Definition.

Necrotizing enterocolitis (NEC) is an ischemic and inflammatory necrosis of the bowel primarily affecting premature
neonates after the initiation of enteral feeding.
II. Incidence. NEC develops in 4% to 10% of infants weighing <1500 g, with the highest incidence in the most premature infants. About
10% of NEC cases occur in term infants, many of whom have preexisting medical conditions.

Pathophysiology. Multifactorial theory has been suggested in which several risk factors, including prematurity, formula feeds,
ischemia, and altered intestinal microbiota, interact to initiate mucosal damage via a final common pathway involving activation of the
inflammatory cascade. A recently proposed unifying hypothesis suggests that the premature intestine exists in a hyperreactive state
with higher expression of tolllike receptor-4 (TLR-4). Activation of TLR-4 by lipopolysaccharide from colonizing gram-negative bacteria
leads to inflammation, impaired healing (impaired crypt stem cell function), and apoptosis of enterocytes. Translocation of bacteria
leads to TLR-4 activation on the endothelium of the bowel mesentery, leading to intestinal ischemia via decreased production of
endothelial nitric oxide. This and other described pathways (eg, those involving platelet-activating factor [PAF]) may lead to intestinal
necrosis. The process can be exacerbated by an upregulation of proinflammatory T-helper cells and activation of intestinal
macrophages.

Risk factors
A. Prematurity. There is an inverse relationship between gestational age (GA), birth
weight, and risk for developing NEC. Although most preterm infants develop NEC at postmenstrual age (PMA) of 30 to 32 weeks,
various factors resulting from premature birth places them at increased risk for NEC. These may involve immature mucosal (mucin)
barrier, mucosal enzymes, and various gastrointestinal (GI) hormones, as well as immature bowel motility and function. Premature
infants have immature local host defenses and may have an imbalance between pro- and antiinflammatory factors, and thus have
increased activation of inflammatory mediators and decreased inactivation of specific mediators such as PAF, which have been linked
to NEC. Abnormal TLR-4 signaling in the premature intestine and increased activation of nuclear factor-κB (NFKB) may play a role in the
pathogenesis of NEC. An inability to effectively regulate the intestinal microcirculation and differences in bacterial colonization may
also make preterm infants more susceptible to NEC.
B. Abnormal intestinal microbiome. Microbial colonization of the intestine starts in utero and is dependent on the mode of delivery,
level of maturity, and exposure to antibiotics. During the first week of life in healthy infants, the intestinal microbiome changes to a
preponderance of organisms (eg, Bifidobacterium longum subspecies infantis and lactobacilli) capable of consuming human milk
oligosaccharides (HMO). These normal microbiota play a symbiotic role with the intestine through toll-like receptors by regulating the
expression of genes involved in intestinal physiology, postnatal maturation and function (eg, barrier, digestion, angiogenesis, and
production of immunoglobulin A [IgA]), and protection against more pathologic organisms. Exposure to prolonged antibiotic courses
(>5 days) or increased use of H 2 blockers can lead to colonization with gram-negative bacteria (intestinal dysbiosis), which promotes
inflammation and apoptosis by signaling pathways such as NFKB. Abundance of proteobacteria (gram-negative facultative bacteria
such as Escherichia coli and Klebsiella) and underrepresentation of obligate anaerobic bacteria such as Firmicutes and Bacteroidetes in
infants’ intestines has been noted before NEC develops. Although several bacteria and viruses have been implicated in NEC, blood
cultures are positive in only 20% to 30% of cases.
C. Enteral feedings. NEC is rare in unfed infants, and 90% to 95% infants with NEC have received at least 1 enteral feed. Enteral feeding
provides necessary substrate for proliferation of enteric pathogens. Hyperosmolar formulas/medications may alter mucosal
permeability and cause mucosal damage. Short-chain fatty acids, produced as a result of colonic fermentation, may add to the damage.
Breast milk significantly lowers risk of NEC. Mammalian breast milk is a biologic fluid that has been highly conserved for millions of
years to provide survival advantage to the newborn. It contains immune cells, growth factors (eg, epidermal growth factor), anti-
inflammatory factors (eg, interleukin [IL]-10), secretory IgA, lactoferrin, and live bacteria. It also contains HMOs that have no nutritive
value for the infant but can be consumed by bacteria such as B infantis and help protect and develop the neonatal GI tract.
