FEBRUARY

JANUARY 2021
2022
Vol. 22
Vol. 23 No.
No. 2
1
www.neoreviews.org
www.neoreviews.org

ARTICLES
ARTICLES
Gastroesophageal Reflux Disease in
Antiracism Neonates:
in the FieldFacts
of Neonatology:
and Figures
A Foundation and Concrete Approaches
Fetal Heart Rate Tracing Category II:
A �road CategoryPartial
in NeedEnteral Discharge
of Stra� fica�on
Programs for High-risk Infants
Maternal Hematologic Condi�ons and
DevelopingOutcomes
Fetal/Neonatal a Quality Improvement
of Pregnancy
Feeding Program for NICU Patients
Obesity and Pregnancy
INDEX OF SUSPICION IN THE NURSERY

SeizuresCOMPLEX
in a TermFETAL CARE
Newborn
Fetal Sacrococcygeal Teratoma and the
Development of Hydrops
Hepatosplenomegaly and
Periventricular Cyst in aDIAGNOSIS
VISUAL Neonate
Sudden Onsetwith
of aDirect Hyperbilirubinemia
Unilateral Erythematous
Preauricular Mass in a Preterm Infant
VISUAL DIAGNOSIS

Whole Genome Sequencing: Early

Diagnostic Tool in Newborns with
Refractory Seizures

NeoReviews® and NeoReviewsPlus™ are supported,

in part, throu�h an educa�onal �rant from A��o�
Nutri�on, a proud supporter of the American Academy
of Pediatrics.

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 NeoReviews
PERSPECTIVE Editor-in-Chief: Dara Brodsky, Boston, MA
Associate Editor: Josef Neu, Gainesville, FL
e1 Antiracism in the Field of Neonatology: A Foundation and Associate Editor, CME: Henry C. Lee, Palo Alto, CA
Associate Editor, NeoQuest: Rita Dadiz, Rochester, NY
Concrete Approaches Associate Editor, Perspectives: Mamta Fuloria, Bronx, NY
Diana Montoya-Williams, Yarden S. Fraiman, Michelle-Marie Pe~
na, Associate Editor, Visual Diagnosis: Beena Sood, Detroit, MI
Associate Editor, Video Corner: Akshaya Vachharajani, Columbia, MO
Heather H. Burris, DeWayne M. Pursley Assistant Editor, CME: Santina A. Zanelli, Charlottesville, VA
Early Career Physician:
Theodore De Beritto, Los Angeles, CA ••
•••
• •

REVIEW ARTICLES Editorial Fellow:

•
•
e13 Partial Enteral Discharge Programs for High-risk Infants
Colby Day, Jacksonville, FL
EDITORIAL BOARD
MOC

•
•
• •
••
•••
Carl Backes, Columbus, OH
Anna Ermarth, Con Yee Ling Alison Chu, Los Angeles, CA
Sergio Golombek, Valhalla, NY
e24 Developing a Quality Improvement Feeding Program Corinne L. Leach, Buffalo, NY
Krithika Lingappan, Houston, TX
for NICU Patients Thomas E. Wiswell, Honolulu, HI
Erika K. Osborn, Sudarshan R. Jadcherla Clyde Wright, Aurora, CO
Brett Young, Boston, MA
Managing Editor: Heidi Willis
Manager, Journal Publishing: Josh Sinason
INDEX OF SUSPICION IN THE NURSERY Medical Copy Editor: Beena Rao
e36 Seizures in a Term Newborn Publisher: American Academy of Pediatrics
President: Sandy L. Chung
Peter Joslyn, Maria Velez, Oritsejolomi Roberts, Michelle Knecht, Chief Executive Officer/Executive Vice President:
Pinki Prasad, Jared Robichaux, Andrea Bauchat, Jeffrey Surcouf Mark Del Monte
Chief Product and Services Officer/SVP Membership, Marketing,
and Publishing:
e40 Hepatosplenomegaly and Periventricular Cyst in a Neonate Mary Lou White
with Direct Hyperbilirubinemia Vice President, Publishing: Mark Grimes
Director, Journal Publishing: Joseph Puskarz
Vignesh Gunasekaran, Judy Squires, James Squires, Marian G. Michaels,
NeoReviews™
John Ibrahim (ISSN 1526-9906) is owned and controlled by the American Academy of Pediatrics. It is
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e45 A Floppy Infant with Facial Dysmorphism Statements and opinions expressed in NeoReviews™ are those of the authors and not
necessarily those of the American Academy of Pediatrics or its Committees. Recommendations
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Pediatrics.
e49 Whole Genome Sequencing: Early Diagnostic Tool in
POSTMASTER: Send address changes to NEOREVIEWS™, American Academy
Newborns with Refractory Seizures of Pediatrics, Member and Customer Care, 345 Park Blvd., Itasca, IL 60143.

Estefani Hee Chung, Julia Frueh, Angela Lai, Andrea Scheurer-Monaghan CME/MOC Information:
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OUTCOMES OF NICU GRADUATES

e60 Follow-up for a Preterm Infant with Beckwith-
Wiedemann Syndrome
Mairead Bresnahan, Monica H. Wojcik

STRIP OF THE MONTH

e67 Maternal Facial Nerve Palsy and a Perinatal Infection
Tyler Lueck, Brett C. Young

Answer Key appears on page e66.

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 PERSPECTIVE

Antiracism in the Field of

Neonatology: A Foundation and
Concrete Approaches
Diana Montoya-Williams, MD,* Yarden S. Fraiman, MD, MPH,† Michelle-Marie Pen
~ a, MD,*
†
Heather H. Burris, MD, MPH,* DeWayne M. Pursley, MD, MPH
*Division of Neonatology, Children’s Hospital of Philadelphia, Philadelphia, PA
†
Department of Neonatology, Beth Israel Deaconess Medical Center, Boston, MA

PRACTICE GAP
Concrete interventions that advance antiracism within the field of
neonatology are required to address neonatal racial/ethnic health
inequities and improve care and outcomes for historically marginalized
patients and families.

OBJECTIVES After completing this article, readers should be able to:

1. Recognize the 4 types of racism seen as social determinants of health.

2. Characterize the unique aspects of the NICU environment that can
either exacerbate or ameliorate racial inequities in health and health
care.
3. Identify specific strategies neonatal clinicians can use to incorporate
antiracism into every role they may play within and outside academic AUTHOR DISCLOSURES Dr Montoya-
medicine. Williams is supported by an NICHD grant
(K23HD102526). Dr Pen ~a is supported by
an NIH grant (T32HL098054-11 Training
in Critical Care Health Policy Research).
ABSTRACT Dr Fraiman is supported by AHRQ
(T32HS000063) as part of the Harvard-
Neonatal patients and families from historically marginalized and wide Pediatric Health Services Research
discriminated communities have long been documented to have Fellowship Program. Drs Burris and
differential access to health care, disparate health care, and as a result, Pursley have disclosed no financial
relationships relevant to this article. This
inequitable health outcomes. Fundamental to these processes is an
commentary does not contain a
understanding of what race and ethnicity represent for patients and discussion of an unapproved/
how different levels of racism act as social determinants of health. The investigative use of a commercial
NICU presents a unique opportunity to intervene with regard to the product/device.

detrimental ways in which structural, institutional, interpersonal, and

internalized racism affect the health of newborn infants. The aim of this
ABBREVIATIONS
article is to provide neonatal clinicians with a foundational
ABP American Board of Pediatrics
understanding of race, racism, and antiracism within medicine, as well
EF-QI equity-focused quality
as concrete ways in which health care professionals in the field of improvement
neonatology can contribute to antiracism and health equity in their QI quality improvement
professional careers. REaL race, ethnicity, and language
data data
SDOH social determinants of health

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 INTRODUCTION (white race). (10)(12) As noted by the evolving classifications
Although the role of racism in every aspect of life in the of race in the United States census, race is not biologic,
United States has been well-researched and documented genetic, or natural, but instead evolving and responsive to
for decades, (1)(2) the murder of George Floyd on May 25, sociopolitical forces that continue to reinforce and normalize
2020, ignited a cultural movement in American society to whiteness as dominant over all other groups. (13)
address systemic racism in concrete ways. (3) Antiracism, Racism refers to the discrimination, marginalization,
the process of actively identifying and opposing racism, can and/or oppression of people of color through the use of
be applied to all fields of medicine, including neonatology. policies, ideas, and actions that differentially structure
(4) In this article, we provide a comprehensive (though not opportunity, behavior, and risk for nonwhite individuals.
exhaustive) compendium of possible approaches neonatolo- As defined by leaders in the field including epidemiologist
gists and other neonatal health care professionals may take and physician Dr Camara Jones, racism creates a system
to conduct antiracist work throughout many aspects of their that restricts the lives of nonwhite individuals and com-
careers. munities while creating advantage for white communities.
(1)(14)(15) Dr Jones defined 3 types of racism: 1) institu-
BACKGROUND AND RATIONALE FOR tional, 2) interpersonal, and 3) internalized. (16) More
ANTIRACIST WORK recently, others have defined structural racism separately
Racism and Social Determinants of Health from institutional racism. (17) Structural racism is the
According to the Centers for Disease Control and Preven- “totality of ways in which societies foster racial discrimina-
tion Healthy People 2030 report, “Social determinants of tion through mutually reinforcing systems of housing,
health (SDOH) are the conditions in the environments education, employment, earnings, benefits, credit, media,
where people are born, live, learn, work, play, worship, healthcare, and criminal justice.”(18) The inequitable dis-
and age that affect a wide range [of healthcare], health tribution of police violence and killing of black men,
[outcomes], functioning, and quality-of-life outcomes and women, and children, the disproportionate number of
risks.” (5) SDOH can be grouped into 5 major domains: 1) incarcerated black and Hispanic/Latinx individuals com-
economic stability; 2) education access and quality; 3) pared to white individuals, and the lack of representation
health care access and quality; 4) neighborhood and built in media, all represent forms of structural racism.
environment; and 5) social and community context. Recog- Institutional racism refers to the “processes of racism that
nition of SDOH can lead to a better understanding of how are embedded in laws … , policies, and practices” within spe-
social context affects biologic risks and outcomes. (5) cific societal institutions. (19) For example, de jure housing
A focus solely on “determinants,” however, fails to recog- discrimination (ie, “redlining”) codified inequitable access to
nize that the distribution of SDOH among the population is mortgages for homeownership, thereby restricting subse-
not random. (6) Instead, social, economic, and political sys- quent wealth attainment and upward mobility. (20)(21) Insti-
tems distribute these “determinants” inequitably across the tutional and structural racism, through their normalization
population. Black, indigenous, and people of color are more of a racialized world, are not actively inflicted by individual
likely to experience reduced access to health care, receive perpetrators. Similarly, complicity in the system may not be
care in lower quality hospitals, live in neighborhoods with immediately apparent. (16)(18)
more risks and fewer resources, have increased exposure to Interpersonal racism refers to personally mediated prejudice,
environmental pollution, be overcriminalized, and have dimin- assumptions, beliefs, and discrimination, as well as differen-
ished access to employment and wealth opportunities. (7)(8) tial behaviors and actions, based on race. Interpersonal racism
The inequitable, racialized distribution of SDOH in the can be intentional or unintentional. Microaggressions experi-
United States highlights the prominent role of racism as a enced by health care professionals of color due to implicit
key factor in SDOH. (9) biases, such as when a clinician of color’s presence or title is
Race is a social construct and has no basis in genetics or questioned, are an example of interpersonal racism. (22)
biology. (10)(11) Race emerged as a concept when European Finally, internalized racism is defined by members of
explorers encountered individuals in the “New World,” and minoritized groups accepting “negative messages about their
sought to establish a human classification system, defined by own abilities and intrinsic worth.” (16)(18) These 4 pillars of
physical appearance and skin color, to construct hierarchies racism work together to perpetuate and normalize race-based
of power and consolidate power in the dominating group inequity, including in the inequitable distribution of SDOH.

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 As a result of racism in its many forms, racial and eth- decades, and both have a major impact across the lifespan and
nic inequities, unexplained by genetic associations, exist contribute to lifelong health inequities. (48)(49) Many SDOH
in perinatal and neonatal health and health care. Black that are concentrated in black, indigenous, and people of color
infants are more than twice as likely to die in the first year communities affect the risk of preterm birth and low birth-
of age compared to their white counterparts, and the gap weight, (50) which in turn drive disparities in infant mortality
is widening. (23) Pregnant patients who identify as black in the population. (51) Mitigating racial/ethnic disparities in
or Hispanic/Latinx receive care in lower quality hospitals perinatal and infant health outcomes requires an understand-
and have higher rates of preterm birth and low birth- ing of the downstream pathophysiology that leads to preterm
weight infants. (24) Black and Hispanic/Latinx infants labor, preeclampsia, poor fetal growth, and infant death. Neona-
admitted to NICUs have been shown to receive lower qual- tologists and other neonatal health care professionals have
ity of care, have lower patient satisfaction scores, and have extensive clinical and academic expertise in these pathophysio-
decreased rates of postdischarge high-risk infant follow- logic processes as well as the care of newborns that can be lev-
up. (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) Studies have eraged to ensure the validity of research questions and
begun to explore how the inequitable racialized distribu- interventions that aim to address infant health disparities. How-
tion of the SDOH, as a result of racism, explains these ever, to do so, neonatal physicians and other clinicians must
inequities. (23)(36)(37)(38)(39)(40)(41)(42)(43) engage in this type of research and implementation science.
Second, racially minoritized families face disproportionate
Conceptual Understanding of Antiracism exposure to the NICU setting given the high rates of preterm
Antiracism has been defined most prominently by the his- birth and low birthweight in these communities. Having an
torian Dr Ibram Kendi as support for and concrete actions infant in the NICU can cause significant parental stress and
toward the creation of policies aimed at dismantling ideas trauma. (52)(53) However, this stress is further compounded
and structures that produce and normalize racial inequal- by ongoing stressors related to socioeconomic status (54) and
ities. (1) The concept of antiracism tackles the historical financial insecurity, interpersonal discrimination, and other
and present-day inertia that has allowed entrenchment of SDOH. (42)(55) The association between chronic stress and
racism throughout society. (44) It recognizes that societal adverse health outcomes—including racial/ethnic disparities
problems are rooted in power structures and policies in birth outcomes—is well-documented. (56) Therefore, recog-
rather than individuals or groups of people. Antiracism nizing, acknowledging, and addressing such intersectional
embodies an active process to redistribute and equitably stressors, many of which are deeply rooted in structural, insti-
share power by changing systems, organizational struc- tutional, and interpersonal racism, is antiracist work.
tures, funding, policies, practices, leadership, and culture. Finally, the NICU experience occurs during a critical
(45) The emphasis is on naming racist policies and actions phase of infant development as well as the development of
and taking active steps for change rather than stances, the parent-infant dyad relationship. Given the existing and
statements, or generalizations. (46) ever-increasing knowledge about the impact of early life
Applying antiracism in medicine is considered not only adversity on neural, endocrine, immune, metabolic, and epi-
a moral imperative but also an efficient one that can help genetic processes, (42)(53) antiracist interventions in the
ensure that every aspect of health care, from clinical prac- NICU have the potential to improve long-term health trajecto-
tice to public health to medical innovation, is equitable. ries for patients and their families. This is especially true if
(45) However, the application of antiracism in medicine interventions are based on an equitable “follow-through”
requires a recognition of the role racism plays in the lives approach that recognizes the responsibility of NICU profes-
of individual health care professionals as well as within sionals toward addressing SDOH for infants even after dis-
health care systems. (47) Ownership of the many avenues charge from the NICU. (57) The NICU stay thus represents
by which racism adversely affects health is fundamental to an opportunity to intervene on systemically racist structures,
antiracist work within medicine. This article will describe institutionally racist policies, and interpersonal instances of
how to operationalize antiracism in neonatology. implicit and explicit bias that may be affecting entire families.

The NICU as an Optimal Setting for Antiracist Work APPLICATION OF ANTIRACISM TO NEONATAL
The field of neonatology is particularly well-suited for antiracist HEALTH CARE
work for 3 main reasons. First, racial/ethnic disparities in fetal Neonatal professionals can contribute to antiracism regardless
and infant health outcomes have been well-described for of the roles they play in academic and health care settings

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 (Fig 1). Below are concrete strategies that could be explored includes training on how to respond when micro- and
within each sector of neonatal medicine. macroaggressions related to discrimination and racism are
witnessed in the medical workplace so that medical per-
Antiracism in Medical Education sonnel feel empowered and knowledgeable to function as
Contributing to antiracism through education can be involved “upstanders” rather than passive bystanders.
accomplished in 3 main ways: through continual self-edu- (65)(66) However, such curricula must be implemented
cation; through the creation of new curricula for medical broadly in medical schools, residency, and fellowship pro-
students, trainees, and staff; and through reform of exist- grams, as well as graduate health care programs for
ing structures and processes in medical education. To nurses, respiratory therapists, physical and occupational
begin, self-education is fundamental and requires an therapists, and other health care clinicians. This includes
acknowledgment that gaps in one’s personal understand- not only education of new staff in all these arenas but also
ing may exist either because of lack of awareness or in continuing education programs and maintenance of
because of implicit biases. Scholars had been writing and certification curricula. Much work remains to be done in
speaking about the historical and present-day impact of this arena. A recent analysis of pediatric general and sub-
racism on health care and health outcomes long before specialty board examination content specifications revealed
the increased social awareness movement of 2020. that only 2 subspecialty content specifications addressed
(16)(58)(59) However, the past year has led to a flourishing implicit bias. (67) Within the American Board of Pediat-
of such literature and multimedia resources. Professional rics (ABP) preparatory information provided for the neo-
organizations, including the American Academy of Pediat- natal-perinatal medicine certification examination, only 2
rics, have created compilations of primary and secondary of 875 content specifications currently address issues of
data, (60) published policy statements, (61) and released race, ethnicity, and health. (67) One is worded as knowing
podcast material (62) intended to educate readers and lis- the relationship between the ethnic origin of the parents
and risk for specific genetic conditions in an infant. The
teners about the impact of racism on pediatric health.
Such material can be used to not only “teach the second asks learners to know the range of normal serum
bilirubin concentration and the effects of an infant's age,
teachers” within health care and medicine, but also to
race, and feeding circumstances on serum bilirubin. To date,
develop longitudinal curricula for medical students, train-
no pediatric examination content specifications address rac-
ees, and staff. There remains a dearth of evidence as to
ism in any form as a contributor to health outcomes.
best practices for how to incorporate concepts of racism,
Neonatal medicine educators can also engage in antira-
bias, and antiracism into medical curricula. (63)(64) This
cism by reforming current ways in which students are
taught to think about the relationship between race/eth-
nicity and health. The 2 ABP neonatal-perinatal medicine
content specifications that currently allude to race test
physiologic associations based on race; they do not test for
an understanding of the root causes of race functioning as
a risk factor for pathology. (67) Genetic explanations for
racial disparities in disease are common in medical curricula
despite the growing understanding of race as a sociocultural
construct and imperfect proxy for social determinants of
both health and ancestry. (68)(69) Indeed, race is commonly
misrepresented in medical curricula and examination prepa-
ratory materials such as widely used question banks, as it is
usually presented in imprecise uncontextualized ways that
pathologize racial groups themselves. (68)(70) For instance,
students may be taught that black patients have higher rates
of hospital readmission without discussion of the underlying
structural causes for these disparities or they may observe
African patients being incorrectly described as African Amer-
Figure 1. Sectors of neonatal-perinatal medicine and health care through
which care providers can contribute to antiracism. ican. Both of these examples have the potential not only to

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 miseducate but also to perform microaggressions against patterns may be masking underlying socioeconomic and
black learners. (70) Thus, neonatal medical educators have sociopolitical factors that affect fetal growth, which may
significant opportunities to critically examine existing curric- contribute to birthweight disparities. (76) Such questions
ula, correct previous educational missteps, and create new are critical for neonatal clinicians to consider, study, and
content that reflects a more accurate and thus useful under- address.
standing of race and ethnicity and how it relates to neonatal
and infant health outcomes. The ABP recently amended its
Antiracism in Quality Improvement
strategic plan, adopted an antiracist action agenda that tar- As with diagnostic algorithms or practice guidelines, qual-
gets these previous educational shortcomings, and is work-
ity improvement (QI) initiatives have the potential to leave
ing to implement new action steps aimed at antiracism
disparities unchanged or widen them, especially if strati-
within pediatrics. (71) Participation of neonatal professionals
fied data are not monitored. (77) QI offers a compelling
in such reforms will be crucial.
approach to improve disparities with targeted antiracist,
inclusive interventions, aiming to reduce a disparity. Spe-
Antiracism in Clinical Care
cifically, equity-focused quality improvement (EF-QI) (73)
Incorporating antiracism in clinical care fundamentally
offers an action-oriented framework whereby equity is
requires an understanding of the causal pathways by
integrated throughout a QI initiative at every stage to
which racism, segregation, and inequality affect both the
address a disparity, from the development of a smart aim
care we offer infants and the health outcomes they experi-
to identifying drivers to designing and testing change
ence. In a seminal piece discussing interventions to
ideas.
reduce racial/ethnic inequities in preterm birth, Beck and
After identifying a disparity, intentionality in mapping
colleagues propose concrete strategies to address the 3
key stakeholders to include patients, families, and relevant
main causal pathways they identified. One strategy to
community partners, with a focus on the group(s)
address the disproportionate preterm birth risk among
experiencing the disparity, is critical to EF-QI. Stakeholders
black patients is equitable access to high-quality prenatal
collaboratively brainstorm root causes focusing on systems,
care for high-risk patients with maternal-fetal medicine
processes, and policies, specifically identifying sources of
physicians who can provide therapies, such as cerclage,
structural racism. (78) These reflective and in-depth discus-
when indicated. (42) To address the socioeconomic disad-
vantage NICU families disproportionately experience, neo- sions among stakeholders can help QI teams design and pri-
natal programs could work on bolstering discharge oritize targeted antiracist interventions centered around the
planning and early intervention programs. Finally, NICUs patient and family voice. EF-QI initiatives are essential to fur-
might begin to address the lower quality of care minori- ther a culture of equity and antiracism and place the value of
tized infants have been shown to receive (30)(32) by insti- equity similar to that assigned to patient safety.
tuting disparity dashboards to track care delivery and For example, black-white disparities in breastfeeding
outcomes by the race, ethnicity, and preferred language of rates have been widely documented in the literature and
an infants’ family (often referred to as REaL data). (72) locally in individual units, prompting several QI initiatives
Clinical dashboards that display REaL data can assist aimed to improve breastfeeding rates, especially among
NICUs in ensuring that existing and new algorithms do black patients who are experiencing this disparity. (31)(79)
not inadvertently perpetuate or widen disparities in quality A multidisciplinary stakeholder group is assembled, includ-
of care or outcomes. Such “intervention-generated inequal- ing patients who identify as black or African American and
ities” have been found among adult inpatients and after community partners who are dedicated to empowering and
certain major public health campaigns but are poorly stud- serving black patients. Qualitative work and interdisciplinary
ied in neonatology. (73) Clinical algorithms used for diag- discussions on root causes, specifically drivers of racism and
nostic or management purposes that adjust or correct for bias within the health care system, inform potential interven-
race may be even more problematic, as there is evidence tions that are subsequently prioritized with stakeholder
that these may contribute to new disparities and inequities input. This process centered around the lived experience of
in access to care and outcomes. (74) Racial/ethnic stand- black patients and community partners helps teams develop
ards for fetal growth are 1 example in the field of perina- targeted, antiracist interventions that can be tested and
tology where race-based corrections exist. (75) It has been refined through plan-do-study-act cycles and potentially
posited that racial/ethnic corrections for fetal growth rate implemented in the future.

