Background <p>Necrotizing enterocolitis (NEC) is a disorder in very low birth weight (VLBW, &lt;1500 g) infants, associated with significant morbidity and mortality. Earlier detection of NEC may improve outcomes. We hypothesized that NEC’s physiological signature resembles that of sepsis and that our model developed for sepsis, the Pulse Oximetry Warning System (POWS), would also predict NEC.</p> Objectives <p>Assess relationships between continuous heart rate (HR) and oxygen saturation (SpO₂) features and NEC risk, and evaluate POWS performance for predicting medical and surgical NEC.</p> Methods <p>In a retrospective multicenter analysis, we studied VLBW infants at four level IV NICUs, identifying cases of late-onset sepsis (LOS) and NEC (Bell stages 2 or 3). Using HR and SpO₂ data, we calculated features and POWS scores and assessed associations with NEC and LOS risk.</p> Results <p>Among 3914 infants evaluated, 5% had NEC and 13% had LOS. Cardiorespiratory data analysis showed that HR/SpO₂ patterns had similar risk associations with NEC and LOS. POWS AUC was 0.758 for NEC, 0.804 for sepsis, 0.791 for NEC or LOS, and 0.808 for NEC requiring surgery.</p> Conclusion <p>NEC shares a cardiorespiratory signature with LOS. POWS predicted NEC with a dynamic rise before clinical diagnosis.</p> Impact <p><UnorderedList Mark="Bullet"> <ItemContent> <p>A cardiorespiratory early warning score analyzing heart rate and oxygen saturation, trained to predict late-onset sepsis within 24h across, predicts necrotizing enterocolitis.</p> </ItemContent> <ItemContent> <p>Heart rate and oxygen saturation features had the same patterns of association with necrotizing enterocolitis as sepsis.</p> </ItemContent> <ItemContent> <p>The results increase understanding of physiologic signatures of neonatal sepsis and necrotizing enterocolitis</p> </ItemContent> </UnorderedList></p>