Necrotizing enterocolitis (NEC) is a severe gastrointestinal condition predominantly affecting preterm infants and is characterized by intestinal inflammation, ischemia, and, in advanced cases, bowel necrosis. Although advances in neonatal care have improved survival, infants with NEC remain at substantially increased risk of long-term neurodevelopmental impairment (NDI), including cognitive, motor, sensory, and behavioral deficits. Clinical severity, surgical NEC, and comorbidities, including intraventricular hemorrhage and metabolic instability, further exacerbate neurodevelopmental risk. Neuroimaging and electrophysiological studies have consistently revealed structural and microstructural brain abnormalities that provide early prognostic markers. While prematurity contributes to baseline vulnerability, growing evidence indicates that NEC-specific factors, such as systemic inflammation, disruption of the gut-brain axis, and immune-mediated injury, play a central role in the pathogenesis of brain injury. Preclinical research targeting inflammation, oxidative stress, microbiome modulation, and high-mobility group box 1-Toll-like receptor 4 (HMGB1-TLR4) signaling has demonstrated promising neuroprotective effects, underscoring the need for translational strategies. This review comprehensively examines the literature on NDI in infants with NEC to compare the clinical outcomes of this population of babies with those of their preterm peers, evaluate the underlying mechanisms of brain injury associated with NEC, and discuss emerging preventative and therapeutic strategies to address this morbidity.