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 Antiracism in Research to the communities and people whose lives the study aimed
Although there has been an explosion of health disparities to describe or improve. (80) Science dissemination efforts
literature in the last decade, research has predominantly are critically important to antiracist research, both for the
focused on identifying or understanding disparities. (80) purposes of feedback and also to increase the likelihood that
Conversely, research aimed at achieving health equity, scientific findings translate into measurable changes in peo-
especially in the field of pediatrics, has significantly ples’ lives.
lagged. (80) Antiracism in research requires an under-
standing that conducting studies focused on exploring Antiracism in Academic and Health Care
health disparities is not necessarily synonymous with anti- Administration
racist health equity–driven research. That is because One of the most important ways to engage in antiracist
health equity requires the creation and application of con- work in a health care setting or academic institution is by
crete goals and processes to move society toward the elimi- diversifying every level of the workforce. The benefits of
nation of health disparities. (80) This requires prioritizing diversifying the medical workforce are well-documented: it
“third- and fourth-generation” research that seeks to solve increases group performance; (88) promotes cultural
existing disparities and evaluate the effectiveness of inter- awareness and humility; increases access to racially and
ventions, respectively. (81) culturally concordant care; increases overall health care
Antiracist research requires thoughtful use of race as a coverage of marginalized patient populations; mitigates
variable in human studies. Clear standards for how to use provider bias issues; and improves patient experiences and
race in research studies are lacking and as such, it has satisfaction in health care systems. (89)(90)(91) In short,
been frequently interrogated in ways that are conflicting, creating a diverse workforce is foundational to repairing
ineffective, and even misleading. (82) Race and the the hard-earned mistrust of medicine and institutional
related, though distinct, concept of ethnicity, are important health care that exists among many minoritized communi-
variables that must be understood as proxies for socioen- ties. (89)(91) It is important to remember that there are
vironmental systems, processes, interactions, opportuni- various mechanisms that interrelate to create a nondiverse
ties, or ancestral heritages that are more challenging or workforce; in particular, administrative committees should
impossible to measure. (69)(82) Until recently, there has examine whether they are experiencing low applicant
been no expectation that scientists and authors state the diversity, appointment biases, departure biases, or a com-
reasons for exploring racial/ethnic differences in their bination of all 3. (88) Addressing retention issues and
study outcomes, or name what upstream driver of health departure biases in particular will require critical evalua-
might be represented as a proxy by race. (82) Given the tion of the workplace culture that exists within divisions
increasing realization of the dangers of such uncontextual- and an acknowledgment that micro- and macroaggres-
ized research questions in upholding racial health inequi- sions are a common experience for people of color in
ties or even bolstering implicit bias, some journals have health care. (92) Each of these factors will require its own
begun to update guidelines with respect to reporting on distinct set of strategies along with leadership buy-in to
race and ethnicity. (83)(84)(85) enact such strategies, including protected, recognized time
Neonatal researchers should ensure that conceptual to do so, especially given how often underrepresented minori-
frameworks are grounded by an understanding not only of tized health care professionals and academicians get called to
what race may be serving as a proxy for but also that they do such work at the expense of time for their own individual
are informed by the academic experience of scholars of career goals and promotion metrics. (93) It will also require a
color and the lived experiences of people of color. (82)(86) distinct look at the diversity of people in subsectors of a divi-
Work framed in this way is critically needed in the perina- sion or department, such as the diversity of those who hold
tal space; there are many unanswered questions regarding leadership positions, receive lecture invitations, or are invited
the impact of racism on neonatal health care delivery and to sit on expert panels.
neonatal outcomes. Few articles specifically examine rac- Documenting both historical and ongoing trends in
ism in the NICU, (36)(73)(87) and none evaluate best prac- workforce diversity is an important first step. A survey
tices or interventions for how to dismantle structural, conducted in 2018 of over 500 neonatologists across the
institutional, interpersonal, or internalized racism that country found that only 10% self-identified as belonging
affect NICU patients and their families. Finally, antiracist to a racial/ethnic group that is underrepresented in medi-
research also necessitates that findings be connected back cine. (94) According to the most recent data released by

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 the Accreditation Council for Graduate Medical Education, Another critical venue for antiracist work is academic
the percentage of neonatal-perinatal medicine fellows in the reform, specifically the paths to promotion, tenure pat-
2019–2020 academic year who self-identify as a race or eth- terns, and existing success metrics. Racial/ethnic dispar-
nicity underrepresented in medicine was 14%; disaggregated ities in scientific publications, teaching evaluations, and
data show an especially severe lack of representation from extramural funding have contributed to the lack of diver-
American Indian/Alaska Native and Native Hawaiian/Pacific sity in senior positions in academic medicine and health
Islander communities (Fig 2). (95) However, these cross- care institutions. (97)(98) This may be due in part to the
sectional data belie the fact that the proportion of underrepre- “minority tax” experienced by many underrepresented fac-
sented minoritized neonatal-perinatal medicine fellows may ulty, which refers to the time spent assisting with institu-
be diminishing over time, as was shown by Montez et al in tional diversity, equity, and inclusion work at the expense
a recent examination of racial/ethnic trends among pediat- of time invested in other activities traditionally prioritized
ric trainees from 2007 to 2019. (96) by promotion and tenure committees. (93) Relatedly,
Finally, workplace diversity does not exclusively apply to underprioritization and underfunding of the advocacy, ser-
physicians in neonatology but also to all health care personnel vice, mentorship, community outreach, and media/dis-
(or staff) within our field. Given the critical roles that all mem- semination efforts that underrepresented minoritized
bers of large neonatal multidisciplinary teams play, workforce individuals are more likely to conduct can also affect their
diversification should also be prioritized among advanced long-term academic success to the detriment of diversity
practice professionals, nurses, pharmacists, respiratory thera- goals in academic medicine. (97) The ongoing COVID-19
pists, occupational/physical/speech therapists, social workers, global pandemic has highlighted the need for clear public
lactation consultants, dieticians, and all other allied health pro- health messaging, strong community engagement, and
fessionals. Administrative committees should thus endeavor trust-building efforts between the medical community and
to collect and continuously track more comprehensive data on the lay public. (99) As such, these types of activities merit
the diversity of all personnel who work in NICUs. comparable consideration and weighting by promotion

Figure 2. Self-reported race/ethnicity of active neonatal-perinatal medicine fellows and pediatric residents in the United States in the 2019–2020 aca-
demic year.

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 and tenure committees. (97) Neonatal divisions can evalu- of including family and community stakeholders by
ate metrics of success and search for evidence of dispro- requiring applicants to describe how they will collaborate
portionate penalization of their underrepresented team with and compensate diverse community members as
members with respect to service, promotion, or compensa- research partners. (86)
tion. However, this will require departmental/unit-wide Importantly, family and community alliances can help
buy-in. Prioritizing the antiracist work that neonatologists bridge the differences between health care sectors and the
and other neonatal health care professionals are doing communities experiencing racism in ways that build trust
through academic policy reform is antiracist work itself. and ensure academic projects and institutional initiatives
are responding to community needs in safe and respectful
Antiracism via Community Engagement ways. Community collaborations have been most widely
Central to antiracist work is the lived experiences of the used by the primary care sector. (102) However, neonatol-
groups experiencing racism. The voices of racialized fami- ogists and other neonatal care professionals engaged in
lies and community stakeholders are thus essential to research, policy, and QI work can and must begin to con-
making antiracist projects authentic and effective. (100) ceptualize ways in which diverse family and community
Projects can (and often do) miss the mark when such per- voices can be included to improve upon the perinatal work
spectives are not incorporated at every step, beginning undertaken in hospitals, newborn nurseries, and NICUs.
with project conception. Furthermore, NICU parents may For instance, the perspectives of minoritized outpatient
be particularly motivated to participate in research as a doulas, lactation consultants, birthing support people, and
way to cope with their own experiences and contribute to birth parents can be invaluable to EF-QI initiatives aimed at
positive change. (101) However, meaningfully integrating improving inpatient postpartum breastfeeding support. (79)
families and community partners into scholarly projects Ultimately, collaboration with family and community stake-
requires 2 main components. The first is to take concrete holders can bolster every aspect of antiracist work discussed
steps to create an inclusive environment to ensure that in previous sections if concrete steps are taken to ensure
stakeholders feel valued, respected, and welcome. This that it is done in an equitable, inclusive, and just manner.
may require eliciting feedback about ways in which aca-
demic or health care environments have not felt inclusive CONCLUSIONS
in the past. Secondly, antiracist integration of community Racism affects health and health care in various ways,
partners also means that all stakeholders benefit from the from macrostructural forces related to governmental poli-
work in tangible and intangible ways. For instance, family cies down to the ways in which interpersonal discrimina-
and community partners could be included as coauthors tion and bias become internalized in individuals and
on abstracts, talks, and scientific papers. Most importantly, communities of color. The field of neonatology and the
they should be compensated for their time, expertise, and care provided to infants in newborn nurseries and NICUs
perspectives. This will entail building in funding for such are not immune to these processes; rather, a comprehen-
compensation into departmental budgets and grant pro- sive view of racism helps explain the pervasive and recalci-
posals. For example, funders can formalize an expectation trant perinatal and neonatal health disparities that exist

Figure 3. Strategies neonatal clinicians can undertake to tackle each level of racism within neonatology.

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 among minoritized communities. As such, it is incumbent (Fig 3). (3) When such work is approached with an attitude
upon neonatologists and other neonatal professionals to of cultural humility that prioritizes lifelong self-evaluation
acknowledge, understand, and intervene on the various and critique, rather than an expectation of learned cultural
pathways by which racism affects health. Actions and competency, (103) the impact is magnified. In short,
interventions that tackle racism at all 4 levels (structural, choosing to integrate antiracism into the work we do for
institutional, interpersonal, and internalized) can be incor- infants is synergistic to our field’s mission to provide
porated into all aspects of work undertaken by all neonatal high-quality, equitable, family-centered care to optimize
health care professionals in practical and measurable ways outcomes.

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 ARTICLE

Partial Enteral Discharge Programs

for High-risk Infants
Anna Ermarth, MD, MS,* Con Yee Ling, MD*
*Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT

PRACTICE GAPS

In recent years, an increasing number of NICUs in the United States have

supported earlier discharge with partial enteral feedings for infants who
are otherwise medically ready for discharge. While this earlier discharge
approach has led to successful outcomes for infants and families who have
appropriate follow-up support, there are still some gaps and controversies
in the current medical literature that need to be addressed by future
studies. Neonatal and pediatric clinicians need to be aware of this
approach and recognize the importance of supporting this medically
complex population.

OBJECTIVES After completing this article, readers should be able to:

1. Identify and distinguish clinical readiness for infants who may qualify for
discharge with home enteral feedings.
2. Review the clinical associations that may affect infants’ postdischarge
feeding success.
3. Describe the need for involvement of multidisciplinary clinicians both
before and after NICU discharge.

ABSTRACT
Premature infants or infants born with complex medical problems are at
AUTHOR DISCLOSURE Drs Ermarth and
increased risk of having delayed or dysfunctional oral feeding ability. These Ling have disclosed no financial
patients typically require assisted enteral nutrition in the form of a relationships relevant to this article. This
nasogastric tube (NGT) during their NICU hospitalization. Historically, once commentary does not contain a
discussion of an unapproved/
these infants overcame their initial reason(s) for admission, they were investigative use of a commercial
discharged from the NICU only after achieving full oral feedings or product/device.
placement of a gastrostomy tube. Recent programs show that these infants
can be successfully discharged from the hospital with partial NGT or ABBREVIATIONS
gastrostomy tube feedings with the assistance of targeted predischarge
BPD bronchopulmonary dysplasia
education and outpatient support. Caregiver opinions have also been ED emergency department
reported as satisfactory or higher with this approach. In this review, we GT gastrostomy tube
NGT nasogastric tube
discuss the current literature and outcomes in infants who are discharged
PMA postmenstrual age
with an NGT and provide evidence for safe practices, both during the NICU PO oral intake
hospitalization, as well as in the outpatient setting. SGA small for gestational age
VLBW very low birthweight

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 INTRODUCTION discharge plans and promoted close follow-up for nutrition
Discharge readiness of infants in the NICU is sometimes and growth, there is no formal guidance about home enteral
prolonged and complicated, and the timing of discharge nutrition due to the lack of studies. (4) To date, the
often relies on the subjective opinion of the neonatology Cochrane Neonatal review group has only evaluated 1 ran-
team. (1)(2)(3)(4) Three physiologic competencies are gen- domized early home enteral nutrition program compared
erally recognized as essential before hospital discharge of with a standard care program; the group with early discharge
the preterm infant: oral feeding sufficient to support with home enteral nutrition showed reduced mean hospital
appropriate growth, the ability to maintain normal body stay of 9.3 days and reduced clinical infections compared
temperature without an isolette/warmer, and respiratory with controls. Yet, no formal recommendations have been
control that is sufficiently mature. (4) Historically, preterm made for early discharge feeding programs, given the evi-
infants and medically complex infants were not typically dence was limited to 1 experimental group. (9) Since this
discharged from the hospital until they reached oral intake review in 2015, there has been a growth of early discharge
(PO) independence. If progress toward enteral tube inde- programs for infants with home enteral nutrition, given the
pendence stalled, a surgical gastrostomy tube (GT) was possibilities of health advantages and family dynamic advan-
often placed before discharge. However, prolonging the tages for infants in the home setting. This review provides
hospital stay also has risks, including, but not limited to, updated information about improved feeding practices and
bloodstream infections, respiratory or other opportunistic outcomes of individualized earlier discharge programs for
infections, and medical errors, as well as parental stress NICU infants with continued oral feeding dysfunction.
from travel and infant separation. (4)(5)
In the last decade, advancements in NICU feeding ORAL READINESS AND FEEDING
practices have included earlier recognition of infants with INTERVENTIONS DURING NICU
delayed or dysfunctional oral feeding, as well as targeted HOSPITALIZATION
interventions to decrease length of stay and allow earlier The incidence of inpatient oral feeding difficulty of medi-
discharge from the hospital. Most NICUs now have spe- cally complex and premature infants can be as high as
cialized feeding therapists who work with infants and fam- 80%, and oral feeding dysfunction remains a main reason
ilies and focus on steps to achieve PO independence as for continued NICU hospitalization of this population.
soon as possible. (6)(7) In 2003, a large, high-powered, (4)(6)(7) Recently, Edwards et al analyzed the Moderate
multicenter, randomized, controlled trial demonstrated Preterm Registry of the National Institute of Child Health
that individualized developmental care of very low birth- and Human Development Neonatal Research Network
weight (VLBW) preterm infants led to several improved and found that for infants born between 29 and 34 weeks’
outcomes compared with controls, including fewer days of PMA, oral feeding dysfunction was either the primary rea-
parenteral feedings; shorter transition periods to full son or a concomitant reason for continued hospitalization,
enteral feeding; better average daily weight gain; younger and 69% of this population still required NICU hospitali-
ages at discharge; fewer days in intensive care and in the zation at 36 weeks’ PMA. (10)
hospital; lower total hospital cost; fewer cases of necrotiz- To address the goal of establishing PO independence
ing enterocolitis; and better growth (weight, height, and sooner in the preterm population, more NICUs are includ-
head circumference) at 2 weeks after intervention. (8) ing therapist-led decision making focused on individual-
Despite these developmental interventions, many infants ized, more intensive oral therapy to the infant's
remain hospitalized in the NICU days to weeks beyond 40 neurodevelopmental therapy plan. (11)(12)(13) Develop-
weeks’ postmenstrual age (PMA) because they continue to mentally, many premature infants are unable to achieve
require enteral tube feedings. partial to full PO ability safely until closer to 34 weeks’
In the last decade, to address this persistent dependence PMA, which means historically many NICUs did not
of patients on enteral tube feedings, many NICUs have introduce feeding therapy until after this gestational age
implemented earlier discharge programs with partial home marker. Recent studies support premature infants practic-
enteral nutrition via either NGT or GT feedings for infants ing using an immature suck as a form of non-nutritive
who have oral feeding dysfunction as the only remaining therapy to build oral feeding skills. (12)(13) In supporting
inpatient medical issue. Although the 2008 and 2018 Amer- an infant’s oral progress, Amaizu et al found that 1 to 2
ican Academy of Pediatrics (AAP) statements on hospital sessions of PO practice per day was just as successful as 6
discharge for high-risk infants emphasized individualized to 8 sessions per day when introduced as early as 26 to 29

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 weeks’ PMA, however, this single-center study had a small teams should now be able to more easily identify preterm
sample size and low power to detect true differences. (14) infants who may be eligible for an earlier safe discharge on
A recent pilot study of 40 premature infants used the pre- partial PO plus home enteral nutrition. Recently, discharge
mature infant oral motor intervention method to encour- feeding programs have been established to discharge NICU
age early PO skills. (15) Infants were randomized to have a patients with supplemental tube feedings once their medical
speech therapist or parent administer daily 5-minute ses- needs have stabilized. Although there are no standardized
sions of stimulation and non-nutritive feeding practice discharge criteria for supplemental tube feedings at present,
starting around 31 to 32 weeks’ PMA. Between the parent the Table summarizes discharge criteria and descriptors of
versus therapist group, mean PMA to first PO was 33 several programs. (21)(22)(23)(24)(25)(26)(27) These programs
weeks in both groups, with similar mean time to full PO included both extremely preterm infants and infants with
of 7.7 days in the parent group and 6.3 days with thera- medical complexity, but they excluded infants discharged
pists. Qualitative measures of parental satisfaction in this from cardiac intensive care units, those who required paren-
study were high and supported individual and family-cen- teral nutrition, and those who had contraindications to gastric
tered hospital care to reduce infant toxic stress, as feedings.
described by the AAP. (16) In general, programs required infants to demonstrate
Compared to controls without intervention, preterm infants clinical stability, including temperature and cardiorespira-
receiving both oral and nonoral tactile sensorimotor therapies tory stability, with a predetermined length of time receiv-
showed earlier suck-swallow strength compared with controls ing oxygen therapy and an apnea-free period off caffeine
starting at 29 weeks' PMA. (17) Similarly, a previous cue- or on caffeine if discharged with a home monitor. Oral
based feeding pathway showed reduced time to PO in another feeding criteria varied: 3 programs required a minimum
study for infants of more than 32 weeks’ PMA. (11) Once PO intake of 50% of enteral feedings before discharge,
these study infants demonstrated suck-swallow coordination (23)(24)(26) whereas 2 did not require a PO minimum.
with a pacifier for 3 minutes, they were then allowed to prac- (21)(25) Although none of the programs required objec-
tice twice daily per feeding therapist and nurse evaluation and tive studies to evaluate feeding dysfunction before dis-
advance PO feeding based on individual cues. By using this charge, such as a video fluoroscopic swallow study or
algorithm, this study showed an earlier time to full PO by 6 fiberoptic endoscopic evaluation of swallowing, pro-
days and improved weight gain in the cue-based group com- grams did assess infants for feeding safety, including
pared with controls. (11) Using this cue-based therapy method, back to sleep with NGT (23) and/or absence of apnea
premature infants develop PO skills earlier, which potentially with NGT in place. (21)(22)(23)(25)(26) Several pro-
allows for earlier discharge. (11)(12)(15)(18)(19) With individual- grams required a home assessment before discharge,
ized therapy and analysis of sucking patterns (eg, consistent which was typically performed by social workers, to
pattern of 1 suck per second), practitioners may be able to ensure that families had appropriate living conditions,
identify infants who can progress toward successful partial availability of caretakers, and psychosocial stability of
PO sooner. (7)(11)(17) In addition, targeted education for all caretakers to feed with an NGT. (22)(24)(25) Some pro-
NICU caregivers such as bedside nurses and therapists on grams in the United States offered discharge with sup-
cue-based feeding practices, rather than using a volume-driven plemental enteral tube feedings as early as 36 weeks’
feeding approach, has been shown to lead to earlier discharge PMA. (23)(27) Two European studies discharged infants
and improved parental involvement. (19)(20) A recent quality with partial NGT feedings as early as 34 weeks’ gesta-
improvement initiative at a quaternary NICU center showed tion without a PMA requirement if they met all other
that standardization of the feeding approach and training of criteria for discharge. (25)(26)
feeding therapists in the cue-based scoring method resulted in Before discharge, some programs also required parents to
a younger PMA for a preterm infant’s first PO intake and a complete a checklist that included demonstrating NGT
mean decrease in length of stay by 10 days compared with replacement, administering milk and medications via an
controls. (20) NGT, and rooming in with the infant to practice using home
equipment. (22)(25)(26) Not all programs required the dem-
DISCHARGE READINESS FOR HOME ENTERAL onstration of NGT insertion, but instead, arranged for fami-
FEEDING PROGRAMS lies to replace NGTs in outpatient clinics or hospitals. (23)(27)
By focusing on oral readiness and earlier introduction of One program provided some infants with a nasal bridle sup-
feeding interventions, feeding therapists and neonatology port for the NGT to help reduce accidental dislodgement. (27)

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 Tube Adverse HOME ENTERAL NUTRITION TUBE SELECTION
AND POSSIBLE DETERMINANTS FOR SELECTION

NGT < GT

NGT < GT

NGT < GT
0 for NGT

0 for NGT

0 for NGT
Unfortunately, there is no current standard approach about
after DC, days (n) Events

the type of home feeding tube (NGT vs GT) that should be

used in an infant who is unable to achieve full PO feedings
and is otherwise ready for discharge. Although NGTs are

CICU=cardiac intensive care unit; DC=discharge; GI=gastroenterology; GT, gastrostomy tube; NGT=nasogastric tube; PCP=primary care provider; TPN=total parenteral nutrition.
Median Time to
Wean off Tube

easy to place, replacement is frequently needed, and appro-

9 (113)

<60 (140)

27 (106)
12 (40)

29 (35)
8 (47)
priate positioning is essential. Although GTs are more sta-
ble than NGTs, the GT procedure has associated risks from
surgery and anesthesia and can have long-term complica-
tions such as soft-tissue infections or a malfunctioning/dis-
placed tube. (22)(28)
Weekly home nurse visits,
24/7 telephone access

GI/therapy/dietitian clinic

GI/therapy/dietitian clinic
PCP 1/- post-NICU clinic
Follow-up Options

PCP within 2 days, post-

Among NICUs in the United States from 2000 to

Post-NICU clinic, 24/7
telephone access

2012, the overall incidence of GT placement in the pediat-

ric population increased in VLBW infants from 11.5 to
NICU clinic

22.9 cases per 1,000 infants. (29) A 2019 study evaluated

114 independent NICUs in the United States from 2010 to
2012 with more than 8,000 NICU inpatients (excluding
those with congenital heart disease) and found that the
PO Minimum PMA Minimum

incidence of surgical GT placement ranged from 0.6% to

No limit

No limit

No limit
>36 wk

>37 wk

>36 wk
(upon DC)

19.6%. (30) Referral and urban NICUs had a higher inci-

dence of placement in this study. Hatch et al also found
that after confounder adjustments, VLBW infants in the
west or southern regional NICUs had a higher odds ratio
(upon DC)
None

None
50%

50%

50%

25%

of 1.6 of GT placement compared with the lowest region

of care, the northeast. (29)
Most recent early home enteral nutrition programs do
not have specific criteria for the timing of GT placement
Nongastric feedings, TPN, GT

CICU patients, nongastric

within 7 days admission,
Not discharged from NICU;
Table. Description of Earlier Home Enteral Nutrition (HEN) Programs

Craniofacial abnormalities,

Craniofacial abnormalities,

(22)(23)(25)(26). One program chose to place a GT in

Exclusion Criteria

abnormalities, social
Craniofacial/syndromic

nongastric feedings

infants who are unable to advance beyond 25% PO within

not GT candidates

2 weeks from the time that they are ready for discharge.
None mentioned
feedings, TPN

(27) Another program suggested GT placement if no oral

hospice
barriers

progress was made beyond 1 to 2 months after discharge.

(24) Before these programs, retrospective studies tried to
recommend GT placement based on inpatient clinical
No. (estimated HEN Type

characteristics. Greene et al gave a logistic prediction

NGT or GT

NGT or GT

NGT or GT

NGT or GT
NGT only

NGT only
(at DC)

model for preterm infants who may be deemed appropri-

ate candidates and showed that infants who were small
for gestational age (SGA), had younger birth PMA, and
Cohort Size,

less exposure to antenatal steroids were at the highest

260 (173)

183 (122)
123 (41)

163 (40)

119 (60)

100 (67)
per year)

risk for GT placement; maternal education level did not

influence placement. (30) Hatch et al found that VLBW
infants who had a surgical patent ductus arteriosus liga-
Van Kampen et al (25)

tion and/or bronchopulmonary dysplasia (BPD) were

Mago-Shah et al (23)

Williams et al (24)

Ermarth et al (22)

more likely to receive a GT before discharge. (29) In the

Schuler et al (26)

Lagatta et al (27)

studies that evaluated earlier discharge on home enteral

Reference

nutrition, common clinical characteristics associated with

GT placement included SGA infants and/or lower birth-
weight (22)(27); those who took less than 20% to 30%

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 PO by the time of discharge (22)(23)(24); and PMA greater PO INDEPENDENCE PROGNOSIS
than 45 weeks at the time of discharge. (22)(23)(27) When determining the prognosis of long-term oral feeding
Although percentage of PO remains a strong predic- success in infants being discharged with partial home enteral
tive clinical characteristic for postdischarge success with nutrition, several factors have been identified. One of the
achieving PO independence at home (see later section), strongest indicators for successful transition to complete oral
there is still some controversy over whether programs feedings is the proportion of PO an infant is taking on the
should use this as a marker for home enteral nutrition day of discharge, (21)(22)(23)(24)(25)(26)(27)(28) with higher
decisions. Some programs had no criteria for percentage PO associated with a shorter time to oral independence. How-
of PO by discharge, (22)(25) one required 25%, (27) and ever, the risk in setting a minimum PO metric for timing of
others did not allow for discharge with NGT unless discharge may lead to an increased length of stay and greater
infants were taking greater than 50% PO. (23)(24)(26) exposure to hospital-associated risks for infants who can go
One program reported that 9% of their GT population home safely with minimal PO intake. Outcomes with a lower
(those who did not reach 50% PO by discharge) achieved association of achieving feeding tube independence include
full PO intake within 60 days after discharge, suggesting infants with BPD, a need for antireflux medications, a history
that a portion of patients who have lower PO at the time of surgical patent ductus arteriosus closure, and/or a history
of discharge could avoid this surgical procedure. (24) of a high number of ventilator days. (22)(23)(27)(28)(29)(30)
For the programs without a PO minimum or less than In terms of growth patterns, Matharu et al. recently studied a
50% at discharge, their NGT population’s median time cohort of infants born at 30 weeks’ gestational age with
to 100% PO was still less than 30 days. (22)(25)(27) chronic lung disease (defined as oxygen at 28 days of age)
These outcomes suggest that centers with a home who were discharged from the hospital with partial enteral
enteral nutrition outpatient program and standardized feedings. (33) The infants in whom GT placement was
follow-up could consider delaying GT placement until avoided and only an NGT was used had larger occipitofrontal
after a trial of home NGT feedings. Furthermore, based circumferences and higher length z scores at discharge, sug-
gesting that hospital growth affects postdischarge feeding out-
on these programs’ outcomes, for those infants who ulti-
comes. (33) Although these specific growth parameters were
mately need GT placement, a preliminary trial of NG
different between this particular NGT and GT cohort, other
feedings at home could give infants the advantages of
home enteral nutrition programs with larger cohorts showed
earlier discharge to the home environment, with the abil-
no differences in adjusted weight at follow-up between tube
ity to increase their growth safely, and thus may also
groups. (22)(23)(24)
reduce complications associated with surgical GT place-
Many studies have reported that lower birthweight and
ment given that they will be bigger and more developed
SGA status were associated with worse inpatient feeding
at the time of surgery.
dysfunction in NICU patients. (10)(22)(23)(30)(34) However,
lower birthweight in grams was not always associated with
POSTDISCHARGE PATIENT METRICS
worse outcomes or a longer time to PO independence after
Postdischarge monitoring in the early home enteral nutrition discharge in 2 programs. (22)(25) Interestingly, several stud-
programs can range from primary care physician follow-up to ies have associated earlier gestational age as a risk factor for
frequent outpatient gastroenterology appointments or multi- in-hospital GT placement (23)(24)(31); however, these studies
disciplinary NICU follow-up clinics designed specifically to did not follow these infants after discharge to evaluate
support the population receiving partial enteral feedings whether gestational age was still associated with prolonged
(Table). Some programs offer access to feeding therapists time to wean off tube feedings, despite needing a GT. Lower
after discharge in addition to medical practitioners. (22)(27) birth gestational age was not found to be a risk factor for the
Another European program provided families with access to inability to wean off enteral feedings after discharge in 2
weekly home nursing and 24-hours-a-day, 7-days-a-week tele- studies. (22)(28)
phone access to a medical care team. (25) In support of the
multidisciplinary follow-up model, an early discharge pro- HOME ENTERAL NUTRITION RISKS AND
gram in Sweden developed a home home enteral nutrition COMPLICATIONS
program with home nursing support and reported reduced In NICU infants who are unable to achieve complete PO,
parental anxiety at the time of discharge when compared the use of home NGT feedings has been shown to be asso-
with parents receiving standard outpatient care. (31)(32) ciated with significantly fewer complications than home

