defects, and transmitted to the pulmonary arteries, with con-
anomalous origin of coronary arteries. A right aortic comitant dilatation of these vessels.
arch is present in one-quarter of patients with TOF. There may be cyanosis in a neonate when the
The initial presentation of TOF depends on the RV pressure is relatively high and when relatively
severity of obstruction of the right ventricular low compliance of the RV decreases the antegrade
outflow tract. flow toward the pulmonary circulation and causes
Neonates with the most severe forms of TOF right-to-left shunting through the VSD. As the RV
present with marked cyanosis. Pulse oximetry is pressure decreases, the cyanosis becomes less evi-
equal in all limbs and demonstrates oxygen satu- dent, and more left-to-right shunt develops. Con-
ration of 70–80% in air. Arterial blood gas analy- gestive heart failure signs might appear when PVR
sis demonstrates hypoxemia. Patients with less drops, causing an increased pulmonary blood flow.
severe variants present during the neonatal period Some babies can present with inspiratory and expi-
with mild-to-moderate cyanosis, but typically ratory stridor due to tracheobronchial tree compres-
without respiratory distress. sion by aneurysmal pulmonary arteries. In most of
The neonatal ECG usually shows right ventric- these cases, PDA is absent.
ular hypertrophy and right QRS axis deviation. A
chest X-ray classically shows a small or absent 67.9.1.5 Severe Ebstein’s Anomaly
main pulmonary artery with decreased pulmonary Ebstein’s anomaly (EA) is an uncommon but
blood flow and, over time, a “boot-shaped” heart severe anatomic lesion when it presents in the
silhouette. neonatal period. Some familial cases have been
Diagnosis is confirmed by echocardiography reported. Overall, recognized EA is rare, account-
and cardiac catheterization is not usually required. ing for less than 1% of CHD (MacLellan-Torbert
and Porter 1998).
67.9.1.4 TOF with Absent Pulmonary Ebstein’s anomaly is characterized by abnormal
Valve attachment of the posterior and septal tricuspid leaf-
Approximately 2–6% of patients described as lets in the RV cavity far from a normally positioned
TOF also have absent pulmonary valve leaflets tricuspid valve annulus. The degrees of leaflet dis-
(Rao et al. 1971). The presence of rudimentary placement are variable. The anterior leaflet is large,
valvar leaflets results in free pulmonary regurgi- often with abnormal cordal attachments. This leaflet
tation throughout fetal life. This chronic may obstruct the RV outlet. The inlet portion of the
67 Cardiovascular Physiology, Pathology, and Clinical Investigation in Neonatal Medicine 1053
RV is usually functionally integrated into the right Cardiac size may vary from nearly normal
atrium (“atrialization of the RV”) and the functional to extreme cardiomegaly, which is rather typical
RV cavity is small. Nearly all patients have a of EA.
coexisting ASD or PFO. Ebstein’s anomaly can be
associated with accessory atrioventricular conduc- 67.9.1.6 Complex CHD with Severe
tion pathways (Wolff-Parkinson-White syndrome). Pulmonary Stenosis or
Clinical presentation depends on the type and Pulmonary Atresia
severity of EA. At birth, pulmonary vascular Some patients with tricuspid atresia, single ventri-
resistance is high, and the degree of cyanosis can cle, and transposition of the great arteries may have
vary with the degree of right-to-left shunting at the severe pulmonary valve stenosis or pulmonary
atrial level. In neonates with relatively mild tri- valve atresia. Postnatally, the degree of restriction
cuspid valve displacement and no RV outflow to pulmonary flow will determine the clinical pre-
tract obstruction, right-to-left shunting usually sentation and physical findings. Most babies pre-
decreases over the first weeks of life due to pul- sent with cyanosis or murmur. In some of these
monary vascular resistance decrease, with a con- neonates, restrictive ASD may be an important
comitant reduction in cyanosis. If there is a problem, especially in neonates with single ventri-
significant portion of RV atrialized or if the tricus- cle and atrioventricular valve stenosis.
pid valve anterior leaflet obstructs the outflow
tract, cyanosis persists and the severity of CHF
increases. Ebstein’s anomaly is one of the few 67.9.2 Duct-Dependent Systemic
disorders that may cause a thrill in a neonate. Blood Flow
There are several characteristic ECG appear-
ances: right QRS axis deviation, right bundle In this group, there is a unique physiology related
branch block, low-voltage QRS complex in the to left ventricular outflow obstruction (LVOTO)
right precordial leads, right atrial enlargement, characterized by total or partial arterial duct-
and first degree AV block. Arrhythmias can dependent systemic perfusion (Table 7). During
occur in more than 50% of patients; most fre- intrauterine development, systemic perfusion is
quently, there are tachyarrhythmias, including not compromised, being maintained by the ductal
paroxysmal supraventricular tachycardia, atrial flow from the right ventricle to aorta. Postnatally,
fibrillation, and atrial flutter. acute impairment of systemic perfusion follows
Fig. 7 Two-dimensional
echocardiogram
(parasternal short axis)
demonstrates a unicuspid
and thickened aortic valve
1054 L. Piazza et al.
ductal constriction. When the PDA closes, infants with cardiovascular collapse, acidosis, organ
present with cardiovascular collapse and symp- injury, and shock. Once the baby is stabilized, a
toms of CHF. complete echocardiographic evaluation is required
to assess the severity and levels of the obstruction,
67.9.2.1 Aortic Stenosis associated cardiac abnormalities, and related hypo-
The normal aortic valve has three leaflets of plasia of the aortic arch and left heart structures.
approximately equal size with a semilunar shape Neonates and infants with less severe obstruc-
at the level of the free margins. Abnormalities of tion may present with failure to thrive and
the aortic valve account for 70–80% of left ven- tachypnea due to the increased work of breathing
tricular outflow tract obstruction. In severe neo- in association with pulmonary vascular conges-
natal aortic stenosis (AS), the valve is often tion due to left atrial hypertension.
unicuspid or bicuspid (Fig. 8). ECG findings vary widely in newborns and
During fetal development, normal growth and infants with AS. The right ventricular hypertrophy
development of the fetus is generally maintained in is the predominant pattern in neonates.
spite of valvar aortic stenosis. LVOTO exposes the Chest X-ray shows global cardiomegaly in
left ventricle to increased afterload and results in most cases. Pulmonary vascular markings are usu-
ventricular hypertrophy and myocardial dysfunc- ally normal, but in 30–50% of cases congestion
tion. Moreover, chronic in utero subendocardial may be evident.
ischemia secondary to hypertrophy and increased Following the anatomic definition by echocar-
intracavitary pressure can lead to coronary ische- diography (Figs. 7, 8 and 9), treatment strategy
mia and development of endocardial fibroelastosis depends on: (i) the degree of aortic stenosis and
which further impairs the ventricular function. the presence of aortic regurgitation, (ii) associated
Additionally, reduced antegrade blood flow cardiac lesions, and (iii) the severity of this dis-
through the aortic valve predisposes to underdevel- ease that can also affect other organs causing
opment of the left heart structures and hypoplasia serious injury, for example, necrotizing
of the mitral valve, left ventricle, and aortic arch. enterocolitis.
The RV supplies an increased proportion of sys-
temic blood flow via the PDA because LVoutput is 67.9.2.2 Coarctation of the Aorta
reduced. Coarctation of the aorta (CoAo) occurs in 8–10% of
Neonates with critical aortic stenosis present all cases of CHD. It is a hemodynamically signifi-
dramatically soon after birth. As the ductus cant narrowing of the aorta located mostly at the
arteriosus begins to close, severe systemic insertion of the ductus arteriosus. It could be iso-
hypoperfusion occurs resulting in decreased coro- lated or associated with other abnormalities, e.g.,
nary perfusion, acute hemodynamic deterioration tubular hypoplasia of the aortic arch, left ventricular
Fig. 8 Subcostal coronal
view: Neonate with aortic
valvar stenosis, concentric
left ventricle (LV)
hypertrophy. Aortic valve
(asterisk)
67 Cardiovascular Physiology, Pathology, and Clinical Investigation in Neonatal Medicine 1055
Fig. 9 Parasternal long-axis view in systole. (a) The valve has a domed appearance, with thickening of cusps (arrow). LA
left atrium, RV right ventricle, LV left ventricle. (b) Color Doppler demonstrating a turbulent flow across the aortic valve
outflow obstruction, bicuspid aortic valve, VSD,
and ASD. CoAo has been classified as preductal,
ductal, and postductal. It is frequently seen in some
chromosomal syndromes such as Turner syndrome.
In newborns or young infants, the presentation is
often dramatic as shock or severe congestive heart
failure. A concomitant large PDA may make the
diagnosis difficult. The most common signs and
symptoms are tachypnea, diaphoresis at feeding,
poor perfusion, hepatomegaly, and metabolic aci-
dosis. If the duct is partially open, preductal is
higher than postductal saturation; there is upper
limb hypertension and weak palpable femoral
pulses. If the duct is completely closed, there is no
discrepancy between upper and lower limb satura-
tion, femoral pulses are absent, and cyanosis or Fig. 10 Severe coarctation of the aorta. Heart is enlarged.
lower limb mottling and upper limb hypertension Pulmonary arterial markings are normal, but there are
are present. CoAo and the absence of four-limb distended pulmonary veins
systolic pressure gradient can occur in the fol-
lowing anatomical and physiological conditions. The most common ECG pattern shows
(i) The duct is still patent, so the RV provides right ventricular hypertrophy initially, while
flow to the lower part of the body; these neonates biventricular hypertrophy usually appears later.
have a differential cyanosis with lower O2 satu- Chest X-ray reveals the hallmarks of cardiomegaly
ration taken from lower limbs. (ii) LV dysfunc- and pulmonary congestion (Fig. 10). Echo color
tion and systemic hypotension are so severe that Doppler is the most sensitive and specific method
it becomes impossible to detect a pressure gradi- for making the diagnosis (Figs. 11 and 12).
ent. (iii) Aberrant right subclavian artery arises
distally to the coarctation site; therefore, right 67.9.2.3 Interrupted Aortic Arch
arm pressure reflects post-coarctation pressure. Interrupted aortic arch (IAA) is an uncommon
The key point is not to exclude diagnosis of congenital cardiovascular malformation. The inci-
CoAo solely through the absence of a gradient dence is 1% of all congenital heart diseases, car-
in pulse volume or systolic pressure between rying a mortality rate higher than 90% in the
upper and lower limbs. neonatal period (Schumacher et al. 1986).
1056 L. Piazza et al.
Fig. 11 Two-dimensional echocardiography of a typical subclavian artery (LSA). Ascending aorta (AAo); right
coarctation viewed from the high left sagittal plane. (a) The innominate artery (RIA); left common carotid (LCC). (b)
aortic coarctation is visualized distal to the origin of the left Color flow picture showing the isthmic coarctation
Fig. 12 Doppler sample: a
continuous wave Doppler
pattern at the level of the
coarctation showing
significant diastolic tail
IAA is defined as either a complete discontinu- Table 8 Anomalies associated with interrupted aortic
ity or non-patent fibrous strand in the transverse arch
arch or aortic isthmus. It is classified into three VSD with posterior malalignment
types according to the site of interruption: type A, Left ventricular outflow tract obstruction
the interruption is distal to the left subclavian artery Truncus arteriosus
origin; type B, between the origin of left subclavian Transposition of great arteries
and left common carotid artery; type C, the rarest Double outlet right ventricle
one, between the origin of the right brachiocephalic DiGeorge syndrome
and the left common carotid artery.
The hemodynamic condition is totally depen-
dent on PDA patency that supplies the lower part In most cases, the pathophysiology of
of the body. Furthermore, most patients have only interrupted aortic arch is similar to critical CoAo
an isolated VSD but IAA can be associated with a in the newborn. Systemic blood flow is dependent
variety of complex cardiovascular anomalies on ductal patency. When the PDA closes, the baby
(Table 8) (Mishra 2009). develops poor perfusion, acidosis, shock, and renal
67 Cardiovascular Physiology, Pathology, and Clinical Investigation in Neonatal Medicine 1057
failure. On physical examination, tachycardia, sys- During fetal life, the PVR is higher than sys-
tolic murmur, hepatomegaly, and weak femoral temic vascular resistance, and the RV maintains
pulses are present. Differential cyanosis between normal perfusion in the aorta and placenta through
the upper and lower limbs is usually difficult to the patent duct. After birth, there is reversal of
appreciate when there is a VSD. If there is a con- vascular resistance in the two circuits, with sys-
cordant ventriculoarterial connection, pulse oxim- temic pressure being higher than pulmonary, and
etry may show higher oxygen saturation in the PDA closure occurs. Additionally, an important
preductal upper limbs compared with postductal anatomic element is the presence of an appropri-
lower limbs. If the great arteries are transposed, ately restrictive interatrial communication. With
the oxygen saturation could be higher in the lower pulmonary and systemic parallel circulation, the
limbs (reversal differential cyanosis). ratio of pulmonary to systemic flow (Qp:Qs)
IAA type B is commonly associated with depends on the balance between pulmonary and
DiGeorge syndrome (broad nasal bridge, systemic vascular resistances. At birth, PVR is
malar hypoplasia, narrow palpebral fissures, elevated but eventually decreases even in children
hypertelorism, low-set posteriorly rotated ears, with HLHS, resulting in increasing pulmonary
retrognathia, small mouth, and submucosal pala- blood flow and increasing RV overload, to pre-
tal cleft, variable thymus, and parathyroid serve adequate systemic output. As Qp:Qs
deficiencies). These physical features are difficult increases, more saturated blood passes from the
to recognize in neonates; therefore, all neonates LA to the RA across a nonrestrictive ASD; con-
with IAA should be genetically investigated to sequently, systemic oxygen saturation approaches
confirm DiGeorge syndrome. The major risk in normal values despite progressive clinical signs of
these patients is graft-versus-host disease after CHF. This mechanism represents the most com-
blood transfusion with nonirradiated blood. mon cause of CHF in the first weeks of life
ECG and chest X-ray are not specific. Echo- (O’Donnel and McIlroy 1962). A different clini-
cardiography is fundamental to make the diagno- cal presentation occurs when the pathophysiology
sis and to detect coexisting defects. is characterized by reduced pulmonary blood flow
secondary to a small or restrictive interatrial com-
67.9.2.4 Hypoplastic Left Heart munication. These babies always present criti-
Syndrome cally with deep cyanosis, marked tachypnea,
Hypoplastic left heart syndrome (HLHS) repre- metabolic acidosis, hypoxemia characterized by
sents a group of defects characterized by varying PaO2 values of 20 mmHg or less, and cardiovas-
degrees of underdevelopment of left-sided heart cular collapse.
structures. Most of the patients have combinations All infants with HLHS should be promptly
of aortic and mitral valve atresia or stenosis commenced on a prostaglandin infusion to main-
(Garson et al. 1998). The severity is determined tain ductal patency and systemic perfusion. Clin-
by the severity of outflow tract obstruction and the ical stabilization includes endotracheal intubation,
degree of aortic hypoplasia. This syndrome vascular access placement, correction of meta-
accounts for 1–3.8% of all CHD (Abbot 1936). bolic acidosis, and oxygen delivery. After the
The LV is a rudimentary non-pumping cham- diagnosis is made by echocardiography, prompt
ber; the pulmonary venous return goes to the left atrial decompression is necessary by
RA through a foramen ovale or atrial septal Rashkind maneuver and stent implantation at the
defect, causing complete venous blood mixing. fossa ovalis or surgical procedure.
The RV maintains the pulmonary and systemic Newborns with HLHS are generally full-term
output in a parallel fashion. The pulmonary arter- babies who initially appear well and healthy; only
ies receive blood from the RV, while cerebral a few are affected by extracardiac anomalies, like
and cardiac perfusion are supplied retrogradely structural brain malformations typical of chromo-
through the arterial duct into the transverse arch somal abnormalities (Natowicz et al. 1988;
and ascending aorta. Gaynor et al. 2002). The magnitude and
1058 L. Piazza et al.
distribution of acquired vital organ dysfunction (Fig. 13) (Ho et al. 1995). This condition is
usually relates to the circulatory impairment at known as simple transposition. By contrast, com-
the time of diagnosis. All the interventions in the plex transposition includes VSD, left ventricular
preoperative period should be done in order to outflow tract obstruction, aortic arch anomalies,
(i) preserve ductal patency and (ii) set or maintain and anomalous venous return.
Qp:Qs ratio of 1:1. Ventricular septal defect is present in 20% of
Differential diagnosis should include all the TGA (Kirklin et al. 1986; Musumeci et al. 1988),
other left-sided obstructive lesions characterized typically in the outlet portion. Malalignment of
by arterial duct-dependent systemic circulation the outlet septum deviated to the right results in
(Table 7) and other nonstructural cardiac diseases variable degrees of PA overriding representing an
with shock-like state clinical presentation such as anatomical entity called double-outlet right ven-
neonatal sepsis or neonatal myocarditis; these tricle with subpulmonary ventricular septal defect
conditions can be easily differentiated by (Taussig-Bing anomaly).
echocardiography. Left ventricular outflow tract obstruction can
be demonstrated in over 30% of the patients with
TGA (Park et al. 1983). Aortic arch obstruction is
67.9.3 Parallel Circulation/ rare in TGA without VSD. Coronary anatomy
Transposition of the Great may show different patterns (Ho et al. 1995). In
Arteries 10% of the cases, this cardiac defect is associated
with other noncardiac malformations (Kirklin
Transposition of the great arteries (TGA) is a et al. 1986).
common form of cardiac anomaly, accounting
for approximately 75–80% of all congenital 67.9.3.1 Transposition Physiology
heart defects (Bichell et al. 2006). TGA is defined Systemic blood goes from RA to RV and then into
anatomically as concordant atrioventricular the aorta without being oxygenated in the lungs.
(AV) connection and discordant ventriculoarterial On the contrary, fully oxygenated pulmonary
connection. In this setting, the morphological RA venous blood returns from the pulmonary veins
is connected to the morphological RV, which into LA and LV and returns to the lungs via the
gives rise to all or most of the aorta; the morpho- pulmonary artery: in this setting, the systemic and
logical LA is connected to the morphological LV pulmonary circulations describe parallel loops.
from which the pulmonary trunk emerges Survival depends on the presence of one or more
Fig. 13 Echocardiography; long-axis view demonstrating the anterior aorta arising from the right ventricle (RV) and the
pulmonary trunk (PT) arising from the left ventricle (LV)
67 Cardiovascular Physiology, Pathology, and Clinical Investigation in Neonatal Medicine 1059
mixing sites between these two circulations such The arterial switch operation is the procedure
as an atrial septal defect, ventricular septal defect, of choice, and it is used to achieve complete
or PDA, to achieve arterial oxygen saturation physiological and anatomical correction.
compatible with life.
