Early Phosphate-to-Amino Acid Provision and Refeeding Syndrome in Extremely Low Birth Weight Infants: A Systematic Review

Early high-amino acid parenteral nutrition is standard care for extremely low birth weight (ELBW) infants, but it has been linked to a neonatal form of refeeding syndrome (RFS) characterized by hypophosphatemia, often with hypercalcemia.This review aimed to synthesize recent evidence on the relationship between early phosphate and amino acid provision and RFS, hypophosphatemia, and related clinical outcomes in ELBW and extremely preterm infants.This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines.PubMed, Scopus, CINAHL, and Embase were searched for original peer-reviewed studies first published online from 1 January 2021 to 19 September 2026, a window chosen to reflect parenteral nutrition practice after the 2018 European guidance on early phosphate provision.Eligible studies enrolled infants with a birth weight below 1000 g or a gestational age below 29 weeks, quantified early amino acid and/or phosphate provision, and reported RFS or hypophosphatemia.Risk of bias was assessed with the revised Cochrane risk-of-bias tool (RoB 2) and the Newcastle-Ottawa Scale, and findings were synthesized narratively.Of 734 records, 425 were screened after duplicate removal, 72 full texts were assessed, and five studies comprising 782 unique infants (after accounting for overlapping trial participants) were included: one multicenter randomized controlled trial, a secondary two-year cohort analysis of that trial, two cohort studies, and one case-control study.Additional parenteral amino acids (1 g/day for five days) increased RFS from 15.7% to 24.4% (adjusted relative risk 1.64; 95% CI 1.09-2.47).In a before-after study in which phosphate, other electrolytes, and routine monitoring were introduced together from birth, RFS decreased from 11.9% to 2.9%, hypophosphatemia from 53.5% to 21.2%, and severe hypophosphatemia from 11.3% to 1.2%, despite a higher protein intake.First-week RFS and hypophosphatemia were associated with death or neurodisability at two years (adjusted odds ratios 1.96 and 1.74, respectively), and RFS severity was associated with postnatal growth failure and bronchopulmonary dysplasia.The randomized trial raised some concerns for bias, and three of four observational studies were at low risk of bias.No included study evaluated a phosphate-to-amino acid ratio directly.The evidence is consistent with the hypothesis that RFS risk in ELBW infants reflects the balance between phosphate and amino acid supply rather than amino acid dose alone, and it supports existing guideline recommendations to provide phosphate from birth alongside amino acids, with first-week biochemical monitoring.Randomized trials of defined phosphate-to-amino acid ratios are needed.