Additionally, breast milk inactivates PAF as well as inhibits TLR-4 signaling. In 1 study, receiving a diet of >50% breast milk in the first 14
days of life resulted in an 83% reduction in the incidence of NEC.
D. Intestinal ischemia. During periods of hypoxia/ischemia, blood is diverted away from the splanchnic circulation (diving reflex). This is
usually followed by reperfusion, which may lead to oxidant damage and bowel injury. Imbalance between vascular dilator (eg,
endothelial nitric oxide) and constrictor (eg, endothelin-1) molecules leads to defective splanchnic blood flow autoregulation and may
contribute to injury. Infants who subsequently develop NEC have been shown (by Doppler flow) to have higher flow resistance in the
superior mesenteric artery on the first day of life. Infants with a symptomatic patent ductus arteriosus are at higher risk for NEC
possibly due to intestinal ischemia associated with aortopulmonary shunt and diastolic steal. A diminished blood supply to the gut in
infants exposed to maternal cocaine (and other vasoconstrictive drugs) may also increase the risk for NEC. Most term infants who
develop NEC have predisposing conditions associated with hypoxia/ischemia including congenital heart disease (eg, hypoplastic left
heart syndrome), polycythemia/hyperviscosity, and birth asphyxia.
E. Other factors. A recent study has found an association between maternal cigarette smoking during pregnancy and development of
NEC in the newborn infant. The underlying mechanism may be the effect of nicotine on blood vessel development in the fetal GI tract.
A significant association between red blood cell transfusion and NEC has been reported in some retrospective studies, with about 25%
to 35% of NEC cases occurring within 48 hours of packed red blood cell (PRBC) transfusions. However, 3 randomized controlled trials
performed to date comparing liberal versus restrictive blood transfusion parameters have not shown a causative relationship. A recent
prospective, multicenter observational cohort study found that, among very low birthweight infants, severe anemia, but not PRBC
transfusion, was associated with an increased risk of NEC. It is possible that anemia may place significant stress on the intestine,
leading to reperfusion-type injury following transfusion. H2-receptor antagonists, which are inhibitors of gastric acid production,
increase the gastric pH, which may enhance pathogenic bacterial growth and increase the risk of NEC. Finally, a genetic predisposition,
through variation in pattern recognition receptors such as TLR-4 and NFKB, can lead to unregulated inflammation and NEC. In addition,
immune-modulating single nucleotide polymorphisms involving certain cytokines (eg, IL-6) and growth factors (eg, transforming growth
factor-β1) have been associated with severe NEC. Similarly, alterations in antioxidants, vascular endothelial growth factor, arginine,
and nitric oxide may also increase the risk for developing NEC.
V. Clinical presentation. Although term infants who develop NEC are often diagnosed in the first week of life, most premature infants
who develop NEC are older than 14 days or at 30 to 32 weeks’ PMA. Most of them are healthy, feeding well, and growing. The early
clinical presentation may include feeding intolerance, increased gastric residuals, and blood in stools. Specific abdominal signs include
abdominal distension, tenderness, abdominal skin discoloration, and bilious drainage from nasogastric tube. Systemic symptoms are
nonspecific (similar to those of neonatal sepsis) and include increased apnea/bradycardia episodes, temperature instability,
hypotension, and circulatory shock. The clinical course of NEC is variable. Although about 30% may have a mild presentation that
responds to medical treatment, about 7% may have a fulminant course with rapid progression to NEC totalis, septic shock, severe
metabolic acidosis, and death. The modified Bell’s staging criteria are often used to classify NEC according to clinical and radiographic
presentations and are broken down into 3 stages.
A. Stage I: Suspected necrotizing enterocolitis. Characterized by nonspecific systemic signs, such as temperature instability, apnea, and
lethargy. Abdominal signs include increased gastric residuals, abdominal distention, emesis, and heme-positive stool. Abdominal
radiographs may be normal or show dilation of the bowel loops consistent with mild ileus. There is disagreement among experts in the
field regarding whether or not the entity described as Bell stage I is actually NEC.
B. Stage II: Proven necrotizing enterocolitis. Includes symptoms and signs of stage I plus absent bowel sounds with abdominal
tenderness. Some infants have cellulitis of the abdominal wall or a mass in the right lower quadrant. Other findings include mild
metabolic acidosis and thrombocytopenia (stage IIb). Radiographic signs include pneumatosis intestinalis with or without portal venous
gas (PVG). (See Figures 12–27 and 12–28.)
