Why the review is important
Children living in malarial areas commonly develop anaemia. Long-term anaemia is thought to delay a child's development and make children more likely to get infections. In areas where anaemia is common, health providers may give iron to prevent anaemia, but there is a concern amongst researchers that this may increase the risk of malaria. It is thought that the iron tablets will increase iron levels in the blood, and this will promote the growth of the Plasmodium parasite that causes malaria. We aimed to assess the effects of oral iron supplementation in children living in countries where malaria is common.
Main findings of the review
Cochrane researchers searched the available evidence up to 30 August 2015 and included 35 trials (31,955 children). Iron did not increase the risk of malaria, indicated by fever and the presence of parasites in the blood (high quality evidence). There was no increased risk of death among children treated with iron, although the quality of the evidence for this was low. Among children treated with iron, there was no increased risk of severe malaria (high quality evidence). Although it is hypothesized that iron supplementation might harm children who do not have anaemia living in malarial areas, there is probably no increased risk for malaria in these children (moderate quality evidence). In areas where health services are sufficient to help prevent and treat malaria, giving iron supplements (with or without folic acid) may reduce clinical malaria. In areas where these services are not available, iron supplementation (with or without folic acid) may increase the number of children with clinical malaria (low quality evidence). Overall, iron resulted in fewer anaemic children at follow up, and the end average change in haemoglobin from base line was higher with iron.
Conclusions
Our conclusions are that iron supplementation does not adversely affect children living in malaria-endemic areas. Based on our review, routine iron supplementation should not be withheld from children living in countries where malaria is prevalent and malaria management services are available.
Iron treatment does not increase the risk of clinical malaria when regular malaria prevention or management services are provided. Where resources are limited, iron can be administered without screening for anaemia or for iron deficiency, as long as malaria prevention or management services are provided efficiently.
Iron-deficiency anaemia is common during childhood. Iron administration has been claimed to increase the risk of malaria.
To evaluate the effects and safety of iron supplementation, with or without folic acid, in children living in areas with hyperendemic or holoendemic malaria transmission.
We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library, MEDLINE (up to August 2015) and LILACS (up to February 2015). We also checked the metaRegister of Controlled Trials (mRCT) and World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) up to February 2015. We contacted the primary investigators of all included trials, ongoing trials, and those awaiting assessment to ask for unpublished data and further trials. We scanned references of included trials, pertinent reviews, and previous meta-analyses for additional references.
We included individually randomized controlled trials (RCTs) and cluster RCTs conducted in hyperendemic and holoendemic malaria regions or that reported on any malaria-related outcomes that included children younger than 18 years of age. We included trials that compared orally administered iron, iron with folic acid, and iron with antimalarial treatment versus placebo or no treatment. We included trials of iron supplementation or fortification interventions if they provided at least 80% of the Recommended Dietary Allowance (RDA) for prevention of anaemia by age. Antihelminthics could be administered to either group, and micronutrients had to be administered equally to both groups.
The primary outcomes were clinical malaria, severe malaria, and death from any cause. We assessed the risk of bias in included trials with domain-based evaluation and assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We performed a fixed-effect meta-analysis for all outcomes and random-effects meta-analysis for hematological outcomes, and adjusted analyses for cluster RCTs. We based the subgroup analyses for anaemia at baseline, age, and malaria prevention or management services on trial-level data.
Thirty-five trials (31,955 children) met the inclusion criteria. Overall, iron does not cause an excess of clinical malaria (risk ratio (RR) 0.93, 95% confidence intervals (CI) 0.87 to 1.00; 14 trials, 7168 children, high quality evidence). Iron probably does not cause an excess of clinical malaria in both populations where anaemia is common and those in which anaemia is uncommon. In areas where there are prevention and management services for malaria, iron (with or without folic acid) may reduce clinical malaria (RR 0.91, 95% CI 0.84 to 0.97; seven trials, 5586 participants, low quality evidence), while in areas where such services are unavailable, iron (with or without folic acid) may increase the incidence of malaria, although the lower CIs indicate no difference (RR 1.16, 95% CI 1.02 to 1.31; nine trials, 19,086 participants, low quality evidence). Iron supplementation does not cause an excess of severe malaria (RR 0.90, 95% CI 0.81 to 0.98; 6 trials, 3421 children, high quality evidence). We did not observe any differences for deaths (control event rate 1%, low quality evidence). Iron and antimalarial treatment reduced clinical malaria (RR 0.54, 95% CI 0.43 to 0.67; three trials, 728 children, high quality evidence). Overall, iron resulted in fewer anaemic children at follow up, and the end average change in haemoglobin from base line was higher with iron.