Oral iron supplements for children in malaria-endemic areas

Abstract

Rationale: Iron deficiency anaemia is a common nutritional disorder among children in malaria-endemic regions and is associated with adverse developmental and health outcomes. However, concerns have been raised that iron supplementation might increase the risk of malaria by enhancing parasite growth, particularly in areas lacking adequate malaria prevention and treatment services.

Objectives: 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, where malaria is intense and occurs year-round.

Search methods: We searched CENTRAL (Wiley), MEDLINE (Ovid), Embase (Ovid), and Global Index Medicus (WHO) up to 30 April 2024. We also searched two trial registries, ClinicalTrials.gov and WHO ICTRP, to 30 April 2024. We conducted a top-up search on 20 May 2025. We contacted trial investigators and scanned references of included trials and reviews for relevant studies.

Eligibility criteria: We included individual and cluster-randomised controlled trials (RCTs) conducted in malaria-endemic regions that enrolled children under 18 years of age. We included trials that compared: (1) oral iron alone versus placebo or no treatment; (2) oral iron plus folic acid versus placebo or no treatment; (3) oral iron (with or without folic acid) versus placebo or no treatment, grouped by malaria prevention and management services for the outcome of clinical malaria only; and (4) oral iron plus antimalarial treatment versus placebo or no treatment. Iron or fortified interventions had to provide ≥ 80% of age-appropriate Recommended Dietary Allowance (RDA). Antihelminthics and micronutrients other than iron and folic acid had to be administered equally to both groups.

Outcomes: The critical outcomes were clinical malaria, severe malaria, and death from any cause. Important outcomes included hospitalisations and clinic visits.

Risk of bias: We assessed risk of bias in the included trials using the Cochrane RoB 1 tool.

Synthesis methods: We used fixed-effect meta-analysis (Mantel-Haenszel or generic inverse variance) and adjusted for clustering in cluster-RCTs. For haemoglobin and anaemia outcomes, we applied a random-effects model due to anticipated heterogeneity. We assessed the certainty of evidence using GRADE and explored heterogeneity through subgroup analysis.

Included studies: Forty trials (33,785 children) met the inclusion criteria.

Synthesis of results: Iron versus placebo/no treatment Iron results in little or no difference in the risk of clinical malaria (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.87 to 1.00; 16 trials, 7843 children; high-certainty evidence) and reduces the risk of severe malaria slightly (RR 0.90, 95% CI 0.81 to 0.98; 5 trials, 3421 children; high-certainty evidence). Iron may result in little or no difference in mortality (RR 1.15, 95% CI 0.76 to 1.74; 20 trials, 8809 children; low-certainty evidence) and hospitalisations or clinic visits (RR 0.99, 95% CI 0.95 to 1.04; 10 trials, 14,011 children; low-certainty evidence). Iron plus folic acid versus placebo/no treatment The evidence for this comparison comes largely from one large trial (Pemba) plus four smaller trials (19,456 children). Clinical malaria was not reported. Iron plus folic acid may result in little to no difference in severe malaria requiring admission (RR 1.11, 95% CI 0.96 to 1.28; 2 trials, 17,575 children; low-certainty evidence); all-cause mortality (RR 1.13, 95% CI 0.90 to 1.42; 5 trials, 18,034 children; low-certainty evidence); and hospitalisations (RR 1.08, 95% CI 0.96 to 1.22; 1 trial, 15,956 children; low-certainty evidence). Iron (with or without folic acid) versus placebo/no treatment; grouped by presence or absence of malaria prevention and management services We also grouped trials by the presence of malaria prevention and management services, analysing 19 trials (25,531 children). In areas with services, iron (with or without folic acid) may reduce clinical malaria slightly (RR 0.91, 95% CI 0.84 to 0.97; 12 trials, 5777 children; low-certainty evidence). In areas without services, iron (with or without folic acid) may increase clinical malaria slightly (RR 1.15, 95% CI 1.02 to 1.30; 7 trials, 19,754 children; low-certainty evidence). Overall, when not grouping by presence of malaria prevention and management services, iron supplementation (with or without folic acid) may have little to no effect on clinical malaria (RR 0.96, 95% CI 0.91 to 1.03; 19 trials, 25,531 children; low-certainty evidence). Iron plus antimalarial prophylaxis versus placebo/no treatment Adding iron to antimalarial prophylaxis results in a large reduction in clinical malaria (RR 0.54, 95% CI 0.43 to 0.67; 3 trials, 728 children; high-certainty evidence); likely results in a large reduction in hospitalisations and clinic visits (RR 0.85, 95% CI 0.81 to 0.89; 2 trials, 5976 child-months; moderate-certainty evidence); and may not reduce all-cause mortality (RR 1.05, 95% CI 0.52 to 2.11; 3 trials, 728 children; low-certainty evidence). Severe malaria was not reported for this comparison.

Authors' conclusions: Iron treatment results in little to no difference in the risk of clinical malaria (high-certainty evidence). Where resources are limited, iron can be administered without screening for anaemia or iron deficiency, as long as malaria prevention or management services are provided efficiently. Where resources for the prevention and treatment of malaria are limited, iron may increase the risk of clinical malaria (low-certainty evidence). These conclusions are consistent with those reported in the previous version of this review (2016).

Funding: The editorial base for the Cochrane Infectious Diseases Group (CIDG) is funded by the UK Department for International Development for the benefit of developing countries. Dafna Yahav (DY) received a grant from the Research Programme Consortium funded by the UK Department for International Development to complete the 2014 update. Ami Neuberger (AN) received funding from the Department of Nutrition for Health and Development, World Health Organization, for the 2016 update.

Registration: Protocol (2007) DOI: 10.1002/14651858.CD006589 Original review (2009) DOI: 10.1002/14651858.CD006589.pub2 Review update (2011) DOI: https://doi.org/10.1002/14651858.CD006589.pub3 Review update (2016) DOI: 10.1002/14651858.CD006589.pub4.