C. Stage III: Advanced necrotizing enterocolitis. Findings include severe respiratory and metabolic acidosis, respiratory failure,
hypotension, oliguria, shock, neutropenia, and disseminated intravascular coagulation (DIC). The abdomen is tense and discolored with
spreading erythema, edema, and induration (signs of peritonitis). The hallmark radiographic sign is pneumoperitoneum (free air; see
Figure 12–26).
Diagnosis. NEC is a tentative diagnosis in any infant presenting with the triad of feeding intolerance, abdominal distension, and grossly
bloody stools.
A. Laboratory studies. These tests should be performed and repeated as necessary:
1. Complete blood count with differential. The white blood cell count is frequently either elevated with increased left shift or
depressed with low neutrophil count (neutropenia). Thrombocytopenia is often seen.
2. C-reactive protein (CRP) correlates with the inflammatory response. Because initial CRP may be normal, serial CRP levels done at 12-
to 24-hour intervals are more useful. Markers of inflammation, such as tumor necrosis factor-α, Il-6, IL-8, fecal calprotectin levels, and
urine intestinal fatty acid-binding proteins, have been suggested as screening tools but have not gained widespread use.
3. Blood culture for aerobes, anaerobes, and fungi (Candida species) is indicated.
4. Stool cultures for rotavirus and enteroviruses may be useful when there is clustering of cases within a single unit.
5. Electrolyte panel may show hyponatremia and hyperkalemia.
6. Arterial blood gas measurements often show metabolic or combined acidosis.
7. Coagulation studies include prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, and fibrin degradation products
(FDP and d-dimer). An elevated PT, PTT, and FDP indicate DIC, a frequent complication of severe NEC.
B. Imaging and other studies
1. Radiographs of the abdomen (supine with left lateral decubitus or crosstable views)
a. Suspicious for necrotizing enterocolitis. Abnormal bowel gas pattern, ileus, dilated or thickened bowel loops.
b. Confirmatory for necrotizing enterocolitis. Pneumatosis intestinalis, PVG (in the absence of umbilical venous catheter (see Figures
12–27 and 12–28), and free air (pneumoperitoneum). Left lateral decubitus or cross-table views are very helpful in confirming free
peritoneal air. Serial radiographic studies of the abdomen should be obtained every 6 to 8 hours in the presence of pneumatosis
intestinalis or PVG to look for pneumoperitoneum because these infants are at risk for bowel perforation within 48 to 72 hours of
disease onset.
2. Abdominal ultrasound. May be useful in the presence of nonspecific clinical and radiologic findings (gasless abdomen) or in infants
with NEC not responding to medical management. Ultrasound (US) can detect intramural intestinal gas (pneumatosis) and intermittent
gas bubbles in the liver parenchyma and the portal venous system. In addition, focal fluid collections, bowel wall thickness, and bowel
motility can be viewed in real time. Color Doppler US is useful in detecting bowel necrosis and mesenteric flow. Point-of-care US is
currently being evaluated and offers some promise for the future. See Chapter 44. 3. Mesenteric oxygen saturation. Recent studies
have shown the possibility of using near-infrared spectroscopy to detect mesenteric oxygen saturations. This provides hope of early
detection and real-time noninvasive monitoring for mesenteric bowel perfusion in infants at risk for NEC. This technique is still
experimental.
VII. Differential diagnosis. The differential diagnosis of NEC includes other conditions that cause rectal bleeding, abdominal distension,
gastric retention, or intestinal perforation. These include infectious enteritis, spontaneous intestinal perforation (see Chapter 121), anal
fissure, neonatal appendicitis, neonatal sepsis (presents similar to stage I NEC), and cow’s milk protein allergy.
VIII. Management. The goal is to provide bowel rest and prevent progression of disease to intestinal perforation, septic peritonitis, and
shock.
A. Medical management
1. Nil per os (NPO) to allow GI rest for 7 to 14 days (shorter course for stage INEC). Total parenteral nutrition (TPN) to provide basic
nutritional needs.

2. Gastric decompression with large-bore orogastric tube (Replogle) at low intermittent or continuous suctioning.
3. Close monitoring of vital signs and abdominal circumference. Check all gastric aspirates and stools for blood.
4. Respiratory support. Provide optimal respiratory support to maintain acceptable blood gas parameters. Progressive abdominal
distension causing loss of lung volume may increase need for positive-pressure ventilation.
