Systematic review and meta-analysis of enteral protein intake effects on growth in preterm infants

Abstract

Background: The optimal enteral protein intake for adequate growth in preterm infants remains unclear. This systematic review evaluates the impact of protein intake from fortified human milk on growth in very preterm infants. Methods: Randomized clinical trials from January 2005 to August 2024 were included. Eligible studies measured true enteral protein intake in preterm infants. Searches were conducted in PubMed, Embase, and Cochrane CENTRAL. Risk of bias was evaluated using the revised Cochrane Risk of Bias Tool. Results: Ten randomized clinical trials (n = 646) were included. Meta-regression revealed a significant linear relationship between protein intake and weight gain (5.73 g/kg/day weight gain for each gram of protein/kg/day, p = 0.001), but not with head circumference or length gain. After adjustment for energy intake, significant relationships were found between protein intake and both weight gain and length growth. In contrast, the forest plot meta-analysis comparing high versus low protein intake showed no significant differences in weight or head circumference gain. However, infants receiving higher protein intake had greater weight at discharge (SMD 0.35, 95% CI 0.12 to 0.57, n = 312, 4 studies, high certainty) and more length growth (SMD 0.5, 95% CI 0.08 to 0.92, n = 174, 3 studies, moderate certainty). Discussion and Conclusion: Moderate to high-certainty evidence suggests that increased enteral protein intake improves growth outcomes in very preterm infants. REGISTRATION: PROSPERO CRD42022287991. Impact: This systematic review is the first to evaluate the impact of enteral protein intake on growth in preterm infants <32 weeks, using studies that measured actual intake. A positive correlation was found between protein intake and weight gain. Meta-regression suggests most premature infants may require 4.0–4.5 g/kg/day to achieve in utero growth rates, rather than 3.5–4.0 g/kg/day. The meta-analysis indicates a positive relationship between protein intake, growth in length, and discharge weight. These findings underscore the critical role of adequate protein intake in growth outcomes and highlight the need to maintain appropriate energy: protein ratios.