Early versus late fortification of breast milk in preterm infants: a systematic review and meta-analysis.

This systematic review and meta-analysis assessed the effects of early fortification (EF) versus late fortification (LF) of breast milk (BM) on growth of preterm infants. Randomized and quasi-randomized controlled trials (RCTs) dealing with the effects of EF versus LF on growth parameters, incidence of adverse events, and duration of hospital stay in preterm infants were included. Data were pooled using the RevMan 5.3 software. Quality of evidence for predefined outcomes was analyzed by GRADE. Available evidence (3 RCTs, 309 preterm infants) showed no statistically significant difference between EF and LF of BM for any of the growth parameters-weight (standardized mean difference (SMD) 0.13; 95% confidence interval (CI) - 0.09, 0.36); length (SMD 0.02; 95% CI - 0.20, 0.25); and head circumference (SMD - 0.10; 95% CI - 0.33, 0.12). Total parenteral nutrition days were similar. Duration of hospital stay was significantly higher with EF (MD 4.29; 95% CI 0.84, 7.75) with a trend of non-significant increase in feed intolerance and necrotizing enterocolitis (NEC).Conclusion: Very low quality evidence did not find any significant difference in growth parameters of preterm infants in association with EF or LF of BM. A significant increase in hospital stay and non-significant increase in feed intolerance and NEC were associated with EF.PROSPERO registration number: CRD42019139235What is Known:• Fortification of breast milk with essential macro- and micronutrients is necessary for optimization of nutrition in preterm infants.• There is no consensus regarding the breast milk feeding volume at which fortification should be initiated.What is New:• Very low quality evidence showed no significant difference between early and late fortification of breast milk on growth parameters of preterm infants.• Early fortification was associated with non-significant increase in feed intolerance and necrotizing enterocolitis and a significant increase in hospital stay.