5. Circulatory support. There may be excessive third spacing of fluid, which requires effective volume replacement. Inotropic support
may be needed to maintain normal blood pressure. Maintain urine output of 1 to 3 mL/kg/h. Remove potassium from intravenous
fluids in the presence of hyperkalemia or anuria.
6. Laboratory monitoring. Check complete blood count and electrolyte panel every 12 to 24 hours until stable. Obtain blood and urine
culture prior to starting antibiotics.

7. Antibiotic therapy. Treat with parenteral antibiotics for 10 to 14 days. Antibiotic regimen should cover pathogens that cause late-
onset sepsis in premature infants. Add anaerobic coverage if bowel necrosis or perforation is suspected. Reasonable antibiotic
regimens include the following:
a. Ampicillin (or vancomycin, in the presence of central line), gentamicin, and clindamycin (or metronidazole).
b. Vancomycin (in the presence of central line) and piperacillin/tazobactam.

8. Monitoring for bleeding and disseminated intravascular coagulation. Infants in stage II and III may develop DIC and require fresh
frozen plasma and cryoprecipitate. PRBC and platelet transfusions may also be needed.

9. Surgical consultation is needed for confirmed stage II and III NEC, especially when the condition is rapidly progressing or there is
evidence of GI perforation. B. Surgical management. Goal is to prevent enteric spillage and resect necrotic intestine while preserving
as much of viable intestine as possible. A pneumoperitoneum is the only absolute indication for surgical intervention but is present in
only half of the infants with intestinal perforation and necrosis at time of surgery. Relative indications for surgery include PVG,
abdominal wall edema and cellulitis (indicating peritonitis), fixed dilated intestinal segment by x-ray (sentinel loop), tender abdominal
mass, and clinical deterioration refractory to medical management. Biochemical markers such as thrombocytopenia, elevated CRP,
fecal calprotectin, intestinal fatty acid binding protein, and elevated IL-6 and IL-8 levels have been suggested as markers to predict
surgical NEC, but their practical clinical application remains questionable.
1. Exploratory laparotomy. This involves examining the bowel and resecting the necrotic segments. A portion of viable bowel is used to
create an enterostomy and mucous fistula. Reanastomosis takes place after 8 to 12 weeks. If NEC only involves a short segment of
bowel with limited resection, primary anastomosis is used by some surgeons; this avoids complications associated with ileostomy and
need for second reanastomosis surgery. In situations of widespread intestinal necrosis, the abdomen may be closed after placement of
a drain and reexplored later. A poor prognosis is associated with severe short bowel syndrome, and
foregoing further treatment may be considered.
2. Peritoneal drain placement. A small transverse incision is made at McBurney’s point. Abdominal layers are bluntly dissected, and a
Penrose drain is threaded into the abdomen and secured. Two multicenter trials have shown that use of a peritoneal drain (PD) and
laparotomy in infants with bowel perforation have similar mortality, need for TPN, and length of hospital stay. Secondary laparotomy
after PD has varied from 38% in the study by Moss et al to 74% in that by Rees et al, without affecting survival. PD is a relatively simple
procedure and can be done with local anesthesia at the bedside. Hence, it is often used as a temporizing procedure in critically sick
infants. However, PD has been questioned by Rees et al because they have shown lack of improvement in physiologic measurements
following PD and the majority of infants required definitive laparotomy later. Currently, the optimal surgical management for infants
with bowel perforation remains controversial. The Necrotizing Enterocolitis Surgery Trial (NEST), which is evaluating survival without
neurodevelopmental impairment at 18 to 22 months for infants undergoing laparotomy or PD for NEC or intestinal perforation, is
currently underway (ClinicalTrials.gov identifier: NCT01029353).
IX. Prevention
A. Human milk has been shown to prevent NEC. Although a mother’s own milk is ideal, a meta-analysis of 9 randomized clinical trials
of donor human milk versus formula suggests that human milk was beneficial; infants randomized to formula had a 2.8 times increased
risk of NEC. The rate of NEC was also shown to be lower in infants receiving human milk fortifier compared to those receiving bovine
milk–based fortifier.
