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‘THE GUIDING SPIRIT [OF INTERNATIONAL EXPERT MEETINGS] IS LED ESSENTIALLY BY THE NUTRITIONAL AGENDA THAT IRON DEFICIENCY IS A COMMON PROBLEM CRYING OUT FOR CORRECTION, AND THAT CLINICAL AND RESEARCH CONCERNS ABOUT THE INTERACTION OF IRON AND INFECTION STRETCHING BACK TO THE 19TH CENTURY ARE NEGATIVE PUBLICITY PROBLEMS TO BE MANAGED RATHER THAN TAKEN SERIOUSLY’ – STEPHEN OPPENHEIMER, 2007 [1]

For decades, iron has been routinely given to treat or prevent anaemia in low- and middle-income coun­tries, often in conjunction with folic acid. The World Health Organization (WHO) started advocating univer­sal oral iron supplementation in children in 2001. There have been serious safety concerns, however, about interventions with these micronutrients, and although WHO supplementation guidelines (Table 1) have changed in view of these concerns, they continue to gener­ate controversy and confusion. This paper aims to summarise the key points of that debate. Because of space limitations, I will focus on iron supplementation in children; for folic acid and for iron supple­mentation in pregnant women, reviews are available elsewhere.[2,3]

Early iron studies and the pemba trial

There is compelling evidence that the human host provides an environment that limits the availability of iron to pathogens and that increased intake of iron can predispose to pathogenic growth and propagation. Starting in the 1970s, there were reports that iron supplementation leads to an increased risk of malaria, respiratory infections and other infections in developing coun­tries,[4] but these findings were mostly based on observational studies and trials that were relatively small and, at least by modern standards, often had method­ological shortcomings. A tipping point came with a large-scale randomised trial conducted among young children in Pemba, Tanzania. This study, pub­lished in 2006, showed that daily oral supplementation with iron and folic acid increased the incidence of severe ad­verse events (hospitalisation and death) by 12% (95% CI: 2%-23%).[5] In 2007, having reviewed the evidence, WHO concluded that the Pemba trial find­ings were likely due to the effect of iron on malaria. The guidelines were then changed. WHO advised against univer­sal iron supplementation in malaria-endemic regions, and recommended that iron supplements be administered only in conjunction with measures to prevent and control malaria, and only in children with iron deficiency or, if screening for iron deficiency was impos­sible, with signs of severe anaemia.[6]

Meta-analyses of iron supplementation effects

A subsequent meta-analysis of trials concluded that iron does not increase the risk of malaria or death when regu­lar malaria surveillance and treatment services are provided, and that there is no need to screen for anaemia prior to iron supplementation.[7] This conclu­sion, however, was mostly based on the risk of malaria. This outcome has low specificity, which may lead to interven­tion effects being underestimated, and it does not account for possible interven­tion effects on the severity of malaria.

The results of the Pemba trial suggested that the risks of iron supplementation were restricted to children who were iron-replete at baseline. Iron status was defined by whole blood zinc protopor­phyrin content or haemoglobin concen­tration, indicators that were recently shown to have low diagnostic value for iron deficiency.[8] By contrast, a more recent trial found that supplementation with iron-containing micronutrients increased malaria incidence by 41% (95% CI 9%-82%) in Tanzanian chil­dren who were initially iron-deficient,[9] and that this risk declined over the time of intervention. A strong point in the latter study [9] is that, contrary to the Pemba trial, it used a highly specific indicator of iron deficiency (plasma ferritin concentration <12 µg/L). In ad­dition, several studies have shown that iron supplementation in iron-deficient individuals leads to increased erythro­poiesis and a transient abundance in circulation of young erythrocytes, which are more susceptible to invasion and propagation by P. falciparum merozoites than mature erythrocytes.[e.g. 10] When considered together [9,10], these findings indicate that a screen-and-treat approach is not feasible, because a gain in haemo­globin concentration in iron-deficient children inevitably comes at a price of a transiently elevated risk of malaria. Subsequent meta-analyses, undertaken by the same group, confirmed the earlier conclusions [8] but emphasised that decisions about iron supplementation should depend on the presence of ma­laria surveillance and treatment rather than on the assessment of iron status.

