Abstract
Background: Necrotizing enterocolitis (NEC) remains a leading cause of morbidity and mortality in very low birthweight (VLBW) infants. Human milk feeding and standardized feeding protocols are protective, but clinical practice varies, particularly in fortifier choice. Whether human milk-derived fortifiers reduce NEC risk compared with cow milk-derived fortifiers remains unclear. Methods: We conducted a systematic state-of-evidence review and meta-analysis, searching PubMed, Web of Science, and Scopus through July 2025. Eligible studies included RCTs and observational cohorts of VLBW infants comparing an exclusive human milk diet (EHMD) including human milk-derived fortifiers to cow milk-derived diets. Two reviewers independently screened and extracted data. Both RCTs and observational studies were included to evaluate consistency of effect estimates across designs and to account for heterogeneity in control group feeding practices. Pooled odds ratios (ORs) with 95% CIs were calculated using a Sidik–Jonkman random-effects model. Sensitivity analyses by study design and exclusion of infant formula from controls were performed. Results: Twenty studies (five RCTs, 15 observational; N = 6794 infants) met inclusion criteria, most enrolling infants born ≤1250 g. Compared with cow milk-containing diets, EHMD was associated with lower odds of Bell Stage ≥ 2 NEC (OR: 0.59; 95% CI: 0.42, 0.81; p < 0.001; n = 4625) and surgical NEC (OR: 0.43; 95% CI: 0.32, 0.58; p < 0.0001; n = 4754). In direct comparisons of fortifier type with a base diet of human milk, estimates suggested lower odds of Bell Stage ≥ 2 NEC by 35% (OR: 0.65; 95% CI: 0.44, 0.97; p = 0.03, n = 2102) and surgical NEC by 49% (OR: 0.51; 95% CI: 0.26, 0.98; p = 0.04; n = 1659) with human milk-derived fortifiers. Effect estimates were generally consistent across study designs, although precision and statistical significance varied. Conclusions: EHMD with human milk-derived fortifiers was associated with lower odds of medical and surgical NEC in VLBW infants, with most evidence from infants born ≤1250 g, reflecting current clinical use in the highest-risk population. Although the number and sample sizes of RCTs remain limited, the consistency of effect estimates across both RCTs and observational studies, together with significance of pooled analyses, strengthens confidence in these findings. Pragmatic and registry-based studies using standardized fortification protocols may provide the most efficient pathway to strengthen the evidence base.