Alternate day versus consecutive day oral iron supplementation in iron-depleted women: a randomized double-blind placebo-controlled study

Abstract

Guidelines to treat iron deficiency recommend daily provision of oral iron, but this may decrease fractional iron absorption and increase side effects. Our objective was to compare consecutive-day versus alternate-day iron supplementation. In a double-masked, randomized, placebo-controlled trial, young Swiss women (n=150; serum ferritin ≤30μg/L) were assigned to: daily 100mg iron for 90d, followed by daily placebo for another 90d (consecutive-day group) or the same daily dose of iron and placebo on alternate days for 180d (alternate-day group). The study period was 24/11/2021-10/8/2022. Co-primary outcomes, at equal total iron doses, were serum ferritin and gastrointestinal side effects; secondary outcomes were iron deficiency and serum hepcidin. Compliance and side effects were recorded daily using a mobile application. Data were analysed using mixed models and longitudinal prevalence ratios (LPR). The trial was registered at ClinicalTrials.gov (NCT05105438). 75 women were assigned to each group and included in the intention-to-treat analysis. Capsule adherence and side effect reporting was >97% in both groups. At equal total iron doses, comparing consecutive-day and alternate-day groups, median serum ferritin was 43.8μg/L (31.7-58.2) versus 44.8μg/L (33.8-53.6) (P=0.98), the LPR for gastrointestinal side effects on days of iron intake was 1.56 (95% CI: 1.38, 1.77; P<0.0001), and median serum hepcidin was 3.0nM (IQR 2.0-5.0) versus 1.9nM (1.4-2.9) (P<0.0001). Iron deficiency prevalence after 3 months was 5.5% versus 4.3% (P=0.74) and after 6 months was 11.4% and 3.0% (P=0.049). At equal total iron doses, compared to consecutive day dosing of iron, alternate day dosing did not result in higher serum ferritin but reduced iron deficiency at 6 months and triggered fewer gastrointestinal side effects. Swiss National Science Foundation, Bern, Switzerland.