Chapter 102 ◆ Digestive System Disorders 869

infants with CF but are occasionally the result of a meconium plug or

in utero intestinal obstruction of another cause. Cases at the most
severe end of the spectrum may be diagnosed on prenatal ultrasonog-
raphy with fetal ascites, polyhydramnios, bowel dilation, intraabdomi-
nal calcifications, and hydrops fetalis. At the other end are cases in
which an intestinal perforation may seal spontaneously with only a
minor meconium leak, so the event may never be detected except when
meconium becomes calcified and is later discovered on radiographs of
the abdomen. Alternatively, the clinical picture may be dominated by
the signs of intestinal obstruction (as in meconium ileus) or chemical
peritonitis. Characteristic clinical findings include abdominal disten-
tion, vomiting, and absence of stools. Treatment consists primarily of
elimination of the intestinal obstruction and drainage of the peritoneal
cavity.

102.2 Necrotizing Enterocolitis

Akhil Maheshwari and Waldemar A. Carlo

NEC is the most common life-threatening emergency of the gastroin-

testinal tract in the newborn period. The disease is characterized by
various degrees of mucosal or transmural necrosis of the intestine. The
cause of NEC remains unclear but is most likely multifactorial. The
incidence of NEC is 1-5% of infants in neonatal ICUs. Both incidence
and case fatality rates increase with decreasing birth weight and gesta-
tional age. Because very small, ill preterm infants are particularly sus-
ceptible to NEC, a rising incidence may reflect improved survival of
this high-risk group of patients.

PATHOLOGY AND PATHOGENESIS

Figure 102-2 Meconium ileus. Impacted meconium with small
amounts of air interspersed can be seen in loops of intestine on the
Many factors may contribute to the development of a the pathologic
right side of the abdomen. The intestinal loops above this impaction findings of NEC including necrotic segment of intestine, gas accumula-
are greatly distended. tion in the submucosa of the bowel wall (pneumatosis intestinalis),
and progression of the necrosis to perforation, peritonitis, sepsis, and
death. The distal part of the ileum and the proximal segment of colon
are involved most frequently; in fatal cases, gangrene may extend from
the stomach to the rectum. Although NEC is a multifactorial disease
primarily associated with intestinal immaturity, the concept of “risk
factors” for NEC is controversial. The triad of intestinal ischemia
(injury), enteral nutrition (metabolic substrate), and bacterial translo-
cation has classically been linked to NEC. The greatest risk factor for
NEC is prematurity. The disorder probably results from an interaction
between loss of mucosal integrity due to a variety of factors (ischemia,
infection, inflammation) and the host’s response to that injury (circula-
tory, immunologic, inflammatory), leading to necrosis of the affected
area. Coagulation necrosis is the characteristic histologic finding in
intestinal specimens. Clustering of cases suggests a primary role for an
infectious agent. Various bacterial and viral agents, including Esche-
richia coli, Klebsiella, Clostridium perfringens, Staphylococcus epidermi-
dis, astrovirus, norovirus, and rotavirus, have been recovered from
cultures. Nonetheless, in most situations, a pathogen is not identified.
NEC rarely occurs before the initiation of enteral feeding and is much
less common in infants fed human milk. Aggressive enteral feeding
may predispose to the development of NEC.
Although nearly 90% of all cases of NEC occur in preterm infants,
the disease can occur in full-term neonates. NEC in term infants is
often a “secondary” disease, seen more frequently in infants with
history of birth asphyxia, Down syndrome, congenital heart disease,
Figure 102-3 Meconium ileus. The colon, outlined by contrast mate- rotavirus infections, and Hirschsprung disease.
rial, is small because meconium has not reached it.
CLINICAL MANIFESTATIONS
Infants with NEC have a variety of signs and symptoms and may have
MECONIUM PERITONITIS an insidious or sudden catastrophic onset (Table 102-1). The onset of
Perforation of the intestine may occur in utero or shortly after birth. NEC is usually in the 2nd or 3rd wk of life but can be as late as 3 mo
Frequently, the intestinal perforation seals naturally with relatively in VLBW infants. Age of onset is inversely related to gestational age.
little meconium leakage into the peritoneal cavity. In some cases, with The first signs of impending disease may be nonspecific, including
long-standing perforation, meconium peritonitis is more pronounced. lethargy and temperature instability, or related to gastrointestinal
Perforations occur most often as a complication of meconium ileus in pathology, such as abdominal distention and gastric retention. In some
870 Part XII ◆ The Fetus and the Neonatal Infant

