Postnatal hemoglobin P50 as a surrogate marker for hypoxia-driven NEC in preterm infants: a mechanistic hypothesis P50 and NEC risk

Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in preterm infants. Despite decades of investigation, clinicians lack an early, physiologically grounded biomarker that signals risk before clinical deterioration. We hypothesize that persistently elevated hemoglobin P₅₀ during the first 72 h of life reflects impaired oxygen unloading and evolving systemic hypoxia, particularly affecting the splanchnic circulation. This rightward shift in the oxygen dissociation curve, driven by increased 2,3-diphosphoglycerate (2,3-DPG), may precede lactate elevation and herald the onset of intestinal injury. Mechanistically, this pathway is underpinned by hypoxia-inducible factor-1α (HIF-1α) stabilization and Toll-like receptor 4 (TLR4) activation, both implicated in NEC pathogenesis. We present a physiologic rationale supported by prior data, including preliminary observations, and propose clinical and experimental approaches to validate the hypothesis. If confirmed, P₅₀ could represent a routinely accessible, noninvasive biomarker for early NEC risk stratification.