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 GT use. Recent studies support the safety of home NGT psychosocial outcomes of families, more studies are needed
feedings; 7% to 15% of tube-related emergency department to accurately assess family satisfaction and infant quality of
(ED) visits after discharge occurred in infants with NGT life after early discharge with home enteral nutrition.
feedings, (22)(24)(28) whereas more than 60% of tube- Educating families about GT care before GT placement
related ED visits occurred in infants with GTs. has been found to lead to lower medical utilization postop-
(22)(24)(28)(35)(36)(37)(38) Hospital readmissions for eratively by more than 30% compared with families who
NGT-related reasons ranged from 2% to 6% (excluding were educated after GT placement. (40)(41)(42) Three pro-
scheduled hospitalizations or procedures), (22)(23)(24) grams that provided GT preplacement family education
whereas GT-related readmissions were higher. found a significant reduction in the number of office visits,
(22)(23)(24)(27)(28) Other studies showed that the risk of ED visits, and readmissions at the 12-month postdischarge
readmissions and ED visits within 90 days after discharge period, as well as a trend toward reduced medical utiliza-
with an inpatient GT placement is 1.6 and 1.7 times more tion at the 3-month postdischarge period. (40)(41)(42) In
likely than for NGTs, respectively, in preterm infants. (37) the program established by Devin et al, patients who were
Most of the causes for GT complications requiring ED pre- discharged with NGT feedings with a plan for GT place-
sentation or rehospitalization include cellulitis, GT dis- ment at a later date and had a “follow-up feeding tube med-
placement, stoma complications, and feeding intolerance. ical home” to assist after discharge, found an unintended
(22)(27)(37)(38)(39) consequence of decreased GT placements in 5% of the
Accurate quantification of the number of true adverse patients, and reduced Nissen fundoplication placement by
events in infants discharged with home NGT or GT feed- 2-fold (48% vs 22%). (41) These patients also successfully
ings is difficult, as some studies use only proportions of weaned off NGT feedings before their surgical date in a
populations. In addition, there is no accepted timeframe for median time of 4 months. (41) Introducing presurgical
follow-up; some programs report events up to 12 months, family education and medical home resources shows prom-
(24) while others report events from 3 to 6 months after ise toward the reduction of complications and avoidance of
discharge. (22)(23)(26)(27)(28) Going forward, more uni- unnecessary medical utilization.
form incidence reporting of outcomes for home enteral
nutrition should be strongly considered and adopted. One
program analyzed adverse events based on “tube exposure Summary
days” over time to provide a more standardized measure of A standardized approach does not exist to provide
reporting. (22) This group calculated an incidence of ED earlier discharge to NICU patients who are medically
visits and hospital readmissions for all NGT or GT-related stable but still require a feeding tube. However,
events for every 500 tube exposure days in their cohort and results from programs currently offering earlier dis-
showed 1.6 ED visits and 0.8 hospital admissions for every charge are encouraging and help to reach this goal.
500 tube days within 6 months of discharge. (22) Cohort studies of these new programs have shown
that the use of home NGT feedings is safe if family
QUALITY OF LIFE WITH EARLIER HOME ENTERAL education and appropriate home monitoring are pri-
NUTRITION oritized. Enteral tube feedings have been shown to
In programs that measured satisfaction of earlier discharge have advantages over home GT placement, such as
with home enteral nutrition, parental satisfaction and quality fewer unplanned ED visits and hospitalizations and
of life were rated highly and anxiety was decreased in parents patient complications. Because the patient popula-
of early discharge infants compared with parents of infants tion requiring home enteral nutrition is quite hetero-
who were not offered earlier discharge. (21)(25)(26)(27) One geneous and vulnerable, randomization of feeding
study even had similar satisfaction between parents whose practices may never be possible to understand the
infants were rehospitalized (for all causes including scheduled absolute best practices and/or exact patient selection
admissions) and those who were not, suggesting that dis- for home NGT versus GTs. Although these earlier
charging an infant sooner, despite medical complexity, has discharge approaches have reported successful out-
the advantages of reducing parental stress and improving comes for infants and families, there are still some
quality of life for the family-infant dyad. (26) However, given gaps and controversies in the current medical litera-
that all programs had variations in follow-up time and sup- ture that need to be addressed by future studies and
port provided, which could affect both the clinical and larger patient consortiums.

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 10. Edwards L, Cotten CM, Smith PB, et al; Eunice Kennedy Shriver
National Institute of Child Health and Human Development.
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Qual Life Outcomes. 2017;15(1):38 tube weaning and predictive clinical characteristics of NICU patients
6. Lau C. Development of infant oral feeding skills: what do we know? with feeding dysfunction. JPEN J Parenter Enteral Nutr.
Am J Clin Nutr. 2016;103(2):616S–621S 2020;44(5):920–927
7. Lau C. To individualize the management care of high-risk infants 23. Mago-Shah D, Malcom WF, Greenberg RG, Goldstein RF. Discharging
with oral feeding challenges: What do we know? What can we do? medically complex infants with supplemental nasogastric tube feeds:
Front Pediatr. 2020;8:296. impact on neonatal intensive care unit length of stay and prevention of
8. Als H, Gilkerson L, Duffy FH, et al. A three-center, randomized, gastrostomy tubes. Am J Perinatol. 2021;38(S1):e207–e214.
controlled trial of individualized developmental care for very low birth 24. Williams SL, Popowics NM, Tadesse DG, Poindexter BB, Merhar
weight preterm infants: medical, neurodevelopmental, parenting, and SL. Tube feeding outcomes of infants in a level IV NICU. J
caregiving effects. J Dev Behav Pediatr. 2003;24(6):399–408 Perinatol. 2019;39(10):1406–1410
9. Collins CT, Makrides M, McPhee AJ. Early discharge with home 25. van Kampen F, de Mol A, Korstanje J, et al. Early discharge of
support of gavage feeding for stable preterm infants who have not premature infants <37 weeks gestational age with nasogastric tube
established full oral feeds. Cochrane Database Syst Rev. 2015; feeding: the new standard of care? Eur J Pediatr.
(7):CD003743 doi: https://doi.org/10.1002/14651858.CD003743.pub2 2019;178(4):497–503

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 26. Schuler R, Ehrhardt H, Mihatsch WA. Safety and parental satisfaction versus abnormal antenatal Doppler characteristics. J Neonatal
with early discharge of preterm infants on nasogastric tube feeding Perinatal Med. 2017;10(1):43–48
and outpatient clinic follow-up. Front Pediatr. 2020;8:505 35. Mason CA, Skarda DE, Bucher BT. outcomes after laparoscopic
27. Lagatta JM, Uhing M, Acharya K, et al. Actual and potential impact gastrostomy suture techniques in children. J Surg Res.
of a home nasogastric tube feeding program for infants whose 2018;232:26–32
neonatal intensive care unit discharge is affected by delayed oral 36. Aprahamian CJ, Morgan TL, Harmon CM, Georgeson KE, Barnhart
feedings. J Pediatr. 2021;234:38–45.e2 DC. U-stitch laparoscopic gastrostomy technique has a low rate of
28. Khalil ST, Uhing MR, Duesing L, Visotcky A, Tarima S, Nghiem- complications and allows primary button placement: experience with
Rao TH. Outcomes of infants with home tube feeding: comparing 461 pediatric procedures. J Laparoendosc Adv Surg Tech A.
nasogastric vs gastrostomy tubes. JPEN J Parenter Enteral Nutr. 2006;16(6):643–649
2017;41(8):1380–1385 37. Duncan TL, Ulugia J, Bucher BT. Association of gastrostomy
29. Hatch LD, Scott TA, Walsh WF, Goldin AB, Blakely ML, Patrick placement on hospital readmission in premature infants. J Perinatol.
2019;39(11):1485–1491
SW. National and regional trends in gastrostomy in very low birth
weight infants in the USA: 2000-2012. J Perinatol. 38. Fox D, Campagna EJ, Friedlander J, Partrick DA, Rees DI,
2018;38(9):1270–1276 Kempe A. National trends and outcomes of pediatric
gastrostomy tube placement. J Pediatr Gastroenterol Nutr.
30. Greene NH, Greenberg RG, O’Brien SM, et al. Variation in
2014;59(5):582–588
gastrostomy tube placement in premature infants in the United
States. Am J Perinatol. 2019;36(12):1243–1249 39. Merli L, De Marco EA, Fedele C, et al. Gastrostomy placement in
children: percutaneous endoscopic gastrostomy or laparoscopic
31. Ortenstrand A, Winbladh B, Nordstr€om G, Waldenstr€om U. Early
gastrostomy? Surg Laparosc Endosc Percutan Tech.
discharge of preterm infants followed by domiciliary nursing care: 2016;26(5):381–384
parents’ anxiety, assessment of infant health and breastfeeding. Acta
40. Richards MK, Li CI, Foti JL, et al. Resource utilization after
Paediatr. 2001;90(10):1190–1195
implementing a hospital-wide standardized feeding tube placement
32. Han C, Shin J, Jeon GW. Development of swallowing function in pathway. J Pediatr Surg. 2016;51(10):1674–1679
infants with oral feeding difficulties. Int J Pediatr.
41. Devin CL, Linden AF, Sagalow E, et al. Standardized pathway for
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feeding tube placement reduces unnecessary surgery and improves
33. Matharu P, Cristea AI, Slaven JE, Becker S, Niehaus JZ. Feeding value of care. J Pediatr Surg. 2020;55(6):1013–1022
outcomes for infants with bronchopulmonary dysplasia
42. Skertich NJ, Lee TK, Grunvald MW, et al. The effect of standardized
discharged on nasogastric feeds. Am J Perinatol. 2021;
discharge instructions after gastrostomy tube placement on
38(9):897–900 postoperative hospital utilization [published online ahead of print
34. Ahamed MF, Dar P, Vega M, Kim M, Gao Q, Havranek T. Early March 26, 2021. J Pediatr Surg. S0022346821002797. https://doi.
feeding tolerance in small for gestational age infants with normal org/10.1016/j.jpedsurg.2021.03.045

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 NEOREVIEWS QUIZ

NEO
QUIZ
1. Preterm infants need to demonstrate physiologic competencies before
discharge from the NICU, including sufficient oral feeding to support
appropriate growth, ability to maintain normal body temperature, and
respiratory control that is sufficiently mature. In a large multicenter,
randomized, controlled trial, individualized developmental care of very low
birthweight preterm infants was shown to lead to discharge at younger
ages. Which of the following statements was NOT a benefit of individualized
developmental care in this trial?

A. Fewer days of parenteral feeding.

B. Shorter transition periods to full enteral feeding.
C. Increased height at 42 weeks’ postmenstrual age (PMA). REQUIREMENTS: Learners can
D. Lower total hospital cost. take NeoReviews quizzes and
E. Decreased incidence of necrotizing enterocolitis. claim credit online only at:
http://pedsinreview.org.
2. Oral feeding dysfunction remains a main reason for continued NICU
hospitalization in medically complex and premature infants. What is the To successfully complete 2022
incidence of inpatient oral feeding difficulty in this population? NeoReviews articles for AMA PRA
Category 1 Credit™, learners
A. Up to 20%. must demonstrate a minimum
B. Up to 40%. performance level of 60% or
higher on this assessment. If
C. Up to 50%.
you score less than 60% on the
D. Up to 60%. assessment, you will be given
E. Up to 80%. additional opportunities to
answer questions until an
3. The goal of establishing oral independence sooner in the preterm overall 60% or greater score is
population is a high research priority. Data suggest that individualized achieved.
intensive oral therapy, including non-nutritive sucking and cue-based
feeding approaches, is beneficial in preterm neonates. What is the PMA at This journal-based CME activity
is available through Dec. 31,
which typical preterm neonates are developmentally able to orally feed
2024, however, credit will be
safely? recorded in the year in which
the learner completes the quiz.
A. 29 weeks’ PMA.
B. 31 weeks’ PMA.
C. 32 weeks’ PMA.
D. 34 weeks’ PMA.
E. 36 weeks’ PMA.
4. Preterm infants able to feed orally partially may be eligible for safe earlier 2022 NeoReviews is approved
discharge from the NICU with a nasogastric tube (NGT) or gastrostomy tube for a total of 30 Maintenance of
Certification (MOC) Part 2
(GT) and the support of a home enteral nutrition program. Which of the credits by the American Board
following clinical characteristics is NOT associated with a need for GT of Pediatrics (ABP) through the
placement in preterm infants discharged with an NGT? AAP MOC Portfolio Program.
NeoReviews subscribers can
A. Small for gestational age status. claim up to 30 ABP MOC Part 2
B. Maternal education level. points upon passing 30 quizzes
(and claiming full credit for
C. Oral intake proportion less than 20% to 30% at NICU discharge time.
each quiz) per year. Subscribers
D. PMA above 45 weeks at NICU discharge time. can start claiming MOC credits
E. Lower birthweight. as early as October 2022. To
learn how to claim MOC points,
go to: https://www.
aappublications.org/content/
moc-credit.

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 5. Infants discharged from the NICU with partial oral intake should be closely
monitored because of associated risks and complications of home enteral
nutrition. What is the rate of hospital readmission in infants discharged with
an NGT?

A. Between 2% and 6%.

B. Between 10% and 14%.
C. Between 16% and 20%.
D. Between 25% and 30%.
E. Between 40% and 50%.

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 ARTICLE

Developing a Quality Improvement

Feeding Program for NICU Patients
Erika K. Osborn, MS, APRN, NNP-BC,* Sudarshan R. Jadcherla, MD*,†,‡
*Innovative Neonatal and Infant Feeding Disorders Research Program, Center for Perinatal Research, The Research Institute at Nationwide Children’s
Hospital, Columbus, OH
†
Divisions of Neonatology and Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH
‡
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH

PRACTICE GAPS

• Evidence-based approaches to feeding premature infants are limited,

which leads to practice variation in NICUs.
• A quality improvement program to improve feeding outcomes in pre-
mature infants needs to be a priority in NICUs.

OBJECTIVES After completing this article, readers should be able to:

1. Describe the epidemiology of feeding difficulties and physiologic

evidence-based approaches that should be incorporated into NICU
feeding guidelines.
2. Recognize the steps required to develop a quality improvement feeding
program in the NICU.
3. Explain how to sustain a NICU feeding program and affect process
change to improve clinical outcomes.

AUTHOR DISCLOSURES Ms Osborn and

ABSTRACT Dr Jadcherla have disclosed no financial
Practices in NICUs vary widely, particularly when clinical decisions involve relationships relevant to this article. This
commentary does not contain a
complex tasks and multiple disciplines, which occurs with feeding preterm
discussion of an unapproved/
infants. Neonatal feeding difficulties in preterm infants often lead to investigative use of a commercial
prolonged tube feeding and therefore lengthened hospital stays. product/device.
Education and compliance with evidence-based protocols and guidelines
are needed on the initiation of feedings and feeding advancement to ABBREVIATIONS
transform enteral and oral feeding practices and thus reduce practice GA gestational age
variation and improve clinical outcomes. GI gastrointestinal
HFNC high-flow nasal cannula
LOHS length of hospital stay
NCPAP nasal continuous positive
INTRODUCTION airway pressure
Feeding difficulties among preterm infants are universally prevalent in NICUs. NEC necrotizing enterocolitis
Challenges can arise at any time between the initiation of enteral feedings soon PMA postmenstrual age
SIMPLE simplified, individualized,
after birth until the achievement of full oral feedings when infants can be safely milestone-targeted, pragmatic,
discharged from the hospital. Variability in feeding practices is common in longitudinal, and educational

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 NICUs globally. (1)(2)(3) Clinical guidelines have been bedside feeding clinicians, and specifying the roles of
used to minimize variability and improve outcomes in parents and clinicians. With an individualized feeding pro-
clinical practice, but these guidelines need to be developed gram, any NICU can improve clinical outcomes as defined
based on evidence to maximize benefits and avoid harm. by the unit’s aims. In this review, we provide an overview
(4) of the evidence that we incorporated into our feeding pro-
Unfortunately, studies evaluating multiple enteral and gram’s guidelines to allow other units to establish a similar,
oral feeding guidelines developed for preterm infants have but unit-specific, program.
found mixed outcomes. (5)(6)(7)(8) The content of these
guidelines varies widely, particularly where the evidence is EPIDEMIOLOGY AND PHYSIOLOGY-BASED
limited or weak. (5)(6)(7)(8) Not surprisingly, a review of INFANT FEEDING GUIDELINES
oral feeding guidelines in premature infants showed that All preterm births (ie, <37 weeks’ gestation) account for
rigorous research on infant feeding is needed. (5) Clinical approximately 15 million births globally each year, which
guidelines require an evidence-based approach when pos- is associated with increased morbidity, mortality, and
sible and must also be developed based on the culture of socioeconomic burden. (11) The total cost of preterm
the unit where they will be implemented with goals based births in the United States was 25.2 billion dollars in
on that unit’s needs. For example, a level II NICU in a 2016. The cost for an infant born at less than 28 weeks’
rural area with only inborn patients will not have the GA is more than 12 times the cost of an infant born at 32
same needs as a level IV NICU in a children’s hospital to 36 weeks’ GA. (12) After discharge, feeding problems
where infants are transferred from other centers. affect approximately 42% of premature infants without
We developed the simplified, individualized, milestone- significant comorbidities, and this number is likely higher
targeted, pragmatic, longitudinal, and educational (SIMPLE) in the presence of multisystemic comorbidities. (13) Fur-
feeding program in our all-referral level IV NICU after we thermore, preterm infants comprise approximately 40% of
observed variability in preterm infant feeding practices infants referred to clinics for chronic feeding issues. (14)
among our clinicians. The program targeted feeding mile- One of the most important determinants of preterm
stones throughout NICU hospitalization, based on available infant growth and development is providing timely enteral
evidence of feeding practices. Infants were included if they nutrition, which is often a challenge in the NICU setting.
were born at less than or equal to 32 weeks’ gestational age Preterm infants often need central venous catheters to
(GA) and were excluded if they had surgical necrotizing provide adequate parenteral nutrition, which places them
enterocolitis (NEC), intraventricular hemorrhage with ven- at increased risk for nosocomial bloodstream infections
tricular dilation or intraparenchymal involvement, chromo- because of their immunocompromised state. To decrease
somal abnormalities, or gastrointestinal (GI) or neurologic the length of central catheter use, preterm infants need to
surgery. This program significantly increased the number of begin gastric feedings and advance to full enteral nutrition
infants who received trophic feedings, decreased the time to as early as possible. Early attainment of full enteral nutri-
full enteral feedings, increased weight gain velocity, and tion is often delayed in premature infants because of per-
decreased length of hospital stay (LOHS) compared with a ceived intolerance or concerns for risk of NEC, though a
baseline group of infants before the program was imple- Cochrane review showed that slow advancement of intra-
mented. (9)(10) The program was developed and sustained gastric feedings (15–20 mL/kg per day, compared with
in a process undertaken by a group that was passionate 30–40 mL/kg per day) did not decrease the risk of NEC in
about infant feeding, with the main goal of improving clini- very preterm or very low-birthweight infants. (15)
cal outcomes related to feeding in the NICU. The initiation of oral feedings and the progression to
A practice guideline such as the SIMPLE program can full oral feedings have also been found to be delayed in
be established in any NICU regardless of size or patient preterm infants. These delays are often attributed to car-
population. When developing preterm feeding guidelines, it diorespiratory instability or inadequate pharyngeal-esopha-
is important to understand the epidemiology of feeding dif- geal motility and airway protective mechanisms that need
ficulties, establish physiologic evidence-based approaches, time for maturation. (16) In a prospective study of 6,017
and customize the program to the individual unit. Sustain- moderately premature infants still hospitalized at 36
ing the program and effecting process change can be weeks’ postmenstrual age (PMA), one-third of the infants
accomplished by tracking feeding milestones, examining who were born at 29 to 33 weeks’ GA remained hospital-
compliance metrics, providing targeted education to ized solely because of inadequate oral intake. (17) Prenatal

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 and postnatal physiology, as well as limited opportunities for randomized trial of early progressive feeding versus
oral feeding experiences, affect the advancement to full oral delayed feeding after 4 days of trophic feeding in infants
feedings in hospitalized preterm infants and could prolong with gestations of less than or equal to 28 weeks showed
hospital stay or lead to discharge with tube feedings. that early progressive feeding significantly reduced the
The American Academy of Pediatrics identifies oral prolonged need for parenteral nutrition (and therefore
feeding competency to sustain growth as 1 of 3 physiologic central catheter use), incidence of culture-positive sepsis,
criteria for hospital discharge of preterm infants with and incidence of poor growth (weight, length, and head
nasogastric feeding as a limited option for discharge in circumference <10th percentile) at 36 weeks’ PMA with
select cases. (18) However, recently many centers are dis- no significant difference in the composite outcome of NEC
charging preterm infants who are receiving nasogastric or death. (22) A Cochrane review of trial data of early full
feedings. Given the complexity of the NICU patient, iden- enteral feeding (60–80 mL/kg per day 1 day after birth) com-
tifying the appropriate patient, the ideal family, a safe pared with gradual advancement of feeding did not provide
home environment, and the ability for close follow-up are sufficient evidence to support either practice. (23)
important for establishing successful home nasogastric
feedings. Home nasogastric feedings also pose postdis Preoral Interventions. Although enteral feeding is
charge risks such as trauma from placement, dislodged or extremely important to the preterm infant, there are pre-
misplaced tube, clogging of tube, and aspiration, all of oral interventions that can enhance feeding-related out-
which lead to an increase in hospital and clinic visits. (19) comes. Oral care with colostrum and expressed breast milk
is an intervention that has the potential to provide improved
Preoral Feeding
immunity, better feeding tolerance, and decreased time to
Trophic Feeding. Multiple studies have examined the bene-
full enteral feeding. (24)(25) Kangaroo care is another treat-
fits and risks of trophic feeding in both animal and
ment that should be provided to all preterm infants. (3) In a
human models. Trophic feeding is defined by McClure as
randomized controlled trial of preterm infants of 32 to 36
“the practice of feeding nutritionally insignificant volumes
weeks’ GA at birth, kangaroo care was shown to significantly
of enteral substrate to the compromised newborn infant
increase the length of breastfeeding time from 2 to 5 months
in order to stimulate and supply nutrients to the develop-
and significantly increase exclusive breastfeeding at multiple
ing GI system.” (20) In a review of randomized controlled
time points (up until 6 months). (26)
trials in preterm infants, trophic feeding was shown to 1)
elevate gastrin, enteroglucagon, and motilin, which stimu-
Introduction to Oral Feeding
late GI growth, function, and motility; 2) increase enteric
The timing of introducing oral feedings to the preterm
blood flow; 3) enhance proximal intestinal motor activity; 4)
infant can vary based on practice variation, clinician pref-
decrease the amount of time to reach full enteral feedings; 5)
erence, the infant’s clinical condition, and other factors.
decrease the risk of sepsis; and 6) decrease the LOHS. (20)
Clear guidelines for when to initiate oral feeding should
In contrast, a Cochrane review of randomized controlled tri-
als in preterm infants born at less than 32 weeks’ GA or be based on preterm physiology and available evidence.
birthweight less than 1,500 g found no evidence to suggest
Fetal Development of Sucking and Swallowing. The develop-
a statistically significant benefit to early trophic feeding (up
ment of sucking and swallowing begins in utero. Swallow-
to 24 mL/kg per day started before 96 hours of age and
ing of amniotic fluid begins around 11 to 12 weeks’
continued for at least 1 week) versus enteral fasting (during
that same period); however, there was no evidence of signif- gestation and is an important regulator of amniotic fluid
icant harm from minimal enteral nutrition such as volume. Sucking movements develop by 18 to 20 weeks’
increased risk of NEC, invasive infection, or mortality. (21) gestation. (27) The fetus swallows approximately 250 mL/kg
Further clinical trials are needed to provide more robust per day of amniotic fluid by 28 weeks’ gestation. (28) After
evidence for trophic feeding. birth, preterm infants are able to swallow their own saliva
and secretions, but they are no longer receiving the in
Enteral Feeding Advancement. Advancement to full enteral utero experience of swallowing large volumes of amniotic
feeding in preterm infants is important so that central fluid continually, which would continue to develop their
catheters can be removed as soon as possible. The practice swallow function. (28) A study that investigated the role
of advancing enteral feedings varies from the initial day of swallowing during sleep found that preterm infants
that feedings are started to 14 days later. A single-center only swallow about once per minute in active sleep at

