Standardised versus individualised fortification of expressed breastmilk for preterm outcomes: a systematic review and meta-analysis

INTRODUCTION: Although the precise nutrient requirements of preterm infants remain uncertain, routine human milk fortification is standard practice despite limited evidence of long-term benefit. Whether current fortification strategies optimally balance benefits, risks, and resource use remains unclear. This review evaluates whether individualised fortification improves preterm infant outcomes. METHODS: Randomised controlled trials comparing individualised with standardised fortification were included, evaluating outcomes including mortality, neurodevelopment, growth, and neonatal morbidities. Four databases and three trial registries were searched. Screening, data extraction and quality assessment were conducted independently by two reviewers using Cochrane Risk of Bias-1 tool. Certainty of evidence was assessed using GRADE. RESULTS: Twelve studies including 575 participants were included. Evidence is very uncertain about the effect of individualised fortification on mortality [181 infants, relative risk (RR) 0.20, 95% confidence interval (CI) (0.02, 1.66), p=0.14, I²=0%] and necrotising enterocolitis [193 infants, RR 0.29 (0.05,1.72), p=0.17, I²=0%], both very low certainty. Effect on neurodevelopment at 18-months remains very uncertain. Individualised fortification likely increases head circumference [224 infants, mean difference (MD) 1.76 (0.76, 2.76) mm/week, p=0.0005, I²=52%], weight gain [454 infants, MD 2.87 (1.36, 4.39) g/kg/day, p<0.0002, I²=79%], length gain [261 infants, MD 3.20 (1.22, 5.18) mm/week, p=0.002, I²=81%] and fat-free mass [106 infants, MD 121.4 (25.6, 217.2) g, p=0.01, I²=0], all with moderate-certainty. It may increase fat mass [106 infants, MD 68.9 (6.1, 131.8) g, p=0.03, I²=63%] with low-certainty. CONCLUSION: Individualised fortification likely increases growth in preterm infants; however, whether this is beneficial to clinical and long-term functional health is uncertain. Further high-quality trials with long-term follow-up are needed.