Iron and Malaria Interactions: Programmatic Ways Forward

Around one-quarter of the world’s children suffer from iron deficiency anemia, and many of them live in malaria-endemic areas. However, there is evidence that iron supplements can increase risk of severe malaria morbidity. The dilemma is how to move forward with interventions to prevent iron deficiency and its consequences in young children, using strategies that minimize risks of malaria and related infections. Screening for iron deficiency is problematic for several reasons. Two complementary strategies are suggested for moving forward with interventions to prevent iron deficiency in children exposed to malaria. The first is to reduce exposure to iron in the form of supplements by: adopting a lifecycle approach to pediatric iron deficiency beginning in utero, using the lowest adequate dose, and giving iron in or with foods. The second is to coordinate iron interventions with malaria control efforts. To stop all iron interventions in malaria-endemic areas is an unreasonable policy option. While research findings continue to increase our understanding, there are also programmatic ways forward with the knowledge at hand. Adv. Nutr. 3: 579–582, 2012. The dilemma It is estimated that one-quarter of the world’s children suffer from iron deficiency anemia (1). Iron-deficient children suffer from defects in neurodevelopment, with effects that persist into middle childhood and adolescence (2). Iron deficiency is common, because it is practically impossible to meet the dietary iron needs of rapidly growing young children with the monotonous, largely plant-based diets that are commonly fed to children in many parts of the world (3). Without provision of bioavailable heme iron, iron-fortified foods, or iron supplements, many infants become iron deficient. Therefore, as a preventive intervention, low-dose oral iron supplements have been routinely recommended for infants and young children beyond the age of 6 mo and for low-birth weight infants beginning at 2 mo of age (4). However, there is evidence that iron supplements can, at least for some children in some circumstances, increase risk of severe malaria morbidity. Evidence of an iron-malaria interaction in the human host is long-standing (5), although the implications for public health programs have been unclear. Most experts have assumed that the tight regulation of iron absorption in the gut could prevent dangerous effects of iron supplements. This assumption was supported by meta-analysis of available randomized clinical trials in 1998, showing no significantly elevated risks of malariarelated outcomes with low-dose oral supplements in children (6). A more recent meta-analysis reached the same conclusion (7). In 2006, a large, individually randomized, placebocontrolled trial of iron + folic acid supplements reported an elevated risk of hospitalization or mortality in infants who received iron compared to those receiving placebo (8). This result, observed in Pemba Island, Zanzibar, an area of very high P. falciparum malaria transmission and mortality, strongly implicated a malaria connection, because a parallel trial done in rural Nepal, where malaria transmission is low, did not find an adverse effect (9). These were the first randomized trials of iron-containing supplements to be designed with child mortality as primary outcomes, and they carried a great deal of weight in the minds of policy-makers. In response to the Pemba trial, the WHO and UNICEF issued a statement in 2007 (10) that for all practical purposes, 1 Published as a supplement to Advances in Nutrition. Presented as part of the symposium entitled “Tackling Iron Deficiency and Anemia in Infants and Young Children in Malaria-Endemic Areas: Moving from Controversy towards Guidance for Safe, Effective and Feasible Policies and Programs” given at the Experimental Biology 2011 meeting, April 10, 2011, in Washington, DC. The symposium was sponsored by the American Society for Nutrition and supported in part by the U.S. Army Military Infectious Disease Research Program. The symposium was chaired by Lynnette M. Neufeld and Angus Scrimgeour. The Guest Editors for this symposium were Lynnette M. Neufeld and Rafael Flores-Ayala. Guest Editor disclosures: Neither Guest Editor had conflicts to disclose. The opinions expressed in this publication are those of the authors and are not attributable to the sponsors or the publisher, Editor, or Editorial Board of Advances in Nutrition. 2 Author disclosure: R. J. Stoltzfus, no conflicts of interest. * To whom correspondence should be addressed. E-mail: [email protected]. ã2012 American Society for Nutrition. Adv. Nutr. 3: 579–582, 2012; doi:10.3945/an.111.000885. 