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 term PMA, illustrating the limited number of swallowing based on an assigned quality score. The focus is on the
opportunities if they are not being orally fed. (29) quality of the feeding rather than the volume of the
Swallowing evolves as early as 11 weeks’ gestation, how- feeding.
ever, studies show that coordination of the processes In the development of our SIMPLE program, cue-based
involved with oral feeding begin by 33 to 34 weeks’ PMA feeding readiness scores were based on the system used
and continue to mature beyond term PMA. (30) The by Davidson et al, which were adapted from Ludwig and
attainment of these skills is influenced negatively by the Waitzman. (36)(37) In this approach, the feeding readiness
presence of neurologic, aerodigestive, and pulmonary score consisted of a 5-point scale that was condensed into
comorbidities. This was shown by a retrospective study of a 3-point scale as the program evolved (Table 1) to make it
premature infants of less than 35 weeks’ gestation that simpler and more user-friendly, such that parents could
found lower gestational age, history of hypotension, and calculate a score. With the new scale of 0, 1, and 2, oral
increased duration of ventilation all correlated with later feeding is only offered with a readiness scale of 2. To initi-
attainment of full oral feeding. (16) ate cue-based feedings, the infant needs a score of 2 for at
least 50% of the feedings during a 24-hour period. The
Initiation of Oral Feeding. The introduction of oral feeding feeding quality scale is based on 5 categories to provide a
is usually attempted in clinically stable infants at approxi- quantitative value to the oral feeding quality, as shown in
mately 32 to 34 weeks’ PMA when they potentially have Table 2. (36) That number can be tracked over multiple
the maturation to control and coordinate the complex feedings or days to indicate improvement or regression
feeding process of sucking and swallowing a bolus feed with feedings without relying solely on the feeding volume
while demonstrating respiratory rhythm regulation. (30) and is not used as a marker of when to hold oral feedings.
Many studies use multiple criteria for determining the
time to begin oral feeding in premature infants. In a ran- Oral Feeding with Respiratory Support. Although there are
domized controlled study of 29 infants of less than 30 mixed results on the safety and feasibility of oral feeding
weeks’ gestation, infants in the intervention group initi- when an infant requires nasal continuous positive airway
ated oral feeding 48 hours after achieving full enteral feed- pressure (NCPAP) and high-flow nasal cannula (HFNC), it
ings (120 kcal/kg per day) whereas the timing of oral has been shown to be feasible in stable infants. A survey
feeding of infants in the control group was left to the dis- in Australia and New Zealand showed varied practices
cretion of the attending physician. (31) The intervention regarding oral feeding of infants and children receiving
group initiated and achieved full oral feeding significantly NCPAP and HFNC. (38) Oral feeding of children receiving
sooner than the control group. (31) Another randomized NCPAP was reportedly done often, sometimes, and rarely
controlled study by Pickler et al examined 4 feeding strate- in 2%, 45%, and 22% of respondents, respectively. Oral
gies starting either at 32 or 34 weeks’ PMA and oral feed- feeding while receiving HFNC support was done often,
ing either with every feeding or gradually increasing from sometimes, and rarely in 38%, 41%, and 17% of respond-
2 to 8 feedings per day over 2 weeks. (32) The authors ents, respectively. (38) A study of infants born between 24
found that the group with the later start (ie, 34 weeks’ and 27 weeks’ GA who were receiving NCPAP at 37 to 42
PMA) who received 8 oral feedings per day took signifi- weeks’ PMA compared 26 infants who were orally fed to
cantly fewer days to advance to full oral feedings. (32) As 27 infants who were exclusively gavage fed until discontin-
all infants mature at a slightly different rate, tools are neces- uing NCPAP. The study showed significantly earlier
sary for evaluating when to begin oral feedings in preterm achievement of full oral feeding by more than 2 weeks
infants. A Cochrane review of tools to assess readiness for with no incidence of clinically significant aspiration pneu-
oral feeding did not find any studies to inform clinical prac- monia in the infants who were orally fed while receiving
tice in this area. (33) NCPAP. (39) Mechanistic studies using manometry evalu-
ation of pharyngoesophageal reflexes and airway safety
Cue-based Feeding. Infant-driven feeding, also known as supported the presence of basal and adaptive aerodigestive
cue-based feeding, has become common in most NICUs reflexes in infants receiving noninvasive respiratory sup-
but is often loosely interpreted and adapted. Most data are port. (40) A retrospective analysis of infants receiving
based on retrospective reviews of quality improvement NCPAP who were either fed orally with cues or not
projects. (34)(35) Cue-based feeding involves using a feed- offered oral feeding showed no statistical difference in out-
ing readiness scale to determine infant readiness for oral comes or morbidities in either group. (41) A quality
feeding and then evaluating the quality of each feeding improvement effort to achieve breastfeeding and bottle

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 Table 1. Oral Feeding Readiness Scale (Original and Revised)
Scale Original Scale Revised
1 Needs increased oxygen (from patient’s baseline) for care 0 Unstable with care, not ready for oral feeding
2 Sleeps through care, no hunger cues 1 Briefly alert, but not showing enough interest in
oral feeding
3 Briefly alert with care, no hunger cues
4* Drowsy or alert once handled, able to elicit rooting or takes pacifier 2* Wakens at feeding time or when handled, roots,
sucks on pacifier
5* Awakens at or before scheduled care, alert or fussy during care,
rooting and/or hands to mouth, takes pacifier

Revised scale modified from original. (36) Original scale used with permission from Elsevier.
*Oral feeding should be offered.

feeding competence in a safe gradual manner developed NEC, sepsis, and severe intraventricular hemorrhage can
an algorithm for offering and advancing oral feeding in all have significantly delayed feeding milestones and may
stable infants at 32 weeks’ PMA with or without CPAP. require more time than the preterm infant without signifi-
They compared their data from the first 6 months of imple- cant comorbidities. (27) This high-risk group may also
menting the algorithm to a baseline group 6 months before require some oral feeding method modifications such as
implementation and found significantly lower PMA at first pacing and different positioning, as well as instrumental
oral feeding and first breastfeeding in the intervention testing to evaluate for gastroesophageal reflux disease (eg,
group, but no significant difference was found with feeding pH impedance) and/or intestinal dysmotility (eg, esopha-
method used at discharge. The group did not observe any geal motility testing). Aspiration can also occur in preterm
cases of suspected aspiration or increased distress related to infants when a bolus penetrates below the vocal cords.
the oral feeding opportunities. (42) This can be antegrade (during oral feedings) or retrograde
(during proximal gastroesophageal reflux). Both of these
Oral Feeding to Discharge require objective diagnostic testing with personalized treat-
Once oral feeding is initiated in preterm infants, it can be ments. (43)(44) Some infants simply require prolonged
advanced based on clinician-driven limitations or on the tube feedings because of dysmaturity.
infant’s cues. Allowing preterm infants to eat based on Thickening of feedings should be reserved for infants with
cues ensures that no feeding opportunities are missed older PMAs and only if clinically indicated. Adding cereal or
when they demonstrate signs of readiness. If oral feeding other additives to formula or breast milk should be avoided, if
does not progress, it is necessary to examine potential bar- possible, because of the higher osmolality, which is not recom-
riers. Preterm infants with multiple comorbidities such as mended for preterm infants. (45)(46) Premature introduction
bronchopulmonary dysplasia, patent ductus arteriosus, of cereal or other prepared thickeners is also associated with

Table 2. Feeding Quality Scale

Category Criteria Score
Alert state Maintains alert state, or if drowsy, suckles without reminders/stimulation 2
Sleepy; able to wake, but falls asleep due to limited capacity for alertness 1
Unable to wake; may be unstable; does not initiate sucking on own 0
Suck/swallow/breathe Maintains safe suck/swallow/breathe coordination throughout 2
coordination Immature skill; requires pacing, positioning, or nipple change 1
Uncoordinated suck/swallow/breathe, resulting in apnea/bradycardia/desaturation 0
Fluid loss Minimal loss; typical drooling/leaking 2
Intermittent fluid loss that does not occur with each suck burst 1
Excessive fluid loss, as evidenced by fluid loss with each suck/swallow 0
Work of breathing No increased work of breathing 2
Increase in work of breathing, as evidenced by increased retractions, tachypnea, or head bobbing 1
Significant increase in work of breathing, requiring discontinuation of feed 0
Volume 100% volume taken 2
50%–99% volume taken 1
<50% taken 0
Total score 0-10

Quality scale used with permission from Elsevier.

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 infection risks, constipation, and risk for childhood obesity. conditions, such as cardiorespiratory illness, are managed
(47)(48) The associated decrease in breast milk or breastfeed- with restricted total fluid volume and increased caloric
ing found with thickened feedings is not ideal as breast milk density. The volume and calories to achieve full oral feed-
has shown benefits of immune defense, GI development, bet- ings need to be personalized to the individual needs of
ter nutrition, and improved neurologic outcomes, particularly the infant based on comorbidities, tolerance, and growth.
with preterm infants in the hospital. (49) In some infants, Premature infants who do not need to be fluid restricted
cereal or other thickeners can lead to excessive effort to extract should be discharged on ad lib oral feedings with follow-
thickened milk via the nipple, which may be particularly diffi- up with both a primary physician and a developmental
cult for infants with lung disease. Appropriate cleaning of bot- follow-up clinic for close monitoring of their growth and
tles, nipples, and inserts when using thickened milk can also nutrition. They should be monitored on full ad lib oral
be difficult and may predispose infants to infections. Added volumes for 1 to 2 days before discharge to ensure ade-
rice starch formulas can lead to decreased availability of cal- quate weight gain (10–20 g/kg per day) with their current
cium, zinc, and protein compared with preterm discharge for- intake. (50) It is important to ensure growth of weight,
mulas. (46) length, and head circumference during and after a NICU
Most cases of feeding dysfunction in preterm infants stay. This requires a discharge plan with reliable follow-
resolve with maturation of oral skills and esophageal function up of feeding, growth, and developmental milestones to
in the presence of good nutrition and growth. As preterm avoid a disconnect in transition from the NICU to the
infants mature, they establish more regulated apneas during community.
the act of deglutition and increased strength and number of Preterm infants may not reach full oral feedings before dis-
pharyngeal contractions. All of this leads to the improvement charge and as a result, may require long-term home tube
of esophageal peristalsis and propagation, bolus clearance, feeding. Home tube feeding can be provided with a nasogas-
and lower esophageal sphincter relaxation to empty boluses tric or gastrostomy tube. Units that discharge infants from
into the stomach (Fig 1). During this time of maturation, the the hospital with nasogastric feeding should define eligibility
number of consistent oral feeding experiences may be the criteria as well as outline a postdischarge management plan.
most important intervention, which requires diligence and (19) (51) To promote eventual full oral feeding, a feeding
patience from both parents and clinicians. plan should be developed with the parents to optimize oral
The definition of full oral feeding volume varies among feeding opportunities at home and provide them with the
populations and ranges from 120 to 200 mL/kg per day knowledge to care for their infant with home tube feedings.
with varying caloric densities, as certain medical Both family education and follow-up are imperative; families

Figure 1. Oral feeding challenge showing that biomarkers improved with maturation over a 4-week period. This figure shows results of an oral feeding
challenge during high-resolution esophageal manometry (with 3- and 2-dimensional views) in a representative 29-week gestational age infant at time 1
(44.14 weeks’ PMA, left panel) and at time 2 (48.14 weeks’ PMA, right panel). This infant was receiving gavage feedings at time 1 and full oral feedings at
time 2. An oral feeding challenge was done for 3 minutes and the infant took 3 mL/min at time 1 and 9 mL/min at time 2. Observations at time 2 showed
improved regulation of breathing, improved regulation and coordination of pharyngeal waveforms, and increased strength and propagation of esopha-
geal contractile peristalsis. LES=lower esophageal sphincter, PMA=postmenstrual age, UES=upper esophageal sphincter.

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 need reliable, knowledgeable resources at their disposal once can be identified, and a key driver diagram can be developed.
they are home. This diagram includes specific aims (what the program is try-
ing to accomplish in exact measurable terms), key drivers
DEVELOPMENT OF THE SIMPLE FEEDING (factors needed to achieve the aims) and interventions (spe-
PROGRAM: A QUALITY IMPROVEMENT cific changes in practice to be implemented). The key driver
INITIATIVE diagram in our SIMPLE feeding program included the spe-
A quality improvement feeding program such as SIMPLE can cific aim of reaching full oral feedings by 38 weeks’ PMA
be established in any NICU regardless of the size or complex- and decreasing LOHS by 10 days over a 12-month period. (9)
ity of the patient referral pattern. The milestones and goals to Before coming up with specific aims, it is necessary to collect
be attained need to address the targeted population in the spe- baseline data, which is where a quality improvement analyst
cific NICU. When establishing a feeding program, it is first can help determine the number of baseline patients needed
necessary to develop common accepted feeding milestones as and the specific data that need to be collected. To measure
goals, based on all available data and evidence from the indi- improvements, it is necessary to establish a baseline before
vidual unit. The feeding milestones used for the initial SIM- the intervention. For the SIMPLE feeding program, data were
PLE feeding program are listed in Table 3. (9) These collected on a baseline population of infants matching the cri-
milestones are targets and encompass all infants of less than teria of infants included in the program.
or equal to 32 weeks’ GA admitted to an all-referral level IV
children’s hospital. Milestones may be slightly different for a Core Group
NICU with a different population and should be modified Once the steering committee agrees on the feeding prob-
over time based on any new emerging evidence. The process lems to be addressed and develops a key driver diagram,
for the successful development and implementation of a feed- the committee needs to identify a core group of people
ing program is described below and summarized in Fig 2. who are passionate about improving feeding outcomes.
The core group should meet on a regular basis to develop
Steering Committee appropriate interventions and education as well as to col-
A steering committee should be developed, which includes lect and monitor data, including baseline data. The core
representatives from the following areas: hospital administra- group should include 2 to 3 physicians, nurse practition-
tion, unit leadership, medical staff (physician and/or nurse ers, and/or physician assistant champions; 2 to 3 nurse
practitioner), nursing leadership, and quality improvement champions; a quality improvement specialist; a dietician; a
(data analyst). This group should include a physician leader lactation consultant; and possibly a parent and feeding
who can infuse enthusiasm and pathophysiology-based therapist. This group may vary based on the unit’s compo-
knowledge about safe feeding approaches into the program. sition of patients, parents, staff, and specialists as well as
Without the support of the institution and administration, the unit’s specific needs. The core group should meet at
the program will not have the financial support and credibil- least monthly to review data, develop educational tools,
ity that it needs to succeed. The steering committee needs to review available evidence, and identify any new feeding
have the common goal of decreasing practice variability while issues. They should recognize active barriers to implemen-
identifying problem areas with feeding in their unit. The tation and determine solutions to resolve them. The core
problem areas will differ based on the patient population and group can also arrange formal trainings to keep staff
unit culture and may include increased gastrostomy tube engaged, provide evidence-based updates, and share data.
rates, minimal parent involvement with feedings, lack of con-
sistency with feeding management, increased NEC rates, or Feeding Champions
lack of breast milk use at the time of discharge, among other Feeding champions should be identified to educate individu-
parameters. Once these issues are recognized, specific aims als and provide support for the program. These champions

Table 3. Feeding Milestones

Milestone Target
Start of trophic feedings <3 d after birth
Full enteral feedings (defined as 120 mL/kg/day) <28 d after birth
First oral feeding <34 wk PMA
Full oral feedings (oral intake of at least 120 mL/kg/day) <38 wk PMA

PMA=postmenstrual age.

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 Figure 2. The organizational structure for successful development and execution of the simplified, individualized, milestone-targeted, pragmatic, longi-
tudinal, and educational (SIMPLE) feeding program is shown. Roles and members of the steering committee, core group, and feeding champions are
described in the text.

typically are the bedside staff who feed patients and possibly process change in the NICU, provide targeted education,
parents involved in the program. They provide support for track accountability and compliance, and identify the roles
the program, educate the rest of the NICU and parents, and of parents and clinicians. These are all necessary for sus-
participate in discussions about feeding. taining a feeding program with ever-changing staff and
families. Feeding milestones should be tracked on a regu-
NICU Education and Implementation lar basis by someone with protected time to ensure accu-
Before implementing the program, all staff members need rate data. The data can be extracted electronically with
to be educated about the program’s goals and the planned computerized charting but should be stored in a database
interventions. Formal education can begin with the feed- and verified for accuracy. Sharing data on a regular basis
ing champions, who then can provide individualized train- with the team encourages buy-in and acceptance of the
ing to the rest of the NICU staff and parents. program. Data sharing and teaching can occur with the
use of bulletin boards, newsletters, educational rounds,
Focus Groups and formal educational sessions. Monitoring accountabil-
Focus groups can be established when the need arises and ity and compliance with the milestones also is a priority.
can consist of a small group of interested participants who Feeding rounds provide an opportunity for members of
identify solutions to more specific feeding problems. For the feeding core group to discuss each infant individually
example, our SIMPLE program included focus groups for with the physician and/or advanced practitioner, bedside
gastrostomy tube use, medication use, education, and cue- nurse, dietician, feeding therapist, and parent(s). In our
based feeding. Each of these groups contained a member program, feeding rounds included the patient care team
from the core group as well as feeding champions. As the and the parents and occurred twice a week. Our rounds
groups defined ideas for improvement, these ideas were were facilitated by a nurse who collected specific informa-
discussed in the core group and then implemented as tion before rounds. The data included the infant’s age,
needed. Often these projects were also discussed in quar- PMA, comorbidities, respiratory support, growth velocity,
terly educational sessions for the NICU staff. feeding status, and parental involvement, including kanga-
roo care and breastfeeding. The team then determined if
METHODS TO SUSTAIN A SUCCESSFUL FEEDING the infant was meeting targeted feeding milestones and
PROGRAM offered suggestions for improving feeding outcomes.
To maintain a feeding program and adapt to changing Whenever the team was not following established feeding
needs, it is necessary to track feeding milestones, achieve guidelines for reaching the milestones, discussions were

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 focused on reestablishing goals and expectations while The impact of home gastrostomy feedings was assessed by a
understanding potential challenges of meeting the goals. qualitative study that interviewed families and identified some
Acceptance of clinical guidelines and process change key challenges for families including disturbed sleep, inability
can be difficult in the NICU setting. For some aspects of to go out and take vacations, lack of child care, family division,
clinical care, there is a long history of providing care the negative attitudes of others, and the missed experience of
way that it has always been done because of a lack of rig- bonding via bottle or breastfeeding (52) The goal of discharge
orous evidence in this population. To establish buy-in with full oral feedings as a result of a feeding program has
from staff, they must be shown the potential benefits of the potential to improve the quality of life for infants and their
change and actively engage as a part of that change. families.

CLINICALLY MEANINGFUL OUTCOMES FOR LESSONS LEARNED AND FUTURE DEVELOPMENT

IMPROVED OVERALL UNIT OUTCOMES In developing the SIMPLE feeding program and observing its
The goal of any feeding program should be to improve evolution over the past 10 years, our group has learned many
clinical outcomes for patients and families while lowering lessons that may benefit other units developing similar quality
economic burden. A primary feeding outcome goal is improvement initiatives. Our program has attempted to tran-
achieving full oral feedings before discharge. Discharging sition clinicians from multiple disciplines into an interdisci-
a patient with nasogastric tube feedings carries the risk of plinary team. For that to happen, everyone needs to practice
multiple complications, such as nasal trauma, obstruction, as a team rather than in silos. Ideally, NICUs would transition
septal deviation, or congestion; nasogastric tube dislodge- from an interdisciplinary to a transdisciplinary approach in
ment; and recurrent hospitalizations, as well as an added which all disciplines are working as one with common goals.
burden of stress for the family. Similarly, gastrostomy This would eliminate confusion and inconsistencies often
feeding carries a risk of complications such as leaking, experienced by parents and staff.
infection, and dislodgement. Better neurologic/develop- Feeding problems have become more complex in the
mental outcomes at 18 to 24 months of age were found in NICU as technology has allowed the treatment of infants
infants who had achieved full oral feedings at discharge of younger gestational age. The complexity of patients
compared with those who received a gastrostomy tube. makes personalized plans for feeding problems impera-
(13) The presence of a gastrostomy tube without complica- tive, allowing teams to account for an infant’s history,
tions also carries an added economic burden of close to comorbidities, medications, stage of development, and
$50,000 in the first year and $180,000 in the first 5 years social dynamics. Feeding rehabilitation in these infants
due to the cost of placement, supplies, follow-up, etc. (44) needs to be based on objective evidence and personalized
One goal of the SIMPLE feeding program is to have to their exact pathophysiology. Parents should be educated
infants achieve full oral feedings before discharge; how- early and provided anticipatory guidance to understand
ever, another important goal is to improve the quality of feeding difficulties so that they can be a part of the inter-
life for infants and their families. Decreasing the LOHS is ventions to improve feeding outcomes from the very
primarily seen as an economic benefit, but it also signifi- beginning. Clinicians also need to be aware of the factors
cantly improves the quality of life for the family. Parents that influence feeding milestones and outcomes. It is
struggle with a lengthy NICU stay, balancing the need to important to empower bedside caregivers to feel comfort-
be with their child while trying to maintain their life at able with the feeding approach because they are at the
home and work. Feeding can be a major source of stress bedside for every care. Feeding guidelines need to be
for parents and providing them with the education and based on relevant evidence with the ability to personalize
ability to improve their infant’s feeding outcome can help the plan for the complex infant. The institutional adminis-
them immensely. Earlier discharge allows the family to be tration also needs to provide structural and financial sup-
home, bonding with their family unit. Decreasing the port to sustain the program.
LOHS decreases morbidities from exposure to hospital- Multiple factors are required to modify infant feeding
acquired infections, decreases the cost of the hospital stay, difficulties in the NICU and improve feeding outcomes.
and frees up scarce hospital resources for other infants (53) These factors are listed in Fig 3 and include:
who need to be hospitalized.
The quality of life can be affected for those infants and 1. Physiology: Understand how neurologic and aerodi-
families who require long-term tube feeding after discharge. gestive functions change as preterm infants mature.

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 feeding and they need to use objective evidence to pro-
vide interdisciplinary care.
6. Procedures: Complete standardized, timely, and prop-
erly interpreted procedural evaluations for infants with
feeding challenges.
7. Precision medicine: Institute innovative treatment
approaches for specific objective diagnoses.
8. Personalization: Provide therapies that are specific to
the needs of the parent-clinician-infant triad.
9. Pragmatism and humanism: Recognize that manage-
ment approaches can alter clinical outcomes.
10. Policy: Tailor institutional policies based on the needs
of the specific NICU.

TAKE-HOME POINTS
• Consensus of care with evidence-based feeding guide-
lines can lead to improved clinical outcomes of infants
Figure 3. Consider the 10 Ps to modify feeding difficulties and improve
outcomes. To develop and modify safe feeding programs for NICU infants, in the NICU.
it is necessary to understand how these 10 Ps play a part in diagnosing • Feeding guidelines in NICU infants need to be based on
and treating NICU infants with feeding difficulties to ensure safe feeding
and improve clinical outcomes. developmental physiology and available evidence.
• Premature infants have rapidly changing neurologic and
2. Pathophysiology: Identify the underlying mechanisms aerodigestive physiology that makes timely interventions
associated with feeding difficulties. imperative.
3. Patient characteristics: Take into account the risk fac- • The development of an effective NICU feeding program
tors and comorbidities that vary with every patient. requires a stepwise process that includes all stakeholders.
4. Parental involvement: Account for varied parental • The maintenance of a feeding program for preterm
involvement, attitudes, culture, and resources when infants requires enthusiastic participants who are dedi-
providing education. cated to tracking feeding milestones, affecting process
5. Providers: Recognize that multiple clinicians have var- change, providing targeted education to families and
ied experiences and knowledge about preterm infant staff, and tracking accountability and compliance.

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 Inadequate oral feeding as a barrier to discharge in moderately
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 NEOREVIEWS QUIZ

NEO
QUIZ
1. Among preterm infants with no significant comorbidities, what is the
approximate proportion who have feeding problems after discharge and are
referred to long-term feeding clinics?

A. 5%.
B. 10%.
C. 25%.
D. 40%.
E. 75%.
2. An enteral feeding protocol may help to reduce the duration of central
catheter placement for providing parenteral nutrition and also optimize
nutrition. A Cochrane review on the advancement pathways for advancing REQUIREMENTS: Learners can
nasogastric feedings showed which of the following regarding necrotizing take NeoReviews quizzes and
enterocolitis (NEC)? claim credit online only at:
http://pedsinreview.org.
A. Feeding protocols that did not initiate enteral feedings until day 7 led
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 INDEX OF SUSPICION IN THE NURSERY

Seizures in a Term Newborn

Peter Joslyn,* Maria Velez,† Oritsejolomi Roberts,‡ Michelle Knecht,* Pinki Prasad,† Jared Robichaux,‡
Andrea Bauchat,§ Jeffrey Surcouf*
*Division of Neonatology, and
†
Division of Hematology/Oncology, Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA
‡
Department of Neurosurgery, Louisiana State University Health Sciences Center, New Orleans, LA
§
Department of Pediatrics, Division of Hematology/Oncology, Emory University Atlanta, GA

PRESENTATION
A 31-year-old gravida 7, para 4 woman delivers a male infant via vaginal delivery
without the use of forceps or vacuum extraction after induction of labor at 39
weeks and 2 days of gestation. The pregnancy was complicated by tobacco use
throughout gestation. The mother received routine prenatal care and her labora-
tory findings were negative for infections, including group B Streptococcus. Mem-
branes ruptured 2 hours before delivery, and the amniotic fluid was meconium
stained. Resuscitation is routine, and the neonate’s Apgar scores are 8 and 9 at
1 and 5 minutes, respectively. The infant’s birthweight of 3,465 g places him in
the 50th to 75th percentile for age and his length and head circumference are
greater than the 90th percentile for age. He undergoes triage in the well-baby
nursery where his admission physical examination findings are normal. He
remains with his mother until approximately 22 hours after birth when he devel-
ops apnea and respiratory distress.
Radiographs of the chest and abdomen are normal. The infant is transferred
to the NICU. On admission, he is noted to have left face and eyelid twitching
and left upper extremity stiffening associated with apnea and hypoxemia con-
cerning for seizures. These episodes last 20 to 40 seconds and resolve spontane-
ously. The patient is given an intravenous phenobarbital load. An arterial blood
gas measurement and complete blood cell count are within normal limits. A
complete metabolic panel shows normal serum electrolytes, glucose, creatinine,
and liver enzymes. A urine toxicology screen is negative. Bacterial blood culture
and blood herpes simplex virus (HSV) polymerase chain reaction (PCR) are per-
formed, and a lumbar puncture is attempted but unsuccessful. Umbilical artery
and venous catheters are inserted, and intravenous ampicillin, gentamicin, and
acyclovir are started. The infant is transferred to a level IV NICU for subspeci-
AUTHOR DISCLOSURES Drs Joslyn, alty care.
Velez, Roberts, Knecht, Prasad, Robichaux,
Bauchat, and Surcouf disclosed no
financial relationships relevant to this
article. This commentary does not DISCUSSION
contain a discussion of an unapproved/
investigative use of a commercial Differential Diagnosis
product/device. The differential diagnosis of seizures in the newborn includes the following:

