A Multicenter Randomized Clinical Trial Comparing Two Human Milk Volumes to Optimize Growth and Gut Health in Infants Born Very Preterm

The nutritional management of very preterm infants (27 to 31 weeks of gestation) is critical due to their increased risk of faltering growth and adverse metabolic outcomes. Current recommendations for human milk intake range widely from 140 to 200 ml/kg/day. This variability reflects a lack of consensus on the optimal volume to support growth while minimizing risks like obesity. Unlike preterm formula, human milk is believed to protect against metabolic diseases due to its unique nutritive and non-nutritive components. Previous randomized clinical trials have not examined the effects of two enteral fluids intakes on very preterm infants fed human milk exclusively. This project aims to address this knowledge gap by exploring how different volumes of human milk affect fat-free mass (FFM) and body fat accumulation, essential for the development of very preterm infants. The primary objectives of this multicenter, unmasked, randomized clinical trial are 1) to assess growth and metabolic outcomes at term-age equivalent of very preterm infants receiving higher volumes of human milk, and 2) to characterize the gut microbiome assembly patterns in response to these human milk volumes. Our central hypothesis is that providing human milk volumes of 180 to 200 ml/kg/day during the first weeks after birth will improve FFM accretion and reduce the risk of adverse metabolic outcomes at term-age equivalent in very preterm infants. To test this hypothesis, we will randomize 486 very preterm infants into two groups: one receiving 180 to 200 ml/kg/day and the other 140 to 160 ml/kg/day. We will measure daily human milk volumes and weekly macronutrient content of human milk diets. We will assess FFM accretion at study entry, study day 14, study completion, and term-age equivalent or discharge. We will also examine how human milk volumes influence the gut microbiome through shotgun metagenome sequencing of serial fecal samples collected during the trial and establish a correlation between specific gut microbiome compositions and untargeted serum metabolomics. This trial aims to generate high-quality clinical and translational data on the interactions between early life diets, the gut microbiome, and growth in very preterm infants. It aligns with the 2020-2030 NIH Nutrition Research Strategic Plan by determining the health benefits of exclusive dietary patterns, investigating host- microbiome interactions, and reducing the burden of disease in clinical settings. If successful, this patient- oriented, comparative-effectiveness trial will provide critical insights into optimal nutrition strategies for very preterm infants, potentially transforming clinical practices worldwide and enhancing the development and long- term health of this vulnerable population. Project Number: 1R01HD117932-01 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Ariel Salas | Institution: UNIVERSITY OF ALABAMA AT BIRMINGHAM, BIRMINGHAM, AL | Award Amount: $467,474 | Activity Code: R01 | Study Section: Nutrition and Metabolism in Health and Disease Study Section[NMHD] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HD11793201