Enteral iron dose effect on iron storage, intestinal barrier, and gut microbiome in preterm infants: a randomized clinical trial.

backgroundPreterm infants routinely receive enteral iron supplementation to support growth, replace phlebotomy losses, and prevent iron deficiency. However, concerns regarding potential harms, including those on the gut microbiome, have contributed to recommendations for lower dosing.

objectivesThis study aimed to compare the effects of 2 enteral iron doses on gut health in very-low-birth-weight preterm infants. We hypothesized that higher iron dose would increase abundances of pathogenic bacteria, intestinal inflammation, and barrier dysfunction.

methodsThis randomized, double-blind clinical trial assigned preterm infants born <1500 g to receive either the recommended dose, 2 mg/kg/d, or a higher dose of 6 mg/kg/d of total enteral iron. The primary outcome was the fecal microbiome after 2 wk on iron, assessed by metagenomic sequencing. Secondary outcomes included biomarkers of intestinal inflammation and barrier function (fecal calprotectin, urinary claudin-3, and urinary intestinal fatty acid-binding protein). Iron status, adverse events, and auditory brainstem response latencies at 36 wk postmenstrual age were also evaluated.

resultsAmong 151 randomly assigned infants who received study iron (77 low dose; 74 high dose), bacterial diversity, individual taxa, virulence potential, bacterial overgrowth, and iron-related functional genes were not significantly different between the treatment groups. In the subgroup analysis of singletons, treatment groups demonstrated significant differences in temporal shifts in overall bacterial community structure. Infants receiving 2 mg/kg/d had higher posttreatment urinary claudin-3 concentrations, indicating possible differences in intestinal permeability, and a higher prevalence of iron deficiency than those receiving 6 mg/kg/d. Other biomarkers, clinical outcomes, adverse events, and auditory latencies did not differ between groups.

conclusionsEnteral iron supplementation at 6 mg/kg/d is associated with improved iron status and lower intestinal barrier dysfunction, without evidence of harms on gut microbiome compared with the recommended 2 mg/kg/d dose. These findings do not support concerns regarding gut microbiome disruption as a justification for lower iron dosing in preterm infants. This trial was registered at clinicaltrials.gov as NCT04497012.