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 • Hypoxic ischemic encephalopathy postoperative day 2 and is quickly weaned to room air.
• Neonatal-onset epilepsy. The blood culture is without growth and the HSV PCR
• Central nervous system infection. from the blood is negative. Antibiotics and acyclovir are
• Electrolyte disturbances. discontinued on day 3 after birth.
• Intracranial or extracranial hemorrhage. The patient is discharged from the hospital on day 15
• Stroke. after birth without major neurologic deficits. FVIII activity
• Metabolic disorders. is less than 1% at 1 and 2 months of age consistent with
severe hemophilia A. The patient has 1 bleeding episode
Actual Diagnosis since discharge lasting several hours after cutting his fin-
Intracranial hemorrhage due to hemophilia A. ger which resolves without medical intervention. He con-
tinues to be followed in the hematology and neurosurgery
Treatment and Management clinics.
Upon admission to the level IV NICU, the patient under-
goes intubation and receives mechanical ventilation for The Condition
severe apnea. Computed tomography of the head without Hemophilia A is an inherited bleeding disorder caused
contrast shows extensive intracranial hemorrhage (ICH) in by a functional deficiency of FVIII, a plasma protein nec-
the pineal region and posterior fossa including the cere- essary for the generation of thrombin and fibrin. (2)
bellum with regional mass effect and compression of the Two-thirds of patients with hemophilia have a family his-
fourth ventricle with obstructive hydrocephalus. Magnetic tory of the disorder, whereas the other one-third of
resonance angiography and venography are subsequently patients represent sporadic cases. (2) Hemophilia A is
performed, which reveal patent intracranial arteries with- inherited in an X-linked fashion and is caused by variants
out arteriovenous or vein of Galen malformations. Due to in F8, located at the distal portion of the X chromosome.
significant mass effect on the brainstem, the infant under- (2) The prevalence of hemophilia A is estimated to be 1
goes a suboccipital craniectomy and cerebellar hemor- in 4,000 male births in developed countries, with severe
rhage evacuation and expansile duraplasty on day 2 after hemophilia A accounting for approximately one-third of
birth, without major complications. The neonate receives cases. (3)
10 mL/kg of fresh frozen plasma (FFP) before the The diagnosis of hemophilia A is often made in the
procedure. setting of a positive family history or after a significant
Although there was no family history of bleeding disor- bleeding event in sporadic cases. Coagulation studies
ders, given the severity of the bleed, a bleeding diathesis often reveal a prolonged partial thromboplastin time
evaluation is initiated. The patient is found to have a (PTT), and the diagnosis is confirmed with plasma factor
slightly prolonged prothrombin time of 16.9 seconds (nor- activity (also called concentration or level). Hemophilia A
mal 10.1–15.9 seconds [1]) and a significantly prolonged is classified as mild, moderate, or severe based on the
activated partial thomboplastin time of 78 seconds (nor- plasma activity of FVIII. (4) If plasma FVIII activity is
mal 31.3–54.5 seconds [1]). International normalized ratio less than 1% of normal, the hemophilia is designated as
and fibrinogen are normal. Plasma clotting factor VIII severe; if FVIII activity is 1% to 5% of normal, the hemo-
(FVIII), factor IX, and factor XIII activity assays are philia is designated as moderate; and if FVIII activity is
obtained approximately 6 hours after the patient received greater than 5% but less than 40% of normal, the hemo-
FFP. Factors IX and XIII activity are normal for age; how- philia is designated as mild. (4) The severity of clinical
ever, FVIII activity is low, at 12% (normal 50%–178% [1]). manifestations is often proportional to the concentration
On postoperative day 1, FVIII replacement therapy is of factor present. (3) Diagnosing hemophilia in the new-
started. The patient receives therapy for a total of 12 days born period presents unique challenges, as neonates
and FVIII activity remains more than 100% while receiv- have prolonged PTT due to a physiologic reduction in
ing inpatient replacement therapy. Serial postoperative factor IX and other vitamin K–dependent factors. (2) Fur-
head imaging studies show residual blood in the central thermore, the stress of birth may transiently increase
nervous system and a decrease in the size of the ventricles FVIII concentration, further confusing the clinical pic-
without additional hemorrhage. ture. (2)
The patient has no additional seizures and phenobarbi- Although ICH during the newborn period is infrequent
tal is discontinued. He undergoes extubation on in the general population, it remains a potentially life-

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 threatening complication in patients with hemophilia. (5) contrast, Ljung et al had a similar cohort with no patients
The first estimate of the incidence of ICH in patients with who developed persistent neurologic sequelae. (13) Most
hemophilia in the newborn period was made by Baehner case series report that at least some newborns with early
and Strauss in 1966. (6) In a cohort of 192 patients with ICH in the setting of hemophilia suffer long-term neuro-
hemophilia, only 1 patient experienced ICH in the new- logic consequences, such as seizures, paralysis, and focal
born period. More recent attempts to quantify the inci- neurologic deficits. (5)(7)(9)
dence of ICH in the newborn period in patients with
hemophilia have placed the number much higher. In a Lessons for the Clinician
review of several case studies, Ljung estimated the true
incidence of ICH in the newborn period in patients with • Medical providers should be open to the possibility of a
hemophilia in developed countries to be 3.5% to 4%. (7) diagnosis of bleeding disorders in newborns with ICH
This is much higher than the ICH incidence in the gen- even in the absence of pertinent family history or diffi-
eral population, which occurs in 1 in 1,900 (0.05%) spon- cult or assisted delivery.
taneous vaginal deliveries, 1 in 907 (0.11%) cesarean • The risk of early ICH appears to be exacerbated by diffi-
sections during labor, and 1 in 860 (0.12%) deliveries after cult labor and the use of instrumentation, such as for-
vacuum extraction. (8) Like newborns without hemophilia, ceps or vacuum extraction, but can occur even in the
the risk of ICH and extracranial hemorrhage (subgaleal absence of labor.
hemorrhage or cephalohematoma) increases after pro-
longed delivery or with use of forceps or vacuum extrac-
tion. (7)(9) While minimizing trauma in the perinatal
American Board of Pediatrics
period decreases the likelihood of ICH in patients with
hemophilia, it does not wholly eliminate the risk, as evi- Neonatal-Perinatal Content
denced by reports of newborns with hemophilia experienc- Specifications
ing ICH after elective cesarean section without labor. (10) • Understand the differential diagnosis and evaluation of
Although the optimal mode of delivery in infants sus- neonatal seizures.
pected of having hemophilia remains a topic of debate, it • Understand the clinical manifestations of neonatal seiz-
is generally agreed that prolonged labor, difficult deliver- ures, and their prognosis.

ies, and use of instrumentation should be avoided if possi- • Know the inheritance patterns of the common coagula-
tion factor deficiencies.
ble. (11)(12)
• Know the causes and pathophysiology of acquired defects
The neurologic prognosis of newborns with hemophilia in hemostasis.
who have ICH varies widely among case series. For exam- • Know the clinical manifestations, laboratory findings, and
ple, Yoffe and Buchanan reported that 62% of patients in management of congenital defects in hemostasis.
their cohort of newborns with hemophilia and early ICH
went on to develop chronic neurologic sequelae. (5) In

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 6. Baehner RL, Strauss HS. Hemophilia in the first year of life. N Engl
References J Med. 1966;275(10):524–528
1. Edstrom CS, Christensen RD, Andrew M. Developmental aspects 7. Ljung RCR. Intracranial haemorrhage in haemophilia A and B. Br J
of blood hemostasis and disorders of coagulation and fibrinolysis Haematol. 2008;140(4):378–384
in the neonatal period. In: Christensen RD, ed. Hematologic
8. Towner D, Castro MA, Eby-Wilkens E, Gilbert WM. Effect of mode
Problems of the Neonate, 1st ed. Philadelphia: WB Saunders Co;
of delivery in nulliparous women on neonatal intracranial injury. N
2000:239–271
Engl J Med. 1999;341(23):1709–1714
2. Di Paola J, Montgomery RR, Gill JC, Flood V. Hemophilia and von
9. Richards M, Lavigne Lissalde G, Combescure C, et al; European
Willebrand disease. In: Orkin SH, Nathan DG, Ginsburg D, Look
Haemophilia Treatment and Standardization Board. Neonatal
AT, Fisher DE, Lux SE IV, eds. Nathan and Oski’s Hematology and
bleeding in haemophilia: a European cohort study. Br J Haematol.
Oncology of Infancy and Childhood. 8th ed. Philadelphia, PA: Elsevier;
2012;156(3):374–382
2015;chap 31:1028–1054
10. Michaud JL, Rivard G-E, Chessex P. Intracranial hemorrhage in a
3. Iorio A, Stonebraker JS, Chambost H, et al; Data and Demographics
newborn with hemophilia following elective cesarean section. Am J
Committee of the World Federation of Hemophilia. Establishing the
Pediatr Hematol Oncol. 1991;13(4):473–475
prevalence and prevalence at birth of hemophilia in males: a meta-
analytic approach using national registries. Ann Intern Med. 2019; 11. Chalmers E, Williams M, Brennand J, Liesner R, Collins P, Richards
171(8):540–546 M; Paediatric Working Party of United Kingdom Haemophilia
Doctors’ Organization. Guideline on the management of
4. Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den
haemophilia in the fetus and neonate. Br J Haematol.
Berg HM, Srivastava A; Subcommittee on Factor VIII, Factor IX
2011;154(2):208–215
and Rare Coagulation Disorders of the Scientific and
Standardization Committee of the International Society on 12. Huq FY, Kadir RA. Management of pregnancy, labour and delivery
Thrombosis and Hemostasis. Definitions in hemophilia: in women with inherited bleeding disorders. Haemophilia.
communication from the SSC of the ISTH. J Thromb Haemost. 2011;17(suppl 1):20–30
2014;12(11):1935–1939 13. Ljung R, Lindgren A-C, Petrini P, Tengborn L. Normal vaginal
5. Yoffe G, Buchanan GR. Intracranial hemorrhage in newborn delivery is to be recommended for haemophilia carrier gravidae.
and young infants with hemophilia. J Pediatr. 1988;113(2): Acta Paediatr. 1994;83(6):609–611
333–336

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 INDEX OF SUSPICION IN THE NURSERY

Hepatosplenomegaly and
Periventricular Cyst in a Neonate
with Direct Hyperbilirubinemia
Vignesh Gunasekaran*, Judy Squires†, James Squires‡, Marian G. Michaels§, and John Ibrahim¶
*
Neonatal-Perinatal Medicine Fellowship Program, Magee-Women’s Hospital of UPMC/Children’s Hospital of Pittsburgh, Pittsburgh, PA
†
Division of Pediatric Radiology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA
‡
Division of Pediatric Gastroenterology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA
§
Division of Pediatric Infectious Disease, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA
¶
Division of Newborn Medicine, Magee-Women’s Hospital of UPMC/Children’s Hospital of Pittsburgh, Pittsburgh, PA

CASE PRESENTATION
An infant is born at 36 weeks to a 27-year-old gravida 4, para 3 woman via pre-
cipitous vaginal delivery through meconium-stained amniotic fluid. The preg-
nancy had been complicated by diet-controlled gestational diabetes. The mother
works as a daycare teacher and had traveled to Europe 12 weeks before delivery.
She had clinical symptoms of an acute upper respiratory illness 3 weeks before
delivery. The neonate’s physical parameters include weight of 2.085 kg (13th per-
centile), length of 43 cm (38th percentile), and head circumference of 31 cm
(16th percentile).
Initial blood glucose level is 23 mg/dL (1.28 mmol/L), and the neonate is
given a D10 bolus and maintenance intravenous fluids are started. The neo-
nate’s initial platelet count is 37 × 103/mL (37 × 109/L) with no active bleeding or
oozing. He is noticed to be thrombocytopenic on subsequent complete blood
cell counts. A sepsis evaluation is done, blood specimens for culture are drawn,
and ampicillin and gentamicin are started. Initial C-reactive protein is 6 mg/dL
(60 mg/L) and white blood cell count is 15,000/mL (15 × 109/L). An initial total
bilirubin is 18.8 mg/dL (321.5 mmol/L) and direct bilirubin is 10 mg/dL (171
mmol/L). Results of a liver function panel are as follows: alanine aminotransfer-
ase (ALT) 117 U/L (1.9 mkat/L), aspartate aminotransferase (AST) hemolyzed,
albumin 2.7 g/dL (27 g/L). Abdominal ultrasonography reveals hepatosplenome-
galy. Result of urine cytomegalovirus (CMV) test is pending at the time of
transport.
The infant is transferred to our tertiary NICU for multidisciplinary manage-
Author Disclosures Drs Gunasekaran,
ment of neonatal direct hyperbilirubinemia and transaminitis. Physical examina-
Judy Squires, James Squires, Michaels,
and Ibrahim have disclosed no financial tion findings are notable for hepatomegaly, splenomegaly, and petechiae on the
relationships relevant to this article. This abdomen and back. Admission laboratory findings are significant for calcium
commentary does not contain a
less than 5 mg/dL (1.25 mmol/L), magnesium 0.6 mg/dL (0.25 mmol/L), albu-
discussion of an unapproved/
investigative use of a commercial min 2 g/dL (20 g/L), total bilirubin 23 mg/dL (393 mmol/L), direct bilirubin
product/device. greater than 16 mg/dL (273.6 mmol/L), ALT 106 U/L (1.7 mkat/L), AST <5 U/L

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 (0.08 mkat/L), alkaline phosphatase 290 U/L (4.8 mkat/L), common cause. HSV is the most common viral agent
ammonia less than 10 mg/dL (7.1 mkat/L), and platelet associated with NALF. Neonates with HSV-associated
count 82 × 103/mL (82 × 109/L). Coagulation profile shows NALF may have disseminated HSV with or without cen-
an international normalized ratio of 1.6 and PTT of 37 sec- tral nervous system infection. In either of those cases,
onds. A hepatitis panel is negative. Abdominal ultrasonog- neonates often lack cutaneous manifestations; therefore, a
raphy reveals hepatosplenomegaly and patent ductus high index of suspicion is required. CMV is very rarely
venosus. Echocardiography findings are normal. Central associated with NALF, but more often with less fulminant
access is established. hepatitis and prominent cholestasis. Enterovirus should be
Hepatology and infectious disease specialists are con- a consideration in evaluating any neonate with a combina-
sulted on admission. For hepatology evaluation, a1-anti- tion of necrotizing enterocolitis and NALF.
trypsin and cholestasis panel are negative. Serum ferritin In our case, the urine CMV result from the birth hospi-
is 1,951 ng/mL (1,951 mg/L). Because the direct reacting tal was positive, consistent with a diagnosis of congenital
(or conjugated) bilirubin level is greater than 50% of the CMV (CMV) and the neonate was subsequently started on
total bilirubin and there are no good data to guide therapy, ganciclovir. The repeat blood and urine samples tested for
phototherapy is started. Double volume exchange and CMV at our NICU confirmed the diagnosis, and EBV poly-
intravenous immunoglobulin are not given at the time. merase chain reaction (PCR) (initially 350 copies/mL and
Evaluation for infections includes repeat CMV, herpes then 1,500 copies/mL) was positive as well. Ganciclovir
simplex virus (HSV), toxoplasma immunoglobulin M, was switched to oral valganciclovir on postnatal day 6. The
Epstein-Barr virus (EBV), adenovirus, and coxsackie virus. neonate failed the otoacoustic emissions test bilaterally.
A lumbar puncture is deferred due to coagulopathy. No The eye examination performed as part of the evaluation
placental pathology is available. for toxoplasmosis, other infections, rubella, CMV, and
Genetics consultation on admission recommends the HSV (TORCH) syndrome showed posterior embryotoxon.
following: urine organic acids to assess for mevalonic acid Re-examination after the diagnosis of CMV was made
and succinyl acetone, oxysterol to assess for Niemann-Pick showed no chorioretinitis.
disease, galactose-1-phosphate uridylyltransferase enzyme
testing and galactose-1-phosphate red blood cells, transfer- The Condition
rin isoelectric focusing, acylcarnitine profile, and plasma Congenital CMV. Human CMV is a human-specific DNA
amino acids. virus of the Herpesviridae family. In the developed world,
The neonate is started on enteral feeds on day 4 and congenital CMV is the leading nongenetic cause of senso-
advanced to full volume feeds. The liver function test rineural hearing loss (SNHL) in children and accounts for
trends are studied (Fig 1) and the infant is started on urso- 21% and 24% of cases of hearing loss at birth and 4 years
diol and fat-soluble vitamins. Feedings are fortified to 24 of age, respectively. (1) In addition, congenital CMV is the
kcal with medium-chain triglycerides for poor weight gain. leading viral cause of neurodevelopmental delay.
Head ultrasonography shows right grade 1 intraventricular The clinical spectrum of congenital CMV varies widely,
hemorrhage and bilateral periventricular temporal lobe from asymptomatic infection to potentially life-threatening
cyst without calcification. Magnetic resonance imaging of disseminated disease. Presentation can be with intrauterine
the brain shows medial temporal horn cysts, banding of growth restriction, preterm labor, petechiae, jaundice, hepa-
the interventricular regions, immature white matter, and tomegaly, splenomegaly, and microcephaly. Laboratory and
cerebellar vermis hypoplasia (Fig 2). imaging findings include thrombocytopenia, transaminitis,
direct hyperbilirubinemia, SNHL, periventricular calcifica-
DISCUSSION tions, and rarely, chorioretinitis. Radiographic findings are
Differential Diagnosis: Neonatal Liver Failure abnormal in 50% to 70% of children with symptomatic
The fetal-neonatal continuum of liver diseases allows the infections at birth and include intracranial calcifications,
occurrence of cirrhosis in cases defined as neonatal acute ventricular dilation, cysts, lenticulostriate vasculopathy, cho-
liver failure (NALF). All neonatal liver failure is “acute” by roid plexus cyst, and echogenic bowel.
definition. The common differential diagnostic considera- Because infants with congenital CMV shed large
tions include viral infections (20%–30%), hemophagocytic amounts of virus in saliva and urine, saliva (at least 1 hour
lymphohistiocytosis, mitochondrial cytopathy, and gesta- after breast feeding) or urine PCR is used for diagnosis.
tional alloimmune liver disease, which is the most The treatment of symptomatic congenital CMV disease is

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 Figure 1. Trend of direct bilirubin and liver enzymes. ALT=alanine aminotransferase, AST=aspartate aminotransferase, SGOT=serum glutamic-oxaloacetic
transaminase, SGPT=serum glutamic pyruvic transaminase.

with intravenous ganciclovir or the oral prodrug valganci- EBV Infection in Neonates and Pregnancy. Whether the
clovir. Neonates receiving valganciclovir for 6 months had infection with EBV in our case was a coincidence or con-
a 2.6-times higher likelihood of improved total hearing at tributed to the disease severity remains uncertain. EBV is
12 and 24 months than those who received only 6 weeks a g herpes virus associated with infectious mononucleosis,
of valganciclovir treatment. (2) Neurodevelopmental out- nasopharyngeal carcinoma, Burkitt lymphoma, B-cell lym-
comes on the language composite of the Bayley Scale III phoma, and posttransplant lymphomas. Infection with
were improved with longer duration of therapy. EBV is extremely common and 90% of adults in the
United States are seropositive before the age of 30 years.
Purtilo and Sakamoto (3) reported that EBV reactivation in
pregnancy is a much more common occurrence than pri-
mary infection due to the high rates of seroprevalence.
Transmission of EBV is usually horizontal, requiring close
contact with the saliva of an infected person; vertical transmis-
sion is felt to be rare. Several case reports of fetal outcomes of
EBV infection during pregnancy have been published, but
there is no specific syndrome that can be described as an out-
come of EBV infection during pregnancy.
In a cohort of 500 women whose serum samples were
studied for EBV nuclear antigen early in pregnancy, 28
neonates had anomalies. Of these, 16 had minor anoma-
lies and 12 had major anomalies including congenital
heart disease, microcephaly, anencephaly, meningomyelo-
cele, and achondroplasia. (4) In a case report by Brown
Figure 2. Magnetic resonance imaging of the brain. Sagittal 3-dimen- and Stenchever, (5) severe congenital anomalies were
sional constructive interference in steady state image demonstrates a
periventricular cyst anterior to the temporal horn of the left lateral
described in an infant exposed to EBV infection from con-
ventricle (white arrowhead) and a ventricular adhesion (black arrow- ception to delivery. Another case report described congeni-
head). Abnormal T2 signal hyperintensity is again seen in the left pari-
etal lobe as well as the left temporal lobe (white arrows). tal anomalies such as cryptorchidism, micrognathia,

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 Table. Coinfection with EBV and CMV During Pregnancy
Reference Study Type Findings Follow-up
Current case Case report: neonatal Hepatitis, thrombocytopenia, Follow-up with resolution of
coinfection with CMV and direct hyperbilirubinemia, hepatitis but the infant
EBV petechiae, developed progressive
hepatosplenomegaly developmental delay and
Diagnosis: PCR blood for CMV SNHL
and EBV
Joncas et al (6) 2 case reports: infant with CMV/ Petechial rash, Gross motor delay with speech
EBV hepatosplenomegaly, delay
thrombocytopenia, peri-
ventricular calcification.
Diagnosis: Positive IgM titers
for CMV and EBV

CMV=cytomegalovirus; EBV=Epstein-Barr virus; IgM=immunoglobulin M; PCR=polymerase chain reaction SNHL=sensorineural hearing loss.

cataract, and hypotonia in a male infant exposed to EBV • Maternal history can serve as an important clue to guide
during pregnancy. Two other reports described liver and postnatal evaluation. In the case described herein, the
bile duct anomalies in infants exposed to EBV during maternal history of working as a daycare teacher and devel-
pregnancy. A case control study of 403 infants born to oping symptoms of upper respiratory infection before deliv-
mothers with EBV infection at 12 to 14 weeks of gestation ery was important.
suggested an increased risk for leukemia.
To our knowledge, this is the third case in literature to
report coinfection with CMV and EBV in neonates. Two
previous cases were reported by Joncas et al (Table). (6) American Board of Pediatrics
Although congenital CMV could explain all of this infant’s Neonatal-Perinatal Content
findings, the severity may have been due to concurrent in Specifications
utero infection with CMV and EBV. • Know the various etiologies, including bacterial,
viral, and protozoal agents, and clinical manifesta-
Follow-up
tions of hepatitis in the newborn.
Our patient was discharged on postnatal day 17, with infectious
• Know the incidence, causes, risk factors, and man-
disease, hepatology, ophthalmology, and audiology follow-up.
agement of congenital hearing loss in the neonate.
Currently, at 2 years of age, he has not undergone brainstem
auditory evoked response testing but has speech delay.

Lessons for the Clinician

• Congenital CMV should be considered in the differential

diagnosis of neonates born with cholestasis and
thrombocytopenia.

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 determinants of lymphoproliferative diseases-a hypothesis. Med
References Hypotheses. 1982;8(4):401–408
1. Dollard SC, Grosse SD, Ross DS. New estimates of the prevalence of 4. Le CT, Chang RS, Lipson MH. Epstein-Barr virus infections during
neurological and sensory sequelae and mortality associated with pregnancy: a prospective study and review of the literature. Am J Dis
congenital cytomegalovirus infection. Rev Med Virol. 2007;17(5):355–363 Child. 1983;137(5):466–468
2. Kimberlin DW, Jester PM, S
anchez PJ, et al; National Institute of 5. Brown ZA, Stenchever MA. Infectious mononucleosis and
Allergy and Infectious Diseases Collaborative Antiviral Study Group. congential anomalies. Am J Obstet Gynecol. 1978;131(1):
Valganciclovir for symptomatic congenital cytomegalovirus disease. N 108–109
Engl J Med. 2015;372(10):933–943 6. Joncas JH, Wills A, McLaughlin B. Congenital infection with
3. Purtilo DT, Sakamoto K. Reactivation of Epstein-Barr virus in cytomegalovirus and Epstein-Barr virus. Can Med Assoc J.
pregnant women: social factors, and immune competence as 1977;117(12):1417–1418

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 INDEX OF SUSPICION IN THE NURSERY

A Floppy Infant with Facial

Dysmorphism
Praneeth Kumar, MD (Ped),* Gayatri Nerakh, DNB (OBG), DNB (Medical Genetics),† Priyanka Katam, DNB (Ped),*
Tejo Pratap Oleti, MD (Ped), DM (Neo),* Sunil Pawar, DNB (Ped)*
*
Department of Neonatology, Fernandez Hospital, Hyderabad, Andhra Pradesh, India
†
Department of Fetal Medicine and Genetics, Fernandez Hospital, Hyderabad, Andhra Pradesh, India

HISTORY
A male neonate was born small for gestational age with a birthweight of 2.36 kg
to a 32-year-old gravida 2 woman in a third-degree consanguineous marriage.
The mother’s history included a spontaneous abortion at 10 weeks of gestation
in the previous pregnancy. The current pregnancy was a product of spontaneous
conception. The antenatal period in this pregnancy was uneventful, with regular
follow-ups. The mother also took iron and folic acid supplementation along with
tetanus toxoid immunization. She has no history of fever, rash, or any terato-
genic exposure during pregnancy. Screening for gestational diabetes, hyperten-
sion, and thyroid disorders in this pregnancy found no abnormalities. Targeted
imaging for fetal anomalies at 20 weeks of gestation had normal findings. Sub-
sequent growth scans showed polyhydramnios but the growth pattern was
appropriate for gestational age. The neonate was delivered at 37 weeks and 6
days of pregnancy via emergency caesarean section in view of decreased fetal
movements. The amniotic fluid was clear at the time of birth. The neonate did
not cry immediately after birth and required positive pressure ventilation for 30
seconds. His Apgar scores were 7, 8, and 8 at 1, 5, and 10 minutes, respectively.
Cord arterial blood gas analysis revealed a pH of 7.23, base excess 5.6 mmol/L,
PCO2 46 mm Hg (6.12 kPa), PO2 24 mm Hg (3.19 kPa), and lactate 1.8 mmol/L
(0.2 mmol/L). There is no significant history suggestive of unexplained death or
any genetic disease in other family members.

PRESENTATION
In view of the respiratory distress, the neonate was transferred to the NICU.
Oxygen support was started in the form of nasal prongs. Vital signs on examina-
tion were as follows: heart rate 128 beats/min, respiratory rate 62 breaths/min,
temperature 97.7 F (36.5 C), oxygen saturation 98% via nasal prongs, and blood
Author Disclosures Drs Kumar, Nerakh,
pressure 66/50 mm Hg (mean 42 mm Hg). On examination, the neonate’s Katam, Oleti, and Pawar have disclosed
weight, length, and head circumference were 2,360 g (5th percentile), 48 cm no financial relationships relevant to this
(30th percentile), and 32.5 cm (20th percentile), respectively. On general exami- article. This commentary does not
contain a discussion of an unapproved/
nation, facial dysmorphism was noted in the form of large fontanels with wide investigative use of a commercial
sutures, low-set ears, hypertelorism, periorbital puffiness with hazy cornea, product/device.

