Fortified Human Milk Compared with Unfortified Human Milk in Preterm Low Birth Weight Neonates: A Systematic Review and Meta-Analysis

Background/Objectives: Our aim was to assess the benefits and risks of fortified vs. unfortified human milk in preterm/low birth weight neonates and to incorporate the INSPECT-SR tool to enhance evidence appraisal. Methods: PubMed and Scopus were searched from inception to 30 November 2025, limited to human studies published in English. Randomized controlled trials in neonates ≤ 34 weeks’ gestation or ≤2500 g birth weight were included. Data extraction followed PRISMA guidelines. Risk of bias was assessed using Cochrane RoB 2, and trustworthiness using the INSPECT-SR tool. Random-effects models were used to pool mean differences (MDs) and odds ratios (ORs); heterogeneity was assessed with I2. Outcomes included weight, length, and head circumference gain velocities, feeding intolerance, necrotizing enterocolitis, late-onset sepsis, chronic lung disease, time to full enteral feeding, length of stay, and mortality. Results: Fifteen randomized controlled trials involving 1079 neonates (546 receiving fortified human milk and 533 receiving unfortified human milk) were included in the analysis. Fortified human milk was associated with significantly greater weight gain (MD 2.74 [1.27–4.22] g/kg/d; I2 = 95%), length gain (MD 0.08 [0.02–0.14] cm/week; I2 = 90%), and head circumference gain (MD 0.06 [0.03–0.10] cm/week; I2 = 87%). No significant differences were observed in feeding intolerance, necrotizing enterocolitis, late-onset sepsis, chronic lung disease, time to full enteral feeding, length of stay, or mortality. Subgroup analyses suggested that the publication era partially contributed to heterogeneity, although substantial residual heterogeneity remained. According to INSPECT-SR, two trials were judged as having no concerns, twelve as having some concerns, and one as having serious concerns regarding trustworthiness. Conclusions: Low-certainty evidence suggests that human milk fortification improves short-term anthropometric growth parameters in preterm and low birth weight infants without increasing major neonatal morbidities. However, the certainty of these findings is limited by substantial heterogeneity and concerns regarding study trustworthiness. Future adequately powered trials using contemporary fortification strategies and long-term follow-up are required to establish the clinical significance of these growth benefits.