Following separation of the placenta, new-
borns with TGA without VSD and small PFO or 67.9.4 Lesions with Complete
ASD have severe cyanosis (a very low PaO2: Intracardiac Mixing
15–20 mmHg) on the first day of life, associated
with high PaCO2 and metabolic acidosis due to a 67.9.4.1 Total Anomalous Pulmonary
severely decreased effective pulmonary Venous Return
blood flow. Total anomalous pulmonary venous return
(TAPVR) is a con- genital defect in which the
67.9.3.2 Diagnosis pulmonary veins drain anomalously into the sys-
The hyperoxia test is suggestive of a cyanotic temic venous circulation causing a complete
congenital heart condition (Martins and Castela blood mixing. TAPVR is classified in four types
2008). Chest X-ray and ECG may be helpful, but based on the anatomical sites of the abnormal
findings are not specific. The definitive diagnosis connection: supracardiac, cardiac, infracardiac,
relies on echocardiography. and mixed.
The initial management aims at increasing
FiO2 and maximizing mixed venous oxygen sat- 1. Supracardiac: the veins drain into a common
uration opening the arterial duct with prostaglan- confluence behind the LA which drain through
din. Resuscitation with mechanical ventilation an anomalous vein into the systemic venous
can be necessary, and the foramen ovale should circulation, usually in the right- sided superior
be emergently enlarged by balloon atrial vena cava or the innominate vein through a
septostomy. This procedure is usually performed persistent vertical vein.
under fluoroscopy in the cardiac catheterization 2. Cardiac: the common venous confluence
laboratory. Balloon atrial septostomy, also known drains either into the coronary sinus or poste-
as the Rashkind procedure, consists of placing a rior portion of RA.
balloon-tipped catheter in the LA, via the foramen 3. Infracardiac: the common venous confluence
ovale; the balloon is then inflated and pulled back passes across the diaphragm through the
into the RA, tearing the atrial septum. Echocar- esophageal hiatus and drains either into the
diographic guidance is mandatory. The aim of this portal vein or ductus venosus or hepatic vein
procedure is to create an interatrial communica- or inferior caval vein.
tion big enough to cause an increase in oxygen 4. Mixed type: this anatomical configuration is the
saturation due to improved blood mixing. In addi- result of combination of different forms of
tion to these measures, medical support is usually TAPVR. It is commonly associated with other
necessary to optimize the clinical condition: cor- major cardiac anomalies.
rection of metabolic acidosis with hyperventila-
tion and sodium bicarbonate to promote alkalosis, In addition, drainage can be obstructed or
lower pulmonary vascular resistance, and increase unobstructed. The majority of supracardiac
pulmonary blood flow. TAPVR cases have some degree of obstruction
In case of good atrial septostomy but persisting which could be secondary to: (i) ascending vein
desaturation, oxygen saturation could be compression between bronchi and pulmonary
improved by: (i) decreasing the whole body oxy- artery or aorta, (ii) vertical vein orifice stenosis,
gen consumption (muscle relaxants, sedation, or (iii) a small and restrictive atrial
mechanical ventilation), (ii) increasing cardiac communication.
output with inotropic agents, and (iii) increasing Heterotaxy syndrome, especially right isomer-
oxygen-carrying capacity by treating anemia. ism, is usually associated with TAPVR (Fyler
1060 L. Piazza et al.
1992). TAPVR is associated with other cardiac 3. Type III, each pulmonary artery arises from the
anomalies such as single ventricle, truncus ipsilateral aspect of common arterial trunk.
arteriosus, transposition of the great arteries, pul- 4. Type IV, the main pulmonary artery is absent
monary atresia, and coarctation of the aorta with the lungs receiving their blood supply
(Lucas 1983). through aortopulmonary collaterals.
There is an obligatory left-to-right shunt from
pulmonary veins to the right heart and an obliga- The common arterial trunk overrides a VSD
tory right-to-left shunt from RA to the left heart to which is often large, nonrestrictive, with the supe-
maintain the systemic output. The factors that rior border being formed by the truncal valve. The
determine blood flow distribution in these two truncal valve may have a variable number of
circuits include: (i) relative size of the atrial com- cusps, most commonly three; it is often anatomi-
munication and (ii) severity of any obstruction in cally abnormal showing different grade of regur-
the extracardiac pulmonary venous channel. gitation and/or stenosis. The pulmonary arteries
In the most common form of TAPVR, patho- are usually of normal caliber although stenosis of
physiology is a combination of pulmonary vein the origin and diffuse hypoplasia can occur. Cor-
obstruction and increased pulmonary blood flow. onary anomalies, in terms of origin and epicardial
This situation results in RV volume overload. Neo- course, can coexist. Truncus arteriosus may also
nates with significant pulmonary vein obstruction be associated with a right-sided aortic arch. The
present with severe cyanosis, tachypnea, and extracardiac anomalies are common and can con-
hemodynamic instability. These babies are fre- tribute to the mortality; association with DiGeorge
quently misdiagnosed as having persistent fetal syndrome, chromosome 22q11 deletion (Bove
circulation or sepsis or severe respiratory distress et al. 1993), is reported in about 30% of cases
syndrome (Cobanoglu and Menashe 1993). (Goldmuntz et al. 1998).
The clinical presentation of TAPVR varies In most cases, the dominant physiology is a
with the degree of obstruction and pulmonary left-to-right shunt at the level of the great arteries.
blood flow. Frequently the newborn presents The pulmonary and the systemic blood flow are
with tachypnea due to RV volume overload, determined, respectively, by pulmonary vascular
whereas babies with the significant pulmonary resistance and systemic vascular resistance. New-
vein obstruction show frank respiratory distress, borns affected by truncus arteriosus generally
pulmonary edema, poor peripheral perfusion, have an elevated pulmonary vascular resistance
hypotension, and metabolic acidosis. Identifica- and are therefore asymptomatic. As pulmonary
tion of this pathology is crucial in critically ill resistance gradually decreases and PBF increases,
neonates, and the diagnosis is usually made by signs of CHF occur. Subsequently the volume and
echocardiography. pulmonary pressure overload leads to pulmonary
vascular disease. Furthermore, signs of CHF can
67.9.4.2 Truncus Arteriosus be worsened by concomitant significant truncal
This defect consists of a single great artery arising valve regurgitation or stenosis. Echocardiography
from the heart which gives rise to systemic arter- provides accurate diagnosis (Figs. 14 and 15).
ies, pulmonary and coronary arteries. Depending Definitive repair of truncus arteriosus consists of
on the anatomical origin of the pulmonary arter- PA branches separation, RV-PA conduit implanta-
ies, four types of truncus arteriosus exist (Collett tion and VSD closure.
and Edwads 1949):
67.9.4.3 Complex Single Ventricle
1. Type I, pulmonary trunk arises from common Physiology of complex single ventricle is charac-
arterial trunk. terized by complete mixing of the systemic and
2. Type II, right and left pulmonary arteries arise pulmonary venous circulations. An anatomical
separately but close to one another from the left definition describes the single ventricle as a mal-
posterolateral aspect of common arterial trunk. formation where both atrioventricular valves enter
67 Cardiovascular Physiology, Pathology, and Clinical Investigation in Neonatal Medicine 1061
Fig. 14 Echocardiogram
(long-axis parasternal view)
of truncus arteriosus.
Truncal vessel gives rise to
the aorta and the pulmonary
arteries (arrow). RV right
ventricle, LV left ventricle
Fig. 15 Subcostal view
demonstrating the
ventricular septal defect
(VSD) overriding the
truncal valve. RV right
ventricle, LV left ventricle
one ventricle, and there is only one identifiable Patients with pulmonary or aortic atresia or
ventricular sinus (Schultz and Kreutzer 2006). A severe hypoplasia of the aortic arch have a duct-
large variety of anatomic lesions exist, generally dependent circulation, and they need treatment with
associated with atresia of atrioventricular or semi- PGE1 as long as palliative surgery is performed.
lunar valves. The great vessels usually arise from
the heart in an abnormal fashion; frequently vari-
able degrees of pulmonary or aortic obstruction 67.9.5 Left-to-Right Shunt Lesions
may be present. Most complex single ventricles
are associated with heterotaxy syndrome: In the group of left-to-right shunt lesions, the most
polysplenia or asplenia, systemic venous return common in neonates are PDA, ventricular septal
anomalies, anomalous pulmonary venous connec- defect, atrioventricular septal defect, and atrial sep-
tion, visceral situs abnormalities, and atrioventric- tal defect. PDA will be fully described in Chap. 69,
ular septal defect. “▶ Patent Ductus Arteriosus.”
The hemodynamic characteristics and the clin-
ical presentation depend on the balance of anat- 67.9.5.1 Ventricular Septal Defect
omy and/or resistance in the systemic and Ventricular septal defect (VSD) is one of the
pulmonary circulation. Patients without pulmo- most common isolated congenital cardiac
nary stenosis show increased pulmonary blood malformations. A ventricular septal defect is a
flow and soon develop signs of congestive heart hole in the interventricular septum resulting in
failure. In cases with pulmonary stenosis, cyanosis direct communication between the left and right
is present according to the degree of obstruction. ventricles. A clinical useful classification schema
1062 L. Piazza et al.
divides VSD in four types, considering interven- 3. Inlet defect, beneath the septal cusp of the
tricular septum from the RV aspect: tricuspid valve.
4. Muscular defect, located anywhere in the mus-
1. Perimembranous, which partially or totally cular septum with all muscular margins
involves the membranous septum. It can (Fig. 16).
extend into the inlet, trabecular, or outlet por-
tions of the septum. This accounts for the VSD may be either isolated or form part of
majority of the cases. complex CHD as in TOF, truncus arteriosus, and
2. Subarterial, located just beneath the pulmonary double-outlet RV.
valve. This defect, also known as “doubly
committed,” occurs most often among Asians. 67.9.5.2 Atrioventricular Septal Defect
Atrioventricular septal defect (AVSD) is a malfor-
mation involving structures normally derived
from the endocardial cushion tissue: ostium
primum atrial septal defect, inlet VSD, and the
common atrioventricular valve (Fig. 17). Differ-
ent forms of AVSD exist but two are the most
common: partial and complete. Partial AVSD
indicates an atrioventricular septal defect with
interatrial communication (ostium primum
ASD), common AV valve but not inlet VSD; the
term complete atrioventricular septal defect
describes an AVSD with both ostium primum
ASD and inlet VSD. There is a strong association
between complete AVSD and Down syndrome,
whereas partial AVSD is more seen in DiGeorge
and Ellis-van Creveld syndromes.
Fig. 16 Ventricular septal defect: VSD may occur any-
where in the ventricular septum. This defect is located in Most neonates with left-to-right shunt defects
the muscular portion of the septum. RV right ventricle, LV present with signs of cardiac failure after 2 weeks
left ventricle of age. During fetal life, even large defects do not
Fig. 17 (a) Two-dimensional echocardiogram (apical four- (apical four-chamber view, anatomical orientation) demon-
chamber view, anatomical orientation) demonstrating strating a complete atrioventricular septal defect. The com-
ostium primum atrial septal defect. Inlet ventricular septal mon atrioventricular valve is indicated (arrow). RA right
defect (asterisk). (b) Two-dimensional echocardiogram atrium, LA left atrium, RV right ventricle, LV left ventricle
67 Cardiovascular Physiology, Pathology, and Clinical Investigation in Neonatal Medicine 1063
have major physiological effects because of high Gaynor JW, Mahle WT, Cohen MI et al (2002) Risk factors
PVR. After birth the normal decline of PVR for mortality after the Norwood procedure. Eur J
Cardiothorac Surg 22:82–89
occurs within the first 2 weeks. In the presence Gikonyo BM, Lucas RV, Edwards JE (1987) Anatomic
of a large shunt, this decline may be delayed by features of congenital pulmonary valve stenosis.
1–3 months. When this phenomenon happens, Pediatr Cardiol 8:109
pulmonary artery blood flow increases, resulting Goldmuntz E, Clark B, Mitchell L et al (1998) Frequency
of 22q11 deletions in patients with conotruncal defects.
in left heart volume overload. J Am Coll Cardiol 32:492–498
Babies with small left-to-right shunt defects Ho SY, Baker EJ, Riggby ML, Anderson RH (1995) Color
usually come to the attention of pediatricians atlas of congenital heart disease – morphologic and
because of cardiac murmurs without symptoms. clinical correlations. Mosby-Wolfe, London
Hoffman JIE, Kaplan S (2002) The incidence of congenital
Children with moderate left-to-right shunt defects heart disease. J Am Coll Cardiol 39:1890–1900
show varying degrees of growth retardation. Kirklin JW, Pacifico AD, Blackstone EH et al (1986)
Large defects cause signs and symptoms of car- Current risks and protocols for operations for double-
diac failure, such as tachypnea, nasal flaring, rib outlet right ventricle. J Thorac Cardiovasc Surg
92:913–930
and sternal retraction, feeding difficulties, irrita- Kutsche LM, Van Mierop LHS (1983) Pulmonary atresia
bility, and excessive sweating. It is extremely rare with and without ventricular septal defect: a different
for partial AVSD to cause abnormal physical signs etiology and pathogenesis for the atresia in the 2 types?
during neonatal period, unless there is significant Am J Cardiol 51:932–935
Lee K, Khoshnood B, Chen L et al (2001) Infant mortality
AV valve regurgitation. from congenital malformation I the United States,
All the neonates with signs of cardiac failure 1970–1997. Obstet Gynecol 98:620–627
should be investigated by echocardiography. Lucas RV (1983) Anomalous venous connection, pulmo-
nary and systemic in heart disease in infants, children
and adolescents. In: Adams FH, Emmanoulides GC
(eds) Heart disease in infants, chil- dren, and adoles-
References cents, 3rd edn. Williams & Wilkins, Baltimore
MacLellan-Torbert SG, Porter CJ (1998) Ebstein’s anom-
Abbot ME (1936) Atlas of congenital cardiac disease. aly of the tricuspid valve. In: Garson A, Bricker JT,
American Heart Association, New York Fisher DJ, Neish SR (eds) The science and practice of
Ashley SM, Lu Le N (2015) The critically III infant with pediatric cardiology, 2nd edn. Williams & Wilkins,
congenital heart disease. Emerg Med Clin N Am Baltimore, pp 1303–1315
33:501–518 Martins P, Castela E (2008) Transposition of the great
Bailliard F, Anderson RH (2008) Tetralogy of Fallot. arteries. Orphanet J Rare Dis 3:27
Orphanet J Rare Dis 13:4–2 Mishra PK (2009) Management strategies for interrupted
Bichell DP et al (2006) Pulmonary atresia with aortic arch with associated anomalies. Eur J
intact ventricular sep- tum. In: Nichols D, Cardiothorac Surg 35:569–576
Ungerleider R, Spevak P (eds) Critical heart disease Mitchell SC, Korones SB, Berendes HW (1971) Congen-
in infants and children. Mosby Elsevier, Philadelphia, ital heart disease in 56,109 births: incidence and natural
pp 767–776 history. Circulation 43:323–332
Bove EL, Lupinetti FM, Pridjian AK et al (1993) Results of Musumeci F, Shumway S, Lincoln C, Anderson RH (1988)
a policy of primary repair of truncus arteriosus in the Surgical treatment for double-outlet right ventricle at
neonate. J Thorac Cardiovasc Surg 105:1057–1065 the Brompton Hospital, 1973 to 1986. J Thorac
Cobanoglu A, Menashe VD (1993) Total anomalous pul- Cardiovasc Surg 96:278–287
monary ve- nous connection in neonates and young Natowicz M, Chatten J, Clancy R et al (1988) Genetic
infants: repair in the cur- rent era. Ann Thorac Surg disorders and major extracardiac anomalies associated
55:43–48 with the hypoplasia left heart syndrome. Pediatrics
Collett RW, Edwads JE (1949) Persistent truncus 82:698–706
arteriosus: a classification according to anatomic O’Donnel TV, McIlroy MB (1962) The circulatory effects
types. Surg Clin North Am 29:1245 of squat-ting. Am Heart J 64:347
Fyler DC (1992) Total anomalous pulmonary venous Olney Richard S, Ailes EC, Sontag MK (2015) Detection
return. In: Fyler DC (ed) Nadas’ pediatric cardiology. of critical congenital heart defects: review of contribu-
Hanley & Belfus, Philadelphia, pp 683–691 tions from prenatal and newborn screening. Semin
Garson A Jr, Bricker JT, Fisher DJ, Neish SR (1998) The Perinatol 39:230–237
science and practice of pediatric cardiology. Williams Park SC, Neches WH, Mathews RA et al (1983) Hemody-
& Wilkins, Baltimore namic function after the Mustard operation for the
1064 L. Piazza et al.
transposition of the great arteries. Am J Cardiol Schumacher G, Schreiber R, Meisner H et al (1986)
51:1514–1519 Interrupted aortic arch: natural history and operative
Rao BNS, Anderson RC, Edwards JE (1971) Anatomic results. Pediatr Cardiol 7:89–93
variations in the tetralogy of Fallot. Am Heart J 81:361 van Vonderen J, Arno R, Siew ML, Walther FJ, Hooper SB,
Schultz AH, Kreutzer J (2006) Cyanotic heart disease. In: Pas AB (2014) Measuring physiological changes dur-
Vetter VL (ed) Pediatric cardiology: the requisites in ing the transition to life after birth. Neonatology
pediatrics, 1st edn. Mosby, London, pp 66–67 105:230–242
Early Diagnosis of Congenital Heart
Disease: When and How to Treat 68
Francesca R. Pluchinotta, Luciane Piazza, Angelo Micheletti,
Javier Fernandez Sarabia, Diana Negura, Carmelo Arcidiacono,
Antonio Saracino, and Mario Carminati
Contents
68.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1066
68.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1066
68.3 When and How to Treat: Preoperative
Management of Neonates with CHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1066
68.3.1 Systemic-to-Pulmonary Artery Shunt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1067
68.3.2 Pulmonary Artery Banding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1068
68.3.3 Norwood Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1069
68.4 Pathologies Which Require Correction in the
Neonatal Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1070
68.4.1 Truncus Arteriosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1070
68.4.2 Transposition of the Great Arteries (TGA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1070
68.4.3 Total Anomalous Pulmonary Venous Return (TAPVR) . . . . . . . . . . . . . . . . . . . . . 1072
68.4.4 Ebstein’s Anomaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1072
68.4.5 Right-Sided Obstructive Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1072
68.4.6 Pulmonary Valve Stenosis (PS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1073
68.4.7 Pulmonary Atresia with Intact Ventricular Septum (PA/IVS) . . . . . . . . . . . . . . . 1075
68.4.8 Left-Sided Obstructive Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1076
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1077
Abstract prevalence is 5.3 cases per 1,000 live births.