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 depressed nasal bridge with broad nose, and high arched seizures at 1 month of age, which required readmission,
palate (Fig 1A). There was a redundant skinfold over the and he was started on antiseizure medication. He did not
nape of the neck. Simian crease and bilateral clubfoot attain any milestones on follow-up and died at 5.5 months
were also noted (Fig 1B). The testes were undescended. of age due to respiratory illness.
Detailed neurologic examination revealed a lethargic neo-
nate with diminished arousal response and markedly EVALUATION
diminished motor responses. Deep tendon reflexes were The neonate was initially evaluated with arterial blood gas
also difficult to elicit, with weak cry and poor sucking and analysis, sepsis screening, measurement of serum glu-
swallowing reflex. The neonate was grossly hypotonic with cose, calcium, and electrolytes, and expanded newborn
significant head lag and shoulder hypotonia (Fig 1C). Pool- screening for neonatal sepsis and metabolic derange-
ing of secretions was also noted, with minimal response ments. Laboratory investigation revealed normal arterial
to light and sound. Abdominal examination revealed a blood gas analysis, sepsis screening (total white blood cell
firm liver that was palpable 2 cm below the right subcostal count 4,000/mL [4 × 109/L], C-reactive protein 0.04 mg/
margin with a smooth surface and no splenomegaly. dL [0.4 mg/L]), and basic metabolic panel (serum glucose
As breathing became shallow and respiratory distress 65 mg/dL [3.6 mmol/L], total serum calcium 9.7 mg/dL
increased, with oxygen saturation falling below 90%, the [2.4 mmol/L], serum sodium 141 mEq/L [141 mmol/L],
neonate was moved to oxygen via high-flow nasal cannula and serum potassium 4.2 mEq/L [4.2 mmol/L]). Liver
with a flow of 6 L/min. The breathing pattern improved function parameters revealed a total bilirubin of 7.8 mg/
later and respiratory supports were weaned off. The neo- dL (133.4 mmol/L], aspartate aminotransferase 24 U/L (0.4
nate was moved on free flow oxygen intake to the moth- mkat/L), and alanine aminotransferase 34 U/L (0.6 mkat/
er’s side in a postnatal room. Supportive therapies were L). Thyroid-stimulating hormone was 1.45 mIU/mL on day
started in the form of oromotor stimulation, physiother- 3. Titers for toxoplasmosis, other agents, rubella, cytomeg-
apy, and non-nutritive sucking. Gradually, he started to alovirus, and herpes simplex (TORCH) syndrome were
feed through a cuplike utensil with a narrow tip used for also within normal limits. Findings of expanded newborn
feeding in India (“paladai”) from day 3. Minimal improve- screening and tandem mass spectrometry were normal,
ment was seen in tone and level of consciousness by day with no metabolic derangements. Total creatine phospho-
7. He was discharged on day 15 after birth after the kinase level was 158 U/L (2.6 mkat/L; reference value <652
mother learned how to care for him. He developed U/L [10.9 mkat/L]). Neurosonography revealed bilateral
pseudocysts of germinal matrix with mild ventriculomegaly.
Ophthalmologic evaluation revealed hypopigmented iris
and fundus with hazy cornea. Two-dimensional echocardi-
ography indicated a 1-mm closing patent ductus arteriosus
on day 2. Abdominal ultrasonography revealed mild hepato-
megaly with bilateral mild pelviectasis in the kidneys with-
out any cystic changes. Skeletal survey showed a narrow
chest (Fig 2A) with punctuate calcifications at the knee joint

Figure 1. A. Facial dysmorphism. B. Bilateral varus deformity. C. Floppy Figure 2. A. Radiograph showing bell-shaped thorax. B. Infantogram
infant. showing punctate calcifications at knee joint.

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 peroxisomal protein import or both (2). These mutations in
PEX genes result in deficiency of functional peroxisomes.
These gene defects were earlier named to the spectrum of
disorders known as Zellweger syndrome, neonatal adrenoleu-
kodystrophy (ALD), infantile Refsum disease, and rhizomelic
chondrodysplasia punctata. (3) Among the first 3 disorders,
Zellweger syndrome is the most severe, infantile Refsum the
least severe, and neonatal ALD is of intermediate severity.
Defective peroxisomal function can lead to impaired fatty acid
metabolism, leading to the accumulation of very long chain
Figure 3. A. Axial T2 WI magnetic resonance imaging of the brain show- fatty acids, phytanic and pristanic acids, C27-bile acid inter-
ing bilateral perisylvian polymicrogyria and caudothalamic germinolytic mediates, and pipecolic acid in plasma, and can have defi-
cysts. B. Axial T2WI image shows bilateral frontal pachygyria.
ciency of plasmalogens in erythrocytes. (4) Accumulation of
(Fig 2B). Magnetic resonance imaging (MRI) and genetic all these metabolites leads to multiorgan dysfunction includ-
testing confirmed the diagnosis. ing neurodevelopmental delay, liver dysfunction, developmen-
tal delay, adrenocortical dysfunction, and hearing and vision
DIAGNOSIS impairment.
Facial profile is also characteristic in the early phase of
Brain MRI showed cysts in the caudothalamic groove
infancy. (5) In our case, the neonate’s facial profile was
bilaterally, abnormal sulcation in the frontal and parietal
not similar to that seen with Zellweger syndrome, but he
lobes with extensive polymicrogyria of both, and sylvian
had central hypotonia and characteristic MRI brain find-
fissure with no evidence of hypoxic injury (Fig 3A and 3B).
ings. (6) Increased levels of very long chain fatty acid and
Based on all these findings, a presumptive diagnosis of
phytanic acid and urinary metabolites like pipecolic acid
peroxisomal disorder was made.
were not detected in our case. Patients with mild Zell-
Clinical exome sequencing showed a pathogenic homo-
weger syndrome disorders may have near-normal bio-
zygous variant, c.589C>T (p.Gly197Ter) (NM_001199319),
in exon 4 of the PEX26 gene known to cause Zellweger chemical findings in plasma and urine. (7)(8) Among the
syndrome. This variant was absent from population data- differential disorders to consider, single peroxisomal
bases with low minor allele frequency in the in-house enzyme deficiencies especially Acyl-CoA oxidase type 1
database. In-silico predictions reported it to be damaging, deficiency and D-bifunctional protein deficiency show sev-
with a combined annotation-dependent depletion score of eral overlapping clinical features. (9)(10)
36.0, and a codon that was conserved across mammalian At present, there is no curative treatment for Zellweger
species. This variant was consistent with the presumptive syndrome. Treatment is mainly supportive like ensuring
diagnosis of the child. Both parents are heterozygous car- proper calorie intake by means of a proper feeding protocol,
riers for the same variant identified in the child. physiotherapy, and early stimulation and interventions for
sensory and motor system and intake of fat-soluble vitamins
DISCUSSION with phytanic acid–restricted diet. Holistic care requires
involvement of a multidisciplinary team including pediatri-
Peroxisomal disorders comprise a wide spectrum of clini-
cians, neurologists, audiologists, ophthalmologists, and ortho-
cally and genetically heterogenous disorders. They are clas-
pedists. Preventive measures should be taken against
sified into 2 subgroups: peroxisome biogenesis disorders
acquiring respiratory tract infections. The cause of death usu-
and single peroxisomal enzyme deficiency. The prototype of
peroxisomal biogenesis disorders is classic Zellweger syn- ally is gastrointestinal bleeding and liver failure.
drome. Zellweger syndrome, also known as cerebrohepa-
torenal syndrome, is a rare genetic disorder which comes Lessons for the Clinician
under the group of peroxisomal biogenesis disorder. Zellweger syndrome should be considered in the differential
It is an autosomal recessive disorder characterized by a diagnosis of a neonate with central hypotonia with dysmor-
defect in peroxisome biogenesis caused by a mutation in one phism. Confirmation of the diagnosis requires good clinical
of the PEX genes (1). PEX genes encode proteins called perox- expertise with adequate collaborative efforts of the neonatolo-
ins and are involved in either peroxisome formation or gist, geneticist, pediatric neurologist, and radiologist.

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 American Board of Pediatrics References
1. Waterham HR, Ebberink MS. Genetics and molecular basis of human
Neonatal-Perinatal Content peroxisome biogenesis disorders. Biochim Biophys Acta. 2012;1822(9):
Specifications 1430–1441
2. Braverman NE, D’Agostino MD, Maclean GE. Peroxisome biogenesis
• Know the disorders for which molecular genetic stud-
disorders: biological, clinical and pathophysiological perspectives. Dev
ies are clinically indicated, such as cystic fibrosis, and
Disabil Res Rev. 2013;17(3):187–196
how to interpret test results.
3. Poll-The BT, Saudubray JM, Ogier HA, et al. Infantile Refsum disease:
• Recognize the diagnostic implications of single vs. an inherited peroxisomal disorder—comparison with Zellweger
multiple anomalies. syndrome and neonatal adrenoleukodystrophy. Eur J Pediatr. 1987;
• Recognize the clinical features and know how to diag- 146(5):477–483
nose and manage congenital anomalies of the lower 4. Wanders RJ, Waterham HR. Biochemistry of mammalian peroxisomes
extremities, such as metatarsus adductus, talipes equi- revisited. Annu Rev Biochem. 2006;75:295–332
novarus, syndactyly, polydactyly, limb reduction. 5. Bowen P, Lee CS, Zellweger H, Lindenberg R. A familial syndrome of
• Know the clinical features and inheritance patterns of multiple congenital defects. Bull Johns Hopkins Hosp.
common syndromes or associations that can be recog- 1964;114:402–414
nized in the newborn period (eg, VATER association 6. Poll-The BT, G€artner J. Clinical diagnosis, biochemical findings and
and DiGeorge syndrome). MRI spectrum of peroxisomal disorders. Biochim Biophys Acta.
• Know the indications, limitations, and techniques for 2012;1822(9):1421–1429
newborn screening for genetic disorders. 7. Zeharia A, Ebberink MS, Wanders RJA, et al. A novel PEX12 mutation
• Know physical findings indicative of neonatal identified as the cause of a peroxisomal biogenesis disorder with mild
encephalopathy. clinical phenotype, mild biochemical abnormalities in fibroblasts and a
mosaic catalase immunofluorescence pattern, even at 40 degrees C. J
• Know the basis for (including genetic), clinical and labora- Hum Genet. 2007;52(7):599–606
tory features (including associated abnormalities), differ-
8. Steinberg SJ, Snowden A, Braverman NE, et al. A PEX10 defect in a
ential diagnosis, evaluation, management, and outcomes
patient with no detectable defect in peroxisome assembly or metabolism
of neonatal hypotonia/neuromuscular weakness.
in cultured fibroblasts. J Inherit Metab Dis. 2009;32(1):109–119
9. Ferdinandusse S, Denis S, Hogenhout EM, et al. Clinical, biochemical,
and mutational spectrum of peroxisomal acyl-coenzyme A oxidase
deficiency. Hum Mutat. 2007;28(9):904–912
10. Ferdinandusse S, Denis S, Mooyer PAW, et al. Clinical and
biochemical spectrum of D-bifunctional protein deficiency. Ann
Neurol. 2006;59(1):92–104

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 VISUAL DIAGNOSIS

Whole Genome Sequencing: Early

Diagnostic Tool in Newborns with
Refractory Seizures
Estefani Hee Chung, MD,* Julia Frueh, MD,* Angela Lai, MD,†,‡ and Andrea Scheurer-Monaghan, MD†,‡
*Homer Stryker MD School of Medicine, Western Michigan University, Kalamazoo, MI
†
Southwest Michigan Neonatology, PC, Kalamazoo, MI
‡
Bronson Children’s Hospital, Kalamazoo, MI

THE CASE
A term male infant born at an outlying hospital to nonconsanguineous parents
was transferred immediately after birth due to facial dysmorphisms and limb
abnormalities (Figs 1A, 1B, 1C).

Prenatal and Birth History

• Born to a 24-year-old gravida 1, para 0 white woman.
• Pregnancy complicated by mild oligohydramnios at 36 weeks’ gestation that
resolved with hydration; prenatal ultrasonography findings unremarkable with
consistent fetal movement throughout pregnancy
• Cesarean section at 38 weeks’ gestation for breech presentation
• Prenatal maternal laboratory findings: Group B Streptococcus negative, hepati-
tis B surface antigen negative, rubella immune, HIV negative, rapid plasma
reagin nonreactive
• Apgar scores: 4 and 9 at 1 and 5 minutes, respectively

Presentation
The infant was cyanotic and hypotonic at birth with no respiratory effort. He
required positive pressure ventilation for approximately 2 min and was then
transitioned to nasal cannula oxygen. His tone improved by 5 minutes of age.
He was transported to a level 3 NICU for evaluation of his dysmorphic features.

PROGRESSION
Vital Signs (Newborn Day)
• Heart rate: 160 beats/min
AUTHOR DISCLOSURE Drs Hee Chung,
• Respiratory rate: 40 breaths/min Frueh, Lai, and Scheurer-Monaghan have
• Blood pressure: 57/41 mm Hg disclosed no financial relationships
• Oxygen saturation: 97% (on high-flow nasal canula 5 L/min, fraction of relevant to this article. This commentary
does not contain a discussion of an
inspired oxygen 0.3) unapproved/investigative use of a
• Temperature: 99.1 F (37.3 C) commercial product/device.

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 Figure 1. A. Photograph showing the infant’s overall appearance, including a broad nose, micrognathia, arthrogryposis of the upper and lower extremities
and bilateral talipes equinovarus. B. Photograph showing retrognathia and low-set ears. C. Photograph showing a broad chest with wide-spaced nipples.

Physical Examination (Newborn Day) • Neurologic: Awake, alert with spontaneous movement of
• Birthweight: 2,640 g (10th percentile), length: 48.5 cm all extremities with increased tone and contractures; inter-
(37th percentile), head circumference: 35.8 cm (85th mittent myoclonic movements with tactile stimulation
percentile) On the second day after birth, he was observed to have
• Head: Cranial molding; microcephaly; retrognathia; micro- myoclonic events that were associated with vital sign
gnathia; long, downward-slanting palpebral fissures; low- instability and staring that lasted 10 to 15 seconds. Video
set ears; prominent nose; broad nasal bridge electroencephalography confirmed epileptiform activity.
• Cardiovascular: Regular rate and rhythm; normal S1, S2; The seizures were multifocal, brief, and clustering, with
no murmurs multiple episodes in a 12-hour period. He was supported
• Lungs: Clear and equal bilaterally; no respiratory distress with orogastric feedings and high-flow nasal cannula
• Chest wall: Pectus carinatum, wide-spaced nipples while an extensive evaluation was initiated.
• Abdomen: Soft, nontender; no masses; 3-vessel cord
• Genitourinary: Normal male genitalia; testes descended; Laboratory Studies
patent anus Investigative studies within normal limits:
• Skeletal: Ulnar deviation of bilateral wrists; arachnodac-
tyly; bilateral talipes equinovarus; arthrogryposis • Infectious evaluation: C-reactive protein, blood and
• Skin: Bruising of bilateral lower extremities; no sacral urine cultures, cerebrospinal fluid (CSF) meningoen-
tufts or dimples cephalitis panel

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 • Michigan newborn screen • Amino acid disorder
• Urine organic acids • Chromosomal abnormality
• Chromosomal microarray • Single gene or multifactorial genetic disorder
• Congenital disorders of glycosylation

ACTUAL DIAGNOSIS
Abnormal laboratory findings with unclear significance:
Single gene or multifactorial genetic disorder
• CSF triene/tetraene ratio 0.099 (normal 0.017–0.083) The results of the infant’s rWGS showed maternal hetero-
• CSF linolenic acid 288 nmol/mL (normal 30–170 nmol/mL) zygous mutation of the c.294dup (p.Leu99ThrfsTer92)
• Serum taurine 7 nmol/mL (normal 8–48 nmol/mL) variant and paternal heterozygous mutation of the
• Serum a-amino-n-butyric acid 5 nmol/mL (normal 7– c.638dup (p.Val214GlyfsTer18) variant. These results were
28 nmol/mL) consistent with a compound heterozygous BRAT1 muta-
• Serum ammonia 40.6 mg/mL (29 mmol/L; normal 75.5– tion that is associated with rigidity and multifocal seizure
126 mg/mL [54–90 mmol/L]) syndrome, lethal neonatal (RMFSL). A multidisciplinary
• Serum 3-methylhistidine 3 nmol/mL (normal <1 nmol/mL) care conference was held that included the neonatologist,
pediatric neurologist, social worker, nurse, and case man-
Radiographic Studies ager. The team discussed with the parents that this diag-
• Radiography (Fig 2) showed prominent cardiothymic sil- nosis is rare, and as a result, it is difficult to provide a
houette and mild thoracolumbar scoliosis definitive prognosis for the infant. Various management
• Brain magnetic resonance imaging (MRI) without con- options were discussed with the family which included,
trast showed diffuse, mild undersulcation and under- but were not limited to, continuing full support with esca-
opercularization; mildly prominent extra-axial CSF; thin- lating care if needed and comfort care with home hospice.
ning of posterior corpus callosum (Figs 3 and 4)
The infant continued to have subclinical seizures despite
multiple antiepileptic drugs (AEDs), including phenobarbi-
tal, levetiracetam, phenytoin, and topiramate. Due to the
risk of respiratory depression with additional medications,
the care team decided to not increase the AED dosages any
further and monitor clinically for seizure activity. Given
that the extensive laboratory and radiographic studies were
unrevealing, the team decided to perform additional genetic
testing. A family history revealed that the parents were non-
consanguineous. A maternal aunt had died at 8 months of
age from a presumed seizure disorder present from birth
and a maternal uncle had died at several weeks of age of
sudden unexpected infant death. Parental consent was
obtained for rapid whole genome sequencing (rWGS),
which was performed during the infant’s second week of
age, and results were obtained within 5 days.

DIFFERENTIAL DIAGNOSIS
• Congenital brain malformation (anencephaly, Chiari
malformation, holoprosencephaly, Dandy Walker spec-
trum, agenesis of the corpus callosum)
• Neuromuscular disorder (spinal muscular atrophy with
progressive myoclonic epilepsy)
• Congenital disorders of glycosylation
• Essential fatty acid disorder Figure 2. Radiograph showing prominent cardiothymic silhouette and
• Urea cycle disorder mild thoracolumbar scoliosis.

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 WHAT THE EXPERTS SAY
We describe a white term male infant born to nonconsan-
guineous parents with facial dysmorphisms, limb abnor-
malities, and AED-resistant seizures requiring respiratory
and enteral support and who was found to have a com-
pound heterozygous BRAT1 mutation.
The infant’s brain MRI on the first day after birth
showed diffuse cerebrum underdevelopment. There were
no other structural abnormalities indicating a disorder of
dorsal induction, ventral induction, or myelination. Serum
analysis of essential fatty acids and amino acids was part
of the diagnostic evaluation as these components have
been implicated in poor neurologic development. As seen
in the infant’s laboratory studies, he had elevated levels of
essential fatty acids with low levels of ammonia and spe-
Figure 3. Sagittal T1 image on brain magnetic resonance imaging with-
out contrast showing thinning of the posterior corpus callosum/splenium cific amino acids. The significance of these results was not
(arrow). clear and did not result in a specific diagnosis.
BRAT1 mutations have been associated with RMFSL
The parents elected to continue current management in
and neurodevelopmental disorder with cerebellar atrophy,
addition to trying a ketogenic diet to attempt to lessen the
with or without seizures. We conducted a literature review
infant’s seizure burden.
and found that since 2012, BRAT1 mutations have been
At 2 weeks of age, the infant was transferred to a facil-
reported in 26 patients, all with a spectrum of neurodeve-
ity with expertise in a ketogenic diet. The infant continued
lopmental and phenotypic anomalies but 1 common vari-
to have myoclonic activity with tactile stimulation, and
contractures of his extremities were still present but able of refractory seizures (Table). Many of these cases
slightly improved. He continued to have multiple clinically have also reported abnormalities on the brain MRI consis-
significant seizures and ultimately developed respiratory tent with global underdevelopment of the cerebrum and
failure requiring intubation. After 5 days on the ketogenic cerebellum. These findings include mild hypoplasia of the
diet, the infant had not achieved ketosis. The parents frontal lobes, delayed or decreased myelination, thin cor-
elected to proceed with hospice care. He died of cardiore- pus callosum, cerebellar hypoplasia, and prominent peri-
spiratory failure at 1 month of age. cerebral extra-axial space. The cases in which the patient
survived long enough to have serial imaging reported a
progressive atrophy. The magnitude of the abnormality
noted on brain MRIs was not found to be predictive of
prognosis. In prior case reports, 12 infants died at or
before age 6 six months, 5 before age 2 years, and 1 at age
5 years. (1)(2)(3)(4)(5)(6)(7)(8) Eight patients were reported
to have milder symptoms and lived until their childhood
years. (3)(9)(10)(11)(12) One study suggested the possibility
that homozygous mutations may have a more severe
presentation than compound heterozygous. (8) How-
ever, our patient presented with severe disease in the
neonatal period despite having a compound heterozy-
gous mutation. The extent to which the inheritance pat-
tern affects the severity of the RMFSL may be more
complex than initially thought, as patients with both
homozygous and compound heterozygous mutations
can present with severe symptoms. This raises the ques-
Figure 4. Axial T2 image on brain magnetic resonance imaging without
contrast showing undersulcation and under-opercularization (arrows), as tion as to whether the true diagnosis is a single gene
well as prominent extra-axial cerebrospinal fluid. disorder or multifactorial disorders.

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Table. Summary of Case Reports of Patients with RMFSL from 2012–2019
Seizure Type and Treatments Leading
Reference (No. of Timing of Dysmorphic Onset (If not Abnormal Brain to Clinical Invasive
Patients) WES/WGS Facies Microcephaly Neonatal) MRI Improvement Interventions Age at Death

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Puffenberger et al (1) Not specified Not specified Yes Multifocal Yes N/A Tube feeding All less than 4
(n=3) mo
Saunders et al (13) After 5 weeks; patient Yes Yes Focal No Transient Intubation 2 mo
(n=1) already placed on improvement with
comfort care at that pyridoxine
time
Saitsu et al (2) (n=2) Pt 1: Not performed Yes Yes Pt 1: GTC and Yes Improvement in Not specified 21 mo and 3
myoclonic apneic spells with mo
zonisamide
Pt 2: At the time of Pt 2: Polymorphic
autopsy
Mundy et al. (9) (n=1) Not specified Yes Yes 3 mo Yes N/A Not specified Alive at 6 y
Hanes et al (11) (n=1) Around age 2 y Yes Yes Focal onset impaired Yes Valproic acid N/A Alive at 3 y
awareness
Straussberg et al (5) Not specified Yes Yes Myoclonic No N/A Gastrostomy tubes in 5 mo and 6 mo
(n=2) both patients
Van de Pol et al (14) Yes 3, 17, and 2 mo
(n=3)
Srivastava et al (12) Not specified Yes Yes Pt 1: No seizures Yes Pt 3: Levetiracetam Pt 4: Tracheostomy, Pt 1: Alive at 10
(n=4) gastrostomy y
Pt 2: Staring spells Pt 2: Alive at 6 y
Pt 3: Staring spells Pt 3: Alive at 4
years
Pt 4: Focal/tonic; focal Pt 4: Alive at 16
electrographic status mo
epilepticus
Smith et al (3) (n=2) Not specified Yes Yes Onset at 4 and 8 mo Pt 1: Yes N/A Not specified Pt 1: 15 months
Pt 2: Not reported Pt 2: Alive at 4 y,
4 mo
Horn et al (4) (n=2) Not specified Yes Yes Pt 1: Myoclonic, started Pt 1: No N/A Pt 1: Gastrostomy 5 y and 2 mo
at 5 mo
Pt 2: Myoclonic Pt 2: Yes Pt 2: NG tube, muscle
biopsy
Fern
andez-Ja
en et al Not specified No Yes No seizures; Yes N/A N/A Alive at age 4 y
(10) (n=1) developmental delay
only
Celik et al (8) (n=1) Not specified No Yes Myoclonic Yes N/A Gastrostomy, 10 mo
tracheostomy
Van ommeren et al (6) Not reported; results led Yes Yes Myoclonic Yes N/A Intubation; palliation 10 wk
(n=1) to initiation of from 6 wk
palliation

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Szyma
nska et al (7) Not specified Yes Reported in 1 Myoclonic, polymorphic Yes N/A Not reported 6 mo and 12
(n=2) of 2 patients mo
Current patient 2 weeks Yes Yes Myoclonic Yes N/A Intubation, NG feeding 2 mo

GTC=generalized tonic-clonic, MRI=magnetic resonance imaging, N/A=not available, NG=nasogastric, Pt=patient, WES=whole exome sequencing, WGS=whole genome sequencing.

