Background: Premature infants benefit from human milk fortifiers for optimal growth, nutrition, neural development and reducing complications. However, the ideal timing for HMF introduction is still debated due to preterm infant’s immature digestive system and inconclusive study results, often marred by methodological flaws.

Objectives: To compare the effects of early human milk fortification (EHMF) vs late human milk fortification (LHMF) on low birth-weight (LBW) preterm neonates.

Methods: A systematic search for Randomized controlled trials comparing EHMF vs LHMF on LBW preterm neonates was conducted, covering databases such as Cochrane CENTRAL, Pubmed, Google Scholar and clinical trials registries iCRTP, ISRCTN and HERDIN from January 2000 to July 2024. Statistical analysis was performed using Review Manager version 5.3, with mean differences for continuous outcomes and risk ratio (RR) for dichotomous outcomes. A sensitivity analysis using the leave-one-out method and meta-regression was conducted to address potential confounding factors and publication biases were assessed through funnel plots.

Results:The EHMF group showed potential benefits in reducing the incidence of retinopathy of prematurity (ROP) and neonatal sepsis, achieving a faster time to regain birth weight. However, there may be an increased risk of bronchopulmonary dysplasia and the effects of necrotizing enterocolitis and feeding intolerance (FI) may be unclear. Interestingly, given the high precision of pooled effects on growth, hospital outcomes (length and time to reach full feeds) and adverse effects (extra-uterine growth restriction) no significant difference between groups were noted.

Conclusions:The study suggests that EHMF could impact growth parameters and reduced adverse outcomes, although most effects were not significant. The wide confidence intervals around some effect sizes suggest a need for more robust studies to resolve these uncertainties.