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Meta-Analysis
. 2016 Feb 27;2(2):CD006589.
doi: 10.1002/14651858.CD006589.pub4.

Oral iron supplements for children in malaria-endemic areas

Ami Neuberger  1 , Joseph Okebe, Dafna Yahav, Mical Paul
Affiliations
Meta-Analysis

Oral iron supplements for children in malaria-endemic areas

Ami Neuberger et al. Cochrane Database Syst Rev. .

Abstract

Background: Iron-deficiency anaemia is common during childhood. Iron administration has been claimed to increase the risk of malaria.

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.

Search methods: 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We contacted the primary investigators of all included trials, ongoing trials, and those awaiting assessment to ask for unpublished data and further trials.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.

Selection criteria: 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.

Data collection and analysis: 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.

Main results: 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.

Authors' conclusions: 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.

PubMed Disclaimer

Conflict of interest statement

AM has no known conflicts of interest. JO has no known conflicts of interest. DY has no known conflicts of interest. MP has no known conflicts of interest.

Figures

1
1
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included trials. The unclear category for incomplete outcome data represents trials that did not report this outcome.
2
2
Methodological quality summary: review authors' judgements about each methodological quality item for each included trial.
3
3
Funnel plot of comparison: 1. Iron versus placebo or no treatment, outcome: 1.1 Clinical malaria (grouped by presence of anaemia).
1.1
1.1. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 1 Clinical malaria (grouped by presence of anaemia).
1.2
1.2. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 2 Clinical malaria (grouped by age).
1.3
1.3. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 3 Clinical malaria (P. falciparum only).
1.4
1.4. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 4 Any parasitaemia, end of treatment (by anaemia at baseline).
1.5
1.5. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 5 All‐cause mortality.
1.6
1.6. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 6 Clinical malaria with high‐grade parasitaemia or requiring admission.
1.7
1.7. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 7 Any parasitaemia, end of treatment ( by age).
1.8
1.8. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 8 Any parasitaemia, end of treatment (P. falciparum only).
1.9
1.9. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 9 Any parasitaemia, end of treatment (by allocation concealment).
1.10
1.10. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 10 High‐grade parasitaemia.
1.11
1.11. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 11 Any parasitaemia, end of follow‐up.
1.12
1.12. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 12 Hospitalizations and clinic visits.
1.13
1.13. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 13 Haemoglobin, end of treatment (by anaemia at baseline).
1.14
1.14. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 14 Weight, end value.
1.15
1.15. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 15 Anaemia, end of treatment.
1.16
1.16. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 16 Weight, change from baseline.
1.17
1.17. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 17 Diarrhoeal episodes per patient‐month (by zinc administration).
1.18
1.18. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 18 Infections per patient‐month.
1.19
1.19. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 19 Haemoglobin, change from baseline, end of treatment.
1.20
1.20. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 20 URTI/pneumonia episodes per patient‐month.
1.21
1.21. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 21 Height, end value.
1.22
1.22. Analysis
Comparison 1 Iron versus placebo or no treatment, Outcome 22 Height, change from baseline.
2.1
2.1. Analysis
Comparison 2 Iron plus folic acid versus placebo or no treatment, Outcome 1 Severe malaria (malaria requiring admission).
2.2
2.2. Analysis
Comparison 2 Iron plus folic acid versus placebo or no treatment, Outcome 2 Severe malaria (cerebral malaria).
2.3
2.3. Analysis
Comparison 2 Iron plus folic acid versus placebo or no treatment, Outcome 3 All‐cause mortality.
2.4
2.4. Analysis
Comparison 2 Iron plus folic acid versus placebo or no treatment, Outcome 4 Any hospitalization.
2.5
2.5. Analysis
Comparison 2 Iron plus folic acid versus placebo or no treatment, Outcome 5 Haemoglobin, end of treatment.
2.6
2.6. Analysis
Comparison 2 Iron plus folic acid versus placebo or no treatment, Outcome 6 Anaemia, end of treatment.
2.7
2.7. Analysis
Comparison 2 Iron plus folic acid versus placebo or no treatment, Outcome 7 Weight, end value.
2.8
2.8. Analysis
Comparison 2 Iron plus folic acid versus placebo or no treatment, Outcome 8 Height, end value.
3.1
3.1. Analysis
Comparison 3 Iron with or without folic acid versus placebo or no treatment, Outcome 1 Clinical malaria (grouped by presence of malaria prevention or management).
4.1
4.1. Analysis
Comparison 4 Iron plus antimalarial versus placebo, Outcome 1 Clinical malaria.
4.2
4.2. Analysis
Comparison 4 Iron plus antimalarial versus placebo, Outcome 2 All‐cause mortality.
4.3
4.3. Analysis
Comparison 4 Iron plus antimalarial versus placebo, Outcome 3 Hospitalizations and clinic visits.
4.4
4.4. Analysis
Comparison 4 Iron plus antimalarial versus placebo, Outcome 4 Haemoglobin at end of treatment.
4.5
4.5. Analysis
Comparison 4 Iron plus antimalarial versus placebo, Outcome 5 Anaemia.
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Gomber 1998 {published data only}
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Hathirat 1992 {published data only}
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ISRCTN85737357 {unpublished data only}
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ISRCTN88523834 {unpublished data only}
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    1. ISRCTN88523834. The prevention of malaria and anaemia in infants through iron supplementation and intermittent malaria treatment administered through the expanded programme on immunization scheme (Tanzania). http://www.controlled‐trials.com/ISRCTN88523834.
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Kanani 2000 {published data only}
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Kurz 1985 {unpublished data only}
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le Cessie 2002 {published data only}
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NCT00301054 {unpublished data only}
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Nguyen 2002 {published data only}
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Roschnik 2004 (C) {published and unpublished data}
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Sungthong 2002 {published data only}
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Zimmermann 2010 {unpublished data only}
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References to studies awaiting assessment

Sazawal 2006 (C)c {published data only}
    1. Olney DK, Pollitt E, Kariger PK, Khalfan SS, Ali NS, Tielsch JM, et al. Combined iron and folic acid supplementation with or without zinc reduces time to walking unassisted among Zanzibari infants 5‐ to 11‐mo old. The Journal of Nutrition 2006;136(9):2427‐34. - PubMed
    1. Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A, et al. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community‐based, randomized, placebo‐controlled trial. Lancet 2006;367(9505):133‐43. - PubMed

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