JANUARY 2022
e53
 In most of the previous case reports, the timing of
• Know the indications and limitations of molecu-
genetic testing relative to the onset of symptoms was not
lar cytogenetic studies (eg FISH), in the diagno-
clear. Many of these infants had progressed to requiring
sis of aneuploidy and microdeletion.
interventions such as gastrostomy tube and/or tracheos-
• Know the indications, limitations, and techni-
tomy and underwent multiple studies that yielded results
ques for newborn screening for genetic
of unknown significance. (4)(5)(6)(8)(12) In infants with
disorders.
AED-refractory seizures in the NICU, the use of rWGS
• Know how age at presentation (in utero, neonate,
has yet to become an established norm during the evalua-
infancy or later) affects the differential diagnosis
tion. WGS has become more cost-effective with a shorter
of the clinical presentation of genetic disorders.
test-result time and high analytic specificity and sensitivity
• Understand the management of neonatal seizures,
of more than 99.5%, making it one of the most compre-
including the role of neurophysiologic monitoring.
hensive tests currently available.
A spectrum of clinical severity has been found to be asso-
ciated with RMFSL. Our patient had findings most consis-
tent with a severe form of RMFSL that results in early death
at 2 months of age. Several affected individuals, including
References
our patient, have common features of intractable seizures, 1. Puffenberger EG, Jinks RN, Sougnez C, et al. Genetic mapping and
exome sequencing identify variants associated with five novel
facial dysmorphisms, and brain underdevelopment. Other
diseases. PLoS One. 2012;7(1):e28936
congenital brain malformations were less likely in this case
2. Saitsu H, Yamashita S, Tanaka Y, et al. Compound heterozygous
as no other structural abnormalities were noted on the brain BRAT1 mutations cause familial Ohtahara syndrome with
MRI. Certain neuromuscular disorders were ruled out with hypertonia and microcephaly. J Hum Genet. 2014;59(12):
687–690
a normal newborn screen and no specific laboratory result
3. Smith NJ, Lipsett J, Dibbens LM, Heron SE. BRAT1-associated
confirmed a disorder of glycosylation, fatty acid metabolism,
neurodegeneration: intra-familial phenotypic differences in siblings.
or urea cycle or amino acid metabolism. The chromosomal Am J Med Genet A. 2016;170(11):3033–3038
array did not detect any gene duplication or deletion. 4. Horn D, Weschke B, Knierim E, et al. BRAT1 mutations are
Although some patients with RMFSL present with associated with infantile epileptic encephalopathy, mitochondrial
later onset of disease, attenuated symptoms, and pro- dysfunction, and survival into childhood. Am J Med Genet A. 2016;
170(9):2274–2281
longed survival, others present with early onset, severe
5. Straussberg R, Ganelin-Cohen E, Goldberg-Stern H, et al. Lethal
symptoms, and early death. This report aims to raise neonatal rigidity and multifocal seizure syndrome–report of another
awareness of RMFSL and its variable presentations and family with a BRAT1 mutation. Eur J Paediatr Neurol. 2015;19(2):
to recognize the usefulness of rWGS in cases of intracta- 240–242

ble seizures from an unknown cause. Early identification 6. Van Ommeren RH, Gao AF, Blaser SI, Chitayat DA, Hazrati LN.
BRAT1 mutation: the first reported case of chinese origin and review
of a genetic diagnosis may facilitate discussions between
of the literature. J Neuropathol Exp Neurol. 2018;77(12):1071–1078
care teams and families and help guide often difficult
7. Szyma
nska K, Laure-Kamionowska M, Szczałuba K, et al. Clinico-
management decisions. More frequent utilization of pathological correlation in case of BRAT1 mutation. Folia
rWGS may reveal a higher prevalence of RMFSL than Neuropathol. 2018;56(4):362–371
previously reported, which in turn, may create advocacy 8. Celik Y, Okuyaz C, Arslankoylu AE, Ceylaner S. Lethal neonatal
rigidity and multifocal seizure syndrome with a new mutation in
for research into possible treatments and facilitate the
BRAT1. Epilepsy Behav Case Rep. 2017;8:31–32
development of a support network for families affected
9. Mundy SA, Krock BL, Mao R, Shen JJ. BRAT1-related disease:
by this rare disease. identification of a patient without early lethality. Am J Med Genet A.
2016;170(3):699–702


10. Fern
andez-Ja
en A, Alvarez S, So EY, et al. Mutations in BRAT1
American Board of Pediatrics cause autosomal recessive progressive encephalopathy: report of a
Spanish patient. Eur J Paediatr Neurol. 2016;20(3):421–425
Neonatal-Perinatal Content 11. Hanes I, Kozenko M, Callen DJ. Lethal neonatal rigidity and
Specifications multifocal seizure syndrome: a misnamed disorder? Pediatr Neurol.
2015;53(6):535–540
12. Srivastava S, Olson HE, Cohen JS, et al. BRAT1 mutations present
• Know when to obtain karyotypes on the subject,
with a spectrum of clinical severity. Am J Med Genet A. 2016;170(9):
parents, or other family members. 2265–2273

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 13. Saunders CJ, Miller NA, Soden SE, Dinwiddie L, Noll A, Alnadi NA, 14. Van de Pol L, Wolf N, Van Weissenbruch M, et al. Early-Onset
et al. BRAT1 mutations present with a spectrum of clinical severity. severe encephalopathy with epilepsy: The BRAT1 gene should be
Am J Med Genet Part A2. 2016;170(9):2265–2273. added to the list of causes. Neuropediatrics. 2015;46(6):392–400

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 VIDEO CORNER

VIDEO
CORNER

Stridor After Tracheoesophageal

Fistula Repair: Where Is the Lesion?
Kumar Ankur, MD, DNB,* Aparna Prasad, DNB,* Ankit Parakh, MD, DNB,† Sanjeev Chetry, MD, DNB,*
Prashant Jain, MS, MCH,‡ Ashish Prasad, DNB‡
*Department of Neonatology, BLK Superspeciality Hospital, New Delhi, India
†
Department of Pediatric Pulmonology, BLK Superspeciality Hospital, New Delhi, India
‡
Department of Pediatric Surgery, BLK Superspeciality Hospital, New Delhi, India

A male infant with a birthweight of 2,500 g (between the 3rd and 10th percen-
tile) is born at 37 weeks’ gestation to a 27-year-old primigravida woman with
severe polyhydramnios (amniotic fluid index of 37 cm). After delivery, the neo-
nate is vigorous, with Apgar scores of 8 and 9 at 1 and 5 minutes of age, respec-
tively. He develops excessive frothy oral secretions, and the neonatology team is
unable to pass a nasogastric tube. Chest radiography shows the coiling of a naso-
gastric tube with air in the stomach suggestive of esophageal atresia (EA) with
tracheoesophageal fistula (TEF).
On day 4 of age, a primary surgical repair of the TEF with eso-esophageal
anastomosis is performed under mild tension. Initially, the neonate receives
minimal ventilator settings (mean airway pressure 8 cm H2O, positive end-expi-
ratory pressure of 5 cm H2O, and fraction of inspired oxygen [FiO2] 0.21) for 4
days. Three days after surgery, the neonate undergoes extubation to noninvasive
positive pressure ventilation and is then weaned to high-flow nasal cannula on
postoperative day 4. Soon after extubation, the infant develops intermittent stri-
dor but is weaned to high-flow nasal cannula by postoperative day 4. The stridor
progresses over the next 48 hours, and a video of the infant at that time is
shown (Video 1).

QUESTION 1
The stridor in this infant occurs in which of the following phases of respiration?

A. Inspiratory phase
B. Expiratory phase
C. Biphasic
AUTHOR DISCLOSURES Drs Ankur, The infant’s stridor was present at rest but worsened with crying. There was
Aparna Prasad, Parakh, Chetry, Jain, and
Ashish Prasad have disclosed no financial
no significant decrease in stridor with neck extension and prone position. An
relationships relevant to this article. This intravenous dexamethasone trial was given after extubation for 3 days with no
commentary does not contain a clinical improvement. The neonate’s baseline oxygen saturation in room air was
discussion of an unapproved/
investigative use of a commercial between 90% and 92%; however, with high-flow nasal cannula (flow of 5 L,
product/device. FiO2 0.21), the oxygen saturations increased to 94% to 98%. To determine the

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 Video 1. Infant at 8 days of age.
Figure 1. Vocal cords during expiration. Note the limited abduction and a
small glottis opening.
cause of the stridor, flexible bronchoscopy was done trans-
nasally using a 2.8-mm video bronchoscope (Video 2); this cord paralysis (VCP). The video also demonstrates the
procedure was performed with minimal sedation to presence of a repaired TEF in the posterior wall of the
ensure spontaneous respirations. midtrachea (Figs 3 and 4) with nonpulsatile narrowing of
the trachea. There was no variability with respirations,
QUESTION 2 thus ruling out tracheomalacia. The lower trachea
Based on this infant’s clinical course and findings in the appeared normal. The infant’s improvement in oxygen sat-
urations with high-flow cannula was likely because of the
flexible bronchoscopy, the most likely diagnosis in this
airway stents. The infant was discharged with orogastric
infant is:
feedings at 3 weeks; he did not have any stridor and was
A. Double aortic arch feeding well on follow-up at 3 months of age.
B. Laryngomalacia VCP is the absence of movements of the vocal folds fol-
C. Subglottic edema or stenosis lowing dysfunction of the recurrent laryngeal nerve. This
D. Tracheomalacia nerve is a branch of the vagus nerve that runs along the
E. Vocal cord palsy lateral surfaces of the trachea near the tracheoesophageal
groove and is vulnerable to injury during surgeries of the
DISCUSSION neck and thorax. (1) Similar to the patient in this case,
bilateral VCP presents with inspiratory stridor at rest that
In infants with stridor, a careful clinical assessment of the
worsens upon agitation. VCP has been reported to occur
stridor can provide information about the type, severity,
in 3% to 11.2% of patients following EA/TEF repair. (1)(2)
and level of obstruction. In Video 1, the infant has inspira-
According to a retrospective review, 48% of the postopera-
tory stridor during agitation that is associated with supra-
tively diagnosed cases were bilateral, and the etiology was
sternal and sternal retractions and oxygen desaturations.
mostly (43%) iatrogenic. (3)(4)
In addition, the infant’s hoarse cry suggests vocal cord
A double aortic arch is a rare cause of stridor in infants
swelling or injury. Of note, bronchoscopy (Video 2) reveals
and is known to be associated with EA/TEF. (5) The mean
that the infant has reduced and paradoxical vocal cord
movements (Figs 1 and 2), suggestive of bilateral vocal

Figure 2. Vocal cords during inspiration. Note the position of cords during
Video 2. Flexible bronchoscopy. inspiration is in adduction, suggesting a paradoxical cord movement.

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 epiglottis with inspiratory supraglottic tissue collapse is the
hallmark of laryngomalacia. (6) However, in our case, flexible
bronchoscopy did not demonstrate these findings, thus ruling
out laryngomalacia.
Subglottic stenosis can be congenital or acquired.
Acquired subglottic stenosis has been recognized as a
postoperative complication in 12.9% of TEF patients. (8) It
has also been seen as a result of subglottic injury caused
by endotracheal intubation, especially if prolonged. The
presence of stridor during both phases of respiration
Figure 3. Midtracheal image showing the tracheal end of the repaired fis- remains the most common symptom of a subglottic
tula (arrow). lesion, which was not noted in our patient. Flexible bron-
choscopy ruled out the possibility of stenosis or edema.
The incidence of congenital tracheomalacia has been
age at diagnosis for this vascular ring is 6 months, but it
reported to be at least 1 in 2,100 and has been found to be
can present earlier. The clinical features are related to
associated with EA. (4) Indeed, a retrospective study found
compression of the esophagus and trachea, such as dys-
that tracheomalacia is the most common airway finding in
phagia or difficulty in feeding and stridor in the expiratory
37.4% of patients with TEF. (8) Localized secondary tracheo-
phase. Computed tomography angiography is considered
malacia may occur due to compression from a vascular mal-
the gold standard for diagnosis. In children with a double
formation (such as a double aortic arch). (5) Acquired forms
aortic arch, flexible bronchoscopy may show pulsatile com-
of tracheomalacia may develop as a result of prolonged venti-
pression in the midtrachea.
lation, tracheostomy, or severe tracheobronchitis. Intratho-
Laryngomalacia typically presents with inspiratory stridor
racic tracheomalacia causes excessive trachea collapse during
and is the most common cause of congenital stridor in neo-
expiration, whereas extrathoracic tracheomalacia causes tra-
nates. (6) Affected patients typically have inspiratory stridor
cheal collapse during the inspiratory phase. This leads to the
that increases with feeding, crying, agitation, supine position-
presence of monophonic (expiratory) wheezing in patients
ing, and upper respiratory tract infections. In patients with
laryngomalacia, the inspiratory stridor decreases with neck with intrathoracic tracheomalacia and inspiratory or biphasic
extension and in the prone position. In this case, the infant stridor in patients with extrathoracic tracheomalacia. In addi-
had stridor mainly when crying, with no significant decrease tion to these symptoms, a ‘barking cough’ and increased
in stridor with neck extension and prone position, making work of breathing is often present. In a patient with tracheo-
laryngomalacia less likely. (7) In a retrospective study, laryn- malacia, bronchoscopy typically shows dynamic tracheal
geal anomalies were associated with approximately 30% of compression with respiration, which was not found in our
cases of TEF, and of these, 4.3% were found to be laryngoma- patient. Preoperative bronchoscopy is not a routine practice;
lacia. (8) Movements of laryngeal structures should be ana- instead, it is need-based.
lyzed in a spontaneously breathing infant to diagnose Correct Responses:
laryngomalacia. During bronchoscopy, an omega-shaped Question 1: A. Inspiratory phase
Question 2: E. Vocal cord palsy

American Board of Pediatrics

Neonatal-Perinatal Content
Specifications

• Know the clinical features of an infant with airway

obstruction.
• Plan appropriate diagnostic evaluation and manage-
ment for an infant with airway obstruction.
Figure 4. Significant midtracheal narrowing.

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 Acknowledgment repaired esophageal atresia/tracheoesophageal fistula. Int J Pediatr
We wish to thank Dr Ramji Bhardwaj and Dr Manazir Otorhinolaryngol. 2018;112:45–47
Hasan Rahmani for producing and editing the video. 4. Pfleger A, Eber E. Assessment and causes of stridor. Paediatr Respir
Rev. 2016;18:64–72
5. Hartenberg MA, Salzberg AM, Krummel TM, Bush JJ. Double aortic
References arch associated with esophageal atresia and tracheoesophageal fistula.
1. Fung SW, Lapidus-Krol E, Chiang M, et al. Vocal cord dysfunction J Pediatr Surg. 1989;24(5):488–490
following esophageal atresia and tracheoesophageal fistula (EA/TEF) 6. Landry AM, Thompson DM. Laryngomalacia: disease presentation,
repair. J Pediatr Surg. 2019;54(8):1551–1556 spectrum, and management. Int J Pediatr. 2012;2012:
2. Mortellaro VE, Pettiford JN, St Peter SD, Fraser JD, Ho B, Wei J. 753526
Incidence, diagnosis, and outcomes of vocal fold immobility after 7. Bluher AE, Darrow DH. Stridor in the Newborn. Pediatr Clin North
esophageal atresia (EA) and/or tracheoesophageal fistula (TEF) repair. Am. 2019;66(2):475–488
Eur J Pediatr Surg. 2011;21(6):386–388 8. Hseu A, Recko T, Jennings R, Nuss R. Upper airway anomalies in
3. Kovesi T, Porcaro F, Petreschi F, Trozzi M, Bottero S, Cutrera R. congenital tracheoesophageal fistula and esophageal atresia patients.
Vocal cord paralysis appears to be an acquired lesion in children with Ann Otol Rhinol Laryngol. 2015;124(10):808–813

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 OUTCOMES OF NICU GRADUATES

OUTCOMES OF
NICU GRADUATES

Follow-up for a Preterm Infant with

Beckwith-Wiedemann Syndrome
Mairead Bresnahan, BS,* Monica H. Wojcik, MD*,†
Divisions of Newborn Medicine* and Genetics and Genomics,† Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School,
Boston, MA

We are excited to introduce this new NeoReviews feature: Outcomes of NICU Grad-
uates. In this article, authors describe the clinical course of a NICU graduate who is
receiving care in a specialty clinic. After providing a brief overview of the NICU hos-
pitalization, the authors review the infant’s post-discharge clinical course including
recommended follow-up and treatments. The article concludes with a short sum-
mary of major take-home lessons from the case as well as a discussion of expected
outcomes for the specific condition. We hope that neonatal clinicians will benefit
from these case presentations by gaining insight into the outpatient management
and long-term outcome of a wide range of NICU diagnoses. If you are interested in
submitting a case, please contact [email protected].
—Dr. Dara Brodsky, Editor in Chief, and Dr. Santina Zanelli, Associate
Editor, Outcomes of NICU Graduates

CASE PRESENTATION
In this article, we describe a female child born preterm with a postnatal diagno-
sis of Beckwith-Wiedemann syndrome (BWS) who has been followed in our
multidisciplinary infant follow-up program.
The infant was born at 31 and 3/7 weeks’ gestation via vaginal delivery to a
30-year-old gravida 2, para 1 woman following spontaneous preterm labor. The
pregnancy had been unremarkable, with a normal second-trimester fetal survey.
The infant initially emerged vigorous with good tone and spontaneous respira-
tory effort, though soon after, she had apnea and bradycardia. She ultimately
required intubation in the delivery room and was transferred to a level III NICU
for further evaluation and management. Her Apgar scores were 6 and 7 at 1 and
5 minutes of age, respectively. Her birth parameters were notable for a length of
47 cm (90th percentile), head circumference of 27.5 cm (90th percentile),
AUTHOR DISCLOSURE Dr Wojcik has and weight of 2,108 g (50th percentile).
worked as a consultant for Change
Healthcare. Dr Bresnahan has disclosed
She underwent extubation and was transitioned to continuous positive airway
no financial relationships relevant to this pressure by 24 hours of age and subsequently to room air by 4 days of age. She
article. This commentary does contain a continued to have occasional apnea/bradycardia/desaturation spells both at rest
discussion of an unapproved/
investigative use of a commercial and with feedings that were initially attributed to prematurity. She was started on
product/device. nasogastric feedings that were advanced without difficulty and she transitioned to

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 full oral feedings by about 1 month of age. Her head ultra- breathing with a prominent obstructive component that was
sound scan at 7 days of age was normal and she passed her well-controlled with bilevel positive airway pressure (BiPAP).
newborn hearing screen. A modified barium swallow study showed oropharyngeal dys-
She continued to have spells both with feedings and at rest phagia and aspiration when she was fed upright with a regu-
despite reaching term postmenstrual age. At 6 weeks of age, lar-flow nipple, but this did not occur when she was fed side-
the neonatology team had observed that her tongue was large lying with a slow-flow nipple. She was discharged to a reha-
and thought that her spells may have an obstructive compo- bilitation facility at 2.5 months of age and ultimately went
nent. She was seen by the genetics team for macroglossia, home at 3 months of age to continue to use BiPAP during
mild hypotonia, and unique facial features. She was clinically naps and overnight sleep.
diagnosed with BWS, based on her features of macroglossia, Our genetics team counseled the family extensively
forehead and glabellar nevus simplex, ear creases and pits, about the diagnosis of BWS based on her clinical features.
umbilical hernia, bilateral infraorbital creases, and generalized The family was appropriately concerned about the poten-
overgrowth (Fig 1A). Genetic testing to determine the underly- tial for medical complications such as intra-abdominal
ing molecular etiology of the infant’s clinical diagnosis tumors. They were also worried about issues related to the
included a karyotype, chromosomal microarray and methyla- macroglossia, which they were reassured should improve
tion analysis (via methylation-sensitive Multiplex Ligation- over time and for which follow-up was arranged with sur-
Dependent Probe Amplification, Mayo Clinic Laboratories, gical subspecialists in the event that a surgical interven-
Rochester, MN), all of which were nondiagnostic. tion was needed.
Due to the clinical diagnosis of BWS, tumor surveillance
with serum a-fetoprotein (AFP) levels and abdominal ultra- FOLLOW-UP COURSE
sonography was recommended. The initial serum AFP was The infant is now 20 months old (Fig 1C) with a corrected
elevated at 17,500 ng/mL (17,500 mg/L), but this was not age of 18 months and has been followed in our multidisci-
unexpected for a former preterm infant with a diagnosis of
plinary infant follow-up program by genetics, physical
BWS because both prematurity and BWS are associated with
therapy, and pediatric psychology in addition to other sub-
elevated AFP levels. (1)(2) Following this initial AFP, a sharp
specialists including pulmonology (for history of sleep-dis-
downtrend was observed (Fig 2). Initial liver ultrasonography
ordered breathing) and plastic and oral surgery (for
showed multiple hypoechoic lesions (Fig 3), suspected to be
history of macroglossia). Her home BiPAP was discontin-
hemangiomas (she was also noted to have a hemangioma
ued at 5 months of age after a normal sleep study. Her
on her posterior scalp), and a splenic cyst.
AFP levels continue to trend downward and are now in
The infant was transferred to our institution at 2 months
the normal range, and subsequent ultrasonography over
of age for a sleep study that showed mixed sleep-disordered
the first 18 months of age demonstrated resolution of all
but 1 of the hepatic lesions. The most recent ultrasound
scan at 18 months of age showed resolution of the final
liver lesion with a stable splenic cyst. Her growth curve
continues to demonstrate overgrowth (Fig 4).
The plastic and oral surgery team monitored the child’s
macroglossia, which was thought to become less clinically
and cosmetically significant over time without intervention
(Figs 1B and 1C); therefore, their plan is to continue to
observe until 2 to 3 years of age before considering a
tongue debulking procedure. She had a slight delay in oral
motor skills for which she was followed by the outpatient
feeding and swallowing team with no further clinical con-
cerns for aspiration. After her last visit to this clinic at 18
Figure 1. Photographs from infancy to present. (A) Photographs of the months of age, she was noted to be doing wonderfully
infant at 6 weeks of age (37 weeks’ postmenstrual age) with notable fea-
tures of macroglossia, forehead and glabellar nevus simplex, transverse
with her oral feeding skills and was discharged from their
ear creases and pits, and bilateral infraorbital creases. These features are clinic with follow-up on an as-needed basis only.
less noticeable at 14 months’ chronologic age (corrected age 12 months),
Developmentally, she continues to make excellent pro-
with decreased prominence of the macroglossia and facial birthmarks (B),
and even less so at a chronologic age of 20 months (C). gress. She is a bright and determined child with a loving

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 Figure 2. a-fetoprotein (AFP) levels over time. Graph shows a sharp decrease in the neonatal period followed by normalization over the next year.

and nurturing attachment to her parents. Neuropsychologi- or likely both. She continues to receive early intervention
cal testing using the Bayley Scales of Infant and Toddler services for developmental support, and increased fre-
Development, 4th edition (Pearson, London, England) at 20 quency of speech therapy has been recommended.
months of age (18 months’ corrected age) demonstrated The search for the genetic cause of the child’s BWS has
gross and fine motor skills that are age-appropriate, cogni- yet to be successful. Additional testing has included
tive skills that are also within the normal range, and a CDKN1C sequencing (Genetic Diagnostic Laboratory, Uni-
receptive and expressive language delay of 6 to 7 months versity of Pennsylvania, Philadelphia, PA), a genome-wide
(accounting for prematurity). She had some atypical self- methylation study (EpiSign, Greenwood Genetics, Green-
stimulatory behaviors and social interactions noted during wood, SC), and MLPA with pyrosequencing (Greenwood
the most recent evaluation that deserve further monitoring. Genetics). All of these results were nondiagnostic with no
It is unclear whether the language delay is related to epigenetic pattern classic for BWS. Due to a potential for
mechanical challenges associated with her macroglossia, or mosaicism, should she undergo the tongue debulking pro-
overall, whether the developmental assessments reflect a cedure, the excised tissue sample may be sent for genetic
predominant influence of the preterm delivery versus BWS, testing.

Figure 3. Liver imaging. Transverse (left) and sagittal (right) views of the liver on ultrasonography showing a small hypoechoic lesion measuring
5.1 × 4.2 × 4.5 mm in the right lobe of the posterior liver. At least 4 other smaller lesions were noted in the left lateral lobe, right lobe of the anterior liver,
right lobe of the liver dome, and the inferior right lobe of the liver with normal directional color Doppler flow in the hepatic vasculature. These lesions
were thought to likely represent multiple small liver hemangiomas.

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 Figure 4. Growth charts. The infant’s height and weight as plotted against corrected age (to account for preterm delivery at 31 weeks’ gestation) on the
growth charts developed by the Centers for Disease Control and Prevention demonstrate continued overgrowth.

DISCUSSION preterm delivery, nevus simplex and hemangiomas, and

BWS is an overgrowth disorder with a varied presenting infraorbital creases are minor criteria (3 minor). With 3
phenotype that is attributed to disorders of genomic major and 3 minor findings associated with BWS, she
imprinting of the 11p15 chromosomal region. Interestingly, meets the criteria for a clinical diagnosis of BWS.
children with BWS are often born preterm. (3) BWS can More recently, to recognize the variable clinical presen-
be diagnosed clinically using major and minor findings tations and molecular etiologies of BWS, the term “BWS
associated with this condition: spectrum” (BWSp) has been adopted. (1) A recent interna-
tional consensus group (1) has abandoned the terminology
• Major findings: Macrosomia, macroglossia, linear/trans- of major and minor associated findings and introduced
verse ear lobe creases and/or posterior pits, lateralized “cardinal” and “suggestive” features of BWSp as well as a
overgrowth or hemihyperplasia, cleft palate, omphalo- scoring system to diagnose clinical BWSp. Cardinal fea-
cele or umbilical hernia, cardiomyopathy, embryonal tures include macroglossia, lateralized overgrowth (hemi-
tumors such as Wilms tumor or hepatoblastoma, viscer- hyperplasia), omphalocele, multifocal Wilms tumor or
omegaly (enlargement of the intra-abdominal organs), nephroblastomatosis, hyperinsulinism, and other features
adrenal cortex cytomegaly, renal abnormalities, placental seen on clinical pathologic examination such as placental
mesenchymal dysplasia, and positive family history mesenchymal dysplasia and adrenal cortex cytomegaly.
• Minor features: Prematurity, hypoglycemia, nevus sim- Suggestive features, or features that also occur frequently
plex or hemangiomas, infraorbital creases, cardiac abnor- in those without a BWSp diagnosis, include polyhydram-
malities, diastasis recti, and advanced bone age nios or placentomegaly, increased birthweight for gesta-
tional age (>2 standard deviations above the mean),
Using these criteria, a clinical diagnosis of BWS can be transient hypoglycemia, facial nevus simplex, ear creases
established in an individual who meets either (a) 3 major or pits, umbilical hernias or diastasis recti, nephromegaly
or (b) 2 major and at least 1 minor criteria. (4) This or hepatomegaly, and embryonal tumors. In this scoring
infant’s macroglossia, umbilical hernia, ear creases, and system, 2 points are given for each cardinal feature and 1
pits meet the major criteria (3 major), and her history of point per suggestive feature. A score of greater than or

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 equal to 4 points is consistent with a clinical diagnosis of overgrowth—but not others. In most sporadic cases of
BWSp. (1) The infant in this case has 1 cardinal feature BWSp, the underlying molecular defect is mosaic at a low
(macroglossia) and 3 suggestive features (nevus simplex, enough level where it may not be detected in the peripheral
ear creases and pits, and umbilical hernia) scoring a total blood genetic testing. (8)
of 5 points. In her initial genetic evaluation, a possible Many individuals with BWSp present in the NICU or
right leg length discrepancy was noted, which would lead newborn nursery, particularly as hypoglycemia related to
to a score of 7, though this finding has not persisted. hyperinsulinism (not seen in our case) and preterm deliv-
On a molecular level, BWSp is associated with various ery (as seen in our case) are common features. Following
abnormalities in chromosome region 11p15 that affect the recognition of this diagnosis, an AFP measurement
imprinted genes. Methylation abnormalities make up the and abdominal ultrasonography are recommended to
most common subgroup, with loss of methylation (LOM) assess for intra-abdominal malignancy. Evaluation for
at the maternal IC2 allele (IC2 LOM) found in 50% of issues related to macroglossia such as poor feeding or
individuals with BWSp and gain of methylation (GOM) at sleep-disordered breathing should be pursued depending
the material IC1 allele (IC1 GOM) in 5% to 10% of cases on the clinical presentation. Intubation may be challeng-
with BWSp. (5) Other underlying molecular etiologies ing depending on the severity of macroglossia. Cardiac
include paternal uniparental isodisomy (pUPD) of 11p15.5 evaluation, including electrocardiography and echocardiog-
in 20% of cases, pathogenic sequence variants in the raphy, may be performed if abnormalities are suggestive
CDKN1C gene in 40% of familial and 5% of sporadic on examination to assess for a possible association with
cases, and other chromosomal abnormalities affecting cardiomyopathy, however, a proportion of individuals with
11p15 in less than 5% of cases. (6) Determining the molec- BWSp have cardiomegaly that resolves spontaneously. (4)
ular etiology of BWSp can better predict the familial recur- Tumor surveillance is of utmost importance for
rence risk, the risk of tumor development, and health patients with BWSp because of the increased risk of tumor
surveillance needs. (1) In pursuing a molecular diagnosis development associated with this syndrome. Tumor sur-
of BWSp, various genetic tests can be used, including veillance can vary based on the molecular etiology of the
methylation analysis (often via MLPA), chromosomal BWSp, another motivation to determine the underlying
microarray analysis, karyotype analysis, and single gene etiology. The overall risk of developing a tumor is lowest
testing of CDKN1C. (2) It is recommended that the first in the IC2 LOM subtype (2.6%), CDKN1C subtype (6.9%),
line of molecular testing should include methylation anal- and in BWSp with no detectable molecular defect (6.7%)
ysis, because methylation abnormalities are present in and highest in the pUPD subtype (16%) and the IC1 GOM
approximately 80% of individuals with BWSp. (7) Methyla- subtype (28.1%). (1) Wilms tumor is most frequent in the
tion testing would indicate the presence or absence of the IC1 GOM subtype as well as the subtype with negative
IC2 LOM and IC1 GOM subtypes. Chromosomal microar- molecular tests. Hepatoblastoma occurs mostly in the IC2
ray analysis can detect microdeletions, microduplications, LOM and pUPD subtypes. In the CDKN1C subtype, neu-
and pUPD subtype, and a karyotype can test for inversions roblastoma is the most common tumor. (9) This risk of
or translocations of the 11p15 region. Single gene testing malignancy decreases with age and in general, the associated
including sequencing and deletion/duplication analysis of tumors are treatable with favorable outcomes provided they
the CDKN1C gene in the 11p15 region is recommended, are detected early. Abdominal ultrasonography every 3 to 4
particularly in familial cases of BWSp. (4) months until age 8 years is the preferred method of tumor
In the present case, as noted earlier, the first line of screening, with serum AFP levels added for increased sensitiv-
genetic testing (ie, methylation analysis, chromosomal micro- ity to detect hepatoblastoma; however, this recommendation
array analysis, and karyotype analysis) and the second round has more recently been called into question. (4)(10)(11) Partic-
of genetic testing (ie, CDKN1C sequencing and further epige- ularly, many families have difficulty with blood draws every 3
netic testing) were nondiagnostic. Thus, despite extensive months for the first 4 years of age, and without evidence of
genetic testing, the molecular etiology of the child’s BWSp substantial benefit over a detailed abdominal ultrasound scan,
remains unknown. This patient is not alone, as about 20% it is thought to be safe to perform surveillance with ultraso-
of patients with a clinical BWSp diagnosis do not have a nography alone. In our case, the initial persistence of the liver
molecular diagnosis. (6) One explanation is related to poten- lesion prompted continuing surveillance using AFP levels,
tial mosaicism, where the pathogenic variant is present in though the lesions have spontaneously resolved as expected
some cells of the body—such as those affected by with the presumed diagnosis of hemangioma.

