BACKGROUND: Hepcidin can determine individuals' responses to iron supplementation, but limited evidence exists from pediatric trials. OBJECTIVE: We aimed to examine the influence of hepcidin on the effects of supplementation with iron syrup and multiple micronutrient powders (MNPs) on hemoglobin and ferritin concentrations and incidence of diarrhea in young children. METHODS: Participants included a subsample of 1281 8-month-old children enrolled in a three-arm, double-blind, double-dummy, individually randomized controlled trial examining the efficacy of 3 months of universal supplementation with daily iron syrup (12.5mg iron), MNPs (containing 12.5mg iron), or placebo in children living in Bangladesh. In all participants at baseline, immediately post-intervention (month 3), and after a further 9 months of follow-up (month 12), serum hepcidin concentrations were measured by ELISA, venous hemoglobin by HemoCue® 301, and incidence of diarrhea by caregiver report. We used a likelihood-based longitudinal data analysis model to examine effect modification from baseline hepcidin on effects of iron syrup or MNPs on hemoglobin and ferritin concentrations and log-binomial model on incidence of diarrhea at months 3 and 12. RESULTS: Hepcidin modified the effect of MNPs, but not iron syrup, compared to placebo on hemoglobin and ferritin concentrations immediately post intervention. The treatment effect of MNPs compared to placebo in the change from baseline to month 3 was larger among children with low compared to not-low baseline hepcidin (hemoglobin: mean difference 11.6g/L (7.2, 15.9) compared to 4.3 (3.09, 5.7), p-interaction=0.002
ferritin: geometric mean ratio 2.4 (1.6, 3.6) compared to 1.5 (1.3, 1.7), p-interaction=0.024). This effect modification was not sustained at month 12. Hepcidin did not modify effects of either intervention on incidence of diarrhea. CONCLUSIONS: Immediate effects of MNPs on child hemoglobin and iron status are larger among those with low compared to not-low hepcidin, indicating that pre-intervention screening could help identify those who would benefit most from MNPs. TRIAL REGISTRATION: ACTRN12617000660381.