Enteral Iron Supplementation in Infants Born Extremely Preterm and its Positive Correlation with Neurodevelopment; Post Hoc Analysis of the Preterm Erythropoietin Neuroprotection Trial Randomized Controlled Trial

Abstract

To test whether an increased iron dose is associated with improved neurodevelopment as assessed by the Bayley Scales of Infant Development, third edition (BSID-III) among infants enrolled in the Preterm Erythropoietin (Epo) Neuroprotection Trial (PENUT). This is a post hoc analysis of a randomized trial that enrolled infants born at 24-28 completed weeks of gestation. All infants in PENUT who were assessed with BSID-III at 2years were included in this study. The associations between enteral iron dose at 60 and 90days and BSID-III component scores were evaluated using generalized estimating equations models adjusted for potential confounders. In total, 692 infants were analyzed (355 placebo, 337 Epo). Enteral iron supplementation ranged from 0 to 14.7mg/kg/d (IQR 2.1-5.8mg/kg/d) at day 60, with a mean of 3.6mg/kg/d in infants treated with placebo and 4.8mg/kg/d in infants treated with Epo. A significant positive association was seen between BSID-III cognitive scores and iron dose at 60days, with an effect size of 0.77 BSID points per 50mg/kg increase in cumulative iron dose (P=.03). Greater iron doses were associated with greater motor and language scores but did not reach statistical significance. Results at 90days were not significant. The effect size in the infants treated with Epo compared with placebo was consistently greater. A positive association was seen between iron dose at 60days and cognitive outcomes. Our results suggest that increased iron supplementation in infants born preterm, at the doses administered in the PENUT Trial, may have positive neurodevelopmental effects, particularly in infants treated with Epo. Clinicaltrials.gov: NCT01378273.