Cardiovascular malformation is the most com- These malformations represent a significant
mon group of congenital malformations. The cause of neonatal morbidity and mortality.
Advances in medical and surgical treatment of
congenital heart disease (CHD) have resulted in
F. R. Pluchinotta (*) improved outcome for conditions which previ-
Department of Pediatric Cardiology, IRCCS Policlinico ously carried high mortality. Unrecognized neo-
San Donato, San Siro, Milan, Italy natal cardiac malformation carries a serious risk
e-mail: [email protected]
of avoidable mortality, morbidity, and handicap.
L. Piazza · A. Micheletti · J. F. Sarabia · D. Negura · C. Routine neonatal examination fails to detect
Arcidiacono · A. Saracino · M. Carminati
many affected babies, because a normal physi-
Centro Cardiologia Pediatrica Policlinico San Donato,
Milano, Italy cal examination does not exclude serious car-
e-mail: [email protected] diac malformation, including hypoplastic left
# Springer International Publishing AG, part of Springer Nature 2018 1065
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_215
1066 F. R. Pluchinotta et al.
heart syndrome or interruption or coarctation of neonatal morbidity and mortality. Advances in
the aortic arch. Babies with a cardiac murmur medical and surgical treatment of congenital heart
detected over the first few days of life should be disease (CHD) have resulted in improved outcome
referred for early pediatric cardiological evalu- in conditions which previously carried high mor-
ation and definitive diagnostic echocardiogra- tality. The antenatal diagnosis of CHD, by fetal
phy. All syndromic babies such as those with echocardiography, carries important advantages:
Down’s syndrome should be referred for early
echocardiographic examination. Echocardiog- 1. Prenatal diagnosis is associated with less
raphy is an essential tool in the evaluation of hypoxia, less preoperative acidosis, fewer
neonates and has dramatically improved the neurologic events, and earlier age to surgery
accuracy of diagnosis of congenital heart dis- (Tworetzky et al. 2001).
ease. The antenatal diagnosis of CHD by fetal 2. It provides opportunities for parental counseling.
echocardiography carries important advantages: 3. It may optimize perinatal care in terms of
less hypoxia and preoperative acidosis, fewer changes in obstetric and neonatal management
adverse neurological events and earlier surgery, with multidisciplinary approach which should
opportunities for parental counseling, and the reduce mortality and morbidity (Berkley
optimization of perinatal care with the selection et al. 2009; Chew et al. 2006).
of an optimal site for delivery.
Routine neonatal examination fails to detect
many affected babies, because a normal examina-
68.1 Salient Points tion does not exclude serious cardiac malforma-
tion, including hypoplastic left heart syndrome or
• About half the babies with cardiac murmur other pathologies such as interruption or coarcta-
detected over the first few days of life have tion of the aortic arch. Considering that about
structural heart disease. half the babies with cardiac murmur, detected
• The preoperative management of patients with over the first few days of life, have a structural
critical congenital heart defects has a dramatic heart disease (Ainsworth et al. 1999), these patients
impact on overall outcome. should be referred for early pediatric cardiological
• A few palliative procedures are used for spe- evaluation and definitive diagnostic echocardiogra-
cific indications: systemic-to-pulmonary artery phy. Unrecognized neonatal cardiac malformation
shunt (prostaglandin and modified Blalock- carries a serious risk of avoidable mortality,
Taussing shunt), pulmonary artery banding, morbidity, and handicap (Silove 1994). Regardless
and Norwood procedure. of this, all syndromic babies such as Down’s
• Pathologies which require correction in the neo- syndrome-affected babies who have a high preva-
natal period are: truncus arteriosus, transposition lence of congenital heart disease should be
of the great arteries, total anomalous pulmonary referred for early echocardiographic examination
venous return, Ebstein’s anomaly, and tetralogy (Wren et al. 1999). The key point is that echocar-
of Fallot with severe right ventricular outflow diography is an essential tool in the evaluation
obstruction, pulmonary atresia with intact ven- of neonates and has dramatically improved the
tricular septum, and coarctation of the aorta. accuracy of diagnosis of congenital heart disease.
68.2 Introduction 68.3 When and How to Treat:
Preoperative Management
Cardiovascular malformation is the most common of Neonates with CHD
group of congenital malformations. The prevalence
is 5.3 cases per 1,000 live births (Wren et al. 1999; The preoperative management of patients with
Ferencz et al. 1985; Kidd et al. 1993). These critical congenital heart defects has a dramatic
malformations represent a significant cause of impact on overall outcome; it requires a
68 Early Diagnosis of Congenital Heart Disease: When and How to Treat 1067
Table 1 Indications for palliative procedure is important to maintain normal blood glucose,
1. Systemic-to-pulmonary arterial shunt calcium levels, and preservation of a neutral ther-
Right-sided obstructive lesion varying in severity from mal environment (Nichols et al. 2006). The mod-
mild pulmonary stenosis to pulmonary atresia ified Blalock-Taussig shunt (MBTS) is the most
Tetralogy of Fallot commonly created systemic-to-pulmonary shunt
Single ventricle with pulmonary stenosis in neonates (Ahamad et al. 2008). This procedure
Tricuspid atresia consists of a polytetrafluoroethylene (Gore-Tex)
Atrioventricular septal defect with severe pulmonary graft placement between the innominate or sub-
stenosis
clavian artery and the ipsilateral pulmonary artery
2. Pulmonary artery banding
Tricuspid atresia with unrestrictive VSD
(de Leval et al. 1981); it aims at increasing pul-
Single ventricle with unrestrictive pulmonary blood flow monary blood flow (PBF) and making pulmonary
3. Norwood procedure arteries grow in order to achieve a favorable ana-
Hypoplastic left heart syndrome tomic condition for future correction. In particular
situations such as Ebstein’s anomaly, pulmonary
atresia with intact ventricular septum or hypoplas-
tic left heart syndrome, transcatheter arterial duct
coordinated, multidisciplinary approach with recanalization, and stenting can be considered as
pediatric cardiologist, pediatric intensivist, sur- an alternative technique to a surgical shunt
geon, anesthesiologist, pediatric nurses, respira- (Santoro et al. 2008a, b; Gewilling et al. 2004).
tory therapists, and family members. The major The postoperative management after Blalock-
goal is to provide supportive care, clinical stabili- Taussig shunt insertion in neonates is generally
zation, and adequate cardiac output to ensure ade- uncomplicated. The saturation is about 75–80% in
quate tissue delivery. Advances in the surgical most of the cases. The extubation is deferred until
repair of congenital heart defects have allowed a pulmonary blood flow is adequate and the arterial
trend toward a single-stage repair. Nevertheless, saturation is stable. When the saturation is not
there are still two palliative procedures used for adequate, the following problems should be
specific indications (Table 1): systemic-to-pulmo- excluded: (i) hypotension; (ii) excessive
nary artery shunt and pulmonary artery banding overload volume until pulmonary edema, requir-
(PAB). ing if necessary reoperation to narrow the shunt
size; (iii) low diastolic pressure, leading to coro-
nary insufficiency; and (iv) acute thrombosis. If
68.3.1 Systemic-to-Pulmonary Artery shunt narrowing or obstruction is detected, fea-
Shunt sible treatment could be percutaneous balloon
angioplasty (Fig. 1a–c), thrombolysis, or sur-
The systemic-to-pulmonary artery shunt is a pal- gery. Immediate postoperative anticoagulation
liative procedure that is used to increase pulmo- with heparin is used, followed by daily aspirin
nary blood flow (PBF) in cardiac defects therapy as long as the shunt is open.
characterized by pulmonary outflow obstruction In some centers, the transcatheter placement of
and clinical cyanosis. In these conditions, before a stent to maintain ductal patency has been used as
surgery, the ductus arteriosus is the main source of an alternative method to provide a source of pul-
pulmonary blood flow; as the ductus closes spon- monary blood. The stenting for PDA appears to be
taneously, severe hypoxemia, metabolic acidosis, an acceptable alternative to the MBTS. The poten-
and death can occur. That is why prostaglandin tial advantages compared to the shunt include a
should be administrated by continuous intrave- reduced procedural-related risks, avoidance of
nous infusion to maintain patency of the ductus cardiopulmonary bypass, and better distribution
arteriosus. In many cases, supporting therapy is of blood through the pulmonary arteries In some
necessary to prevent vasoconstriction and avoid cases, after the shunt, we can observe asymmetry
hypoxia, acidosis, and hypercapnia, which may or pulmonary blood flow irregularity caused by
increase pulmonary vascular resistance (PVR). It distortion (sprain, twist) or localized stenosis of
1068 F. R. Pluchinotta et al.
Fig. 1 (a) Injection in the right Blalock-Taussig shunt; the injection in the right modified Blalock-Taussig shunt; com-
shunt is completely occluded. (b) Recanalization of the plete recanalization (asterisk). Right subclavian artery (cir-
shunt with a balloon catheter. (c) Post-balloon angioplasty: cle), AO aorta, PA pulmonary artery
pulmonary arteries, mainly at the level of the the child grow properly, and to prevent the devel-
anastomosis of the shunt in the pulmonary artery. opment of pulmonary vascular disease.
The banding procedure consists of surrounding
the main pulmonary artery with a synthetic band
68.3.2 Pulmonary Artery Banding in order to create a stenosis limiting the pulmo-
nary blood flow (Fig. 2) It can be performed either
Pulmonary artery banding (PAB) is a palliative through sternotomy or anterolateral thoracotomy.
procedure performed in neonates affected by PAB is an initial palliative strategy for select
CHD associated with high pulmonary blood patients, mainly in patients suffering from single
flow and CHF poorly controlled by medical ther- ventricle and unrestricted pulmonary blood with
apy. The aim is to control the symptoms, to make or without arch aortic obstruction.
68 Early Diagnosis of Congenital Heart Disease: When and How to Treat 1069
Fig. 2 Echocardiogram
picture of pulmonary artery
banding. (a) Pulmonary
valve (PV); pulmonary
banding (asterisk). LPA left
pulmonary artery, RPA right
pulmonary artery. (b) Color
flow picture showing flow
acceleration across the
banding
68.3.3 Norwood Procedure affect survival of these patients, although periodical
and surgical management advances might neutral-
The Norwood procedure is performed to treat the ized the effect of anatomic factor survival.
conditions that result in single ventricle circulation. The surgical treatment for HLHS consists of
Since in these conditions, the most urgent problem is three steps:
that the heart is unable to pump blood to the systemic
circulation, the object of the Norwood procedure is 1. Initial palliative reconstruction (Stage I – Nor-
to connect the single ventricle to the systemic circu- wood procedure)
lation. This procedure is prescribed in the treatment 2. Bidirectional Glenn shunt
of hypoplastic left heart syndrome (HLHS), an asso- 3. Fontan operation
ciation of anatomical anomalies involving the left 4. Transplantation
side of the heart. HLHS includes varying degrees of
hypoplasia of the left ventricle (LV), critical stenosis, The first stage (Norwood procedure) is
or atresia of the mitral and/or aortic valve, with some performed to provide a systemic perfusion indepen-
degree of hypoplasia in the aortic arch (Tworetzky dent from the arterial duct, to preserve function to
et al. 2001). It is fatal without surgical interventions. the single ventricle by minimizing excess pressure
The HLHS survival estimate is increate in the recent and volume work, and to allow normal maturation
years but still accounts for 25–40% of all neonatal of the pulmonary vasculature. An extensive aortic
cardiac mortality. The prematurity, low weight, arch reconstruction, the pulmonary artery and aorta
genetic syndromes, and extracardiac anomalies are used to create the “neoaorta.” A connection with
1070 F. R. Pluchinotta et al.
the systemic right ventricle (RV) with the systemic systemic resistance is the consequence of truncus
circulation and a modified Blalock-Taussig shunt or arteriosus. In the absence of pulmonary artery ste-
Sano shunt (RV to main pulmonary artery conduit) nosis, the normal fall in pulmonary vascular resis-
is performed. Septectomy is performed to avoid tance (PVR) results in significant left-to-right
obstruction of pulmonary venous return and to shunting, pulmonary overcirculation, and symp-
allow blood flow from the left atrium (LA) to the toms of CHF. Due to the rapid development of
right atrium (RA) (Kilian 2006). pulmonary overcirculation, pulmonary hyperten-
The Sano shunt, compared with the BT shunt, sion and subsequent vascular obstructive, disease
determines in a higher elevation of the diastolic can occur as early as 3 months of life. Therefore,
blood pressure. Because the coronary arteries are the policy of many centers is to perform complete
perfused in diastole, the advantage expected in the correction during the neonatal period (Grotenhuis
Sano strategy is supposed to be a better coronary et al. 2016). The surgical repair consists of ventric-
perfusion (Bradley et al. 2001). ular septal defect (VSD) patch closure, pulmonary
A new approach to the HLHS is known as artery removal from the common arterial trunk, and
“hybrid” procedure which consists of transcatheter RV to PA conduit implantation.
stent implantation in the ductus arteriosus for main- The combination of other cardiac malformations
tenance of systemic output, as well as surgical and truncus arteriosus, such as aortic arch interrup-
bilateral PA branches banding to prevent pulmo- tion, outflow tract obstruction, and multiple VSDs,
nary overcirculation. The stent maintains sys- carries high mortality with high risk of reintervention
temic perfusion, whereas the bands limit in survivors (Konstantinov et al. 2006).
pulmonary blood flow (Lim et al. 2006;
Akintuerk et al. 2002). This procedure should
be performed either in a catheterization labora- 68.4.2 Transposition of the Great
tory or in a theater where both angiographic and Arteries (TGA)
surgical capabilities and equipment should be
available. The hybrid approach avoids cardiopul- TGA is a ventriculoarterial discordant lesion in
monary bypass surgery and theoretically is better which the aorta arises from the RV and the pulmo-
for the preservation of the RV function. (20) On nary artery from the LV. (The physiology is
the other hand, the complication of PA obstruc- described in ▶ Chap. 67, “Cardiovascular Physiol-
tion due to the banding has a negative clinical ogy, Pathology, and Clinical Investigation in Neo-
implication. This condition needs a diagnosis natal Medicine”) Once fetal diagnosis is made, a
based on a method of image like cardiac cathe- multidisciplinary team approach helps to improve
terization or computed tomography The cardiac outcomes. Most infants with TGA are diagnosed
catheterization is the most used because it not shortly after birth. This malformation requires
only allows to put in evidence the stenosis of early surgical repair during the neonatal period.
pulmonary branch end or band migration, but, Usually, the babies need a balloon atrial
in the same session, also stenosis with angio- septostomy (Fig. 3). Additional medical support
plasty and stent implantation could be treated. is necessary to optimize clinical conditions. A con-
tinuous infusion of prostaglandin is indicated to
maintain opened the PDA and improve the mixing.
68.4 Pathologies Which Require The arterial switch operation (ASO) is the pro-
Correction in the Neonatal cedure of choice used to achieve complete physio-
Period logical and anatomic correction. Current indications
for ASO in newborns and infants must be taken into
68.4.1 Truncus Arteriosus account in planning operative strategy, because the
optimal time depends on anatomic features such as
Complete mixing at the ventricular and arterial multiple VSDs or unbalanced ventricles. The key
levels, with blood flow to the systemic and pulmo- point is the morphologically left ventricular pressure
nary circulation determined by pulmonary and at the time of presentation. Currently, the optimal
68 Early Diagnosis of Congenital Heart Disease: When and How to Treat 1071
Fig. 3 Cross-sectional echocardiography from the the interatrial septum. (c) The interatrial communication
subcostal approach demonstrating the septostomy proce- (arrows) after balloon septostomy. LA left atrium, RA right
dure. (a) Short frame demonstrating the interatrial septum atrium, RV right ventricle, LV left ventricle
before the septostomy. (b) Catheter in the left atrium across
timing of ASO for babies with TGA without VSD operation may be prolonged exposure to PGE, lon-
varies from 5 to 15 days. Occasionally, newborns ger duration of hypoxemia, and lower cerebral oxy-
with TGA do not undergo early surgery because of gen delivery, and for these reasons, the potential
later presentation, later diagnosis, or both or improvements obtained by this delay must be
coexisting medical problems such as septic condi- closely monitored. The timing of ASO may be
tions or necrotizing enterocolitis (NEC). Delaying extremely difficult for premature and low-birth-
the surgery allows the LV to pump against the lower weight neonates.
resistance pulmonary circulation, determining myo- In the ASO operation, the aorta and pulmonary
cardial deconditioning. In such cases during the artery are sectioned, and their distal extremities
postsurgery period, the LV could develop acute are transposed and anastomosed; (LeCompte
ventricular failure requiring cardiac pacing, extra- maneuver) coronary arteries are then translocated
corporeal membrane oxygenation (ECMO), and to the neoaorta (Villafañe et al. 2014). This trans-
peritoneal dialysis. It results in a poor outcome. fer of the coronary origins is the key to successful
There is benefit in waiting several days after birth ASO. The next step is for the surgeon to close any
to perform the ASO when physiological conditions intracardiac communication.
have normalized. These benefits could be (i) more An alternative procedure is an atrial switch oper-
complete transition from fetal to neonatal circula- ation (Senning or Mustard operation) leaving the
tion, (ii) pulmonary functional improvement, and morphological right ventricle in the systemic cir-
(iii) kidney and liver function improvement. (23) - cuit. Despite the technical difficulties associated
However, the possible disadvantages of delaying with the arterial switch operation and the problems
1072 F. R. Pluchinotta et al.
related to postoperative management, early mortal- valve repair (da Cruz et al. 2007). Mortality is
ity is now similar to that of the atrial switch oper- strongly related to severe tricuspid regurgitation
ation, whereas long-term results are better for the and pulmonary hypoplasia.
former procedure (Castaneda 1999; Daebritz
et al. 2000; HassF et al. 1999).