Table 102-1 Signs and Symptoms Associated with

Necrotizing Enterocolitis
GASTROINTESTINAL
Abdominal distention
Abdominal tenderness
Feeding intolerance
Delayed gastric emptying
Vomiting
Occult/gross blood in stool
Change in stool pattern/diarrhea
Abdominal mass
Erythema of abdominal wall
SYSTEMIC
Lethargy
Apnea/respiratory distress
Temperature instability
“Not right”
Acidosis (metabolic and/or respiratory)
Glucose instability
Poor perfusion/shock Figure 102-4 NEC. A kidney-ureter-bladder film demonstrates
Disseminated intravascular coagulopathy abdominal distention, hepatic portal venous gas (arrow), and a bubbly
Positive results of blood cultures appearance of pneumatosis intestinalis (arrowhead; right lower
From Kanto WP Jr, Hunter JE, Stoll BJ: Recognition and medical management quadrant). The latter 2 signs are thought to be pathognomonic for
of necrotizing enterocolitis, Clin Perinatol 21:335–346, 1994. neonatal NEC.

extremely low birthweight infants, NEC may develop following a red

cell transfusion. Bloody stools are seen in 25% of patients. Because of
nonspecific signs, sepsis may be suspected before NEC. The spectrum
of illness is broad, ranging from mild disease with only guaiac-positive
stools to severe illness with bowel perforation, peritonitis, systemic
inflammatory response syndrome, shock, and death. Progression may
be rapid, but it is unusual for the disease to progress from mild to
severe after 72 hr.

DIAGNOSIS
A very high index of suspicion in treating preterm at-risk infants is
crucial. Plain abdominal radiographs are essential to make a diagnosis
of NEC. The finding of pneumatosis intestinalis (air in the bowel wall)
confirms the clinical suspicion of NEC and is diagnostic; 50-75% of
patients have pneumatosis when treatment is started (Fig. 102-4).
Portal venous gas is a sign of severe disease, and pneumoperitoneum Figure 102-5 Intestinal perforation. A cross-table abdominal roent-
indicates a perforation (Figs. 102-4 and 102-5). Hepatic sonography genogram in a patient with a neonatal NEC demonstrates marked
may detect portal venous gas in some infants with normal abdominal distention and massive pneumoperitoneum as evidenced by the free
air below the anterior abdominal wall.
x-rays.
The differential diagnosis of NEC includes specific infections (sys-
temic or intestinal), gastrointestinal obstruction, volvulus, and isolated
intestinal perforation. Idiopathic focal intestinal perforation can occur and correction of hematologic, metabolic, and electrolyte abnormali-
spontaneously or after the early use of postnatal steroids and indo- ties are essential to stabilize the infant with NEC.
methacin. Pneumoperitoneum develops in such patients, but they are The patient’s course should be monitored closely by means of fre-
usually less ill than those with NEC. quent physical assessments; sequential anteroposterior and cross-table
lateral or lateral decubitus abdominal radiographs to detect intestinal
TREATMENT perforation; and serial determinations of hematologic, electrolyte, and
Rapid initiation of therapy is required for suspected as well as proven acid–base status. Gown and glove isolation and grouping of infants at
cases of NEC. There is no definitive treatment for established NEC, so similar increased risks into cohorts separate from other infants should
therapy is directed at giving supportive care and preventing further be instituted to contain an epidemic.
injury with cessation of feeding, nasogastric decompression, and A surgeon should be consulted early in the course of treatment.
administration of intravenous fluids. Careful attention to respiratory Indications for surgery include evidence of perforation on abdominal
status, coagulation profile, and acid–base and electrolyte balances are x-ray (pneumoperitoneum) or positive result of abdominal paracente-
important. Once blood has been drawn for culture, systemic antibiotics sis (stool or organism on Gram stain preparation from peritoneal
(with broad coverage based on the antibiotic sensitivity patterns of the fluid). Failure of medical management, a single fixed bowel loop on
gram-positive, Gram-negative, and anaerobic organisms in the par- radiographs, abdominal wall erythema, and a palpable mass are rela-
ticular neonatal ICU) should be started immediately. If present, umbil- tive indications for exploratory laparotomy. Ideally, surgery should be
ical catheters should be removed, but good intravenous access needs performed after intestinal necrosis develops but before perforation and
to be maintained. Ventilation should be assisted in the presence of peritonitis occur. In unstable premature infants with perforated NEC,
apnea or if abdominal distention is contributing to hypoxia and hyper- peritoneal drainage can be cautiously considered as an alternative to
capnia. Intravascular volume replacement with crystalloid or blood exploratory laparotomy, although the best surgical approach in these
products, cardiovascular support with fluid boluses and/or inotropes, infants remains unresolved. The type of surgical operation did not
 Chapter 102 ◆ Digestive System Disorders 871

