Efficacy and heterogeneity: an exclusive human milk diet for necrotizing enterocolitis prevention in very preterm infants-a systematic review and meta-analysis of 11 studies.

Abstract

Necrotizing enterocolitis (NEC) remains a leading cause of morbidity and mortality in very preterm infants. While human milk is known to reduce NEC risk, the efficacy of an exclusive human milk diet (EHMD), which avoids all bovine-based products, remains quantitatively uncertain. To systematically evaluate the association between EHMD and NEC incidence in very preterm infants. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs), cohort, and case-control studies involving infants born at <32 weeks' gestation and/or with birth weight <1,500 g. The EHMD was defined as ≥90% human milk with exclusive use of human milk-derived fortifiers. The comparator was any diet containing bovine-based formula. Studies where human milk was supplemented with bovine-derived fortifiers were excluded to isolate the effect of a strict EHMD. The primary outcome was definite NEC (Bell stage ≥II). Secondary outcomes included surgical NEC, all-cause mortality before hospital discharge, and time to full enteral feeds. Pre-specified subgroup analyses were performed by study design (RCTs vs. observational). Data were pooled using a random-effects model. Heterogeneity was assessed with the I 2 statistic. Risk of bias was assessed with Cochrane RoB 2.0 and Newcastle-Ottawa tools. Eleven studies involving 11,309 infants were included. EHMD was associated with a 39% reduction in definite NEC that did not reach statistical significance [Risk Ratio (RR) = 0.61, 95% CI: 0.30-1.22, p = 0.16], though heterogeneity was high ( I 2 = 89%). Subgroup analysis revealed a significant protective effect in RCTs (RR = 0.52, 95% CI: 0.36-0.78) but not in observational studies (RR = 1.18, 95% CI: 0.95-1.48). EHMD also reduced surgical NEC (RR = 0.48, 95% CI: 0.35-0.66) and mortality (RR = 0.52, 95% CI: 0.33-0.80), and shortened time to full enteral feeds (MD = -2.42 days, 95% CI: -3.31 to -1.53). Evidence of publication bias was present. Evidence from RCTs indicates that EHMD significantly reduces NEC risk in very preterm infants. The discordant findings from observational studies highlight the influence of study design and potential confounding. These results support the use of EHMD while underscoring the need for rigorous implementation and further research. https://www.crd.york.ac.uk/PROSPERO/recorddashboard.