68.4.5 Right-Sided Obstructive Lesions
68.4.3 Total Anomalous Pulmonary 68.4.5.1 Tetralogy of Fallot (TOF)
Venous Return (TAPVR) There is a wide spectrum of anatomical variability
in TOF with and without pulmonary atresia
TAPVR is a congenital defect in which the pulmo- (TOF/PA). As noted in the previous section, clin-
nary veins drain anomalously into a systemic venous ical presentation depends on the severity of the
structure (see ▶ Chap. 67, “Cardiovascular Physiol- anatomical defects, particularly on the degree of
ogy, Pathology, and Clinical Investigation in Neona- right ventricular outflow tract obstruction, the
tal Medicine”). In obstructed TAPVR, correction is amount of right-to-left shunt through the ventric-
usually performed at the time of presentation, espe- ular septal defect, and the size of pulmonary arter-
cially when the child is markedly cyanotic (da Cruz ies. Echocardiographic examination provides
et al. 2007). In unobstructed TAPVR, timing of all the information required to plan surgical
correction varies with the severity of the clinical strategy (Figs. 4 and 5). Therefore, cardiac cathe-
features: generally, babies present with symptoms terization is needed only when the diagnostic
of CHF later in infancy; at that time correction should dilemma is still not sorted out like pulmonary or
be carried out. coronary artery anatomy and the presence of
aortopulmonary collateral arteries.
All patients with TOF and TOF/PA require
68.4.4 Ebstein’s Anomaly surgical intervention. Initial medical management
depends on clinical presentation, which also
Hemodynamic abnormalities in this malforma- depends on the severity of right ventricular out-
tion are related to the severity of tricuspid regur- flow tract obstruction (RVOTO). When RVOTO
gitation, the size of the functional RV, and the is significant, neonates present with cyanosis,
degree of right-to-left shunting across the atrial hypoxemia, and metabolic acidosis: prostaglandin
septal defect (ASD). Ebstein’s anomaly may be infusion should be started to maintain ductal
associated with ASD and pulmonary outflow patency, and surgical palliation or repair after
obstruction. If there is severe tricuspid regurgita- stabilization should be planned. Most commonly,
tion in utero, massive cardiomegaly, secondary palliation consists of a subclavian-pulmonary
pulmonary hypoplasia, hydrops fetalis, or a com- artery shunt such as the modified Blalock-Taussig
bination of these can occur (Lang et al. 1991). shunt, performed without cardiopulmonary
Ebstein’s anomaly has a clinical spectrum that bypass. Due to advances in neonatal cardiac sur-
varies from severe cyanosis and circulatory col- gery, some centers have been performing com-
lapse in the newborn to minimal or no symptoms plete repair during the neonatal period (Lang
in the child or adult. Once the diagnosis is made, et al. 1991; da Cruz et al. 2007). Major concerns
the newborn may require support with PGE1 remain regarding cardiopulmonary bypass com-
infusion and nitric oxide, and definitive surgical plications, associated risk of longer stay in the
management is undertaken. For neonates, ther- intensive care unit, neurobehavioral abnormalities
apy is tailored to the severity of the malformation (Bailliard and Anderson 2008; Limeropoulos
and the degree of RV outflow tract obstruction. et al. 1999), and anatomical issues. In this setting,
Surgery may involve ligation of the duct, place- percutaneous RVOT stenting could serve as an
ment of a systemic-to-pulmonary shunt, creation alternative treatment to a surgically constructed
of a functional tricuspid atresia, or tricuspid systemic-to-pulmonary artery shunt or ductal
68 Early Diagnosis of Congenital Heart Disease: When and How to Treat 1073
Fig. 4 (a) Right subcostal
anterior oblique view in
tetralogy of Fallot
demonstrating the antero-
cephalad deviation of the
outlet septum into the right
ventricular outflow tract.
Infundibular pulmonary
stenosis (asterisk).
Significant hypoplasia of
the pulmonary trunk and
pulmonary arteries. Aorta
(AO), pulmonary artery
(PA). (b) Color Doppler
imaging showing
turbulence and flow
acceleration in the right
ventricular outflow tract.
The turbulence continues
into the pulmonary trunk
and pulmonary arteries
Fig. 5 Two-dimensional
echocardiogram (modified
parasternal long axis view)
demonstrating large
ventricular septal defect,
aortic override, and the right
ventricular hypertrophy
typical of tetralogy of Fallot
stenting. This procedure is feasible and achieves and Anderson 2008; Nicholls et al. 2006)
increased pulmonary blood flow in a physiologi- although it is a common practice to proceed to
cal direction with correct pulsating inflow complete correction within 4–6 months of age.
resulting in an immediate increase in oxygen sat-
uration and the patient’s condition. Other con-
cerns include VSD patch closure, subpulmonary 68.4.6 Pulmonary Valve Stenosis (PS)
obstruction relief, and pulmonary artery recon-
struction using a transventricular approach PS is characterized by thickened, doming pulmo-
(Hirsch et al. 2000; Stewart et al. 2005). The nary valve leaflets with a hypertrophied RV and
ideal age for complete correction is still under normal tricuspid valve annulus. In critical PS,
discussion (Tamesberger et al. 2008; Bailliard transcatheter balloon dilatation is the procedure
1074 F. R. Pluchinotta et al.
Fig. 6 A right ventriculogram in neonate with pulmonary the right ventricle (RV). The balloon is inflated with diluted
valve stenosis. (a) A lateral view demonstrating systolic contrast until the balloon “waist” disappears. (c) A repeat
doming of the stenotic leaflets and narrow jet of contrast right ventriculogram showing markedly improved
into PA (arrow). Right ventricle (RV), pulmonary artery antegrade flow through the stenotic pulmonary valve
(PA). (b) A guidewire is passing through the catheter from (arrow)
of choice. The procedure is also recommended such as in Noonan syndrome, valvuloplasty is less
when RV pressure exceeds half the systemic pres- effective, requiring subsequent surgical
sure. Angiography and invasive pressure mea- valvotomy. Quite often, after critical PS balloon
surements during cardiac catheterization confirm dilatation, cyanosis persists due to a persistent
the echocardiographic diagnosis and allow mea- right-to-left shunt at the level of the foramen
surement of the pulmonary valve which is funda- ovale as a result of significant RV hypertrophy
mental to performing balloon valvuloplasty and diastolic dysfunction; in this situation, ade-
(Fig. 6). An oversized balloon, 1.2–1.4-fold the quate pulmonary flow may be achieved either by
size of the annulus is used. Balloon valvuloplasty keeping the arterial duct open with PGE1 infusion
is effective and restenosis is uncommon (Stewart or stent implantation or by performing an MBT
et al. 2005). In the presence of dysplastic valves shunt between the aorta and pulmonary artery.
68 Early Diagnosis of Congenital Heart Disease: When and How to Treat 1075
68.4.7 Pulmonary Atresia with Intact decompress the right ventricular cavity and to
Ventricular Septum (PA/IVS) reduce tricuspid valve regurgitation (Alwi
et al. 2000). Subsequent postcatheterization man-
PA/IVS is a congenital heart defect with wide mor- agement may be challenging because of arterial
phological heterogeneity. Morphology varies with duct stenting, or an MBT shunt insertion may be
respect to tricuspid valve size, RV hypoplasia, infun- necessary to optimize the effective pulmonary
dibular development, and the presence of coronary blood flow.
stenosis or coronary-RV cavity fistulas, called sinu- Another alternative approach could be surgical
soids. These connections are considered persistent pulmonary valvotomy with or without MBT shunt
communications, which do not involute during intra- at the same time.
uterine life due to the development of RV Babies with sinusoidal-coronary artery-depen-
suprasystemic pressure; they are found in up to dent circulation should not undergo right ventric-
50% of cases (Joshi et al. 1966). Morphological ular decompression as this procedure could cause
aspects should be investigated by echocardiography myocardial infarction due to an acute reduction of
and cardiac catheterization. Complete hemodynamic RV cavity pressure and consequently in the coro-
and angiographic study is essential even if a detailed nary artery perfusion pressure (Santos and
diagnosis is carried out by echocardiography. Azevedo 2004). Therefore a palliative surgical
Transcatheter pulmonary valve radiofrequency approach (MBT shunt and atrial septostomy in
perforation followed by pulmonary valve balloon case of restrictive ASD) could be a good option
dilatation is an effective procedure (Fig. 7) to for these cases.
Fig. 7 Transcatheter
intervention for pulmonary
atresia. (a) Lateral view of a
right ventricular (RV)
injection in neonate with
pulmonary atresia and intact
ventricular septum
(asterisk). The RV outflow
tract ends blindly at the
level of the atretic
pulmonary valve. No
contrast crosses the
pulmonary valve plate.
(b) The lateral view
angiography in the
infundibulum: the tip of the
radiofrequency perforation
wire just positioned below
the atretic pulmonary valve
(arrow). (c) A balloon
catheter submaximally
inflated across the atretic
valve. (d) Injection in the
right ventricle (RV)
demonstrating the
continuity created between
the RV and the pulmonary
artery (PA)
1076 F. R. Pluchinotta et al.
68.4.8 Left-Sided Obstructive Lesions the duct closes. At that time, systemic perfusion
fails, and hypotension and acidosis occur. PGE1
68.4.8.1 Aortic Valve Stenosis (AS) infusion should be given to keep ductal patency
The treatment of AS depends on the degree of and supply systemic circulation as a palliative
obstruction and the presence of systemic measure until surgical intervention is performed.
hypoperfusion. Neonates presenting with collapse Treatment options vary from surgery to
or congestive heart failure need emergency treat- transcatheter intervention. Surgery with coarcta-
ment. PGE1 infusion should be started to maintain tion resection and end-to-end anastomosis or the
ductal-dependent systemic flow. In many cases, subclavian artery flap technique is currently the
inotropic support is also required. The treatment first choice. However, balloon angioplasty may be
of choice for neonatal congenital aortic stenosis is performed in circumstances where the infant is a
transcatheter balloon valvuloplasty (Fig. 8). Vas- poor candidate for surgery because of cardiovas-
cular access is usually retrograde using the carotid cular collapse (Kilian 2006). Surgery for neonatal
artery. However, an antegrade approach using the CoAo is associated with fewer reinterventions,
umbilical or the femoral arteries has been improved aortic arch growth, no aortic aneurism
described. The antegrade approach is associated formation, and a decreased need for antihyperten-
with a lower morbidity compared with the retro- sive medications when compared with neonates
grade approach (Maeno et al. 1997; Magee treated primarily with balloon angioplasty
et al. 1997). Balloon valvuloplasty in neonates (Andrew et al. 2005).
may be markedly effective; however, limited
long-term data have shown development of sig- 68.4.8.3 Interrupted Aortic Arch (IAA)
nificant aortic valve regurgitation in up to 25% of IAA consists of a disconnection between the
patients treated with this technique (Maeno ascending and descending aorta. Clinical presenta-
et al. 1997). tion, preoperative management, and timing of sur-
gery are similar to critical CoAo. AVSD and patent
68.4.8.2 Coarctation of the Aorta (CoAo) ductus arteriosus are present in more than 90% of
The most common type of coarctation is located at the cases (Fyler 1992). VSD patch closure could be
the level of the isthmus, in the thoracic aorta, approached either during the same operation or in a
distal to the origin of the left subclavian artery. second stage after having performed pulmonary
Neonates with CoAo develop symptoms once artery banding at the same time as IAA repair.
Fig. 8 (a) Carotid artery injection showing bicuspid aortic valve. (b) Balloon inflated across the aortic valve for
valvuloplasty. (c) Injection in the left ventricle (LV) after valvuloplasty
68 Early Diagnosis of Congenital Heart Disease: When and How to Treat 1077
References circulation: new techniques, better results. J Am Coll
Cardiol 43:107–112
Ahamad U, Fatimi SH, Naqvi I et al (2008) Modified Grotenhuis HB, Ruijsink B, Chetan D et al (2016) Impact
blalock-taussig shunt: immediate and short-term of norwood versus hybrid palliation on cardiac size and
follow-up results in neonates. Heart Lung Circ function hypoplastic left heart syndrome. Heart 0:1–9
17:54–58 Hass F, Wottke M, Popper H, Meisner H (1999) Long-term
Ainsworth SB, Wyllie JP, Wren C (1999) Prevalence and survival and functional follow-up in patients after arte-
clinical significance of cardiac murmurs in neonates. rial switch operation. AnnThorac Surg 68:1962–1967
Arch Dis Child 80:F43–F45 Hirsch J, Mosca R, Bove E (2000) Complete repair of
Akintuerk H, Miche-Behnke I, Valeske K et al (2002) tetralogy of fallot in the neonate: results in the modern
Stenting of the arterial duct and banding o f the pulmo- era. Ann Surg 232:508–514
nary arteries: basis for combined Norwood stage I and Joshi VS, Brawn WJ, Mee RB (1966) Pulmonary atresia
II repair in hypoplastic left heart syndrome. Circulation with intact ventricular septum. J Thorac Cardiovasc
105:1009–1103 Surg 91:192–197
Alwi M, Geetha K, Bilkins AA et al (2000) Pulmonary Kidd SA, Lancaster PAL, McCredie RM (1993) The inci-
atresia with intact ventricular septum: percutaneous dence of congenital heart disease in the first year of life.
radiofrequency-assisted valvulotomy and balloon dila- Am Paediatric Child Health 29:3444–3449
tation versus surgical valvotomy and Blalock-Taussig Kilian K (2006) Left-sided obstructive congenital heart
shunt. J Am Coll Cardiol 35:468–476 defects. Newborn Infant Nurs Rev 6:128–136
Andrew CF, Fischer LK, Schwartz T et al (2005) Compar- Konstantinov IE, Karamlou T, Blackstone EH et al (2006)
ison of angioplasty and surgery for neonatal aortic Truncus arteriosus associated with interrupted aortic
coarctation. Ann Thorac Surg 80:1659–1665 arch in 50 neonates: a congenital heart surgeons society
Bailliard F, Anderson RH (2008) Tetralogy of fallot. study. Ann Thorac Surg 81:214–222
Orphanet J Rare D 4:2 Lang D, Obenhoffer R, Cook A et al (1991) Pathologic
Berkley EMF, Goens MB, Karr S, Rappaport V (2009) spectrum of malformations of the tricuspid valve in
Utility of fetal echocardiography in postnatal manage- prenatal and neonatal life. J Am Coll Cardiol
ment of infants with prenatally diagnosed congenital 17:1161–1167
heart disease. Prenat Diagn 29:654–658 Lim DS, Peeler BB, Matherne GP et al (2006) Risk-
Bradley SM, Simsic JM, Atz AM (2001) Hemodynamic stratified approach to hybrid transcatheter-surgical pal-
effects of inspired carbon dioxide after the norwood liation of hypoplastic left heart syndrome. Pediatr
procedure. Ann Thorac Surg 72:2088–2094 Cardiol 27:91–95
Castaneda AR (1999) Arterial switch operation for simple Limeropoulos C, Majnemer A, Shevell MI et al (1999) Neu-
and complex TGA: indication criteria and limitations rologic status of newborns with congenital heart defects
relevant to surgery. Thorac Cardiovasc Surg 39:151–154 before open heart surgery. Pediatrics 103:402–408
Chew C, Stone S, Donath SM, Penny DJ (2006) Impact of Lincoln CR, Rigby ML, Mercanti C et al (1988) Surgical
antenatal screening on the presentation of infants with risk factors in total anomalous pulmonary venous con-
congenital heart disease to a cardiology unit. J Pediatr nection. Am J Cardiol 61:608–611
Child Health 42:704–708 Maeno Y, Akagi T, Hashino K et al (1997) Carotid artery
da Cruz E, Billieux MH, Beghetti M (2007) A neonate with approach to balloon aortic valvuloplasty in infants with
isolated combined aortic and pulmonary valvar steno- critical aortic valve stenosis. Pediatr Cardiol 18:288–291
sis. J Cardiol 116:e13–e14 Magee AG, Nykanen D, McCrindle BW et al (1997) Bal-
Daebritz SH, Noller G, Sachweh JS et al (2000) Anatom- loon dilation of severe aortic stenosis in the neonate:
ical risk factors for mortality and cardiac morbidity comparison of antegrade and retrograde catheter
after arterial switch operation. Ann Thorac Surg approaches. J Am Coll Cardiol 30:1061–1066
69:1880–1886 Martins P, Castela E (2008) Transposition of the great
de Leval MR, Mckay R, Jones M et al (1981) Modified arteries. Orphanet J Rare D 3:27
blalock-taussig shunt: use of subclavian artery orifice Mckrindle BW, Kan JS (1991) Long-term results after bal-
as flow regulator in prosthetic systemic pulmonary loon pulmonary valvuloplasty. Circulation 83:1915–1922
artery shunts. J Thorac Cardiovasc Surg 81:112–119 Nicholls DG, Ungerleider RM, Spevak PJ et al (2006)
El B, Lupinetti FM, Pridjian AK et al (1993) Results of a Critical heart disease in infants and children, 2nd edn.
policy of primary repair of truncus arteriosus in the Mosby Elsevier, Philadelphia, pp 755–766
neonates. J Thorac Cardiovasc Surg 105:1057–1065 Nichols DG, Ungerleider RM, Spevak PJ et al (eds) (2006)
Ferencz C, Rubin JD, McCarter RJ et al (1985) Congenital Critical heart disease in infants and children, 2nd edn.