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 Adults with BWSp are expected to have normal intelli- ropsychological challenges associated with this condition,
gence and a normal lifespan, though little research has though further research into the associated neurodevelop-
been conducted on health outcomes in adulthood. An mental outcomes is needed. In our case, the combination of
older study surveying 87 children with BWSp (mean age preterm birth and clinical diagnosis of a genetic syndrome
9.7 years) and their parents noted higher scores than the prompted referral to a specialized developmental follow-up
general population on a social/behavioral questionnaire program at our institution for infants with genetic conditions
indicating a higher frequency of behavioral issues. Six where developmental service needs have been identified.
children, or 6.8% of the cohort, had a diagnosis of autism
spectrum disorder, higher than the general population.
(12) Another study has shown developmental delay and American Board of Pediatrics
mild intellectual disability in about 26% of 34 adults with Neonatal-Perinatal Content
BWSp, though this was usually referring to mild speech Specifications
delay. For the rare cases with severe delays, co-occurring
• Know the evolution of neurodevelopmental impai-
perinatal events such as severe hypoglycemia or hypoxic-
rments during development and the difference
ischemic encephalopathy also affected these outcomes. Most
between transient and permanent impairments in
medical issues in adulthood reflect the evolution of BWSp
NICU graduates (eg, developmental delay vs.
features noted in infancy or the consequences of surgical
intellectual disability; tone abnormalities vs. cerebral
intervention. (13) This highlights the need for preventive fol-
palsy).
low-up care and treatment of associated medical problems
• Know the value and limitations of the Bayley Scales
during childhood. Many features of BWSp such as macro-
of Infant Development and other tests of
glossia and lateralized overgrowth improve with age but can
psychomotor development in assessing current
potentially cause lasting effects into adulthood such as
function and predicting long-term outcomes.
speech and swallow difficulties or orthodontic abnormalities,
• Know the etiology, molecular phenotype, and clinical
scoliosis, or back pain related to lateralized overgrowth.
manifestations of disorders associated with genetic
(1)(13) One study, with substantial limitations such as a small
imprinting, such as Prader-Willi syndrome.
sample size, showed an increased risk of tumor development
• Know the etiology, molecular phenotype, and clinical
in adults with BWSp, though it is more generally believed
manifestations of disorders associated with
that there is not enough evidence to make this claim or
uniparental disomy.
change any tumor surveillance protocols. (13)

TAKE HOME LESSONS

Recognizing the clinical features of BWSp in the neonatal
period is important, as tumor surveillance in these cases may Acknowledgment
The authors thank the child’s family for their willingness
be lifesaving. The overall prognosis for this condition is excel-
and enthusiasm to participate in this report. They also
lent, and the clinical and cosmetic impact of issues such as thank the multidisciplinary team of the NICU Growth
macroglossia and asymmetric overgrowth tends to wane over and Developmental Support Program (NICU GraDS) at
time. Developmental surveillance may aid in management Boston Children’s Hospital for their thoughtful and
due to the higher risk of developmental delays or other neu- insightful care of this child and her family.

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 7. Kalish JM, Boodhansingh KE, Bhatti TR, et al. Congenital
References hyperinsulinism in children with paternal 11p uniparental isodisomy
1. Brioude F, Kalish JM, Mussa A, et al. Expert consensus document: and Beckwith-Wiedemann syndrome. J Med Genet. 2016;53(1):53–61
clinical and molecular diagnosis, screening and management of 8. Alders M, Maas SM, Kadouch DJ, et al. Methylation analysis in
Beckwith-Wiedemann syndrome: an international consensus tongue tissue of BWS patients identifies the (EPI)genetic cause in 3
statement. Nat Rev Endocrinol. 2018;14(4):229–249 patients with normal methylation levels in blood. Eur J Med Genet.
2. Blohm MEG, Vesterling-H€orner D, Calaminus G, G€obel U. Alpha 2014;57(6):293–297
1-fetoprotein (AFP) reference values in infants up to 2 years of age. 9. Maas SM, Vansenne F, Kadouch DJ, et al. Phenotype, cancer risk,
Pediatr Hematol Oncol. 1998;15(2):135–142 and surveillance in Beckwith-Wiedemann syndrome depending on
3. Wangler MF, Chang AS, Moley KH, Feinberg AP, Debaun MR. molecular genetic subgroups. Am J Med Genet A. 2016;170(9):
Factors associated with preterm delivery in mothers of children with 2248–2260
Beckwith-Wiedemann syndrome: a case cohort study from the BWS 10. DeBaun MR, Tucker MA. Risk of cancer during the first four years
registry. Am J Med Genet A. 2005;134A(2):187–191 of life in children from The Beckwith-Wiedemann Syndrome
4. Shuman C, Beckwith JB, Weksberg R. Beckwith-Wiedemann Registry. J Pediatr. 1998;132(3 Pt 1):398–400
Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. 11. Rao A, Rothman J, Nichols KE. Genetic testing and tumor
GeneReviewsV
R . Seattle, WA: University of Washington, Seattle; 2000 surveillance for children with cancer predisposition syndromes. Curr
Mar 3:1993–2021. (Updated August 11, 2016) Opin Pediatr. 2008;20(1):1–7
5. Eggermann T, Algar E, Lapunzina P, et al. Clinical utility gene 12. Kent L, Bowdin S, Kirby GA, Cooper WN, Maher ER. Beckwith
card for: Beckwith-Wiedemann syndrome. Eur J Hum Genet. Weidemann syndrome: a behavioral phenotype-genotype study. Am
2014;22(3):7–10 J Med Genet B Neuropsychiatr Genet. 2008;147B(7):1295–1297
6. Choufani S, Shuman C, Weksberg R. Beckwith-Wiedemann 13. Gazzin A, Carli D, Sirchia F, et al. Phenotype evolution and health
syndrome. Am J Med Genet C Semin Med Genet. 2010;154C(3): issues of adults with Beckwith-Wiedemann syndrome. Am J Med
343–354 Genet A. 2019;179(9):1691–1702

ANSWER KEY FOR JANUARY 2022 NEOREVIEWS

Developing a Quality Improvement Feeding Program for NICU Patients 1. D; 2. E; 3. A 4. B; 5. B;
Partial Enteral Discharge Programs for High-risk Infants 1. C; 2. E; 3. D; 4. B; 5. A;

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 STRIP OF THE MONTH

STRIP OF
THE MONTH

Maternal Facial Nerve Palsy and a

Perinatal Infection
Tyler Lueck,* Brett C. Young*
*Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Boston, MA

ELECTRONIC FETAL MONITORING CASE REVIEW SERIES

Electronic fetal monitoring (EFM) is a popular technology used to establish fetal well-being. Despite its widespread use, the ter-
minology used to describe patterns seen on the monitor has not been consistent until recently. In 1997, the National Institute
of Child Health and Human Development (NICHD) Research Planning Workshop published guidelines for interpretation of
fetal tracings. This publication was the culmination of 2 years of work by a panel of experts in the field of fetal monitoring and
was endorsed in 2005 by both the American College of Obstetricians and Gynecologists (ACOG) and the Association of Wom-
en’s Health, Obstetric and Neonatal Nurses (AWHONN). In 2008, ACOG, NICHD, and the Society for Maternal-Fetal Medi-
cine reviewed and updated the definitions for fetal heart rate (FHR) patterns, interpretation, and research recommendations.
Following is a summary of the terminology definitions and assumptions found in the 2008 NICHD workshop report. Normal
arterial umbilical cord gas values and indications of acidosis are defined in the Table.

ASSUMPTIONS FROM THE NICHD WORKSHOP

Definitions are developed for visual interpretation, assuming that both the FHR and uterine activity recordings are of adequate
quality
Definitions apply to tracings generated by internal or external monitoring devices

• Periodic patterns are differentiated based on waveform, abrupt or gradual (eg,

late decelerations have a gradual onset and variable decelerations have an
abrupt onset)
• Long- and short-term variability are evaluated visually as a unit
• Gestational age of the fetus is considered when evaluating patterns
• Components of FHR do not occur alone and generally evolve over time

DEFINITIONS
Baseline FHR

• Approximate mean FHR rounded to increments of 5 beats/min in a 10-minute

AUTHOR DISCLOSURES Drs Lueck and
segment of tracing, excluding accelerations and decelerations, periods of marked Young have disclosed no financial
variability, and segments of baseline that differ by >25 beats/min relationships relevant to this article. This
• In the 10-minute segment, the minimum baseline duration must be at least 2 commentary does not contain a
discussion of an unapproved/
minutes (not necessarily contiguous) or the baseline for that segment is investigative use of a commercial
indeterminate product/device.

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 Table. Arterial Umbilical Cord Gas Values
pH Pco2 (mm Hg) Po2 (mm Hg) Base Excess
Normal* $7.20 (7.15 to 7.38) <60 (35 to 70) $20 #–10 (–2.0 to –9.0)
Respiratory acidosis <7.20 >60 Variable #–10
Metabolic acidosis <7.20 <60 Variable $–10
Mixed acidosis <7.20 >60 Variable $–10

*Normal ranges from Obstet Gynecol Clin North Am. 1999;26:695.

• Bradycardia is a baseline of <110 beats/min; tachycardia Early Decelerations

is a baseline of >160 beats/min
• Sinusoidal baseline has a smooth sine wave-like undu- • Gradual decrease in FHR (onset to nadir $30 seconds)
lating pattern, with waves having regular frequency and below the most recently determined baseline, with nadir
amplitude occurring coincident with uterine contraction
• Also considered a periodic pattern

Baseline Variability Variable Decelerations

• Fluctuations in the baseline FHR of $2 cycles per • Abrupt decrease in FHR (onset to nadir <30 seconds)
minute, fluctuations are irregular in amplitude and fre- • Decrease is $15 beats/min below the most recently deter-
quency, fluctuations are visually quantitated as the mined baseline lasting $15 seconds but <2 minutes
amplitude of the peak to trough in beats per minute • May be episodic (occurs without a contraction) or periodic
• Classification of variability:Absent: Amplitude range is
undetectableMinimal: Amplitude range is greater than Prolonged Decelerations
undetectable to 5 beats/minModerate: Amplitude range
is 6–25 beats/minMarked: Amplitude range is >25 • Decrease in the FHR $15 beats/min below the most
beats/min recently determined baseline lasting $2 minutes but <10
minutes from onset to return to baseline
• Decelerations are tentatively called recurrent if they occur
Accelerations with $50% of uterine contractions in a 20-minute period
• Decelerations occurring with <50% of uterine contrac-
• Abrupt increase in FHR above the most recently deter-
tions in a 20-minute segment are intermittent
mined baseline
• Onset to peak of acceleration is <30 seconds, acme is
Sinusoidal FHR Pattern
$15 beats/min above the most recently determined base-
line and lasts $15 seconds but <2 minutes
• Visually apparent, smooth sine wave-like undulating pat-
• Before 32 weeks’ gestation, accelerations are defined by
tern in the baseline with a cycle frequency of 3 to 5 per
an acme $10 beats/min above the most recently deter-
minute that persists for $20 minutes
mined baseline for $10 seconds
• Prolonged acceleration lasts $2 minutes but <10
minutes Uterine Contractions

• Quantified as the number of contractions in a 10-minute

Late Decelerations window, averaged over 30 minuteso Normal: #5 con-
tractions in 10 minuteso Tachysystole: >5 contractions
• Gradual decrease in FHR (onset to nadir $30 seconds) in 10 minutes
below the most recently determined baseline, with nadir
occurring after the peak of uterine contractions Interpretation
• Considered a periodic pattern because it occurs with A 3-tier FHR interpretation system has been recom-
uterine contractions mended as follows:

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 • Category I FHR tracings: Normal, strongly predictive of general management principles. ACOG Practice Bulletin No.
normal fetal acid-base status and require routine care. 106. Washington, DC: American College of Obstetricians and
These tracings include all of the following: Gynecologists; 2009.
Baseline rate: 110 to 160 beats/min We encourage readers to examine each strip in the case
Baseline FHR variability: Moderate presentation and make a personal interpretation of the
Late or variable decelerations: Absent findings before advancing to the expert interpretation
Early decelerations: Present or absent provided.
Accelerations: Present or absent
• Category II FHR tracings: Indeterminate, require evalua- THE CASE
tion and continued surveillance and reevaluation. Exam-
Presentation
ples of these tracings include any of the following:
A 33-year-old gravida 1, para 0 woman had an uncomplicated
Bradycardia not accompanied by absent variability
pregnancy until 32 weeks’ gestation when she developed mal-
Tachycardia
aise, fever, and a mildly elevated blood pressure at home. She
Minimal or marked baseline variability
also reported neurologic symptoms of transient tingling in
Absent variability without recurrent decelerations
her extremities and a nonpositional headache. She was evalu-
Absence of induced accelerations after fetal stimulation
ated and noted to be afebrile and normotensive. Given her
Recurrent variable decelerations with minimal or mod-
reported mild-range blood pressure at home and headache,
erate variability
she was evaluated for preeclampsia. Serum laboratory results
Prolonged decelerations
Recurrent late decelerations with moderate variability demonstrated transaminitis with an alanine aminotransami-
Variable decelerations with other characteristics, such nase (ALT) of 60 U/L (1 mkat/L; normal <40 U/L [0.67
as slow return to baseline mkat/L]). During her evaluation, the patient developed a
• Category III FHR tracings: Abnormal, predictive of noticeable unilateral facial palsy and slurred words due to her
abnormal fetal acid-base status and require prompt facial droop. A code stroke was called and she had an emer-
intervention. These tracings include: gent evaluation by neurology including a noncontrast head
Absent variability with any of the following: computed tomography scan. This urgent head imaging was
• 䊏 Recurrent late decelerations unrevealing; she was diagnosed with Bell palsy of unclear eti-
䊏 Recurrent variable decelerations ology. She was administered betamethasone for fetal benefit
䊏 Bradycardia and transferred to our facility for further evaluation. The fetal
nonstress test performed on arrival at our facility is shown in
Sinusoidal pattern Fig 1.
Data from Macones GA, Hankins GDV, Spong CY, Hauth
J, Moore T. The 2008 National Institute of Child Health and • Variability: Moderate
Human Development workshop report on electronic fetal • Baseline rate: 150 beats/min
monitoring. Obstet Gynecocol. 2008;112:661-666 and Ameri- • Episodic patterns: None
can College of Obstetricians and Gynecologists. Intrapartum • Periodic patterns: None
fetal heart rate monitoring: nomenclature, interpretation, and • Uterine contractions: None

Figure 1. Electronic monitoring strip 1.

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 Figure 2. Electronic monitoring strip 2.

• Interpretation: Category I • Interpretation: Category I

• Differential diagnosis: The FHR tracing is reassuring • Differential diagnosis: The FHR tracing is reassuring
with moderate variability and accelerations; there are no with moderate variability and accelerations; there are no
signs of fetal distress signs of fetal distress
• Action: Expectant management and ongoing evaluation • Action: Expectant management and ongoing evaluation
The patient was admitted and initially underwent evalu- Serologic testing for Lyme disease returned positive
ation to identify the cause of the Bell palsy and for possi- results; given her neurologic symptoms, a lumbar punc-
ble preeclampsia. She remained normotensive and had no ture was recommended because of the potential risk for
proteinuria. Serial laboratory evaluation demonstrated Lyme meningitis. She was started on ceftriaxone for
increasing ALT up to 400 U/L (6.68 mkat/L). Neurology empiric treatment of disseminated Lyme disease. Ulti-
and infectious disease consultations were obtained. Head mately, confirmatory Lyme studies returned negative, and
magnetic resonance imaging was unrevealing. The patient CMV serologies demonstrated a positive immunoglobulin
was started on acyclovir for empiric treatment of a possi- (Ig)M and positive IgG with an intermediate avidity IgG.
ble viral infection causing her Bell palsy. Evaluation for an Primary CMV during pregnancy could not be excluded.
infectious process continued with serologic testing for The fetal nonstress test at 32 weeks and 6 days of gesta-
Lyme disease and cytomegalovirus (CMV). An inpatient tion is shown in Fig 3.
fetal nonstress test at 32 weeks and 4 days is shown in Fig 2.
• Variability: Moderate
• Variability: Moderate • Baseline rate: 140 beats/min
• Baseline rate: 140 beats/min • Episodic patterns: None
• Episodic patterns: None • Periodic patterns: None
• Periodic patterns: None • Uterine contractions: Irritability
• Uterine contractions: None • Interpretation: Category I

Figure 3. Electronic monitoring strip 3.

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 • Differential diagnosis: The FHR tracing is reassuring DISCUSSION
with moderate variability and accelerations; there are no CMV is a perinatal infection that has a risk of adverse tera-
signs of fetal distress togenic effects for the neonate. CMV is a double-stranded
• Action: Expectant management and ongoing evaluation DNA herpes virus transmitted by contact with bodily flu-
The patient was discharged after an 8-day hospitalization ids (blood, saliva, semen, vaginal fluid, or feces.). CMV is
with spontaneously improved transaminitis and improvement a common childhood infection and it is estimated that up
in her facial palsy. She received outpatient management with to 70% of children in day care will acquire the virus. (1)
close maternal and fetal surveillance until a scheduled early- However, many adults do not have immunity and there-
term induction of labor. She was induced at 37.5 weeks’ gesta- fore remain susceptible to the virus. In adults, infections
tion; her induction was uncomplicated. A representative FHR range from asymptomatic to systemic symptoms including
tracing during her induction is demonstrated in Fig 4. fevers, malaise, headache, myalgias, or facial nerve palsy.
While there is a chance of CMV reactivation, the vast majority
• Variability: Moderate of fetal implications from CMV infection in pregnancy are
• Baseline rate: 140 beats/min caused by primary infection. It is estimated that the incidence
• Episodic patterns: None of primary CMV infection in pregnant women ranges from
• Periodic patterns: Variable decelerations 0.7% to 4%. (2)
• Uterine contractions: Every 3 to 4 min CMV is one of the most common congenital infections
• Interpretation: Category II in the United States, occurring in approximately 1 in every
• Differential diagnosis: The FHR tracing has reassuring 150 live births. (3) Transmission to the fetus is far more
variability, but showed recurrent variable decelerations likely for a primary infection than a secondary infection,
with contractions and the infection risk increases with each trimester.
• Action: Re-position patient, intravenous fluid bolus, con- Although the likelihood of fetal infection is highest in the
sider intrauterine pressure catheter/amnioinfusion third trimester, the risk of symptomatic illness and long-
term sequalae in the infant is highest when transmission
Outcome occurs during the first trimester. (3)
The patient delivered a female infant via uncomplicated spon- About 11% of infants born with congenital CMV will
taneous vaginal delivery with Apgar scores of 9 and 9 at 1 develop symptoms or long-term sequelae. (3) CMV is the lead-
and 5 minutes, respectively; the neonate had a birthweight of ing cause of congenital nonfamilial sensorineural hearing loss
2,465 g (22nd percentile) with a normal head circumference in the United States. (1)(2) Symptomatic infants may be small
for gestational age. The neonate had no rashes or petechiae. for gestational age or have microcephaly, ventriculomegaly,
Results of polymerase chain reaction testing of the neonate’s chorioretinitis, jaundice, hepatosplenomegaly, or petechiae/
urine and serum samples were positive for CMV. The urine thrombocytopenia. Long-term sequelae include hearing loss,
demonstrated a viral count of 5,658 U/mL. A neonatal head vision loss, and cognitive impairment.
ultrasound scan was normal. Following pediatric infectious Maternal CMV infection is evaluated using serologic
disease consultation, the neonate was started on valganciclovir testing with confirmatory testing requiring amniotic fluid.
for primary CMV treatment with planned outpatient infec- Testing is done either in the setting of maternal illness
tious disease follow-up. suspicious for CMV infection, such as mononucleosislike

Figure 4. Electronic monitoring strip 4.

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 symptoms, or if congenital CMV is suspected after abnor- among young children, especially those in day care, preg-
malities, such as lateral ventriculomegaly, microcephaly, nant women should be especially vigilant of handwashing
echogenic bowel, hepatosplenomegaly, intracranial calcifi- and hygiene around young children. (1)
cations, ascites and fetal hydrops, are noted on fetal ultra- In this case, a broad differential diagnosis for the
sonography. The presence of IgM antibodies with low maternal clinical presentation of facial nerve palsy helped
avidity IgG antibodies is most indicative of primary infec- diagnose primary CMV and optimize prompt treatment in
tion. (1)(4) the newborn period.
Universal screening for CMV is not recommended
given the lack of treatment during pregnancy, high false-
positive rates, and risk of secondary infection in women American Board of Pediatrics
with an existing seropositive status. (1) Neonatal-Perinatal Content
Currently there is no standard treatment for CMV Specifications
infection during pregnancy or established medical inter-
vention to prevent transmission of CMV to the fetus. Very • Understand the rationale, interpretation, and limita-
limited data support the use of antiviral medications, such tions of maternal detection of fetal movement, of
as ganciclovir or valacyclovir during pregnancy to treat the biophysical profile, the non-stress test, and the
infection or prevent transmission to the fetus. (1) In addi- contraction stress test as means of assessing fetal
tion, multiple studies have looked at the use of CMV well-being
hyperimmune globulin infusions during pregnancy to pre- • Know the epidemiology, prevention, and pathogene-
vent transmission to the fetus. In a recent study, the sis of perinatal infections with herpes 1, herpes 2,
administration of CMV hyperimmune globulin did not cytomegalovirus, Epstein-Barr virus, and varicella-
result in a lower incidence of congenital CMV infection zoster
compared with placebo. (5) • Know the clinical manifestations, diagnostic fea-
Primary prevention strategies to decrease the risk of tures, management, and complications of perinatal
CMV infection during pregnancy include frequent hand- infections with herpes 1, herpes 2, cytomegalovirus,
washing with soap and warm water, careful handling of Epstein-Barr virus, and varicella-zoster
used diapers and other possibly infected items, and avoid-
ing sharing utensils. Given the high prevalence of CMV

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 3. Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology
References of congenital cytomegalovirus (CMV) infection. Rev Med Virol. 2007;17(4):
1. Carlson A, Norwitz ER, Stiller RJ. Cytomegalovirus infection in 253–276
pregnancy: should all women be screened? Rev Obstet Gynecol. 4. Lazzarotto T, Guerra B, Lanari M, Gabrielli L, Landini MP. New
2010;3(4):172–179 advances in the diagnosis of congenital cytomegalovirus infection. J Clin
2. American College of Obstetrics & Gynecology. Cytomegalovirus, Virol. 2008;41(3):192–197
parvovirus B19, varicella zoster, and toxoplasmosis in pregnancy. 5. Revello MG, Lazzarotto T, Guerra B, et al; CHIP Study Group. A
Obstet Gynecol. 2016;127(2):405 randomized trial of hyperimmune globulin to prevent congenital
cytomegalovirus. N Engl J Med. 2014;370(14):1316–1326

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