Early versus Delayed Fortification of Human Milk in Preterm Neonates: A Randomised Controlled Trial

Background Preterm very low birth weight infants are at high risk of postnatal growth failure due to limited nutrient reserves and high metabolic demands. Human milk fortification is essential to optimize growth, but the timing of initiation remains controversial, with concerns regarding feeding tolerance and metabolic complications. Objectives To compare the effects of early versus delayed initiation of human milk fortification on feeding tolerance, growth outcomes, and neonatal morbidities in preterm infants. Methods This randomised controlled Trial enrolled 66 preterm neonates ≤34 weeks of gestation, who were grouped between an Early Fortification Group (n = 32), in which fortification was initiated once enteral feeds reached 60 ml/kg/day and baby tolerated for next two feeds, and a Late Fortification Group (n = 34), in which fortification was initiated at enteral feeds of 100 ml/kg/day and tolerated for next two feeds . Baseline maternal and neonatal characteristics were recorded. The primary outcome was the time to achieve full enteral feeds. Secondary outcomes included feeding intolerance, time to regain birth weight, growth velocity, duration of intravenous fluids, hospital stay, gestational age at discharge, incidence of extrauterine growth restriction, and other neonatal morbidities. Results The two groups were comparable at baseline. The mean time to reach full enteral feeds was 10.06 ± 2.14 days in the Early Fortification Group and 11.00 ± 3.62 days in the Late Fortification Group, with no statistically significant difference (p = 0.215). Feeding intolerance occurred in 21.9% of the early group and 32.4% of the late group (p = 0.339). Birth weight was regained earlier in the early group (12.21 ± 6.14 days) compared with the late group (15.23 ± 6.87 days), showing a trend towards significance (p = 0.065). Growth velocity in terms of weight, length, and head circumference was similar in both groups. The mean duration of hospital stay was 36.37 ± 18.08 days in the early group and 38.82 ± 14.73 days in the late group (p = 0.548). The mean gestational age at discharge was significantly higher in the early fortification group (37.09 ± 1.89 weeks vs. 36.13 ± 1.65 weeks, p = 0.031). Extrauterine growth restriction was observed in 24.2% of the overall cohort, with no significant difference between groups (21.9% vs. 26.5%, p = 0.663). No cases of necrotizing enterocolitis ≥ Stage 2b or retinopathy of prematurity requiring treatment were seen. Osteopenia of prematurity occurred in 34.4% of the early group and 35.3% of the late group (p = 0.938). The incidence of sepsis, patent ductus arteriosus, periventricular leukomalacia, and intraventricular hemorrhage was similar in both groups. Conclusion Early initiation of human milk fortification was safe, well tolerated, and not associated with increased feeding intolerance or gastrointestinal morbidity. Although most growth outcomes were comparable, early fortification demonstrated a favorable trend toward earlier regaining of birth weight and was associated with a significantly higher gestational age at discharge. These findings suggest that early fortification may be beneficial in moderately preterm infants without compromising safety.