heart disease: prevalence at live birth. Am J Epidemiol Philadelphia, Mosby Elsevier
121:31–36 ParK M (2002) Pediatric cardiology for practitioners, 4th
Fyler DC (ed) (1992) Nadas’ pediatric cardiology. Hanley edn. CV Mosby, St. Louis
& Bel- fus, Philadelphia Rao S (2005) Diagnosis and management of acyanotic
Gewilling M, Boshoff DE, Dens J et al (2004) Stenting the heart disease. Part 1: obstructive lesions. Indian J
neonatal arterial duct in duct-dependent pulmonary Pediatr 72:495–502
1078 F. R. Pluchinotta et al.
Santoro G, Palladino MT, Russo G, Calabrò R (2008a) Tamesberger MI, Lechner E, Mair R et al (2008) Early
Neonatal patent ductus arteriosus recanalization and primary repair of tetralogy of fallot in neonates and
stenting in critical Ebstein’s anomaly. Pediatr Cardiol infants less than four months of age. Ann Thorac Surg
29:176–179 86:1928–1935
Santoro G, Gaio G, Palladino MT et al (2008b) Stenting of Tworetzky W, McElhinney DB, Reddy VM et al (2001)
the arterial duct in newborns with duct-dependent pul- Improved surgical outcome after fetal diagnosis of
monary circulation. Heart 94:925–929 hypoplastic left heart syndrome. Circulation
Santos MA, Azevedo VMP (2004) Angiographic morpho- 103:1269–1273
logic characteristics in pulmonary atresia with ventric- Villafañe J, Lantin-Hermoso R, Tweddell JS et al (2014)
ular septum. Arq Bras Cardiol 82:5 D-transposition of the great arteries. The current era of
Silove ED (1994) Assessment and management of congen- the arterial switch operation. J Am College Cardiol
ital heart disease in the newborn by the district Paedi- 64:498–511
atrician. Arch Dis Child 70:F71–F74 Wren C, Richmond S, Donaldson L (1999) Presentation of
Stewart RD, Backer CL, Young L, Mavroudis C (2005) congenital heart disease in infancy: implications for
Tetralogy of fallot: results of a pulmonary valve- routine examination. Arch Dis Child Fetal Neonatal
sparing strategy. Ann Thorac Surg 80:1431–1439 Ed 80:49–53
Patent Ductus Arteriosus
69
Bart Van Overmeire
Contents
69.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1080
69.2 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1080
69.3 Physiology and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1081
69.4 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1082
69.4.1 Pulmonary Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1082
69.4.2 Systemic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1083
69.4.3 Cerebral Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1083
69.5 Pharmacological Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1083
69.5.1 Hemodynamic Significance of the PDA-Shunt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1084
69.5.2 Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1084
69.5.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1084
69.5.4 Risks of Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085
69.5.5 NSAID Dosing Schemes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1086
69.6 Surgical Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1086
69.7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1087
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1087
Abstract gestation. Spontaneous closure of the ductus
Patent ductus arteriosus (PDA) continues to be a occurs in 30% of infants with very low birth
frequent complication of extremely premature weight (<1500 g). When the PDA is hampering
birth, despite the more generalized use of ante- the neonate’s well-being, judicious evaluation
natal steroids, postnatal surfactant administra- and tailoring of the best therapeutic strategy
tion, and the improvement of noninvasive should be performed. Ibuprofen actually seems
ventilatory strategies. Its incidence is inversely to be the preferred drug for pharmacological
related to gestational age, such that it affects treatment because of its favorable risk/benefit
almost 60% of infants less than 28 weeks’ ratio; the therapeutic response of the most
immature infants however is limited. Surgical
ligation of the duct should be considered as a
B. Van Overmeire (*)
backup treatment due to the risks of serious
Neonatology Service, Erasmus Hospital Université Libre
de Bruxelles, Brussels, Belgium complications during and after the procedure.
# Springer International Publishing AG, part of Springer Nature 2018 1079
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_219
1080 B. Van Overmeire
69.1 Salient Points Table 1 Closed or non-symptomatic PDA among VLBW
infants surviving >12 h
• PDA continues to be a frequent complication of 501–750 g 750–1000 g 1001–1250 g 1251–1500 g
extremely premature birth (60% of infants less n = 4,046 n = 4,266 n = 4,557 n = 5,284
than 28 weeks’ gestation), despite the more 51 (17–80) 62 (40–89) 77 (52–91) 87 (67–93)
generalized use of antenatal steroids, postnatal Data expressed as % (center range) from (Fanaroff et al.
surfactant administration, and the improvement 2007)
of noninvasive ventilatory strategies.
• A large left to right shunt may cause profound Table 2 Spontaneous closure of PDA in 210 VLBW
infants
hemodynamic disturbances to local organs and
the brain. Closed Gestational Closed
Birthweight (g) ductus (%) age (w) ductus (%)
• Ibuprofen actually seems to be the preferred
500–750 44 24–25 54
drug for pharmacological treatment because of
751–1000 62 26–27 54
its favorable risk/benefit ratio; the therapeutic
1001–1250 60 28–29 60
response of the most immature infants however
1251–1500 74 30–31 79
is limited.
Data from (Overmeire et al. 2004a)
• Surgical ligation of the duct should be consid-
ered as a backup treatment due to the risks of
serious complications during and after the in a double blind randomized trial of ibuprofen
procedure. prophylaxis, high spontaneous closing rates on
the 3rd to 4th day of life were confirmed by
echocardiographic assessment (Overmeire et al.
69.2 Epidemiology 2004a). Data are displayed for five birthweight
and gestational age categories (Table 2).
Patent ductus arteriosus (PDA) is the most com- Data from the neonatal registry of the Belgian
mon cardiac abnormality of the preterm infant. Its college of physicians, demonstrate a closed or
incidence is inversely related to gestational age, non-symptomatic PDA in 46.7% of 2635 VLBW
such that it affects almost 60% of infants less than infants for the years 2007–2009 (College of Physi-
28 weeks’ gestation. Data published in 2007 dem- cians for the Mother and Newborn, Section Neo-
onstrated that spontaneous closure of the ductus natology). As compared to these numbers, the
occurs in 30% of infants with birthweights below closure rates described by Koch et al (2006) in
1500 g (very low birth weight [VLBW]) (Fanaroff the United States seem lower, e.g., 34% on the
et al. 2007). It is obvious that percentages are third day of life in a group of 122 infants with
decreasing for each lower birthweight category birth weights below 1000 g. Other US data report
(Table 1), but also that a markedly wide variation 31% closure below 1000 g and 67% in a group of
exists among centers. This may reflect the influ- 65 VLBW infants (Nemerofsky et al. 2008). It is
ence of varying factors on the closure of the ductus. clear that a wide variation exists in spontaneous
Higher closing rates, and as a consequence ductal closure in preterm infants. In addition to
lower incidences of PDA, have been reported in immaturity, which is the factor that contributes
several papers for European infants. A random- most to PDA, various cofactors affect the occur-
ized comparative multicenter trial that compared rence of PDA. For many years, the presence of
early (day 3) versus late (day 7) indomethacin severe RDS has been recognized as a delaying
treatment for PDA in preterm infants with gesta- factor for closure (Bancalari et al. 2005), as is the
tional ages between 26 and 31 weeks and suffer- association with sepsis (Gonzalez et al. 1996).
ing from respiratory distress syndrome (RDS), Intrauterine growth restriction also affects the
revealed that 281 of 380 (74%) spontaneously behavior of the ductus (Robel-Tillig et al. 2003).
closed their duct by the age of 7 days (Overmeire The group of Rakza demonstrated convincingly
et al. 2001a). In 210 infants who received placebo that hypotrophic infants had significantly larger
69 Patent Ductus Arteriosus 1081
left to right shunts appearing earlier after birth and Many pharmacologic agents that are commonly
needing earlier treatment than eutrophic controls used in the early neonatal period may influence the
(Rakza et al. 2007). The authors explain that behavior of the ductus. Although caffeine has no
chronic hypoxia in utero may have caused a faster direct effect on preterm sheep ductus’ contractility
decrease of the pulmonary vascular resistance (Clyman and Roman 2007), markedly less treat-
through the production of higher noradrenaline ment for PDA was observed in the group of infants
levels. Additionally, major anomalies of both the who received caffeine in a large multicenter clinical
intima and media of the ductal vessal wall have trial including 2,006 subjects (Schmidt et al.
been described (Ibara et al. 1994). It is a common 2006a). In contrast to what was suggested years
belief that excessive fluid administration during the ago, there actually seems less evidence for a reduc-
first days of life is associated with the occurrence of ing effect of the postnatal administration of thyroid
PDA. Unfortunately, poor evidence exists to sup- hormone (Osborn and Hunt 2007) and the
port this view. A systematic meta-analysis on this shielding of the thorax during phototherapy
topic was last updated in 2008. Four of the five (Travadi et al. 2006) on the occurrence of PDA.
included trials date from the era before antenatal The administration of furosemide, by increasing
steroids and exogenous surfactant therapy and the circulating prostaglandin E2 levels, has been asso-
one from 1999 shows very weak evidence. Never- ciated with an increased incidence of PDA in a
theless, the authors conclude that the practice of study of 66 infants with RDS (Green et al. 1983).
restricting water intake to physiological needs in Six of seven studies that investigated the use of
preterm infants might be expected to decrease the furosemide in preterm infants with RDS of less
risk of PDA (Bell and Acarregui 2008). The role of than 5 days of age were performed before the
cortisol was highlighted by the studies of systematic application of prenatal steroids, surfac-
Watterberg demonstrating an inverse relationship tant or fluid restriction. However, a systematic
between serum cortisol levels on postnatal days review combining the trials indicated an increased
3–4 and 5–6 and the occurrence of PDA risk of PDA and hypovolemia (Brion and Soll
(Watterberg et al. 2000). It is known that both 2008). More recent data on the concomittant use
antenatal (Abbasi et al. 2000; Chorne et al. of furosemide during NSAID treatment for PDA
2007a) and postnatal steroid administration are underscore the risk of inducing transient renal fail-
associated with lower incidences of PDA (Halliday ure (Toyoshima et al. 2010) but do not confirm the
et al. 2001; Doyle et al. 2010). The prenatal use of clinical effect of delaying the closure of the ductus
NSAIDs as tocolytics has an impact on the postna- (Andriessen et al. 2009; Lee et al. 2009).
tal reactivity of the ductus. Indomethacin and ibu- Various other frequently used drugs in the
profen freely cross the placenta (Hammerman et al. NICU may have unexpected vasodilatory actions
1998; Norton et al. 1993). During pregnancy they on the ductus. To date, no clinically relevant effect
have a vasoconstrictive effect on the ductus and on the behavior of the ductus has been described
fetal pulmonary circulation which increases with by the inhalation of nitric oxide (Schreiber et al.
advancing gestational age. Antenatally induced 2003; Askie et al. 2010; Mercier et al. 2010).
changes in the fetal ductal wall lead to a decreased Aminoglycosides, cimetidine, ranitidine and hep-
reactivity of the ductus to postnatal NSAID treat- arin are other possible candidates with dilating
ment with an increased rate of treatment failure effects on the ductus meriting further prospective
(Reese et al. 2009; Soraisham et al. 2010). The evaluation (Reese et al. 2010).
use of magnesium sulfate in pregnant women has
been associated with a higher risk of developing
PDA in extremely low birth weight infants (Moral 69.3 Physiology and Pathogenesis
et al. 2007) and with a reduced responsiveness to
indomethacin prophylaxis (Katayama et al. 2010). During fetal life the patency of the ductus is essen-
Other large studies did not confirm these observa- tial. It allows 90% of the right ventricular output to
tions (Rouse et al. 2008). bypass the highresistance pulmonary vascular bed.
1082 B. Van Overmeire
Fetal patency of the ductus before birth and the tissue hypoxia, initate remodeling and ultimately
closure after birth is the result of a balanced inter- definitive closure of the ductus (Kajino et al.
action of locally produced and circulating media- 2001). This carries an increased risk of reopening.
tors, low oxygen tension and the unique structure A similar mechanism is believed to contribute to
of the vessel wall. Prostaglandins, converted from the failure of ductal closure of fetus previously
arachidonic acid by COX enzymes, play a major exposed to maternal indomethacin (Clyman et al.
role in maintaining ductal patency in utero. There 2001). In addition, there is evidence that the major
are two separate genes encoding COX proteins, vasorelaxant nitric oxide (NO) plays a role in the
COX-1 and COX-2, and a variant of COX-1 infor- very immature ductus. Inhibition of NO synthase
mally termed COX-3 has also been identified was found to exert a greater effect in closing the
(Chandrasekharan et al. 2002). COX-1 is mostly ductus of the more immature fetus whereas COX
constitutive whereas COX-2 is highly expressed inhibition exerted a greater effect in the near-term
during inflammation. COX-2 has been found to fetus. The combined treatment with NO synthase
be increasingly expressed in the fetal ductus and COX inhibitors was more effective than sim-
arteriosus with advancing gestation and is the ply using COX inhibitors, but severe side effects
main contributor to local PGE2 generation in the precluded the introduction of this approach in
ductus at term (Smith et al. 2001). Of the five major clinical practice (Seidner et al. 2001).
prostanoids (PGE2, PGF2α, PGD2, PGI2 and
TXA2), predominantly PGE2 and PGI2 have high
levels in the fetus because of high placental pro- 69.4 Pathophysiology
duction and low clearance by the fetal lungs. They
are the most potent ductal relaxants. Almost all morbidity associated with PDA in pre-
The increase in postnatal oxygen tension along term infants may be explained by the persistent
with a decreased sensitivity of the ductus to PGE2 left to right shunt through the vessel, causing a
as the fetus approaches term, initiate the closure of systemic hypoperfusion and a pulmonary hyper-
the ductus (Schneider and Moore 2006). In the perfusion. In most infants, the heart can cope with
term infant constriction begins within the first few the increasing demands by increasing left ventric-
hours after birth and functional closure is usually ular stroke volume and heart rate.
completed within 24–48 h of age.
After the initial functional constriction, a phase
of neointimal thickening and remodeling occurs, 69.4.1 Pulmonary Effects
leading to anatomical occlusion after several days
(Clyman et al. 1998). Recent experiments have The lungs receive an increased perfusion which
shown that platelets play a crucial role by promot- may lead to decreased lung compliance, lung
ing a thrombotic sealing and supporting luminal edema, and increased risk of pulmonary hemor-
remodeling for the definite closure of the ductus rhage (Stefano et al. 1991; McCurnin et al. 2008).
(Echtler et al. 2010; Clyman and Chemtob 2010). Symptoms and signs appear as the limits of com-
In the preterm infant the closure usually takes pensatory mechanisms are reached. An association
longer. The immature ductus has an increased between the duration of the left to right shunt and
sensitivity to PGE2 and its constriction after birth the development of bronchopulmonary dysplasia
is weaker. At comparable O2 concentrations the has been demonstrated (Marshall et al. 1999),
ductus of the very immature fetus generates far although the simultaneous presence of an infection
lower tensions than those observed in the near- largely increases the risk (Gonzalez et al. 1996).
term fetus precluding definitive closure. NO syn- Unfortunately, in studies of prophylactic treatment
thase expression in the vasa vasorum of the vessel of PDA the incidence of BPD was not reduced.
media is further increased and impedes the critical This may be explained by the study design, as all
degree of contraction which is essential to elicit infants in the control group were given a back-up
69 Patent Ductus Arteriosus 1083
treatment only 1–3 days after the randomization. clearly associated with all above-mentioned mor-
Alternatively, indomethacin may promote BPD in bidities, in many situations, its causal role is not
itself by inducing moderate renal dysfunction lead- straightforward.
ing to increased lung fluid (Schmidt et al. 2006b).
Experiments in baboons confirmed that a negative
influence of a moderate left to right shunt increases 69.5 Pharmacological Treatment
clearly pulmonary to systemic flow ratio and exerts
a negative effect on pulmonary mechanics. The Because left to right shunt through the ductus is
most striking observation was an arrested alveolar associated with increased morbidity and mortality
growth and a reduced alveolar branching causing a and because prostaglandins play a major role in
significantly lower alveolar surface area and patency of the ductus, for decades cyclooxygen-
complexicity in the subjects that were exposed to ase inhibitors have been used to treat PDA (Evans
persisted shunting (McCurnin et al. 2008). 2003). Successful closure of the duct has been
reported to occur in 40–80% of treated infants.
The risk of reopening increases to above 20% in
69.4.2 Systemic Effects
the smallest infants. Because the process of inti-
mal cushion formation during closure of the duct
Other organ systems may suffer hypoperfusion,
is inhibited by blockade of prostaglandins in the
including the gut, kidneys and the brain. A persis-
most immature infants, COX inhibitors are para-
tent patency of the ductus has been shown to be a
doxically less effective in extremely preterm neo-
risk factor for increased mortality. (Brooks et al.
nates (Yokoyama et al. 2006; Ivey and Srivastava
2005; Noori et al. 2009). Disturbances in renal
2006). Until 2004, indomethacin was the only
perfusion have been shown (Romagnoli et al.
COX inhibitor approved for treatment of PDA in
2000). The decrease in mesenteric blood flow
most countries. Since late 1990s ibuprofen has
(Meyers et al. 1991; McCurnin and Clyman 2008)
been studied as an alternative for the treatment
has been associated with increased risk of gut ische-
and prophylaxis of PDA.
mia, necrotizing enterocolitis (Coombs et al. 1990),
The decision to start with pharmacological
and causing a prolonged interval to full feeds
treatment in an individual infant depends on
(Patole et al. 2007). In infants with PDA the supe-
many factors. It is obvious that if factors in favor
rior mesenteric artery flow velocities were signifi-
of a spontaneous closure of the duct are present,
cantly lower postprandially as compared to those
many clinicians will postpone pharmacological
with closed duct (McCurnin and Clyman 2008).
treatment by a few days. The appearance of
signs and symptoms in the lungs or other organ
69.4.3 Cerebral Effects systems should motivate to the initiation of more
prompt treatment.
Already in the early 1980s hypoperfusion of the Schematically, three approaches are possible.
neonatal brain as a result of ductal left to right Firstly, a conservative management with restric-
shunt was demonstrated by Doppler flow studies tion of fluids combined with optimized respiratory
(Perlman et al. 1981) and confirmed repeatedly on support including positive end expiratory pres-
many occasions with other imaging techniques sure; secondly, the pharmacological treatment
(Lundell et al. 1986; Shortland et al. 1990). with either ibuprofen or indomethacin; and finally
More recently, an impressive lowering of the surgical ligation of the ductus. Benefits and risks
regional oxygen saturation in the brain could be of each approach should be balanced, taken into
visualized in infants with a moderate ductal shunt account the specific characteristics of the infant
by use of near infrared spectroscopy (NIRS), and such as birth weight, postnatal age, antenatal
a prompt amelioration after closure of the ductus exposure to corticosteroids or NSAIDs, and the
(Lemmers et al. 2008). Although PDA has been presence of comorbidities or infection.
