Heme iron compared with ferrous iron salts to treat iron deficiency anemia in Gambian children: a randomized controlled trial

Background: Supplementation with conventional ferrous salts has limited efficacy in controlling anemia and improving iron status in children at high risk of inflammation. We assessed whether heme iron polypeptide (HIP), an alternative form of supplemental iron with a distinct absorption pathway, might improve outcomes. Objectives: We compared hemoglobin and ferritin concentrations in anemic Gambian infants aged 6–12 mo after supervised daily oral supplementation with HIP or ferrous sulfate. Methods: Between March 2023 and February 2024, 208 anemic infants, aged 6–12 mo (hemoglobin, 7.0 to <11.0 g/dL) were randomly assigned to 84 d of directly observed daily supplementation with 10 mg elemental iron as HIP or ferrous sulfate. Primary outcomes were hemoglobin and ferritin concentrations at end of intervention. Analysis was by intention-to-treat with multiple imputations to replace missing data. Results: Adherence to treatments was ∼90%. The primary end points of hemoglobin and ferritin concentrations both improved by day 84 with no difference between treatments. For the secondary end point of anemia, the prevalence went from 83.7% to 46.2% in the ferrous sulfate group and from 84.6% to 47.1% in the HIP group. Infants who received HIP had higher serum iron concentration (by 48.4%; 95% CI: 15.4%, 91.0%), higher transferrin saturation (by 52.3%; 95% CI: 17.9%, 96.7%), lower soluble transferrin receptor concentrations (by −9.7%; 95% CI: −16.3%, −2.6%) and lower unsaturated iron-binding capacity (by −7.8%; 95% CI: −13.4%, −1.7%). In a post hoc analysis, HIP had a greater effect on inflammation-adjusted serum ferritin concentrations (by 22.9%; 95% CI: 5.6%, 43.1%). No group differences were found in the frequency of adverse events. Conclusions: There is no benefit of HIP on the primary end points of hemoglobin and ferritin. However, HIP is superior to ferrous sulfate for 5 secondary measures of iron status and might therefore improve iron supply to rapidly developing organs. This trial is registered with the Pan African Clinical Trial Registry as PACTR202210523178727 (https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=23910).