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

Hanna K von Siebenthal; Sara Gessler; Florence Vallelian; Joachim Steinwendner; Urs-Martin Kuenzi; Diego Moretti; Michael B Zimmermann; Nicole U Stoffel

doi:10.1016/j.eclinm.2023.102286

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

EClinicalMedicine. 2023 Nov 3:65:102286. doi: 10.1016/j.eclinm.2023.102286. eCollection 2023 Nov.

Authors

Hanna K von Siebenthal¹, Sara Gessler¹, Florence Vallelian², Joachim Steinwendner³, Urs-Martin Kuenzi³, Diego Moretti⁴, Michael B Zimmermann^{1

5}, Nicole U Stoffel^{1

5}

Affiliations

¹ Laboratory of Human Nutrition, Department of Health Sciences and Technology, ETH Zurich, Switzerland.
² Division of Internal Medicine, University Hospital and University of Zurich, Zurich, Switzerland.
³ Laboratory of Web Science, Swiss Distance University of Applied Sciences, Zürich, Switzerland.
⁴ Nutrition Research, Department of Health, Swiss Distance University of Applied Sciences, Zürich, Switzerland.
⁵ Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.

Abstract

Background: 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.

Methods: In a double-masked, randomized, placebo-controlled trial, young Swiss women (n = 150; serum ferritin ≤30 μg/L) were assigned to: daily 100 mg iron for 90 d, followed by daily placebo for another 90 d (consecutive-day group) or the same daily dose of iron and placebo on alternate days for 180 d (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).

Findings: 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 43.8 μg/L (31.7-58.2) versus 44.8 μg/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 3.0 nM (IQR 2.0-5.0) versus 1.9 nM (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).

Interpretation: 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.

Funding: Swiss National Science Foundation, Bern, Switzerland.

Keywords: Alternate day; Daily; Deficiency; Gastrointestinal side effects; Hepcidin; Iron; Supplementation.

Associated data

ClinicalTrials.gov/NCT05105438