1084 B. Van Overmeire
69.5.1 Hemodynamic Significance 69.5.2 Prophylaxis
of the PDA-Shunt
A vast amount of studies have investigated the
Because invasive catheterization is not possible in timing of pharmacological treatment of PDA. Pro-
small preterm infants, echocardiographic assess- phylactic, early pre-symptomatic and symptom-
ment is the method of choice to evaluate ductal atic treatment strategies have been compared
patency and magnitude of PDA shunting (Clyman 1996). More than 30 studies and reviews
(Kluckow et al. 2008). The technique allows mon- addressed prophylaxis with non-steroidal anti-
itoring the effects of intervention and has been inflammatory drugs (NSAIDs) in preterm infants.
used to guide both doses and the duration of The last updated meta-analyses available demon-
pharmacological treatment (Sperandio et al. strate that both prophylactic indomethacin and
2005; Carmo et al. 2009; Waal and Kluckow ibuprofen reduce significantly the risk of develop-
2010). It is generally accepted that a left atrium- ing a symptomatic PDA and the need for ductal
to-aortic-root diameter ratio of 1.4 in the para- ligation (Ohlsson and Shah 2011; Fowlie et al.
sternal long axis view, a ductal diameter of 2010). Nineteen prophylactic indomethacin trials
1.4 mm/kg body weight, and flow reversal in were eligible in which 2,872 infants were
diastole in the descending aorta, indicate a hemo- included. The incidence of symptomatic PDA
dynamically significant left to right shunt was very significantly reduced: typical relative
(El Hajjar et al. 2005). When the mean end dia- risk (RR) 0.44; 95% confidence interval
stolic flow velocity in the left pulmonary artery (CI) 0.38–0.50. In the studies eligible for the
exceeds 0,2 m/s, there needs to be an additional ibuprofen review the ductus had closed spontane-
high index of suspicion of significant left to right ously in 58% of the infants of the control group by
shunt (Sehgal and McNamara 2009). the third day of life. Based on available data the
Because frequent echocardiographic studies prophylactic administration of ibuprofen cannot
may destabilize the infant and in some NICUs it be recommended. Indomethacin offers the addi-
is not easy to obtain a bedside cardiac ultrasound, tional effect of reducing the occurrence of intra-
biomarkers such as B-type natriuretic peptide ventricular hemorrhage (IVH) (typical RR 0.66
(BNP), NT-pro-BNP and cardiac troponin T 95% CI 0.53–0.82). No positive effect on any
(cTNT) are now more frequently used to detect other outcome parameter could be demonstrated.
“symptomatic” PDA and to guide treatment In particular, no decrease in the rates of
(Holmström et al. 2001; Choi et al. 2005; Sanjeev bronchopulmonary dysplasia, death, necrotizing
et al. 2005; Attridge et al. 2009). BNP is a enterocolitis, or white matter disease. Notwith-
vasoregulatory peptide that is released by the ven- standing the decrease of IVH, no improved
tricles in response to increases in cardiac volume neurodevelopmental outcome has been demon-
and pressure (El-Khuffash and Molloy 2008). strated (Fowlie et al. 2010; Schmidt et al. 2001).
BNP levels did correlate very well with the mag-
nitude of the left to right shunt as examined by
echocardiography and reflected the moment of 69.5.3 Treatment
closure. Nevertheless, the high variability in the
BNP measurements preclude their use as monitor- Indomethacin and ibuprofen have also been
ing for changes in shunt magnitude (Chen et al. extensively studied for the treatment of PDA.
2010). The combination of measurement of bio- Ibuprofen disturbs significantly less regional cir-
markers as a screening tool in those centers where culations, which may offer less dysfunction of
echocardiography is not readily available, a high kidney, intestines, and brain (Overmeire et al.
clinical suspicion and a comprehensive cardiac 1997; Patel et al. 2000; Pezzati et al. 1999).
ultrasound and Doppler assessment, is probably Urine production was less affected in preterm
an optimal approach to guide timely treatment of infants (n = 148) that were treated on day 2–3 of
PDA (Chiruvolu et al. 2009). life with ibuprofen than in those receiving
69 Patent Ductus Arteriosus 1085
indomethacin (Overmeire et al. 2000). This obser- unexpected hypoxemia caused a lot of concern.
vation resulted in ibuprofen being introduced for Acute pulmonary hypertension developed in three
clinical use in preterm infants. Necrotizing entero- preterm infants immediately after the infusion of
colitis was diagnosed twice as often in the indo- ibuprofen THAM-buffered solution (Gournay et al.
methacin group (8 versus 4; p = 0,37) (Overmeire 2002). A clear explanation for this phenomenon is
et al. 2000). Cerebral oxygen availability has lacking. One infant of 169 treated with ibuprofen-
repeatedly been shown to be less affected with lysine presented the same adverse effect, but no
ibuprofen (Patel et al. 2000; Mosca et al. 1997). causal relationship could be found between PPHN
Systematic reviews of the trials that evaluated and ibuprofen-lysine in another 229 treated infants
indomethacin or ibuprofen for early treatment of (Overmeire et al. 2004a; Mosca et al. 2002; Aranda
a non-symptomatic or symptomatic PDA con- et al. 2009). Additional studies could not confirm a
firmed a comparable efficacy of both drugs clear association between the use of ibuprofen-
(Thomas et al. 2005). The most recently updated lysine and severe hypoxemia. Although the trial
systematic meta-analysis included 20 studies that first reported this serious adverse effect was
(Ohlsson et al. 2010). There was no statistically halted by the national authorities (Gournay et al.
significant difference between indomethacin and 2004), the ibuprofen formulation under investiga-
ibuprofen efficacy or in failure to close the ductus tion became registered for clinical use in Europe in
in 19 comparative studies including 956 infants 2004. Ibuprofen-lysine was registered for treatment
with a typical relative risk (RR) of 0.94 (95% CI and prophylaxis of PDA in preterm infants in the
0.76–1.17). Infants receiving ibuprofen treatment US in 2006. Ibuprofen is insoluble in water and
have less evidence of transient renal failure and more than 90% bound to serum albumine (Aranda
less risk of developing necrotizing enterocolitis: et al. 1997). An in vitro model demonstrated that at
15 studies including 865 infants; typical RR 0.68 higher ibuprofen concentrations (750 μmol/L or
(95% CI 0.47–0.99). No other differences were 150 mg/L) in infant serum containing bilirubin,
noted, e.g., mortality, reopening of the ductus, the fraction of unbound bilirubin increases fourfold
need for ligation, duration of ventilatory support, (Ahlfors 2004). This displacement of bilirubin from
duration of supplementary oxygen and develop- albumin binding sites may be clinically relevant in
ment of BPD. jaundiced preterm infants, as high levels of free
The conventional doses of indomethacin and bilirubin are associated with brain damage, hearing
ibuprofen are different, based on their respective loss and kernicterus (Ahlfors 2004; Ahlfors et al.
pharmacokinetic parameters. Adapted dosing 2006). When ibuprofen is administered in the
schemes have been tried to augment efficacy/ recommended dosages of 10, 5 and 5 mg/kg at
side effect ratio of indomethacin, however, with 24 hourly intervals to neonatal infants, ibuprofen
variable success (Herrera et al. 2007) (see also serum peak levels of 20–40 mg/L are reached
section “NSAID Dosing Schemes”). (Overmeire et al. 2001b). According to the in vitro
model, an increase of 10% of the free fraction of
bilirubin can be expected at such ibuprofen levels.
69.5.4 Risks of Treatment Three smaller studies exploring the rise of unbound
bilirubin were rather reassuring (Overmeire et al.
Indomethacin and ibuprofen are not devoid of 2004b; Amin and Miravalle 2011; Diot et al. 2010).
adverse drug reactions. Due to their vasoconstric- Additional risks of NSAID use for closing PDA
tive effects, both drugs affect the perfusion of var- in preterm infants are the occurrence of an isolated
ious organ systems to a certain extent, e.g., the gut, ileal perforation, particularly when there is concom-
kidney and brains. Although ibuprofen initially itant use of steroids (Watterberg et al. 2004;
seemed to have a more favorable safety profile Paquette et al. 2006). Although predominantly
with less disturbance of regional circulations (Over- reported for indomethacin, the risk may be similar
meire et al. 1997, 2000; Patel et al. 2000; Pezzati for ibuprofen as its mechanism is related to micro-
et al. 1999; Mosca et al. 1997), the occurrence of vascular changes and not to disturbances of the
1086 B. Van Overmeire
regional perfusion of the gut (Tatli et al. 2004). improvement for BPD, IVH or mortality rates has
Increased bleeding tendency has been described been obtained. A lower proportion of infants with
after indomethacin use (Corazza et al. 1984), but diminished urine output was observed (typical RR
except for some increased occult blood appearing in 0.27; 95% CI 0.13–0.6) but at the expense of an
stools this does not seem to cause clinically relevant increased risk of NEC (RR 1.87; 95% CI
problems. Some neonatal intensive care units are 1.07–3.27) (Herrera et al. 2007).
reluctant to continue or introduce enteral feedings The continuous infusion of indomethacin has
during NSAID treatment. Eighty percent of the been advocated to avoid disturbances in cerebral
infants that participated in the European trials of perfusion (Christmann et al. 2002), but was
prophylactic and early therapeutic NSAID for PDA reported later to be less effective in extremely low
were receiving trophic feedings without any appar- birthweight infants (Vries et al. 2005). Interest-
ent untoward effect (Overmeire et al. 2000, 2001a, ingly, by applying a stepwise increasing dosage
2004a; Gournay et al. 2004). The most recent meta- of indomethacin based on echographic evaluation,
analysis showed that necrotizing enterocolitis is the group of Sperandio et al (Sperandio et al. 2005)
less likely to occur post ibuprofen than post indo- obtained ductal closing rates up to 80% without
methacin treatment (Ohlsson et al. 2010). apparently increasing side effects. After an initial
standard treatment, subsequent doses were given if
the ductus persisted as assessed by echocardio-
69.5.5 NSAID Dosing Schemes Doppler. Cumulative indomethacin doses were as
high as 6 mg/kg (Sperandio et al. 2005). As the
The pharmacokinetic parameters vary widely in efficacy of ibuprofen at extremely low gestational
preterm infants due to physiological changes that ages is comparably reduced to indomethacin
occur after birth. Studies have shown large pro- (Su et al. 2008), the administration of additional
longed half-life for indomethacin (11–36 h) and doses has been investigated. In a group of
reduced clearance rate in the preterm infant, both 25 VLBW infants that received a second course
of which reveal marked interindividual variations of three doses of ibuprofen the additional closure
(Thalji et al. 1980; Shaffer et al. 2002). The vol- was 48% (Lago et al. 2002). Su et al (Su et al. 2008)
ume of distribution also varies and is influenced obtained an additional closure rate of 50% by
by the patency of the ductus (Gal et al. 1991). administrating up to six doses of ibuprofen. Similar
Accordingly, optimal therapeutic dosing is diffi- efficacy was demonstrated after the first and second
cult to establish (Guimarães et al. 2009). The most course in a study population of 160 infants with
widely used doses for indomethacin are three birthweight below 1000 g with a cumulative clo-
times 0.1–0.25 mg/kg administered every sure rate of 65% (Richards et al. 2009). In order to
12–24 h. The lower dose with longer interval is optimize the efficacy of ibuprofen, an adapted dos-
recommended when treatment is initiated on the ing scheme based on postnatal age has been pro-
first day. The registered dosing scheme for ibu- posed (Hirt et al. 2008). Further studies are
profen consists of a first dose of 10 mg/kg warranted to investigate whether an individualized
followed by a second and third dose of 5 mg/kg ibuprofen dosing scheme would result in an
at 24 hourly intervals. increased benefit/risk ratio.
In order to improve efficacy/side effect ratio of
NSAID during treatment for PDA, a variety of
adapted dosing schemes have been studied. As it 69.6 Surgical Treatment
has been observed that PGE2 production resurges
within 5 days of indomethacin treatment (Seyberth Since the introduction of indomethacin in the
1983), a prolonged course consisting of additional 1980s, surgical ligation has been reserved for
indomethacin doses has been tried (Herrera et al. those infants for whom treatment with NSAIDs
2007). Unfortunately, no significant benefit for clo- fails or is contraindicated (Gersony et al. 1983).
sure rates, not less reopenings or ligations, and no Beyond the third to fourth week of life, efficacy of
69 Patent Ductus Arteriosus 1087
COX-inhibitors rapidly declines as the patency of closure of the ductus does not seem advisable
the ductus is less regulated by prostaglandins. (Malviya et al. 2008).
Ligation then becomes an option, however it
remains nonetheless associated with a number of
complications such as pneumothorax, bleeding, 69.7 Conclusions
IVH, chylothorax as a result of thoracic duct
injury, vocal cord paralysis, wound infection, PDA continues to be a frequent complication of
hypotension, and left ventricular dysfunction in extremely premature birth, despite the more gen-
the days after the procedure (Little et al. 2003; eralized use of antenatal steroids, postnatal sur-
Sørensen et al. 2010; McNamara et al. 2010; factant administration and the improvement of
Seghaye et al. 1997; Moin et al. 2003). The mor- non-invasive ventilatory strategies. Many perina-
bidity rate ranges from 1 to 16% and mortality tal factors influence the development of a symp-
from 0% to 10%. In a large retrospective study, tomatic PDA. A large left to right shunt may cause
surgical ligation and indomethacin treatment for profound hemodynamic disturbances to local
significant PDA were associated with a compara- organs and the brain. From the NSAIDs studied,
ble risk for NEC or NEC-related gastrointestinal ibuprofen actually seems to be the preferred drug
complications (O’Donovan et al. 2003) but for pharmacological treatment because of its more
mechanics of breathing significantly improved favorable benefit/risk ratio. The therapeutic
after ligation (Szymankiewicz et al. 2004). How- response of the most immature infants, however,
ever, there are no recent controlled comparisons is limited for all investigated COX-inhibitors. Sur-
between pharmacological, conservative and sur- gical ligation of the duct should be considered as a
gical methods of PDA closure. Only one trial in backup treatment, because it carries the risk of
1983 enrolling 154 infants, compared initial sur- serious complications and destabilization of the
gical ligation versus medical treatment (Gersony infant. Unfortunately, in spite of many studies,
et al. 1983). No statistically significant difference investigations and trials, there is no generally
was found between the groups for mortality, accepted and conclusive evidence to decide at
chronic lung disease, NEC or IVH. An increase which moment and to which infants the treatment
in pneumothorax (RR = 2.68; CI 1.45–4.03) and of the ductus should be pursued in order to
retinopathy of prematurity (RR = 3.80; CI improve their long-term outcome.
1.12–12.93) was observed in the ligated group.
The use of prophylactic ligation cannot be
recommended based on the limited current evi-
dence (Mosalli and Alfaleh 2008). Additional data
References
from the TIPP study indicated that ligation of the Abbasi S, Hirsch D, Davis J et al (2000) Effect of single
ductus was associated with a higher risk of BPD, versus multiple courses of antenatal corticosteroids on
severe retinopathy of prematurity and neurosen- maternal and neonatal outcome. Am J Obstet Gynecol
sory impairment (Kabra et al. 2007). A retrospec- 182:1243–1249
Ahlfors CE (2004) Effect of ibuprofen on bilirubin-
tive analysis of 446 infants showed that ligation albumin binding. J Pediatr 144:386–388
was significantly associated with chronic lung Ahlfors CE, Marshall GD, Wolcott DK et al (2006) Mea-
disease (Chorne et al. 2007b). In a group of surement of unbound bilirubin by the peroxidase test
20 infants, a further decrease of oxygenation of using zone fluidics. Clin Chim Acta 365:78–85
Amin SB, Miravalle N (2011) Effect of ibuprofen on
the brain was observed by use of near infra red bilirubin-albumin binding affinity in premature infants.
spectroscopy (Lemmers et al. 2010). No increased J Perinat Med 39:55–58
brain injury, however, was noted in a preterm Andriessen P, Struis NC, Niemarkt H et al (2009) Furose-
baboon model (Loeliger et al. 2009). Because of mide in preterm infants treated with indomethacin for
patent ductus arteriosus. Acta Paediatr 98:797–803
the associated risks of ductal ligation in preterm Aranda JV, Varvarigou A, Beharry K et al (1997) Pharmaco-
infants in recent papers and the absence of recent kinetics and protein binding of intravenous ibuprofen in
comparative clinical trials, the primary surgical the premature newborn infant. Acta Paediatr 86:289–293
1088 B. Van Overmeire
Aranda JV, Clyman R, Cox B et al (2009) A randomized, Clyman R, Chemtob S (2010) Vessel remodeling in the
doubleblind, placebo-controlled trial on intravenous newborn: platelets fill the gap. Nat Med 16:33–35
ibuprofen l-lysine for the early closure of non- Clyman RI, Roman C (2007) The effects of caffeine on the
symptomatic patent ductus arteriosus within 72 hours preterm sheep ductus arteriosus. Pediatr Res
of birth in extremely low-birth-weight infants. Am J 62:167–169
Perinatol 26:235–245 Clyman RI, Waleh N, Black SM et al (1998) Regulation of
Askie LM, Ballard RA, Cutter G et al (2010) Inhaled nitric ductus arteriosus patency by nitric oxide in fetal lambs:
oxide in preterm infants: a systematic review and indi- the role of gestation oxygen tension and vasa vasorum.