influence survival or other clinically important early outcomes in one has undergone conjugation in the liver cell microsome by the enzyme
multicenter study, but another large randomized trial showed that a uridine diphosphoglucuronic acid (UDP)–glucuronyl transferase to
majority of infants who were initially treated with peritoneal drains form the polar, water-soluble glucuronide of bilirubin (direct-
required a delayed secondary laparotomy. There are also some con- reacting). Although bilirubin may have a physiologic role as an anti-
cerns about the long-term outcome (death or neurodevelopmental oxidant, elevations of indirect, unconjugated bilirubin are potentially
outcome) for infants treated with peritoneal drainage. neurotoxic. Even though the conjugated form is not neurotoxic, direct
Patients with isolated intestinal perforation (not related to NEC) hyperbilirubinemia indicates a potentially serious hepatic disorders or
tend to have a lower birthweight, are less likely to be receiving oral a systemic illness.
feeding, and are prone to perforation at an earlier postnatal age than
are patients with perforation related to NEC. In many patients with ETIOLOGY
isolated intestinal perforation treated by drainage, no further surgical During the neonatal period, metabolism of bilirubin is in transition
procedure is needed; a small subgroup may require later surgery to from the fetal stage, during which the placenta is the principal route
repair an intestinal stricture or fistula. of elimination of the lipid-soluble, unconjugated bilirubin, to the adult
stage, during which the water-soluble conjugated form is excreted from
PROGNOSIS hepatic cells into the biliary system and gastrointestinal tract. Uncon-
Medical management fails in approximately 20-40% of patients with jugated hyperbilirubinemia may be caused or increased by any factor
pneumatosis intestinalis at diagnosis; of these, 10-30% die. Early post- that (a) increases the load of bilirubin to be metabolized by the liver
operative complications include wound infection, dehiscence, and (hemolytic anemias, polycythemia, bruising or internal hemorrhage,
stomal problems (prolapse, necrosis). Later complications include shortened red blood cell life as a result of immaturity or transfusion of
intestinal strictures, which develop at the site of the necrotizing lesion cells, increased enterohepatic circulation, infection); (b) damages or
in approximately 10% of surgically or medically managed patients. reduces the activity of the transferase enzyme or other related enzymes
Resection of the obstructing stricture is curative. After massive intes- (genetic deficiency, hypoxia, infection, thyroid deficiency); (c) com-
tinal resection, complications from postoperative NEC include short- petes for or blocks the transferase enzyme (drugs and other substances
bowel syndrome (malabsorption, growth failure, malnutrition), requiring glucuronic acid conjugation); or (d) leads to an absence or
complications related to central venous catheters (sepsis, thrombosis), decreased amounts of the enzyme or to reduction of bilirubin uptake
and cholestatic jaundice. Preterm infants with NEC who require surgi- by liver cells (genetic defect, and prematurity). Gene polymorphisms
cal intervention or who have concomitant bacteremia are at increased in the hepatic uridine diphosphate glucuronosyltransferase isoenzyme
risk for adverse growth and neurodevelopmental outcome. 1A1 (UGT1A1) and the solute carrier organic anion transporter 1B1
(SLCO1B1) alone or in combination influence the incidence of neona-
PREVENTION tal hyperbilirubinemia. The toxic effects of elevated serum concentra-
Newborns exclusively breastfed have a reduced risk of NEC. There have tions of unconjugated bilirubin are increased by factors that reduce the
been concerns about early and aggressive increase in feeding volumes retention of bilirubin in the circulation (hypoproteinemia, displace-
in raising the risk of NEC in VLBW infants, although a safe feeding ment of bilirubin from its binding sites on albumin by competitive
regimen remains unknown. Gut stimulation protocols consisting of binding of drugs such as sulfisoxazole and moxalactam, acidosis, and