B. Use of standardized feeding regimens with initial period of trophic feeds has been shown to decrease the incidence of NEC. A
cautious approach to feeding in high-risk infants with circulatory compromise or congenital heart disease or those receiving PRBC
transfusions is recommended.
C. Probiotics. Probiotics are live nonpathogenic microbial preparations that colonize the healthy intestine. They have the potential to
prevent NEC by promoting colonization of the gut with beneficial organisms, preventing colonization by pathogens and improving the
maturity and function of gut mucosal barrier and modulation of the immune system. Probiotics have been studied extensively to
prevent NEC; the largest clinical trial to date of 1315 preterm infants (GA 23–30 weeks) demonstrated no difference in the incidence of
Bell stage II or III NEC between patients randomly assigned to receive the probiotic Bifidobacterium breve BBG-001 compared with the
placebo group (9% vs 10%). A recent meta-analysis, which included 38 trials (total of 10,520 preterm infants), showed a significant
reduction of NEC (relative risk [RR], 0.43; confidence interval [CI], 33–0.56) and mortality (RR, 0.79; CI, 0.68–0.93) with no significant
change in incidence of culture-proven sepsis (RR, 0.88; CI, 0.77–1). However, this benefit was not seen in the most premature infants
with birthweight <1 kg. Because probiotics are considered nutritional supplements and not “drugs,” they are not controlled by the US
Food and Drug Administration. As such, there are no established regimens of optimal strain and dosing and no quality control
regulations to ensure consistency and safety of these products; therefore, they cannot be recommended at this time. In addition, there
have been some case reports of bacteremia from the probiotic strain used and 1 case of fatal mucormycosis in a preterm infant
exposed to probiotics.
D. Prebiotics, or nutrients that enhance the growth of beneficial microbes, have been proposed as a preventive strategy. These
include oligosaccharides, inulin, galactose, fructose, lactose, and others. Although prebiotics enhance the proliferation of endogenous
flora, their efficacy in prevention of NEC is unclear.
E. Avoidance of prolonged empiric antibiotic use. Antibiotics alter the gut flora, promoting growth of pathogens, and should be
avoided in premature infants. This is supported by a retrospective study that showed that extremely low birthweight infants receiving
an initial antibiotic course of >5 days had an increased risk of NEC or death. The association was confirmed in a recent systematic
review and meta-analysis.
F. Avoidance of H2 blockers. Innate GI immunity provided by gastric acid may be important in preventing the cascade of infectious and
inflammatory events leading to NEC. A large retrospective study from the National Institute of Child Health and Human Development
(NICHD) Neonatal Research Network showed that infants with NEC were more likely to have received H 2 blockers compared to
matched controls (odds ratio, 1.71; CI, 1.34–2.19). Therefore, routine use of H 2 blockers in premature infants should be avoided.
X. Complications
A. Recurrence of NEC may occur in about 5% to 10% of cases.
B. Colonic strictures may occur in 10% to 20% cases and present with recurrent abdominal distension and persisting feeding
intolerance. Contrast radiographic studies are usually diagnostic. The most common site for stricture formation is the colonic splenic
flexure.
C. Short bowel syndrome may develop in infants undergoing extensive resection of bowel (occurs in 9% of surgical NEC cases). The
traditional limits of intestinal length for successful survival (at least 20 cm of viable small bowel remaining with an intact ileocecal
valve, or 40 cm viable remaining small bowel with loss of ileocecal valve) are now being challenged with improvements in short bowel
management by multidisciplinary teams. Fewer infants are now being referred for intestinal transplant after the use of intestinal
lengthening procedures such as serial transverse enteroplasty and improved TPN and infection prevention strategies. Intestinal (with
or without liver) transplant remains an option for some of these infants. D. Total parenteral nutrition–associated liver disease occurs
more frequently in infants with surgical therapy for NEC.

XI. Prognosis. Risk of mortality is 20% to 30%; the mortality is higher with lower GA and surgical interventions. Infants with surgical
NEC have been shown to have significant growth and neurodevelopmental impairment. They are at risk for developing periventricular
leukomalacia, cerebral palsy, deafness, and blindness. In a report from NICHD, only half the infants with surgical NEC survived. Among
the survivors, 56.7% had neurodevelopmental impairment (cerebral palsy, mental development index <70, physical development index
<70, blindness, or deafness). Overall, mortality or neurodevelopmental impairment was present in 82.3% of infants in this high-risk
group.