DESCRIPTION

Necrotizing enterocolitis (NEC) is a life-threatening gastrointestinal (GI) emergency that occurs in the newborn period and consists of diffuse necrotic injury to the bowel. This injury can result in subserosal collections of gas, which in turn can lead to intestinal necrosis that can manifest as intestinal perforation. The entire small bowel and colon are susceptible, but the most frequently involved areas are the distal small bowel and proximal colon. Lesions vary from focal areas of necrosis to more diffuse disease. Systemic signs and symptoms related to the inflammatory GI injury are accompanied by characteristic radiographic findings of pneumatosis intestinalis.

EPIDEMIOLOGY

• The incidence of NEC is variable and ranges from 1 to 7% of all neonatal intensive care unit admissions or 1 to 3 per 1,000 live births.
• Preterm infants account for most of NEC cases; the risk increases with decreasing gestational age and birth weight.
• Up to 10% of cases occur in term infants, many of whom have underlying comorbidities, such as gastroschisis or congenital heart disease.
• NEC typically has an onset at 2 to 5 weeks of life. The more premature the infant, the longer the child is at risk for developing NEC, with cases reported as late as 3 months of age.

ETIOLOGY

• Various factors that cause direct and indirect mucosal disruption, which in turn may lead to an increased permeability in the gut of agents that lead to injury, include the following:
  • Hypoxia/ischemia leading to mucosal injury
  • GI tract immaturity
  • Immature host defense
  • Enteral feedings
  • Decreased diversity of bacteria within the GI lumen
  • It is noteworthy that each of these factors can increase expression of immune receptors including toll-like receptor 4 (TLR4) in the gut.
• Enteral alimentation
  • Because 95% of infants who develop NEC have been enterally fed, initiation of feedings has been implicated as an important contributor to the etiology of NEC.
  • The composition of the formula and the immaturity of the mucosa have been implicated as factors.
• Because of the frequent report of epidemic, cluster-type episodes, a variety of microorganisms have been implicated in the development of NEC, although there is no single causative organism.
  • Blood cultures may be positive in 20–30% of cases, often gram-negative organisms that are enriched in TLR4 ligands.
• Immaturity of the intestinal mucosal defense system, including factors such as reduced levels of defensins and impaired mucin production, may impair defense against invading organisms, leading to NEC.
• Certain medications may cause direct mucosal injury.

RISK FACTORS

The greatest risk factor for NEC is prematurity. Additional risk factors for both preterm and full-term infants include the following:

• Enteral feeding with formula
• Cardiovascular instability
• Respiratory compromise resulting in recurrent or prolonged hypoxia
• Congenital heart disease
• Polycythemia
• Exchange transfusion
• Gastroschisis
• Perinatal asphyxia
• Intrauterine growth restriction
• Small size for gestational age
• Maternal intraamniotic infection
• Maternal preeclampsia
• Antenatal cocaine abuse
• Prolonged use of IV antibiotics
• Gastric acid suppression with H₂ blockers

GENERAL PREVENTION

• Exclusive maternal breast milk feeding has been advocated. When maternal breast milk is unavailable, use of donor human milk decreases the risk of developing NEC when compared to formula.
• Standardized feeding protocols can decrease the risk of NEC.
• Judicious use of empiric postnatal antibiotics
• Specific probiotic strains have been shown to decrease the incidence of NEC for very low birth weight (VLBW) infants. Concern has been raised regarding lack of quality standards and an increased risk of sepsis when using probiotics.
• Immunonutrient supplementation with agents such as arginine, glutamine, lactoferrin, and omega-3 polyunsaturated fatty acids have been investigated, but there is currently insufficient evidence to make any recommendations for their use.

PATHOPHYSIOLOGY

• The exact mechanism of injury in NEC is unclear, but research suggests a multitude of factors in an immature host leads to activation of the inflammatory cascade with subsequent tissue injury and necrosis.
• Prior to the onset of NEC, neonates develop dysbiosis of the microflora within the intestinal tract, characterized by bacteria that are enriched in ligands for the innate immune receptor, TLR4.
• TLR4 signaling in the intestinal tract plays a critical role in the development of NEC.
  • Specifically, TLR4 activation by dysbiotic bacteria inhibits the body’s ability for intestinal repair and increases the release of inflammatory cytokines, causing further epithelial injury.
  • In preterm infants, expression of TLR-4 is elevated, increasing risk for overactivation, intestinal injury, and NEC.
• The most common sites for NEC include the terminal ileum, ileocecal region, and ascending colon.
  • 50% of infants have both colonic and small intestine disease, with the other 50% divided between isolated ileal and colonic involvement.