Cochrane Column

The aim of the Column is to highlight relevant Cochrane Reviews to public health and to stimulate debate on relevance, feasibility and acceptability. Iron deficiency is a common public health problem. This month we feature the review assessing the effects of iron administered to children living in malaria-endemic settings. Rebecca Stoltzfus provided comments on the review relevance. The Cochrane Collaboration (http://www.cochrane.org) is an international, non-profit organization that prepares and disseminates up-to-date systematic reviews on the effects of health-care interventions in order to help people make well-informed decisions. Systematic reviews aim to answer focused health care questions by systematically identifying and evaluating all relevant research studies and synthesizing their results. *Corresponding author. Department of Paediatrics, Ebonyi State University, PMB 077, Abakaliki, Ebonyi State, Nigeria. E-mail: julieojk@yahoo.com Until recently, iron supplement was recommended for routine use in infants and children in resource-poor settings. However, in malaria-endemic areas, iron supplementation may increase the risk of malaria and thus be potentially harmful.1,2 A recent large trial in a malaria holoendemic area showed an overall increased risk of severe illness/death in pre-school children and the risk was higher in iron-replete infants and young children.1 As a result, the World Health Organization changed the current guidelines. They no longer recommend universal supplementation for children aged <2 years in malaria-endemic areas; and require providers to screen children to identify iron-deficient children before giving iron. However, the World Health Organization changed its global guidelines by examining a single, albeit large, trial. It did not draw on the totality of the evidence contained in all relevant randomized controlled trials. This review assessed the effects of iron administered to children living in malaria-endemic settings. Standard Cochrane search strategy includes Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (2009, Issue 1); MEDLINE (1966 to March 2009); EMBASE (1980 to March 2009); and LILACS (1982 to March 2009) and the metaRegister of Controlled Trials (mRCT) using ‘iron’ and ‘malaria’ as search terms. We approached authors for missing data. Individual or cluster-randomized controlled trials were conducted in malaria-endemic settings (defined from hypoendemic to holoendemic3) in children aged <18 years to compare orally administered iron ± folic acid vs placebo or no treatment. Iron fortification was excluded. Anti-malarial and/or anti-parasitic drugs could be administered to either group. Additional micronutrients could only be administered equally to both groups. Two authors independently applied the inclusion criteria, selected the studies, assessed trial quality and extracted data. The primary outcomes were malaria-related events and deaths. Secondary outcomes included haemoglobin, anaemia, other infections, growth, hospitalizations and clinic visits. Data were entered into Review Manager version 5.0.183 by one author. Risk ratios (RRs) for dichotomous outcomes and absolute mean differences were pooled using random effects meta-analysis. Adjusted effect estimates were used for cluster-randomized trials (reported in the primary publications or calculated using estimated design effects). Subgroup analyses and meta-regression were used to assess the effects of covariates on results. Sixty-eight trials (42 981 children), reporting one or more review-defined outcomes, fulfilled the inclusion criteria. Malaria-related outcomes were reported in 17 trials: 14 trials assessing iron for prevention or treatment of anaemia and 3 trials assessing iron for treatment of malaria-related anaemia during an attack of malaria. Overall, iron supplementation did not increase the risk of clinical malaria [RR: 1.00, 95% confidence interval (CI): 0.88–1.13; 22 724 children, 14 trials, random-effects model] (Figure 1). The risk was similar among children who were non-anaemic at baseline (RR: 0.96, 95% CI: 0.85–1.09). Sazawal et al.1 was the only trial to assess the intervention of iron with folic acid. An increased risk of malaria with iron was observed in trials that did not provide malaria surveillance and treatment. The risk of malaria parasitaemia was higher with iron (RR: 1.13, 95% CI: 1.01–1.26), but there was no difference in adequately concealed trials. Higher doses of iron were associated with lower RRs for malaria. No other covariates affected results, including study years, age, baseline prevalence of parasitaemia and baseline haemoglobin. Iron did not increase the risk of parasitological failure when given during malaria. Clinical malaria. SE, standard error. Deaths were reported only in 28/68 trials and no deaths occurred in 16. Overall, there was no increased risk of death (RR: 1.11, 95% CI: 0.91–1.36; 12 trials, 21 272 children). Iron supplementation increased haemoglobin, with significant heterogeneity; malaria endemicity did not affect the degree of increase. Growth, other infections, hospitalizations and clinic visits were mostly not affected by iron supplementation. Iron does not increase the risk of clinical malaria or death, even in hyperendemic areas and in non-anaemic children at baseline, when regular malaria surveillance and treatment services are provided. It is associated with some increase in the risk of parasitaemia. Iron supplementation improves haemoglobin and reduces the prevalence of anaemia, mainly among anaemic children. Based on our review, routine iron supplementation should not be withheld for children living in malaria-endemic areas. Iron supplementation in malaria-endemic areas need not be based on baseline iron assessment; rather emphasis should be on appropriate malaria prevention and surveillance. The full text of the review is available in The Cochrane Library: Ojukwu JU, Okebe JU, Yahav D, Paul M. Oral iron supplementation for preventing or treating anaemia among children in malaria-endemic areas. