The exact etiology of necrotizing enterocolitis is not clear. It is believed that an ischemic insult damages the intestinal lining, leading to increased intestinal permeability and leaving the intestine susceptible to bacterial invasion. NEC rarely occurs before enteral feedings have begun and is less common among breastfed infants. However, once feedings are begun, ample substrate is present for proliferation of luminal bacteria, which can penetrate the damaged intestinal wall, producing hydrogen gas. The gas may collect within the intestinal wall (pneumatosis intestinalis) or enter the portal veins.

The initial ischemic insult may result from vasospasm of the mesenteric arteries, which can be caused by an anoxic insult triggering the primitive diving reflex that markedly diminishes intestinal blood flow. Intestinal ischemia may also result from low blood flow during an exchange transfusion, during sepsis, or from the use of hyperosmolar formulas. Similarly, congenital heart disease with reduced systemic blood flow or arterial oxygen desaturation may lead to intestinal hypoxia/ischemia and predispose to NEC.

NEC may occur as clusters of cases or as outbreaks in neonatal ICUs. Some clusters appear to be associated with specific organisms (eg, Klebsiella, Escherichia coli, coagulase-negative staphylococci), but often no specific pathogen is identified.