Is Iron Supplementation Harmful in Populations Where Iron Deficiency Is Not the Cause of Anemia? Protocol for a 12 Week RCT in Cambodia

In 2016, the World Health Organization set a global policy recommending daily iron supplementation (60 mg elemental iron) for women living in countries with anemia prevalence >40%, such as in Cambodia (45%). However, recent studies have shown the prevalence of iron deficiency (ferritin < 15 μg/L) to be low in Cambodian women (∼3%). Further, iron supplementation may be harmful in women with genetic hemoglobin disorders, which are common in Cambodia (60%), as they are already at an increased risk of iron overload. Iron salts (e.g., ferrous sulfate) are the most common form of iron supplement but have poor bioavailability. Less than 20% of the iron is absorbed in the gut, and the remaining 80% passes unabsorbed into the colon, potentially increasing the risk of pathogen growth and gut inflammation. Alternatively, ferrous bisglycinate is a newer form of iron supplement that has 2–4x higher bioavailability than ferrous sulfate. Our objectives are to assess in women of childbearing age in Cambodia: i) the non-inferiority of 18 mg iron as ferrous bisglycinate as compared to 60 mg iron as ferrous sulfate on mean ferritin concentrations; and ii) if ferrous sulfate administration is associated with increased intestinal inflammation and enteropathogen abundance, as compared to placebo or ferrous bisglycinate. We will undertake a double-blind three-arm RCT in Kampong Thom province, Cambodia. We will recruit and randomize 480 non-pregnant women (18–45 years) to receive 60 mg ferrous sulfate, 18 mg ferrous bisglycinate, or placebo, for 12 weeks. We will collect blood and stool samples at baseline and 12 weeks, which will be used to measure hemoglobin and ferritin concentrations for iron status, fecal calprotectin, a marker of gut inflammation, and perform multiplex molecular enteropathogen testing. N/A The findings of this trial will contribute to the evidence for safe and effective iron supplementation for women worldwide. Canadian Institutes of Health Research.