Human Milk-Derived Versus Bovine Protein-Based Fortifiers for Preterm Infants Fed Human Milk: A Systematic Review and Meta-Analysis

Background: Human milk-derived fortifiers (HumBMF) are an alternative to bovine protein-based fortifiers (BovBMF) for preterm infants, but their comparative effectiveness and safety remain uncertain. We evaluated the effects of HumBMF versus BovBMF in preterm or very low birth weight infants. Methods: Randomised controlled trials (RCTs) comparing use of HumBMF versus BovBMF to fortify human milk were identified through four databases and three trial registries (to 11 May 2026). At least two reviewers independently screened studies, extracted data, and assessed risk of bias. Fixed-effect meta-analyses and GRADE assessments were performed. Prespecified analyses separated trials comparing fortifier type alone, in which any mother’s own milk (MOM) shortfall was supplemented with donor human milk (DHM) in both arms; and dual-intervention trials, in which MOM shortfall was also randomised to DHM in the HumBMF arm or preterm formula in the BovBMF arm. Results: Nine RCTs were included. In trials comparing fortifier type alone, there was no evidence that HumBMF reduced mortality (RR 0.60 (95% CI 0.29–1.23), low-certainty) or necrotising enterocolitis (NEC; RR 0.83 (0.39–1.78), very low-certainty). In dual-intervention trials, where MOM shortfall was supplemented with DHM rather than formula, NEC was lower (RR 0.45 (0.20–0.99), moderate-certainty). Conclusions: Current evidence does not demonstrate clinical advantages of HumBMF over BovBMF when added to the same human milk diet. Reductions in NEC occurred only where DHM also replaced preterm formula and cannot be attributed to fortifier type alone. Future research should distinguish the independent effects of fortifier composition from those of an exclusive human milk feeding strategy.