Current who guidelines regarding iron supplementation in children

These conclusions are reflected in WHO’s most recent guide­lines [11], which state that:

a. in malaria-endemic areas, infants and children should be supple­mented with iron in conjunction with public health measures to pre­vent, diagnose and treat malaria;
b. in malaria-endemic areas with limited malaria prevention and clinical care, universal iron supple­mentation may be associated with an increased risk of malaria;
c. oral iron interventions should not be given to children who do not have access to ma­laria prevention strategies.

It is plausible and perhaps not surpris­ing that adverse effects associated with malaria are no longer an issue if malaria is adequately controlled. A key problem, however, is that the meta-analyses arbi­trarily divided and analysed trials into two groups, depending on whether or not regular malaria prevention or man­agement services were provided, and that this classification may be difficult to translate into practice. For example, the trial by Veenemans et al.[9] provided excellent access to prompt diagnosis and rapid, efficacious chemotherapy, but nonetheless found that supplementation with iron-containing micronutrients increased malaria incidence in children with iron deficiency (see preceding para­graphs). In addition, data on the current state of malaria control, much of which can be found in a recent WHO report [12], is sobering:

a. in areas of stable malaria and under trial conditions, insecticide-­impregnated mosquito nets can reduce overall child mortality by only one-sixth and it can only halve the incidence of uncom­plicated malarial episodes;
b. only two-thirds of children less than 5 years old in sub-­Saharan Africa sleep under insecticide-treated nets, whilst vector resistance to pyrethroids is spreading and intensifying;
c. indoor residual spraying protects only 6% of the population in all of sub-Saharan Africa, with cover­age declining in recent years;
d. in 2014, 84% of children under the age of 5 with malaria did not receive appropriate drugs, primarily because a high propor­tion of children with fever are not taken to a health facility or use the informal private sector.

Bacterial infections

Most of the debate has focused on malaria, but there is increasing evidence that iron interventions can also increase the susceptibility to both gastrointes­tinal and systemic infections. Most bacteria scavenge host iron by secreting and resorbing small proteins that bind iron in the environment, by competi­tively removing iron that is bound to host proteins, by acquiring iron through receptor-mediated uptake of host iron-­containing proteins, or by releasing toxins that damage host cells, leading to the release of ferritin, the cellular iron storage protein, or (in case of erythro­cytes) haemoglobin. Both iron supple­mentation and iron fortification can increase the abundance and virulence of enteropathogenic bacteria [e.g. 13], many of which are commonly found in commu­nity surveys among children. In an ex vivo study among healthy male volun­teers, oral iron supplementation led to a markedly elevated growth of Escherichia coli, Yersinia enterocolitica, Salmonella en­terica serovar Typhimurium, and Staphy­lococcus epidermidis in sera collected 4 h after intake compared to before taking the tablets.[14] In addition to causing diarrhoea, these infections can lead to bacteraemia, a relatively rare but serious and often fatal condition, and possibly environmental enteropathy, an asymp­tomatic but highly prevalent condition among children in developing countries that is marked by increased intestinal permeability, impaired gut immune function, malabsorption, growth falter­ing, and, potentially, oral vaccine failure.

Conclusions

In most if not all endemic settings, the coverage and efficacy of malaria control measures remain grossly inadequate, and WHO’s current recommendations should not be interpreted as a licence for large-scale iron supplementation programmes in malaria-endemic set­tings. Further studies are needed to identify antimalarial interventions that can be co-administered so that children receive iron supplementation under the protection of those measures.

Table 1. Current WHO recommendations on iron supplementation in children
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References

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  2. Mwangi MN, Prentice AM, Verhoef H. Safety and bene­fits of antenatal oral iron supplementation in low-income countries: a review. Br J Haematol 2017;177:884-95.
  3. Verhoef H, Veenemans J, Mwangi MN, Pren­tice AM. Safety and benefits of interventions to increase folate status in malaria-endemic areas. Br J Haematol 2017;177:905-18.
  4. Drakesmith H, Prentice AM Hepcidin and the iron-infection axis. Science 2012;338:768-72.
  5. Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A, Dhingra U, Kabole I, Deb S, Othman MK, Kabole FM. 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, randomised, placebo-controlled trial. Lancet 2006;367:133-43.
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