Effect of Multi-Nutrient Milk Fortification on Preterm Neonate Outcomes: A Network Meta-Analysis

Background/Objectives: Optimal feeding regimens for preterm neonates, including the role of multi-nutrient fortification, are unknown, leading to large practice variation in comparing different feeding regimens that include fortification and their impact on outcomes for preterm infants. Methods: Using a network meta-analyses design, two reviewers independently extracted data. A Cochrane CENTRAL, Medline, Embase, and CINAHL search was conducted for all studies published up to 27 June 2023. Randomized clinical trials of feeding regimens for preterm infants that included multi-nutrient fortification were included. Outcomes were mortality, necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), sepsis, periventricular leukomalacia (PVL), bronchopulmonary dysplasia (BPD), time to full enteral feeds, and the Bayley II MDI developmental score. Results: Fifty-nine studies were included. For mortality, NEC, and time to reach full enteral feeds, the top-ranked treatment class was the mother's own milk with donor milk and a human-milk-based fortifier. For ROP and BPD, the top-ranked treatment class was mother's own milk with a phosphorus fortifier. For sepsis, the top-ranked treatment class was mother's own milk with formula. For PVL, the top-ranked treatment classes were mother's own milk and mother's own milk with donor milk and a bovine fortifier in the two disconnected networks. For the Bayley II MDI score, the top-ranked treatment class was mother's own milk with formula and bovine fortification. Conclusions: Treatment rankings are consistent with the underlying hypothesis that increased mother's own milk intake appears to be associated with better clinical outcomes. This review provides the first global view of interventions and highlights insufficient high-quality evidence to support or refute one fortification feeding regimen over another.