There is limited evidence regarding the potential risk of untargeted iron supplementation, especially among individuals who are iron-replete or have genetic hemoglobinopathies. Excess iron exposure can increase the production of reactive oxygen species, which can lead to cellular damage. We evaluated the effect of daily oral supplementation on relative leukocyte telomere length (rLTL) and blood mitochondrial DNA (mtDNA) content in non-pregnant Cambodian women (18–45 years) who received 60 mg of elemental iron as ferrous sulfate (n = 190) or a placebo (n = 186) for 12 weeks. Buffy coat rLTL and mtDNA content were quantified by monochrome multiplex quantitative polymerase chain reaction. Generalized linear mixed-effects models were used to predict the absolute and percent change in rLTL and mtDNA content after 12 weeks. Iron supplementation was not associated with an absolute or percent change in rLTL after 12 weeks compared with placebo (ß-coefficient: −0.04 [95% CI: −0.16, 0.08]; p = 0.50 and ß-coefficient: −0.96 [95% CI: −2.69, 0.77]; p = 0.28, respectively). However, iron supplementation was associated with a smaller absolute and percent increase in mtDNA content after 12 weeks compared with placebo (ß-coefficient: −11 [95% CI: −20, −2]; p = 0.02 and ß-coefficient: −11 [95% CI: −20, −1]; p= 0.02, respectively). Thus, daily oral iron supplementation for 12 weeks was associated with altered mitochondrial homeostasis in our study sample. More research is needed to understand the risk of iron exposure and the biological consequences of altered mitochondrial homeostasis in order to inform the safety of the current global supplementation policy.

There is a lack of evidence for the safety of untargeted daily iron supplementation in women, especially in countries such as Cambodia, where both anemia and hemoglobinopathies are common. Our aim was to assess serum non-transferrin bound iron (NTBI), a toxic biochemical that accumulates in blood when too much iron is absorbed, in Cambodian women who received daily iron supplements in accordance with the 2016 global World Health Organization (WHO) guidelines. We used fasting venous blood samples that were collected in a 2015 supplementation trial among predominantly anemic Cambodian women (18–45 years). Serum NTBI was measured with use of the FeROS™ eLPI assay (Aferrix Ltd., Tel-Aviv, Israel) in randomly selected sub-groups of women who received 60 mg daily elemental iron as ferrous sulfate (n = 50) or a placebo (n = 50) for 12 weeks. Overall, n = 17/100 (17%) of women had an elevated serum NTBI concentration (≥0.1 μmol/L) at 12 weeks; n = 9 in the Fe group and n = 8 in the placebo group. Elevated serum NTBI concentration was not associated with age, iron supplementation, transferrin saturation or severe hemoglobinopathies (p > 0.05). In this population of women with a high prevalence of hemoglobinopathies, we found that daily iron supplementation was not associated with elevated serum NTBI concentrations at 12 weeks, as compared to placebo.

Objectives Our aim was to assess serum NTBI concentrations in non-pregnant Cambodian women who received daily iron supplements (60 mg elemental iron as ferrous sulfate) in accordance with the 2016 global World Health Organization (WHO) guidelines. Methods Serum NTBI concentration was measured with the use of the FeROS™ eLPI assay (Afferix Ltd., Israel) in fasting venous blood samples collected during a 2015 supplementation trial among predominantly anemic Cambodian women (18–45 years). Samples were randomly selected from sub-groups of women who received 60 mg daily elemental iron as ferrous sulfate (n = 50) or a placebo (n = 50) for 12-weeks. Results Overall, n = 17/100 (17%) of women had an elevated serum NTBI concentration (≥0.1 μmol/L) at 12-weeks; n = 9 in the Fe group and n = 8 in the placebo group. Of the n = 100 women, a total of 82% of the women were iron-replete (n = 82/100, inflammation-adjusted ferritin >15 µg/L) and 67% (n = 67/100) had some form of a hemoglobinopathy (namely, Hb E variants or α-thalassemia). Elevated serum NTBI concentration was not associated with age, iron supplementation, transferrin saturation or severe hemoglobinopathies (P >0.05). Conclusions In this population of Cambodian women with a high prevalence of hemoglobinopathies, we found that daily iron supplementation was not associated with elevated serum NTBI concentrations at 12-weeks, as compared to placebo. Funding Sources International Life Sciences Institute (ILSI) North America.