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD006589. DOI: 10.1002/14651858.CD006589.pub2. The specter of adverse effects of iron supplementation to children infected with malaria has existed in the literature for decades.1 And yet, iron deficiency is arguably the most prevalent form of malnutrition in children globally, with the potential to adversely affect children’s development.2 Supplementation is the most rapid way to correct deficiency and has been widely recommended, based on an earlier review which concluded that the benefits of iron supplementation appeared to outweigh the risks, even in malaria-endemic regions.3 Then, in 2006, a large randomized trial of iron supplements to children in Pemba Island, Zanzibar,4 was stopped, because the risk of hospitalization was significantly higher (by 11%) in children who were allocated iron and folic acid, compared with placebo, and the risk of mortality was increased similarly (but not significantly). The setting was one of high malaria transmission with no functioning control programme. In the same setting, but a different study sample provided with active surveillance for malaria and free treatment for infection, iron and folic acid supplements reduced severe morbidity by 49% in iron-deficient anaemic children. WHO convened a consultation to review the evidence on iron supplementation in malaria-endemic areas and concluded: ‘Universal iron supplementation for children under the age of 2 years is not recommended in malaria-endemic areas. However, iron therapy may have an important positive impact on child survival if it is directed to iron-deficient children in the setting of appropriate treatment of malaria and the complicating bacterial infections. Prior screening to identify iron-deficient children should be a necessary component of any such intervention’.5 This is problematic, as the requirement to screen children for iron deficiency or anaemia prior to iron supplementation is practically impossible in many resource-poor communities where malaria and iron deficiency are the most severe. In light of this, it is particularly important and interesting that Ojukwu and her colleagues conclude: ‘Iron supplementation does not increase risk of clinical malaria or death, when regular malaria surveillance and treatment services are provided. There is no need to screen for anaemia prior to iron supplementation’ (p. 2). Thus, the authors differentiate their conclusion from that of the recent WHO/UNICEF statement, putting the emphasis on the prevailing extent of malaria control rather than the iron or anaemia status of the individual child. This conclusion is plausible. Even if iron supplementation truly exacerbates malaria risk in some children, that risk can be contained through protection from infective mosquito bites and prompt diagnosis and treatment. And still, we are left with the question of how to define and measure the critical threshold of malaria control needed to make iron supplementation safe for all children. The dichotomization of malaria control employed in the Cochrane review of research trials (surveillance and treatment vs not) is difficult to translate into levels of programmatic coverage. Unless a randomized trial of varying programmatic levels of malaria control with iron supplementation is carried out with sufficient power to detect malaria-related severe outcomes in children, careful judgement is required. In the meantime, when treating children with iron supplements, clinicians should provide protection from malaria through appropriate provision of anti-malarial prophylaxis or treatment and education of caregivers about how to seek prompt treatment for fever. The Cochrane review confirms that iron supplements are efficacious to improve haemoglobin, even when malaria is endemic. Fortunately, public health initiatives to control malaria and to improve child nutrition (including prevention of iron-deficiency anaemia) are simultaneously gaining priority in sub-Saharan Africa. Many child nutrition programmes in sub-Saharan Africa are using micronutrient-fortified lipid-based spreads or cereal blends, which provide food iron that is handled more safely by the body than supplemental iron. The reduction of anaemia prevalence and severity is a common goal of both malaria control and nutrition interventions. While planning programmes to provide iron supplements, good judgement suggests the need to assess the context of malaria transmission and control, and to integrate health actions at the household level to prevent and treat malaria.

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