Necrotizing enterocolitis (NEC) is an ischemic and inflammatory necrosis of the bowel primarily affecting premature neonates after the initiation of enteral feeding.
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.
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 toll-like 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.
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 anti-inflammatory 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.
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 H2 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 ...