579 Downloaded from https://academic.oup.com/advances/article-abstract/3/4/579/4591519 by guest on 30 March 2018 halted progress in iron interventions in many malariaendemic areas: “Universal iron supplementation (i.e., use of medicinal iron as pills or syrups) should not be implemented without the screening of individuals for iron deficiency, because this mode of iron administration may cause severe adverse events in iron-sufficient children.” Although the statement allowed for iron supplements if targeted to iron-deficient children, no programs were implemented with that strategy because of logistical barriers to screening. The statement also allowed the use of iron-fortified complementary foods, but many programs seeking to utilize iron-fortified foods, micronutrient powders, or lipid-based nutrition supplements for children were also stymied due to concerns about adverse events. But dietary iron deficiency is not a solution to malaria morbidity or mortality. Iron-malaria interactions notwithstanding, children who are iron deficient, as well as those who are iron replete, suffer and die from malaria. Effective prevention and treatment strategies for malaria exist and the current funding for those interventions, although still inadequate, is unprecedented (11). Many malaria control programs are achieving impressive measures of success (12,13). The dilemma is how to move forward with interventions to prevent iron deficiency and its consequences in young children, using strategies that minimize risks of malaria and related infections. The dilemma is especially difficult, because our knowledge is imperfect. This is not a unique circumstance. Public health practice is often confronted with problems that are complex, involve uncertain risks and multiple competing objectives, and engage stakeholders with different perspectives (14). To stop all iron interventions in malaria-endemic areas is a policy option. But given the consternation of the international nutrition community (evidenced, e.g., by this symposium), this option appears to be unacceptable to public health communities of practice, malaria as well as nutrition. Why the recommended solution of screening is problematic In the ideal world, we would target iron interventions only to the children who would benefit from those interventions and therefore not devote any resources to nonbenefitters. In the real world, we are often unable to predict the potential to benefit with high accuracy, and the costs of predicting (i.e., screening or targeting) may exceed the costs of delivering the intervention to nonbenefitters. In a substudy of the Pemba, Zanzibar trial in which children’s iron status at baseline was characterized, children who were iron deficient had no adverse risks with iron supplementation but in fact benefited greatly, with a highly significant 49% (8) reduction in the risk of hospitalization or mortality. On this basis, the WHO 2007 statement left open the possibility of providing iron supplements after screening for iron deficiency. This recommendation was problematic in multiple ways. First, the best screening indicator is unknown. Zinc protoporphyrin (measured in whole blood using a hematofluorometer) was the indicator used in the Pemba trial (8), but this methodology is not widely available and the interpretation of values and cutoffs is known to vary with infections and lead exposure. Furthermore, cost-effective delivery systems for targeting have been discussed in theory (15) but not tested in any programmatic setting. Iron interventions could be targeted to infants diagnosed with iron deficiency (as per the WHO recommendation). But pending better and cheaper technologies [as discussed by Crowley et al. (16) in this supplement], this would be feasible only in rather well-equipped clinical settings. Even if it could be implemented, to target children with known iron deficiency is a treatment strategy, not a prevention strategy. If the effects of iron deficiency on child development are not fully reversible, prevention is paramount (17). Another recommended form of targeting is to supplement low-birth weight infants, who are known to be at high risk of iron deficiency (4). This long-standing recommendation has never gained widespread global coverage, most probably due to poor documentation of birth weight in many settings. Even if this were widely implemented, many normal-birth weight infants would also develop iron deficiency and would be missed. In addition, in the past decade, single micronutrient interventions such as iron supplements have given way to a broader agenda to improve infant and young child nutrition. Thus, most current programs seek to employ strategies and products that combine several micronutrients (e.g., micronutrient powders) and, often in combination with some macronutrients, in the form of fortified lipid pastes or processed cereals. Strategies for specifically targeting a single nutrient such as iron become even more impractical within integrated nutrition interventions. Programmatic ways forward I suggest 2 strategies for moving forward with interventions to prevent iron deficiency in children exposed to malaria. These are not mutually exclusive but rather should be considered in combination. Shift interventions from supplements to lower-dose, food-based interventions. The most fundamental strategy for reducing risk is to reduce the iron dose. In support of this strategy, programs should adopt a lifecycle approach to pediatric iron deficiency beginning in utero. Once iron is absorbed into the body, it is efficiently stored and highly conserved through recycling of senescent red cells. Therefore, the iron status of a young child is strongly influenced by its prior status, over a period of weeks and months or even years. The developing fetus accumulates iron from its mother and is born with an iron endowment that is designed to sustain its physiologic needs for several postnatal months. Total body iron (TBI) at birth was estimated in Zimbabwean neonates, and the quartile of TBI at birth strongly predicted the risk of anemia in the infant up to 12 mo postnatally (18). Adequate body iron at birth was a function of