Antenatal Iron Use in Malaria Endemic Settings: Evidence of Safety?

Anemia related to iron deficiency during pregnancy occurs in 19% of women worldwide and in 20% of women in subSaharan Africa.1 Findings from observational studies reveal a linear, inverse relationship between maternal anemia and risk of maternal mortality across the entire distribution of hemoglobin concentrations, although confounding may be an issue.2,3 Severe anemia in pregnancy may result in maternal death due to cardiac failure. The current World Health Organization (WHO) guideline is to provide 30 to 60 mg of elemental iron and 400 μg of folic acid daily throughout pregnancy. This recommendation is mainly based on the proven effects of supplementation in reducing maternal anemia, iron deficiency, and low birth weight.4 In addition, approximately 35 million pregnant women, nearly all of whom live in sub-Saharan Africa, are at risk of Plasmodium falciparum infection annually.5 Across Africa, the prevalence of infection among children aged 2 to 10 years has declined from 26% in 2000 to 14% in 2013.5 Still, in 2013, an estimated 437 000 malaria deaths occurred in children younger than 5 years, representing 83% of all deaths due to malaria in Africa.5 A meta-analysis of 12 high-quality randomized clinical trials (RCTs) has shown iron-folic acid supplementation to be associated with a mean increase in birth weight of 69 g (95% CI, 38-100) and a reduction in low birth weight of 18% (relative risk, 0.82; 95% CI, 0.72-0.94). This metaanalysis also found an association between maternal iron supplementation and a 50% relative reduction in the risk of anemia, providing evidence that half of all maternal anemia may be related to iron deficiency, although there is regional variation.3 In many sub-Saharan African countries, malaria is an important cause of anemia. Anemia related to iron deficiency among children in subSaharan Africa has the same 20% prevalence as among pregnantwomen.6However, iron supplementation for children in a malaria endemic setting has been reported to be significantly associated with an increased risk of adverse outcomes, including death and hospitalization.7 This risk led the WHO to recommend that malaria control and prevention be ensured in endemic areaswhen providing iron supplementation for children who are iron-deficient (based on screening tests) or have clinical symptoms of severe anemia.8 The recommendation also indicated that folic acid shouldnot beprovidedbecausesomeevidence,9albeitconflicting,7 suggests that folic acidmay reduce the efficacy of antifolatemalarial drugs. Currently theWHO does not have guidelines for iron supplementation in children aged 6 to 24 months. Additional concern involves whether these cautions should be extended to the use of antenatal iron supplements, folic acid supplements, or both in areas where pregnant women may be at risk for malaria infection. However, according to international guidelines for these endemic malaria settings, pregnant women should receive intermittent preventive treatment (IPT) for malaria.10 The safety of iron-folic acid use during pregnancy in malaria endemic areas has not been carefully evaluated despite current guidelines recommending iron-folic acid supplementation. In a recent trial in Tanzania among iron-replete nonanemic pregnant women (n = 1500), iron supplementation compared with placebo (in the presence of malaria screening, prophylaxis, and treatment) did not increase the risk of placental malaria; iron supplementation did increase hemoglobin and iron levels at delivery, but it did not affect birth weight.11 In this issue of JAMA, Mwangi and colleagues12 demonstrate, in adouble-blind, placebo-controlled randomized trial, that iron (60mg) supplementationduring pregnancy in amalaria endemic area of Kenya did not increase the prevalence of P falciparum malaria infection at delivery or the occurrence of adverse events. The trial was conducted among 470 rural Kenyanwomen aged 15 to 45 years with singleton pregnancies whowere enrolled in the early part of the second trimester and either were nonanemic or had mild anemia; iron deficiency was highly prevalent in this population at about 50%. P falciparum prevalencewas 50.9% in the iron group vs 52.1% in the placebo group (crude risk difference, −1.2%; 95% CI, −11.8% to 9.5%; P = .83). The study size was relatively small, and thus the risk of severe adverse effects that occur at low frequency could not be ruled out. The power of the study was sufficient to detect only large differences (ie, increased infection rate of 35% or more). Loss to follow-up and missing data resulted in further attenuating the sample size. A major limitation of this trial was that incident malaria during pregnancy was not monitored and placental samples were missing in a high number of participants (27%), which did not allow for adequate assessment of infection. Nevertheless, the findings of the study provide support for iron use during pregnancy in settings with endemic malaria. Supplementation in this trial did not include folic acid, which is included in the WHO recommendation.4 Not combining the 2 nutrients in the study yielded clearer evidence regarding iron but did Related article page 1009 Opinion