vidual patient data meta-analysis. BMC Pediatr 10:15 Pediatr Res 43:633–644
Attridge JT, Kaufman D, Lim DS (2009) B-type natriuretic Clyman RI, Chen YQ, Chemtob S et al (2001) In utero
peptide to guide therapy of patent ductus arteriosus. remodeling of the fetal lamb ductus arteriosus: the role
Arch Dis Child Fetal Neonatal Ed 94:F178–F182 of antenatal indomethacin and avascular zone thickness
Bancalari E, Claure N, Gonzalez A (2005) Patent ductus on vasa vasorum proliferation, neointima formation,
arteriosus and respiratory outcome in premature and cell death. Circulation 103:1806–1812
infants. Biol Neonate 88:192–201 College of Physicians for the Mother and Newborn,
Bell EF, Acarregui MJ (2008) Restricted versus liberal water Section Neonatology. Federal Public Health Services,
intake for preventing morbidity and mortality in preterm Belgium
infants. Cochrane Database Syst Rev (1):CD000503 Coombs RC, Morgan ME, Durbin GM et al (1990) Gut
Brion LP, Soll RF (2008) Diuretics for respiratory distress blood flow velocities in the newborn: effects of patent
syndrome in preterm infants. Cochrane Database Syst ductus arteriosus and parenteral indomethacin. Arch
Rev (1):CD001454 Dis Child 65:1067–1071
Brooks JM, Travadi JN, Patole SK et al (2005) Is surgical Cooper-Peel C, Brodersen R, Robertson A (1996) Does
ligation of patent ductus arteriosus necessary? The ibuprofen affect bilirubin-albumin binding in newborn
Western Australian experience of conservative man- infant serum? Pharmacol Toxicol 79:297–299
agement. Arch Dis Child 90:F235–F239 Corazza MS, Davis RF, Merrit TA et al (1984) Prolonged
Carmo KB, Evans N, Paradisis M (2009) Duration of bleeding time in preterm infants receiving indometh-
indomethacin treatment of the preterm patent ductus acin for patent ductus arteriosus. J Pediatr 105:
arteriosus as directed by echocardiography. J Pediatr 292–296
155:819–822 de Vries NK, Jagroep FK, Jaarsma AS et al (2005) Con-
Chandrasekharan NV, Dai H, Roos KL et al (2002) COX-3, tinuous indomethacin infusion may be less effective
a cyclooxygenase-1 variant inhibited by acetamino- than bolus infusions for ductal closure in very low
phen and other analgesic/antipyretic drugs: cloning, birth weight infants. Am J Perinatol 2:71–75
structure, and expression. Proc Natl Acad Sci de Waal K, Kluckow M (2010) Functional echocardiogra-
99:13926–13931 phy; from physiology to treatment. Early Hum Dev
Chen S, Tacy T, Clyman R (2010) How useful are B-type 86:149–154
natriuretic peptide measurements for monitoring del Moral T, Gonzalez-Quintero VH, Claure N et al (2007)
changes in patent ductus arteriosus shunt magnitude? Antenatal exposure to magnesium sulfate and the inci-
J Perinatol 30:780–785 dence of patent ductus arteriosus in extremely low birth
Chiruvolu A, Punjwani P, Ramaciotti C (2009) Clinical and weight infants. J Perinatol 27:154–157
echocardiographic diagnosis of patent ductus arteriosus Diot C, Kibleur Y, Desfrere L (2010) Effect of ibuprofen on
in premature neonates. Early Hum Dev 85:147–149 bilirubin-albumin binding in vitro at concentrations
Choi BM, Lee KH, Eun BL et al (2005) Utility of rapid observed during treatment of patent ductus arteriosus.
B-type natriuretic peptide assay for diagnosis of symp- Early Hum Dev 86:315–317
tomatic patent ductus arteriosus in preterm infants. Doyle LW, Ehrenkranz RA, Halliday HL (2010) dexameth-
Pediatrics 115:e255–e261 asone treatment in the first week of life for preventing
Chorne N, Jegatheesan P, Lin E et al (2007a) Risk factors bronchopulmonary dysplasia in preterm infants: a sys-
for persistent ductus arteriosus patency during indo- tematic review. Neonatology 98:217–224
methacin treatment. J Pediatr 151:629–634 Echtler K, Stark K, Lorenz M et al (2010) Platelets con-
Chorne N, Leonard C, Piecuch R, Clyman RI (2007b) tribute to postnatal occlusion of the ductus arteriosus.
Patent ductus arteriosus and its treatment as risk factors Nat Med 16:75–82
for neonatal and neurodevelopmental morbidity. Pedi- El Hajjar M, Vaksmann G, Rakza T et al (2005) Severity
atrics 119:1165–1174 of the ductal shunt: a comparison of different markers.
Christmann V, Liem KD, Semmekrot BA, van de Bor M Arch Dis Child Fetal Neonatal Ed 90:F419–F422
(2002) Changes in cerebral, renal and mesenteric blood El-Khuffash AF, Molloy EJ (2008) Influence of a patent
flow velocity during continuous and bolus infusion of ductus arteriosus on cardiac troponin t levels in preterm
indomethacin. Acta Paediatr 91:440–446 infants. J Pediatr 153:350–353
Clyman RI (1996) Recommendations for the postnatal use Evans N (2003) Current controversies in the diagnosis and
of indomethacin: an analysis of four separate treatment treatment of patent ductus arteriosus in preterm infants.
strategies. J Pediatr 128:601–607 Adv Neonatal Care 3:168–177
69 Patent Ductus Arteriosus 1089
Fanaroff AA, Stoll BJ, Wright LL et al (2007) Trends in infants with intrauterine growth retardation. J Perinatol
neonatal morbidity and mortality for very low birthweight 14:411–416
infants. Am J Obstet Gynecol 196(147):e1–e8 Ivey KN, Srivastava D (2006) The paradoxical patent
Fowlie PW, Davis PG, McGuire W (2010) Prophylactic ductus arteriosus. J Clin Invest 116:2863–2865
intravenous indomethacin for preventing mortality and Kabra NS, Schmidt B, Roberts RS et al (2007) Neurosen-
morbidity in preterm infants. Cochrane Database Syst sory impairment after surgical closure of patent ductus
Rev (7):CD000174 arteriosus in extremely low birth weight infants: results
Gal P, Ransom JL, Weaver RL et al (1991) Indomethacin from the Trial of Indomethacin Prophylaxis in Pre-
pharmacokinetics in neonates: the value of volume of terms. J Pediatr 150:229–234
distribution as a marker of permanent patent ductus Kajino H, Chen YQ, Seidner SR et al (2001) Factors that
arteriosus closure. Ther Drug Monit 13:42–45 increase the contractile tone of the ductus arteriosus
Gersony WM, Peckham GJ, Ellison RC et al (1983) Effects also regulate its anatomic remodeling. Am J Phys
of indomethacin in premature infants with patent Regul Integr Comp Phys 281:R291–R301
ductus arteriosus: results of a national collaborative Katayama Y, Minami H, Enomoto M et al (2010) Antenatal
study. J Pediatr 102:895–906 magnesium sulfate and the postnatal response of the
Gonzalez A, Sosenko IR, Chandar J et al (1996) Influence ductus arteriosus to indomethacin in extremely preterm
of infection on patent ductus arteriosus and chronic neonates. J Perinatol 31:21–24
lung disease in premature infants weighing 1000 Kluckow M, Seri I, Evans N (2008) Echocardiography and
grams or less. J Pediatr 128:470–478 the neonatologist. Pediatr Cardiol 29:1043–1047
Gournay V, Savagner C, Thiriez G et al (2002) Pulmonary Koch J, Hensley G, Roy L et al (2006) Prevalence of
hypertension after ibuprofen prophylaxis in very pre- spontaneous closure of the ductus arteriosus in neo-
term infants. Lancet 359:1486–1488 nates at a birth weight of 1000 grams or less. Pediatrics
Gournay V, Roze JC, Kuster A et al (2004) Prophylactic 117:1113–1121
ibuprofen versus placebo in very premature infants: a Lago P, Bettiol T, Salvadori S et al (2002) Safety
randomised, doubleblind, placebo-controlled trial. and efficacy of ibuprofen versus indomethacin in
Lancet 364:1939–1944 preterm infants treated for patent ductus arteriosus:
Green TP, Thompson TR, Johnson DE, Lock JE (1983) a randomised controlled trial. Eur J Pediatr
Furosemide promotes patent ductus arteriosus in pre- 161:202–207
mature infants with the respiratory-distress syndrome. Lee BS, Byun SY, Chung ML et al (2009) Effect of furo-
N Engl J Med 308:743–748 semide on ductal closure and renal function in
Guimarães H, Rocha G, Tomé T et al (2009) Non-steroid indomethacin-treated preterm infants during the early
anti-inflammatory drugs in the treatment of patent neonatal period. Acta Paediatr 98:797–803
ductus arteriosus in European newborns. J Matern Lemmers PMA, Toet MC, van Bel F (2008) Impact of
Fetal Neonatal Med 22(Suppl 3):77–80 patent ductus arteriosus and subsequent therapy with
Halliday HL, Patterson CC, Halahakoon CW, Behalf of indomethacin on cerebral oxygenation in preterm
the European Multicenter Steroid Study Group (2001) infants. Pediatrics 121:142–147
A multicenter, randomized open study of early cortico- Lemmers PM, Molenschot MC, Evens J et al (2010) Is
steroid treatment (OSECT) in preterm infants with cerebral oxygen supply compromised in preterm
respiratory illness: comparison of early and late treat- infants undergoing surgical closure for patent ductus
ment and of dexamethasone and inhaled budesonide. arteriosus? Arch Dis Child Fetal Neonatal Ed 95:
Pediatrics 107:232–240 F429–F434
Hammerman C, Glaser J, Kaplan M et al (1998) Indometh- Little DC, Pratt TC, Blalock SE et al (2003) Patent ductus
acin tocolysis increases postnatal patent ductus arteriosus in micropreemies and full-term infants: the
arteriosus severity. Pediatrics 102:E56 relative merits of surgical ligation versus indomethacin
Herrera C, Holberton J, Davis P (2007) Prolonged versus treatment. J Pediatr Surg 38:492–496
short course of indomethacin for the treatment of patent Loeliger M, Inder TE, Dalitz PA et al (2009) Develop-
ductus arteriosus in preterm infants. Cochrane Data- mental and neuropathological consequences of ductal
base Syst Rev (2):CD003480 ligation in the preterm baboon. Pediatr Res
Hirt D, Van Overmeire B, Treluyer JM et al (2008) An 65:209–214
optimized ibuprofen dosing scheme for preterm neo- Lundell BP, Sonesson SE, Cotton RB (1986) Ductus clo-
nates with patent ductus arteriosus, based on a popula- sure in preterm infants. Effects on cerebral hemody-
tion pharmacokinetic and pharmacodynamics study. Br namics. Acta Paediatr Scand Suppl 329:140–147
J Clin Pharmacol 65:629–636 Malviya M, Ohlsson A, Shah S (2008) Surgical versus
Holmström H, Hall C, Thaulow E (2001) Plasma levels of medical treatment with cyclooxygenase inhibitors for
natriuretic peptides and hemodynamic assessment of symptomatic patent ductus arteriosus in preterm
patent ductus arteriosus in preterm infants. Acta Paediatr infants. Cochrane Database Syst Rev (1): CD003951
90:184–191 Marshall DD, Kotelchuck M, Young TE et al (1999) Risk
Ibara S, Tokunaga M, Ikenoue T et al (1994) Histologic factors for chronic lung disease in the surfactant era: a
observation of the ductus arteriosus in premature North Carolina population-based study of very low
1090 B. Van Overmeire
birth weight infants. North Carolina Neonatologists Osborn DA, Hunt RW (2007) Prophylactic postnatal thy-
Association. Pediatrics 104:1345–1350 roid hormones for prevention of morbidity and mortal-
McCurnin D, Clyman RI (2008) Effects of a patent ductus ity in preterm infants. Cochrane Database Syst Rev (1):
arteriosus on postprandial mesenteric perfusion in pre- CD005948
mature baboons. Pediatrics 122:e1262–e1267 Paquette L, Friedlich P, Ramanathan R, Seri I (2006) Con-
McCurnin D, Seidner S, Chang LY et al (2008) Ibuprofen- current use of indomethacin and dexamethasone
induced patent ductus arteriosus closure: physiologic, increases the risk of spontaneous intestinal perforation
histologic, and biochemical effects on the premature in very low birth weight neonates. J Perinatol 26:486–492
lung. Pediatrics 121:945–956 Patel J, Roberts I, Azzopardi D et al (2000) Randomized
McNamara PJ, Stewart L, Shivananda SP et al (2010) doubleblind controlled trial comparing the effects of
Patent ductus arteriosus ligation is associated with ibuprofen with indomethacin on cerebral hemodynam-
impaired left ventricular systolic performance in pre- ics in preterm infants with patent ductus arteriosus.
mature infants weighing less than 1000 g. J Thorac Pediatr Res 47:36–42
Cardiovasc Surg 140:150–157 Patole SK, Kumaran V, Travadi JN et al (2007) Does
Mercier JC, Hummler H, Durrmeyer X et al (2010) Inhaled patent ductus arteriosus affect feed tolerance in pre-
nitric oxide for the prevention of bronchopulmonary term neonates? Arch Dis Child Fetal Neonatal Ed 92:
dysplasia in premature babies (EUNO): a randomised F53–F55
controlled trial. Lancet 376:346–354 Perlman JM, Hill A, Volpe JJ (1981) The effect of patent
Meyers RL, Alpan G, Lin E, Clyman RI (1991) Patent ductus arteriosus on flow velocity in the anterior cere-
ductus arteriosus, indomethacin, and intestinal disten- bral arteries: ductal steal in the premature newborn
sion: effects on intestinal blood flow and oxygen con- infant. J Pediatr 99:767–771
sumption. Pediatr Res 29:569–574 Pezzati M, Vangi V, Biagiotti R et al (1999) Effects of
Moin F, Kennedy KA, Moya FR (2003) Risk factors pre- indomethacin and ibuprofen on mesenteric and renal
dicting vasopressor use after patent ductus arteriosus blood flow in preterm infants with patent ductus
ligation. Am J Perinatol 20:313–320 arteriosus. J Pediatr 135:733–738
Mosalli R, Alfaleh K (2008) Prophylactic surgical ligation Rakza T, Magnenant E, Klosowski S et al (2007) Early
of patent ductus arteriosus for prevention of mortality hemodynamic consequences of patent ductus arteriosus
and morbidity in extremely low birth weight infants. in preterm infants with intrauterine growth restriction. J
Cochrane Database Syst Rev (1):CD006181 Pediatr 151:624–628
Mosca F, Bray M, Lattanzio M et al (1997) Comparative Reese J, Waleh N, Poole SD et al (2009) Chronic in utero
evaluation of the effects of indomethacin and ibuprofen cyclooxygenase inhibition alters PGE2-regulated
on cerebral perfusion and oxygenation in preterm infants ductus arteriosus contractile pathways and prevents
with patent ductus arteriosus. J Pediatr 131:549–554 postnatal closure. Pediatr Res 66:155–161
Mosca F, Bray M, Stucchi I, Fumagalli M (2002) Pulmo- Reese J, Veldman A, Shah L et al (2010) Inadvertent
nary hypertension after ibuprofen prophylaxis in very relaxation of the ductus arteriosus by pharmacologic
preterm infants. Lancet 360:1023–1024 agents that are commonly used in the neonatal period.
Nemerofsky SL, Parravicini E, Bateman D et al (2008) The Semin Perinatol 34:222–230
ductus arteriosus rarely requires treatment in infants Richards J, Johnson A, Fox G, Campbell M (2009) A
1000 grams. Am J Perinatol 25:661–666 second course of ibuprofen is effective in the closure
Noori S, McCoy M, Friedlich P et al (2009) Failure of a clinically significant PDA in ELBW infants. Pedi-
of ductus arteriosus closure is associated with atrics 124:e287–e292
increased mortality in preterm infants. Pediatrics Robel-Tillig E, Knüpfer M, Vogtmann C (2003) Cardiac
123:e138–e144 adaptation in small for gestational age neonates after
Norton ME, Merrill J, Cooper BA et al (1993) Neonatal prenatal hemodynamic disturbances. Early Hum Dev
complications after the administration of indomethacin 72:123–129
for preterm labor. N Engl J Med 329:1602–1607 Romagnoli C, De Carolis MP, Papacci P et al (2000)
O’Donovan DJ, Baetiong A, Adams K et al (2003) Necro- Effects of prophylactic ibuprofen on cerebral and
tizing enterocolitis and gastrointestinal complications renal hemodynamics in very preterm neonates. Clin
after indomethacin therapy and surgical ligation in pre- Pharmacol Ther 67:676–683
mature infants with patent ductus arteriosus. J Perinatol Rouse DJ, Hirtz DG, Thom E et al (2008) A randomized,
23:286–290 controlled trial of magnesium sulfate for the prevention
Ohlsson A, Shah S (2011) Ibuprofen for the prevention of of cerebral palsy. N Engl J Med 359:895–905
patent ductus arteriosus in preterm and/or low birth Sanjeev S, Pettersen M, Lua J et al (2005) Role of plasma
weight infants. Cochrane Database Syst Rev (7): B-type natriuretic peptide in screening for hemody-
CD004213 namically significant patent ductus arteriosus in pre-
Ohlsson A, Walia R, Shah S (2010) Ibuprofen for the term neonates. J Perinatol 25:709–713
treatment of patent ductus arteriosus in preterm and/or Schmidt B, Davis P, Moddemann D et al (2001) Long-term
low birth weight infants. Cochrane Database Syst Rev effects of indomethacin prophylaxis in extremely-low-
(4):CD003481 birth-weight infants. N Engl J Med 344:1966–1972
69 Patent Ductus Arteriosus 1091
Schmidt B, Roberts RS, Davis P et al (2006a) Caffeine treatment of patent ductus arteriosus in extremely pre-
therapy for apnea of prematurity. N Engl J Med mature infants: a randomized controlled trial. Arch Dis
354:2112–2121 Child 93:F94–F99
Schmidt B, Roberts RS, Fanaroff A et al (2006b) Indo- Szymankiewicz M, Hodgman JE, Siassi B, Gadzinowski J
methacin prophylaxis, patent ductus arteriosus, and the (2004) Mechanics of breathing after surgical ligation of
risk of bronchopulmonary dysplasia: further analyses patent ductus arteriosus in newborns with respiratory
from the Trial of Indomethacin Prophylaxis in Preterms distress syndrome. Biol Neonate 85:32–36
(TIPP). J Pediatr 148:713–714 Tatli MM, Kumral A, Duman N et al (2004) Spontaneous
Schneider DJ, Moore JW (2006) Patent ductus arteriosus. intestinal perforation after oral ibuprofen treatment of
Circulation 114:1873–1882 patent ductus arteriosus in two very-low-birthweight
Schreiber MD, Gin-Mestan K, Marks JD et al (2003) infants. Acta Paediatr 93:999–1001
Inhaled nitric oxide in premature infants with the respi- Thalji AA, Carr I, Yeh TF et al (1980) Pharmacokinetics of
ratory distress syndrome. N Engl J Med 349:2099–2107 intravenously administered indomethacin in premature
Seghaye MC, Grabitz R, Alzen G et al (1997) Thoracic infants. J Pediatr 97:995–1000
sequelae after surgical closure of the patent ductus Thomas RL, Parker GC, Van Overmeire B, Aranda JV
arteriosus in premature infants. Acta Paediatr 86:213–216 (2005) A meta-analysis of ibuprofen versus indometh-
Sehgal A, McNamara PJ (2009) Does echocardiography acin for closure of patent ductus arteriosus. Eur J
facilitate determination of hemodynamic significance Pediatr 164:135–140
attributable to the ductus arteriosus? Eur J Pediatr Toyoshima K, Momma K, Nakanishi T (2010) In vivo
168:907–914 dilatation of the ductus arteriosus induced by furose-
Seidner SR, Chen YQ, Oprysko PR et al (2001) Combined mide in the rat. Pediatr Res 67:173–176
prostaglandin and nitric oxide inhibition produces ana- Travadi J, Simmer K, Ramsay J et al (2006) Patent ductus
tomic remodeling and closure of the ductus arteriosus arteriosus in extremely preterm infants receiving pho-
in the premature newborn baboon. Pediatr Res totherapy: does shielding the chest make a difference?
