Association of anemia and necrotizing enterocolitis in neonates: Systematic review and meta-analysis of transfusion thresholds, erythropoietin trials, and observational studies

Background Meta-analyses of observational studies evaluating association between blood transfusion and necrotizing enterocolitis (NEC) have shown mixed results and an independent association between anemia and NEC requires further evaluation. Objective To investigate the association of NEC with anemia in preterm infants via meta-analysis of (1) randomized controlled trials (RCTs) evaluating transfusion thresholds and recombinant erythropoietin (rEpo)/darbepoetin and (2) case–control studies comparing hematocrit levels between NEC cases and controls. Data sources PubMed, Embase, Scopus, and the Cochrane Database were searched in August 2025, and the results were supplemented by other sources. Study selection (1) Transfusion threshold and rEpo RCTs evaluating NEC rates in preterm infants with lower hemoglobin (Hb) levels compared with higher Hb levels. (2) Case–control studies comparing hematocrit levels between NEC cases and controls. Primary outcome The incidence of any stage NEC in infants with low versus high Hb group. Results RCTs evaluating transfusion threshold (n = 4, 3307 participants) showed no difference in NEC incidence between the low versus high Hb group [OR: 1.14 (CI: 0.89, 1.46), p 0.647]. RCTs evaluating rEPO versus placebo ( n = 11, 4173 participants) showed higher incidence of NEC in the low versus high Hb group [OR: 1.43 (CI: 1.13, 1.80), p 0.003]. Meta-analysis of case–control studies ( n = 3, 1016 participants) showed association of lower hematocrit levels in NEC cases compared with controls (standardized mean difference −0.28; CI −0.56, −0.002; p 0.048). Conclusion Our analysis suggests an association between NEC and lower hemoglobin levels. Well-designed and adequately powered prospective studies are required to confirm our findings.