Necrotizing Enterocolitis

Necrotizing Enterocolitis

Kathleen J. Motil

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in the infant. This disorder encompasses several distinct disease entities that differ from the most common form of the disease, that is, idiopathic NEC (Box 59.1). Although the etiology of idiopathic NEC is unknown, specific precipitating factors may be implicated in many instances. The clinical manifestations of idiopathic NEC may mimic the symptoms and signs of various neonatal gastrointestinal disorders, and these may be indistinguishable from those of sepsis. NEC has become the single most common surgical emergency in neonatal intensive care units (NICUs). Early recognition and aggressive treatment of this disorder during the last 10 years has led to a markedly improved clinical outcome.


The overall incidence of NEC is 2.4:1000 live births (range, 0.0:1000 to 7.2:1000) or 2.1% (range, 1.0% to 7.7%) of all admissions to NICUs. The incidence of NEC averages 3% to 4% in infants whose birth weight is less than 2,000 g, and decreases significantly to 1% in infants whose birth weight is greater than 2,000 g. The incidence of NEC in very low-birth-weight infants continues to increase in both absolute and relative terms. Males and females are affected equally. Black and white infants are affected more commonly than are those of Hispanic origin, but the racial patterns reflect the populations served by individual neonatal centers. Seasonal variation does not affect the incidence of NEC. Periodic clusters of cases or epidemics have been reported.


The precise etiology of idiopathic NEC is unknown, but it probably is caused by multiple factors in a susceptible host. The features most commonly implicated in the pathogenesis of the disease are ischemic insult to the gut, the presence of bacterial or viral organisms in the intestinal tract, the availability of intraluminal substrate (usually formula or human milk) to promote bacterial proliferation or induce mucosal injury, and altered host defense (Box 59.2). The first two factors (ischemia, infectious agents) are thought to be the predisposing variables that initiate the pathogenesis of NEC. Other factors, such as inflammatory mediators (cytokines), oxygen radicals,
and bacterial fermentation products and toxins, are thought to propagate the disease process. Despite recent advances, the pathogenesis of NEC remains an enigma.

The regulation of mesenteric blood flow to the gut is understood poorly in the infant, but is thought to mimic the “diving reflex” in aquatic animals. During hypoxic conditions, this reflex is a defense mechanism that protects the brain and heart from ischemic damage by shunting blood away from the mesenteric, renal, and peripheral vascular beds. Comparable studies in asphyxiated neonatal piglets have demonstrated that blood flow to the stomach, ileum, and colon is reduced dramatically during a hypoxic episode. With resuscitation, perfusion rebounds, leading to vascular congestion and mucosal hemorrhages secondary to ischemic injury to the blood vessels. These studies support the hypothesis that ischemia contributes to the pathogenesis of NEC in the human infant.

Many perinatal events predispose the neonate to hypoxia. Birth asphyxia, respiratory distress syndrome, apnea, hypotension, hypothermia, patent ductus arteriosus, congestive heart failure, umbilical vessel catheterization, polycythemia, and exchange transfusion have been implicated as ischemic factors in the pathogenesis of neonatal NEC. Nevertheless, some infants with no evidence of these risk factors have the disorder. Moreover, in studies of multiple births in which risk factors such as perinatal asphyxia and respiratory distress are less common in the first-born than in the second-born infant, NEC occurred in the first-born twin in all cases, and in no case did only the second-born twin have NEC. Finally, when infants with NEC are compared with matched controls, few, if any, ischemic risk factors are identified consistently.

The intestinal microflora provides an additional component in the development of ischemic necrosis of the intestinal tract. A number of bacterial, viral, and fungal organisms have been isolated in sporadic and epidemic outbreaks of NEC. Bacterial organisms normally found in the distal gastrointestinal tract, including Escherichia coli (56%), Klebsiella pneumoniae (28%), Pseudomonas (11%), and Clostridium difficile, have been recovered from the blood and peritoneal cavities of about one-third of all infants with NEC. Viral particles have been identified concurrently in the feces of infants with NEC and their mothers, the midwives, and the nursing staff involved in treatment of the infants. Fungi also have been isolated from infants born to immunocompromised mothers.