minimal enteral feeds followed by judicious volume advancement increased free fatty acid concentration secondary to hypoglycemia,
decreased the incidence of NEC in smaller study cohorts, but signifi- starvation, or hypothermia). Neurotoxic effects are directly related not
cant benefits were not detected in a meta-analysis of all randomized only to the permeability of the blood–brain barrier and nerve cell
studies. In other studies, slow advancement or delayed introduction of membranes but also to neuronal susceptibility to injury, all of which
enteral feedings did not protect against NEC. Emerging evidence indi- are adversely influenced by asphyxia, prematurity, hyperosmolality,
cates that the use of inhibitors of gastric acid secretion (H2-receptor and infection. Early and frequent feeding decreases, whereas breast-
blockers, proton pump inhibitors) or prolonged empirical antibiotics feeding and dehydration increase, serum levels of bilirubin. Delay in
in early neonatal period is associated with increased risk of NEC. passage of meconium, which contains 1 mg bilirubin/dL, may contrib-
Prophylactic enteral antibiotics reduced the risk of NEC in a study but ute to jaundice by enterohepatic recirculation after deconjugation by
although concerns about adverse outcomes persist, particularly related intestinal glucuronidase (Fig. 102-6). Drugs such as oxytocin (in the
to the development of resistant bacteria. Extensive data and meta- mother) and chemicals used in the nursery such as phenolic detergents
analyses show that probiotic preparations decrease the incidence of may also produce unconjugated hyperbilirubinemia. Table 102-2 lists
severe NEC (stage II or higher) and mortality in preterm infants but the risk factors for unconjugated hyperbilirubinemia. Additional risk
an FDA-approved preparation is not available. factors include polycythemia, infection, prematurity, and having a dia-
betic mother.
Bibliography is available at Expert Consult.
CLINICAL MANIFESTATIONS
Jaundice usually appears during the early neonatal period, depending
on etiology. Jaundice usually becomes apparent in a cephalocaudal
102.3 Jaundice and Hyperbilirubinemia progression, starting on the face and progressing to the abdomen and
then the feet, as serum levels increase. Dermal pressure may reveal
in the Newborn the anatomic progression of jaundice (face, ≈ 5 mg/dL; mid-abdomen,
Namasivayam Ambalavanan and Waldemar A. Carlo ≈ 15 mg/dL; soles, ≈ 20 mg/dL), but clinical examination cannot be
depended on to estimate serum levels. Jaundice to the midabdomen,
Hyperbilirubinemia is a common and, in most cases, benign problem signs or symptoms, high-risk factors that suggest nonphysiologic jaun-
in neonates. Jaundice is observed during the 1st wk after birth in dice, or hemolysis must be evaluated further (see Tables 102-2 and
approximately 60% of term infants and 80% of preterm infants. The 102-3). Noninvasive techniques for transcutaneous measurement of
yellow color usually results from the accumulation of unconjugated, bilirubin that correlate with serum levels may be used to screen infants,
nonpolar, lipid-soluble bilirubin pigment in the skin. This unconju- but determination of serum bilirubin level is indicated in patients with
gated bilirubin (designated indirect-acting by nature of the Van den elevated age-specific transcutaneous bilirubin measurement, progress-
Bergh reaction) is an end product of heme-protein catabolism from a ing jaundice, or risk for either hemolysis or sepsis. Whereas jaundice
series of enzymatic reactions by heme-oxygenase and biliverdin reduc- from deposition of indirect bilirubin in the skin tends to appear bright
tase and nonenzymatic reducing agents in the reticuloendothelial cells. yellow or orange, jaundice of the obstructive type (direct bilirubin) has
It may also be partly caused by deposition of pigment from conjugated a greenish or muddy yellow cast. Infants with severe hyperbilirubine-
bilirubin, the end product from indirect, unconjugated bilirubin that mia may present with lethargy and poor feeding and, without