When It Is Not NEC: Recognizing Mimics of Necrotizing Enterocolitis in Preterm Infants

Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in preterm infants, yet it remains one of the most challenging neonatal diagnoses to establish with certainty. No single clinical, laboratory, or radiographic finding is pathognomonic, and the modified Bell's staging system is limited because features such as abdominal distension, bloody stools, pneumatosis intestinalis, and portal venous gas are common in preterm infants or are mimicked by other conditions. A wide range of disorders in preterm and term neonates can therefore resemble NEC, including spontaneous intestinal perforation, sepsis-associated ileus, dysmotility of prematurity, malrotation with or without volvulus, cow's milk protein allergy, Hirschsprung-associated enterocolitis, cardiogenic colitis, viral enterocolitis, intussusception, neonatal appendicitis, meconium obstruction, incarcerated inguinal hernia, and food protein-induced enterocolitis syndrome. Misclassification of these mimics leads to over- and under-estimation of NEC incidence, contaminates outcome data, and may delay surgical intervention. This review summarizes the epidemiology, risk factors, pathophysiology, and distinguishing clinical, radiographic, and histopathological features of the common mimics of NEC, with particular emphasis on spontaneous intestinal perforation. We also highlight the inherent diagnostic challenges and future directions, including the need for reliable biomarkers and the evolving role of artificial intelligence.