Higher versus lower protein intake in formula-fed low birth weight infants.

Systematic review of randomized trials in hospitalized formula-fed preterm or low birth weight infants, including appropriate-for-gestational-age and small-for-gestational-age infants, during the initial neonatal hospital stay. Infants were not receiving parenteral nutrition and formula was not supplemented with human milk.

Higher-protein formula feeding in formula-fed preterm or low birth weight infants during the initial hospital stay, compared with lower-protein formula. Across trials, protein intakes ranged from about 3.0 to 4.0 g/kg/d for higher-protein arms, with lower-protein comparators around 2.2 to 2.8 g/kg/d; very high-protein regimens reached 4.26 g/kg/d and 6 to 7.2 g/kg/d in some studies. Several trials used isocaloric formulas so that protein content was the main variable.

Higher protein intake probably improved early growth, especially weight gain, but the certainty of evidence was low to very low. Pooled results favored higher protein for weight gain by 2.36 g/kg/d, 95% CI 1.31 to 3.40, and for nitrogen accretion by 143.73 mg/kg/d, 95% CI 128.70 to 158.77. There was probably little to no difference in linear growth (MD 0.16 cm/week, 95% CI -0.02 to 0.34), and head growth was uncertain despite one pooled estimate favoring higher protein (MD 0.37 cm/week, 95% CI 0.16 to 0.58). Necrotizing enterocolitis was not clearly increased (RD 0.00, 95% CI -0.12 to 0.12), and sepsis or diarrhea did not show clear increases, but adverse event data were limited. Very high protein intake may increase weight gain further, but evidence is imprecise and intakes above 4 g/kg/d should be considered experimental.

Overall certainty was low to very low because of risk of bias, heterogeneity, and small numbers of studies and infants for several outcomes. Neurodevelopmental outcomes were poorly measured, and safety outcomes such as necrotizing enterocolitis, sepsis, diarrhea, blood urea nitrogen, and metabolic acidosis were limited and imprecise. Findings may not generalize beyond the studied hospitalized formula-fed preterm or low birth weight population, and the optimal protein dose remains uncertain.