The role of gastrointestinal microorganisms in the pathophysiology of NEC remains unclear. Current hypotheses suggest that either a bacterial invasion of tissue occurs in a passive manner after ischemic damage to the mucosal barrier of the gut, or enteric bacteria and viruses cause the disease directly. Several clostridial species have been implicated causally in the development of NEC because of their production of toxins, their association with pseudomembrane formation, and most important, their ability to produce submucosal and subserosal gas blebs and intestinal gangrene. Enterobacter sakazakii, a known contaminant of powdered milk formula, also can contribute to outbreaks of NEC in NICUs. Nevertheless, in many epidemics of NEC, specific pathogens either cannot be identified or, when they are present, are isolated from healthy infants without the disease. Thus, a cautious interpretation of the pathogenicity of specific microorganisms is warranted.

Recent evidence suggests that inflammatory mediators, especially platelet activating factor (PAF), may play a pivotal role in NEC. PAF, an endogenous phospholipid mediator with potent proinflammatory actions associated with hypotension, increased vascular permeability, hemoconcentration, lysozyme enzyme release, and platelet and neutrophil aggregation, induces tissue necrosis. In experimental models of NEC, neutrophil activation and adhesion to intestinal venules initiate a local inflammatory reaction in which PAF triggers tissue injury via tumor necrosis factor (TNF) generation and reactive radical formation. Xanthine oxidase, the major source of reactive oxygen species, aggravates tissue injury by promoting the peroxidation of unsaturated lipids in cellular and mitochondrial membranes. Subsequent norepinephrine release and mesenteric vasoconstriction result in splanchnic ischemia and reperfusion. Translocation of bacterial endotoxins further amplifies the inflammatory process. Nitric oxide may be a protective modulator of inflammatory injury because it promotes vasodilatation and microvascular integrity, inhibits leukocyte adhesion and activation, and scavenges oxygen radicals. Studies in premature infants with NEC have demonstrated elevated levels of PAF, TNF, and interleukin-6 (IL-6). Magnesium and copper have been implicated in the pathogenesis of NEC, because a deficiency of these minerals may activate the synthesis or activity of cytokines and oxygen free radicals.

Because bacterial involvement in NEC may be associated with usual intestinal flora, topical antibiotics were considered to be potentially useful in the prevention of the disease. The topical administration of aminoglycosides into the gastrointestinal tract either prophylactically or at the time of diagnosis decreases the total colony count of enteric flora. These antibiotics, however, do not provide protection from the development of NEC; do not alter its course, complications, or mortality rate; and may be associated with the emergence of resistant strains of enteric organisms and potentially ototoxic complications in the infant. Therefore, the use of topical aminoglycosides is not recommended for the routine prevention of NEC.

Milk feedings also have been implicated in the pathogenesis of neonatal NEC. About 93% of all infants in whom NEC develops have been fed enterally. Human milk and commercial formulas serve as substrates for bacterial proliferation in the gut. Because neonates partially malabsorb the carbohydrate and fat constituents in milk, reducing substances, organic acids, carbon dioxide, and hydrogen gas may be produced by the bacterial fermentation of these nutrients. When NEC develops, neonates have increased intestinal loss of carbohydrates, leading to reducing substances in the feces and hydrogen-filled cysts within the gut mucosa. Although these observations identify milk feedings as a contributory factor in the development of NEC, the disease may develop in some infants who have never been fed. Additional factors, such as the volume of milk and its rate of administration, may contribute to the development of NEC.

NEC may result from direct mucosal injury induced by hyperosmolar formulas. Although such formulas are used rarely in neonatal nurseries, medications that frequently are administered orally may contain hypertonic additives that irritate the intestinal mucosa and precipitate disease (Table 59.1). Other hyperosmolar agents instilled directly into the bowel for
diagnostic studies may precipitate NEC, presumably because of fluid shifts, bowel distention, and ischemia. Care should be taken to only use isotonic contrast media to avoid this complication.


