Twenty-six studies were assessed in this review; they reported various effects associated with preventive iron supplementation in children aged 0–4 y. The outcomes of anemia, development, growth, infectious disease morbidity, and mortality were considered, and the following conclusions were drawn.
For anemia, hemoglobin concentrations were consistently increased in iron-supplemented children who were anemic or had iron-deficient anemia at baseline. Improvements or increases in iron status indicators were also associated with iron supplementation in both iron-deficient and iron-replete children at baseline, although the response was less in the latter group. Iron supplementation may have had some positive effects on a number of developmental outcomes, primarily through reducing preexisting deficits or preventing losses over time in cognitive and motor skill development among preschool-aged children who were iron deficient or anemic before supplementation. Treatment at lower doses for 2–12 mo appeared to be more beneficial than very short courses of supplementation. The variations in developmental responses to iron supplementation, combined with the poor or unknown correlations of the measured outcomes with longer-term cognition, make interpretation or quantification of the possible benefits difficult.
In terms of growth, we found evidence from trials of various sizes for significant adverse effects on weight gains in iron-replete subgroups of young children. For height or linear growth, results varied. Two studies found a positive effect of iron supplementation on height increases in iron-deficient children, but 2 found a negative effect and 2 found no effect on height or length in iron-replete children.
With respect to infectious disease morbidity and mortality outcomes, our review found mixed evidence for increased incidence, duration, or severity of all infections in association with iron supplementation. Nearly all of the studies to date have been too small to enable examination of severe disease events or deaths. The only trials of sufficient size for these outcomes are those in Nepal and Zanzibar. In Nepal, no benefit or adverse effect of iron + folic acid supplements on mortality was found in young children. In Zanzibar, clear evidence shows that iron + folic acid supplementation, in a population of children with high rates of malaria and other infectious diseases and with limited access to disease-control programs, results in a significant increase in serious adverse events, including deaths. Additional evidence from this setting suggests that the degree of infectious-disease treatment and the child’s baseline iron status are critical determinants of who benefits and who is harmed in terms of serious infectious-disease outcomes when the population is provided low-dose oral iron supplements. Insufficient data are available on iron supplementation in relation to HIV or tuberculosis outcomes for conclusions to be drawn about possible benefits or risks.
One general conclusion that may be drawn from this analysis is that baseline hemoglobin and iron status indicators appear to be important determinants of these outcomes (). Our review found this through results from 12 trials screening for and including children according to hemoglobin or iron status at baseline (11
) and 8 trials that later stratified or adjusted for hemoglobin and iron status parameters in analyses associating supplementation with various outcomes (16
). In the first case of screening or restriction design, the ability to generalize to the larger population may be absent, although several studies showed effects with screening in all outcome categories. Larger, well-designed RCTs were among those finding differential effects of baseline hemoglobin and iron status markers on development, growth, and morbidity outcomes that support this conclusion. Only 2 studies reported an interaction between iron supplementation and initial hemoglobin concentration: significant findings for development outcomes were reported from Zanzibar (16
), and marginal significance for morbidity outcomes was found in Honduras (26
). Studies from industrialized countries may also suggest the potential for interaction. A trial in Greek preschoolers aged 3–4 y (n
= 49) found a significant interaction with cognitive performance (choice reaction time) for baseline iron status and treatment group (73
). Additional analyses of the interaction of anemia and iron status at baseline for iron supplementation are needed.
Effects determined by baseline hemoglobin, iron status, or both
In the substudy of the Zanzibar trial in which substantial malaria treatment was provided, in contrast with the larger trial, children with iron deficiency anemia had a reduction in adverse events. However, an elevated rate of adverse events was observed in those without iron deficiency. Detection and treatment of iron deficiency anemia at an individual level may be required to provide the best overall balance of health benefits and risks. Particular caution is advised in areas with high rates of malaria and other serious infections. Futhermore, there may be irregularities in both iron absorption and metabolism when particular genetic polymorphisms—ie, those that may also be associated with infection variables—are present. A study in Zimbabwe found a significant interaction effect with ferroportin Q248H mutation and elevated C-reactive protein (CRP) for higher ferritin concentrations (74
). More research is needed in this area. Ultimately, in the consideration of supplementation of young children with low doses of oral iron, an assessment of the balance of risks and benefits should be integral to the decision-making process.
We recognize that the realities of nutrition and disease-control programs may be vastly different from those of the controlled environment of these trials. The availability of resources, both financial and staffing, may be a problem if screening for iron deficiency and targeting treatment regimens are necessary to avoid causing harm to some children in the population. At the individual level, problems of compliance have often been cited with respect to implementing effective iron-supplementation programs. Alternative prevention and control strategies such as diet-based approaches may be preferred, if vulnerable population groups have access to foods, because those groups may be able to avoid the adverse effects associated with supplementation.
The need to address the problem of iron deficiency and the related consequences affecting millions worldwide is undisputed. Finding the appropriate response, however, particularly for young children living in developing countries, is a more difficult endeavor. This review presents the available evidence from carefully designed trials and offers context and individual-specific results with respect to a variety of outcomes. Further research is warranted, especially with respect to populations affected by malaria, HIV, and tuberculosis. In the short term, these findings suggest that the current recommendations regarding preventive iron supplementation should be reexamined.