50:365–373 A randomized, controlled trial. Acta Paediatr 95:
Seyberth HW (1983) Effect of prolonged indomethacin 1418–1423
therapy on renal function and selected vasoactive hor- Van Overmeire B, Follens I, Hartmann S et al (1997)
mones in VLBW infants with symptomatic patent Treatment of patent ductus arteriosus with ibuprofen.
ductus arteriosus. J Pediatr 103:979–984 Arch Dis Child 76:F179–F184
Shaffer CL, Gal P, Ransom JL et al (2002) Effect of age and Van Overmeire B, Smets K, Lecoutere D et al (2000) A
birth weight on indomethacin pharmacodynamics in comparison of ibuprofen and indomethacin for closure
neonates treated for patent ductus arteriosus. Crit Care of patent ductus arteriosus. N Engl J Med 343:674–681
Med 30:343–348 Van Overmeire B, Van de Broek H, Van Laer P et al
Shortland DB, Gibson NA, Levene MI et al (1990) Patent (2001a) Early versus late indomethacin treatment for
ductus arteriosus and cerebral circulation in preterm patent ductus arteriosus in premature infants with respi-
infants. Dev Med Child Neurol 32:386–393 ratory distress syndrome. J Pediatr 138:205–211
Smith GC, Wu WX, Nijland MJ et al (2001) Effect of Van Overmeire B, Touw D, Schepens PJC et al (2001b)
gestational age, corticosteroids, and birth on expression Ibuprofen pharmacokinetics in preterm infants with pat-
of prostanoid EP receptor genes in lamb and baboon ent ductus arteriosus. Clin Pharmacol Ther 70:336–343
ductus arteriosus. J Cardiovasc Pharmacol 37:697–704 Van Overmeire B, Allegaert K, Casaer A et al (2004a)
Soraisham AS, Dalgleish S, Singhal N (2010) Antenatal Prophylactic ibuprofen in premature infants: a multi-
indomethacin tocolysis is associated with an increased centre, randomised, doubleblind, placebo-controlled
need for surgical ligation of patent ductus arteriosus in trial. Lancet 364:1945–1954
preterm infants. J Obstet Gynaecol Can 32:435–442 Van Overmeire B, Vanhagendoren S, Schepens PJ, Ahlfors
Sørensen CM, Steensberg JN, Greisen G (2010) Surgical CE (2004b) The influence of ibuprofen-lysine on
ligation of patent ductus arteriosus in premature infants. unbound bilirubin plasma levels in preterm neonates.
Dan Med Bull 57:A4160 Pediatr Res 55:474A
Sperandio M, Beedgen B, Feneberg R et al (2005) Effec- Watterberg KL, Scott SM, Backstrom C et al (2000) links
tiveness and side effects of an escalating, stepwise between early adrenal function and respiratory out-
approach to indomethacin treatment for symptomatic come in preterm infants: airway inflammation and pat-
patent ductus arteriosus in premature infants below ent ductus arteriosus. Pediatrics 105:320–324
33 weeks of gestation. Pediatrics 116:1361–1366 Watterberg KL, Gerdes JS, Cole CH et al (2004) Prophy-
Stefano JL, Abbasi S, Pearlman SA et al (1991) Closure of laxis of early adrenal insufficiency to prevent
the ductus arteriosus with indomethacin in ventilated bronchopulmonary dysplasia: a multicenter trial. Pedi-
neonates with respiratory distress syndrome; effects on atrics 114:1649–1657
pulmonary compliance and ventilation. Am Rev Respir Yokoyama U, Minamisawa S, Quan H et al (2006) Chronic
Dis 143:236–239 activation of the prostaglandin receptor EP4 promotes
Su BH, Lin HC, Chiun HY et al (2008) Comparison of hyaluronan-mediated neointimal formation in the
ibuprofen and indomethacin for early-targeted ductus arteriosus. J Clin Invest 116:3026–3034
Cardiac Emergencies in the Newborn
70
Liam Mahoney, Hector Rojas-Anaya, and Heike Rabe
Contents
70.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094
70.2 Shock/Circulatory Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094
70.2.1 Cardiac Tamponade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094
70.2.2 Tension Pneumothorax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1096
70.2.3 Duct-Dependent Systemic Circulation Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1097
70.3 Cyanosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099
70.3.1 Duct-Dependent Pulmonary Circulation Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099
70.4 Acute Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1101
70.4.1 Stepwise Emergency Treatment of Duct-Dependant Systemic Circulation
Lesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1102
70.5 Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1103
70.5.1 Atrial Tachyarrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1103
70.5.2 Ventricular Tachyarrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1106
70.6 Bradyarrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1107
70.6.1 Third-Degree Heart Block . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1107
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1108
Abstract (5–9 per 100,000 infants) which can lead to
There are a number of different cardiac emer- hemodynamic decompensation in the neonate.
gencies that can face the neonatologist. Many Furthermore, iatrogenic injuries caused by
of these relate to the initial presentation of interventions can lead to emergencies such as
congenital cardiac lesions (incidence 6–13 per cardiac tamponade. These particular patholo-
1,000 live births). Rarer causes also include gies can present acutely and require prompt
cardiac arrhythmias (1 in 25,000 for supraven- treatment by the attending physician. For the
tricular tachycardia) and cardiomyopathies purposes of this chapter, the pathologies are
split into four common presentations with the
aim of providing a practical approach to car-
L. Mahoney · H. Rojas-Anaya · H. Rabe (*) diac emergencies in newborn: shock/circula-
Academic Department of Paediatrics, Royal Alexandra tory failure, cyanosis, acute heart failure, and
Children’s Hospital, Brighton, UK arrhythmias.
e-mail: [email protected]
# Crown 2018 1093
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_216
1094 L. Mahoney et al.
These particular pathologies can present • The most common cardiac arrhythmia in the
acutely and require prompt treatment by the newborn is supraventricular tachycardia.
attending physician. For the purposes of this When such an arrhythmia has been sustained
chapter, the pathologies are split into four com- throughout the antenatal period, the infant may
mon presentations with the aim of providing a present as hydrops fetalis. A fetal tachycardia
practical approach to cardiac emergencies in detected during labor by cardiotococar-
newborn. diography may be interpreted as fetal distress
and prompt the delivery of an infant.
• Shock/circulatory failure
• Cyanosis
• Acute heart failure 70.2 Shock/Circulatory Failure
• Arrhythmias
Circulatory failure is defined as a state of circula-
tory dysfunction which leads to lack of adequate
70.1 Salient Points oxygen and nutrients to tissues or organs resulting
in anaerobic respiration. Its etiology is split com-
• Various cardiac emergencies can face the neo- monly into four categories (Table 1).
natologist. Four common presentations are This chapter focuses on obstructive shock with
shock and circulatory failure, cyanosis, acute sudden onset requiring immediate actions. Pathol-
heart failure, and arrhythmias. ogies in the other categories, while in need of
• Many relate to the initial presentation of con- prompt intervention, either may present more
genital cardiac lesions (incidence 5–13 per indolently or are covered extensively by other
1,000 live births) but rarer causes include chapters in this book.
cardiac arrhythmias (1 in 25,000 for supraven-
tricular tachycardia) and cardiomyopathies
(5–9 per 100,000 infants), which can lead to 70.2.1 Cardiac Tamponade
hemodynamic decompensation in the neonate.
• Iatrogenic injuries, caused by interventions Cardiac tamponade is the accumulation of fluid
such as central venous line migration, can or air in the pericardial space that causes
lead to cardiac tamponade. The most common increased pressure sufficient to impair passive fill-
presentation in a neonate is sudden cardiovas- ing of the heart and leading to impaired myocardial
cular collapse, and it can be readily detected on contraction and consequent cardiorespiratory
echocardiography via a simple subcostal or decompensation (Iyer et al. 2014). The most
apical view. It carries a high mortality (50%). common presentation in a neonate is of sudden
Table 1 Types of shock/circulatory failure
Type of shock Etiology Example pathologies
Distributive Abnormalities in vessel tone secondary to the release of Sepsis, PPHN
inflammatory cytokines, problems with endothelial nitric
oxide production, or immature neurovascular regulatory
pathways
Hypovolemic Loss of fluid from the intravascular space through blood loss Twin-to-twin transfusion, IVH,
or from movement of fluid to extracellular spaces (e.g., third DIC, sepsis, NEC
spacing)
Cardiogenic Immature or impaired contractility of the heart’s myocardium Perinatal asphyxia,
leading to poor cardiac output cardiomyopathy, myositis
Obstructive A physical obstruction to blood flow from the heart resulting Congenital cardiac lesions, tension
in poor cardiac output pneumothorax, cardiac tamponade
70 Cardiac Emergencies in the Newborn 1095
cardiovascular collapse. Classical features such as secondary to central venous line migration. Thus,
distended neck veins or muffled heart sounds are cardiac tamponade needs to be considered in any
often hard to detect in a newborn baby. However, it infants with a central venous catheter (CVC) that
can be readily detected on echocardiography via a suddenly clinically deteriorates. The quoted inci-
simple subcostal or apical view (Fig. 1) (Iyer dence is around 1% of neonates with a central
et al. 2014). The urgent need for intervention in venous catheter (CVC) and carries a high mortal-
this condition means that often emergency treat- ity (50%) (Cartwright 2004; Beardsall et al. 2003;
ment needs to be instigated before the diagnosis is Warren et al. 2013; Abdellatif et al. 2012). This
confirmed. highlights the need to frequently image the posi-
There are numerous causes of pericardial effu- tion of the CVC in neonatal intensive care to
sions leading to tamponade (Table 2). The most ensure they are in a safe position (Warren
common cause that will present to neonatologist is et al. 2013).
70.2.1.1 Stepwise Emergency Treatment
of Cardiac Tamponade via
Pericardiocentesis
• Adequate respiratory and circulatory support
as per an ABC approach.
• Attach a venous cannula to a three-way tap and
a 10 ml syringe (Fig. 2).
• Clean the skin below the xiphisternum with an
alcohol wipe.
• Aim to enter the skin just below and to the left
of the infant’s xiphisternum.
• Advance the cannula though the skin at an
angle of about 30 aiming toward the left
shoulder (Fig. 3).
Fig. 1 Cardiac echocardiogram of a pericardial effusion
(white arrow)
Table 2 Cause of cardiac tamponade
Classification Underlying pathology
Iatrogenic CVC line migration
Chest drain misplacement
Cardiac Hydrops fetalis
Myocarditis
Infectious pericarditis (viral, bacterial,
and fungal)
Pericardial tumors e.g., rhabdomyomas
Respiratory Pneumopericardium secondary to lung
pathology, e.g., PIE
Metabolic Disorders of glycosylation
Pompe disease Fig. 2 Equipment needed for an emergency
pericardiocentesis
1096 L. Mahoney et al.
culture, fungal culture, tuberculosis culture, and
polymerase chain reaction for viral pathogens.
70.2.2 Tension Pneumothorax
A pneumothorax is the progressive increase of an
You might also like
- 2025 Nelson's Pediatric Antimicrobial Therapy 31st EditionNo ratings yet2025 Nelson's Pediatric Antimicrobial Therapy 31st Edition407 pages
- ACoRN Acute Care of At-Risk Newborns A Resource and Learning Tool For Health Care Professionals 2nd Edition100% (4)ACoRN Acute Care of At-Risk Newborns A Resource and Learning Tool For Health Care Professionals 2nd Edition473 pages
- Fuhrman and Zimmerman x27 S Pediatric Critical Care Sixth Edition 2021100% (11)Fuhrman and Zimmerman x27 S Pediatric Critical Care Sixth Edition 20212,609 pages
- Point-of-Care Ultrasound For The Neonatal and Pediatric Intensivist100% (1)Point-of-Care Ultrasound For The Neonatal and Pediatric Intensivist321 pages
- 50 Studies Every Neonatologist Should KnowNo ratings yet50 Studies Every Neonatologist Should Know369 pages
- Questions From NeoReviews A Study Guide For Neonatal Perinatalpdf100% (1)Questions From NeoReviews A Study Guide For Neonatal Perinatalpdf646 pages
- Vascular Access in Neonates and Children 2022No ratings yetVascular Access in Neonates and Children 2022405 pages
- Neonatology Review Q & A, 3rd Edition 2016100% (1)Neonatology Review Q & A, 3rd Edition 2016787 pages
- Wiley - Neonatology at A Glance, 4th Edition - 978-1-119-51319-30% (1)Wiley - Neonatology at A Glance, 4th Edition - 978-1-119-51319-32 pages
- Neonatal Ventilation - Basics of Mechanical Ventilation: Authors: Sam Wallis - Catriona Firth100% (1)Neonatal Ventilation - Basics of Mechanical Ventilation: Authors: Sam Wallis - Catriona Firth21 pages
- Succinct Pediatrics Evaluation and Management For Common and Critical Care 1st EditionNo ratings yetSuccinct Pediatrics Evaluation and Management For Common and Critical Care 1st Edition846 pages
- Toronto Residents Handbook of Neonatology 2022100% (3)Toronto Residents Handbook of Neonatology 2022212 pages
- Atlas of Procedures in Neonatology 5th Edition92% (13)Atlas of Procedures in Neonatology 5th Edition446 pages
- A Killjoy Survival Kit + A Killjoy ManifestoNo ratings yetA Killjoy Survival Kit + A Killjoy Manifesto34 pages
- Pediatric Fluid, Electrolyte, and Acid Base Disorders A Case Based100% (4)Pediatric Fluid, Electrolyte, and Acid Base Disorders A Case Based226 pages
- Neonatología - Fanaroff & Martin - Neonatal-Perinatal Medicine 10th Ed Table of Content50% (2)Neonatología - Fanaroff & Martin - Neonatal-Perinatal Medicine 10th Ed Table of Content4 pages
- Nelson's Pediatric Antimicrobial Therapy 28th Edition 2022No ratings yetNelson's Pediatric Antimicrobial Therapy 28th Edition 2022382 pages
- The Placenta and Neurodisability 2nd EditionFrom EverandThe Placenta and Neurodisability 2nd EditionIan CrockerNo ratings yet
- Dara Brodsky MD, Mary Ann Ouellette MS APRN IBCLC-Primary Care of The Premature Infant (2007)100% (2)Dara Brodsky MD, Mary Ann Ouellette MS APRN IBCLC-Primary Care of The Premature Infant (2007)312 pages
- A Guide To The Newborn Intensive Care Unit (NICU)100% (3)A Guide To The Newborn Intensive Care Unit (NICU)36 pages
- Newborn Infant Nutrition: A Clinical Decision Support Chart100% (1)Newborn Infant Nutrition: A Clinical Decision Support Chart32 pages
- Neonatal Infections - Pathophysiology, Diagnosis, and Management 2018 PDFNo ratings yetNeonatal Infections - Pathophysiology, Diagnosis, and Management 2018 PDF254 pages
- ISHLT Guidelines for the Management of Pediatric Heart FailureFrom EverandISHLT Guidelines for the Management of Pediatric Heart FailureNo ratings yet
- AAP January 2024 Complete Issue NeoReviewsNo ratings yetAAP January 2024 Complete Issue NeoReviews71 pages
- Guidelines For Acute Care of The Neonate 22eNo ratings yetGuidelines For Acute Care of The Neonate 22e181 pages
- Blueprints - Pediatric Infectious Diseases PDF100% (1)Blueprints - Pediatric Infectious Diseases PDF140 pages
- Neuroimaging Techniques in Clinical Practice100% (1)Neuroimaging Techniques in Clinical Practice340 pages
- General Pathology Presentation (Cellulitis)No ratings yetGeneral Pathology Presentation (Cellulitis)17 pages
- The Clinical Conundrum of Periapical Lesions: Granuloma or Cyst?No ratings yetThe Clinical Conundrum of Periapical Lesions: Granuloma or Cyst?3 pages
- Neovascular Glaucoma NVG SEEOS Tirane 18-06-2010 MR Sci DR Halil Ajvazi Prof DR Ilhami Goranci DR Ardiana Goranci DR Dafina GoranciNo ratings yetNeovascular Glaucoma NVG SEEOS Tirane 18-06-2010 MR Sci DR Halil Ajvazi Prof DR Ilhami Goranci DR Ardiana Goranci DR Dafina Goranci27 pages
- Approach To Liver Disease, Liver Function Tests, HyperbilirubinemiaNo ratings yetApproach To Liver Disease, Liver Function Tests, Hyperbilirubinemia34 pages
- Broiler Management: - Dr. Rahul Mittal PGDM (ABM) 2014-16 ManageNo ratings yetBroiler Management: - Dr. Rahul Mittal PGDM (ABM) 2014-16 Manage34 pages
- Presentation ON Polycythemia: Presented By: Ms. Dimple Chauhan M. Sc. (N) Iind YearNo ratings yetPresentation ON Polycythemia: Presented By: Ms. Dimple Chauhan M. Sc. (N) Iind Year28 pages
