Maternal and perinatal risk factors for necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) remains among the most devastating complications of prematurity, carrying significant mortality and lifelong morbidity despite decades of mechanistic and translational research. Although NEC is classically framed as an inflammatory disease of intestinal immaturity, driven by microbial dysbiosis and exaggerated immune signaling, this model does not fully explain the uneven distribution of disease burden across infants, hospitals and communities. In this review, we reframe NEC within a broader maternal-perinatal systems context grounded in the Developmental Origins of Health and Disease (DOHaD) framework. This review synthesizes evidence linking maternal psychosocial stress to activation of the hypothalamic-pituitary-adrenal axis. This alters placental signaling and disrupts fetal gut development and microbiome establishment. This is further compounded by paternal stress-related epigenetic mechanisms, suboptimal maternal nutrition, poor metabolic health and environmental pollutants that disproportionately affect socioeconomically disadvantaged neighborhoods. These prenatal influences intersect with postnatal modifiers within neonatal intensive care units and health systems. Social and structural determinants of health further affect prenatal exposures and the delivery of neonatal care. This framework does not replace traditional pathogenesis models of NEC but rather contextualizes them within broader developmental and health systems. This perspective may help identify earlier targets for prevention while supporting more equitable and multidisciplinary approaches to reducing the burden of NEC.