Individualized versus standard diet fortification for growth and development in preterm infants receiving human milk.

Systematic review and meta-analysis of 7 randomized controlled trials, reported across 8 publications, in preterm infants receiving human milk in neonatal intensive care units. The population included infants born before 37 weeks' gestation or with birth weight under 2500 g, including very low birth weight infants, and compared individualized fortification strategies with standard fortification.

Individualized human milk fortification was delivered as either targeted fortification, using milk macronutrient analysis to add fortifier, protein, or cream to meet nutrient targets, or adjustable fortification, using biochemical response such as blood urea nitrogen to titrate fortification. These regimens were compared with standard nonindividualized fortification of human milk feeds in preterm infants, and were generally maintained for 2 to 4 weeks or until 35 to 36 weeks' postmenstrual age or discharge targets were reached.

Individualized fortification probably improves in-hospital growth during the intervention period, with benefits seen for weight, length, and head circumference versus standard fortification. Pooled weight gain increased by 1.88 g/kg/d for individualized fortification versus standard (6 studies, 345 participants), and targeted and adjustable strategies also improved weight gain separately: 1.87 g/kg/d for targeted versus standard (4 studies, 269 participants) and 2.86 g/kg/d for adjustable versus standard (3 studies, 96 participants). Head circumference growth also improved with adjustable fortification versus standard, with an MD of 0.36 mm/d (3 studies, 96 participants), while targeted versus adjustable favored targeted for weight gain by 2.49 g/kg/d (2 studies, 72 participants). Clinical safety outcomes remained uncertain: effects on mortality, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, and retinopathy of prematurity were imprecise and based on sparse, very low certainty evidence.

Evidence is based on a small number of heterogeneous trials with short intervention periods and substantial statistical heterogeneity for growth outcomes. Important clinical and safety outcomes were sparse and of very low certainty, with limited power to detect harms or longer-term benefits. Optimal fortification method and whether targeted or adjustable fortification is superior remain unclear.