In 2016, the World Health Organization (WHO) set a global policy recommending daily oral iron supplementation (60 mg iron) for 12 weeks for all women living in countries where anemia prevalence is >40%, such as in Cambodia. However, recent studies have shown the prevalence of iron deficiency to be low in Cambodian women and that supplementation would likely only benefit ~10% of women.

Iron supplementation may be harmful in women with genetic blood disorders (e.g. thalassemia), which are common in Cambodia, as these individuals are already at an increased risk of iron overload. The risks are made greater by the fact that iron absorption from most common form of supplementation, ferrous sulfate, is low. Typically less than 20% is absorbed in the gut; the remaining 80% passes unabsorbed into the colon where it can increase the risk of pathogen growth and gut inflammation. Alternatively, ferrous bisglycinate is a newer supplemental form of iron. This amino acid chelate has 2-4x higher bioavailability than ferrous sulfate and is associated with fewer GI side-effects.

In view of WHO policy and risks of supplementation, there is a need to determine the potential for harm, and if novel forms of iron supplements are safer.

The World Health Organization (WHO) set a Global Nutrition Target to reduce anemia in women of reproductive age by 50% by 2025. In 2016, the WHO implemented a global policy recommending oral iron supplementation (60 mg daily for 12 weeks) for all women where anemia prevalence is more than 40%, such as in Cambodia.

However, recent studies have shown the prevalence of iron deficiency to be low in Cambodian women. If iron deficiency is not the cause of anemia, then iron supplementation will not be effective at treating it. Further, iron supplementation may be harmful in some individuals, especially those with anemia caused by genetic blood disorders (which are common in Cambodia), as these individuals are already at an increased risk of iron overload. The risks are made greater by the fact that the type of iron that is commonly used in supplements (ferrous sulfate) is poorly absorbed. Typically, less than 20% is absorbed in the gut; the remaining 80% is unabsorbed in the colon where it can increase the risk of pathogen growth and gut inflammation.

To investigate the safety of untargeted iron supplementation, we will undertake a new study in Cambodia, where we will evaluate a newer type of iron supplement that may be absorbed better, and thus, safer than the conventional type. We will recruit non-pregnant women (18-45 years) and ask them to take one of the two forms of iron (ferrous sulfate or ferrous bisglycinate) or a placebo for 12 weeks (in line with the WHO global policy). We will measure hemoglobin and ferritin levels, which are markers of anemia and iron status, and markers of gut inflammation and gut pathogen abundance, before and after the intervention. This study will contribute to the evidence for safe and effective iron supplementation for women worldwide.

Inclusion Criteria:

• apparently healthy
• consent to participate in the study and provide blood, flocked rectal swab and stool samples
• expected to reside in the study location for the study period.

Exclusion Criteria:

• any known illness or disease
• pregnant
• taking antibiotics, non-steroidal anti-inflammatory drugs, dietary supplements, or vitamin and mineral supplements in the previous 12 weeks.

There is not a plan to make IPD available.

The manufacturers of the tablets (Dr. Simon Wood, Natural Factors) will be responsible for allocation concealment of the three tablet formulations at time of packaging. All tablets will be non-distinguishable in size, colour, and packaging. Trial investigators, research staff, and participants will all be blinded to the assigned interventions