Generic Drug Osmolarity (mOsm/L) Concentration (mg/mL)
Ampicillin 1,843 50
Nystatin 3,022 100,000*
Multivitamins 6,023
Vitamin E 605 36
Ferrous chloride 5,079 157
Calcium gluconate 319 50
Caffeine 90 30
Theophylline 1,012 193
Methyl digoxin 15,250 0.6
*Concentration expressed as units/mL.

Altered host resistance as a result of immunologic and gastrointestinal immaturity in the neonate is believed to play a primary role in the development of NEC. At birth, the human intestinal mucosa has no secretory IgA, the major gastrointestinal immunoprotective antibody. Because human milk contains specific and nonspecific protective factors, such as immunocompetent cells, secretory IgA, lactoferrin, lysozyme, and the Lactobacillus bifidus growth factor, it has been fed to neonates to reduce the incidence and severity of NEC. These studies support the protective role of human milk in the prevention of NEC. Despite the presence of these protective factors, NEC has occurred in neonates who were fed refrigerated, pasteurized, or frozen human milk.

The issue of the developmental immaturity of the gastrointestinal tract may be central to the pathogenesis of NEC. One study demonstrated that the risk of developing NEC is diminished significantly in infants whose mothers received antenatal corticosteroids; however, this outcome is not a universal finding. Although their mechanism of action is unclear, corticosteroids may function as nonspecific enzyme inducers, leading to accelerated maturation of the intestinal tract and enhanced protection from disease. Infants who received erythropoietin for anemia of prematurity also had a lower incidence of NEC. Erythropoietin may confer a beneficial effect by protecting against programmed cell death in intestinal epithelium.

The use of vitamin E in the treatment of retinopathy of prematurity has been associated with an increased incidence of NEC. This association was noted primarily in infants whose birth weights were less than 1,500 g, and whose serum tocopherol levels were higher than 3.5 mg/dL. It was hypothesized that the mechanism of excessive scavenging of oxygen radicals, which leads to diminished antimicrobial defenses, increased the risk of developing NEC in these infants. Subsequent trials of vitamin E therapy for the prevention of neonatal intracranial hemorrhage failed to demonstrate an association with NEC, presumably because serum alpha-tocopherol levels were maintained in a range less than 3.5 mg/dL.

Predisposing Factors

Risk factors that predispose the premature infant to NEC have been the subject of controversy (Box 59.3). Risk factors for the development of NEC may be the same in low-birth-weight infants with or without the disease, because the disease affects predominantly low-birth-weight infants who require intensive care. Univariate analysis of a large neonatal database showed that premature infants who developed NEC had lower birth weights and younger gestational ages; were more often African American; had been exposed more often to medications, including pre- and postnatal glucocorticoids, surfactant, caffeine, erythropoietin, and indomethacin; had been exposed more often to invasive procedures such as umbilical vessel catheterization and mechanical ventilatory support, and were less likely to receive human milk than premature infants who did not develop NEC. A multivariate analysis of this same neonatal database showed that the most important risk factor associated with the development of NEC was low birth weight. Other factors independently associated with an increased risk for NEC included being on a ventilator on the first day of life, having received antenatal glucocorticoids, being exposed to both glucocorticoids and indomethacin during the first week of life, and depressed Apgar scores at 5 minutes of life. One additional study suggests that NEC occurred with equal frequency in premature infants who received indomethacin therapy for patent ductus arteriosus and those who did not (13% versus 14%, respectively). The analyses of smaller databases suggest that a longer duration of morphine use and treatment for cocaine exposure increase the risk of NEC.

Additional risk factors have been identified for infants who average more than 2,000 g at birth. Polycythemia (peripheral venous hematocrit greater than 65%); respiratory distress, defined by the need for supplemental oxygen for more than 24 hours; and hypoglycemia (serum glucose level less than 30 mg/dL) are the most common clinical features associated with the development of NEC in this group of infants. NEC in term infants, although rare, has been associated with underlying conditions such as congenital heart disease and endocrine disorders, including panhypopituitarism, hypothyroidism, hypoparathyroidism, and congenital adrenal hyperplasia.

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Jul 24, 2016 | Posted by in PEDIATRICS | Comments Off on Necrotizing Enterocolitis
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