Update of pre- and postnatal iron supplementation in malaria endemic settings

Abstract

This review focuses on pre- and post-natal iron supplementation in malaria endemic settings. Although iron supplementation can reduce iron deficiency, malaria infection may counteract this effect by the increase of hepcidin, and iron supplementation may further worsen malaria infection by providing additional iron for the parasites. However, most iron supplementation intervention studies in pregnant women with malaria have not shown a negative impact, although malaria treatment with iron supplementation may be beneficial in terms of improving birth outcomes. In infants and young children in malaria endemic settings, the adverse effects of iron supplementation has been well documented and malaria prevention and treatment with iron supplementation is recommended. Besides fostering the growth of malaria parasites, iron may also promote potential pathogens in the gut and cause an inflammatory response in young children. Overall, iron supplementation is beneficial of treating iron deficiency, but needs to be considered in the context of malaria prevention and treatment in pregnant women, infants and young children for safety and effectiveness.

INTRODUCTION

Iron is an essential micronutrient that supports hemoglobin synthesis, oxygen delivery and other important metabolic functions. Iron deficiency is the most common micronutrient deficiency in the world and greatly affects pregnant women and the developing fetus, infants and young children (1). For these vulnerable life stages, iron needs often cannot be adequately acquired through diet, due to inadequate total intake and/or low bioavailability. Iron supplementation is a common strategy to prevent or treat iron deficiency in high-risk populations and is recommended by the World Health Organization (WHO) (2, 3). However, infections, especially malaria, interact with iron metabolism and may thus alter the efficacy and possibly the risk of iron supplementation. Here we review the current status of pre- and postnatal iron supplementation interventions in malaria endemic countries, including both risks and benefits of iron supplementation.

IRON NEEDS DURING PREGNANCY

Maternal adaptation to pregnancy results in an increase of iron needs. During pregnancy, blood volume will increase by approximately 50% to maintain circulation and oxygen delivery (4). Although red blood cell mass does not increase as drastically, an additional ~450 mg iron is still needed during pregnancy for erythropoiesis and red blood cell mass expansion (5). Moreover, the placenta and fetus also need a substantial amount of iron to maintain normal growth. Blood volume and red blood cell mass remain relatively unchanged during the first trimester and progressively increase until 34–36 weeks (4); iron needs follow this pattern in parallel. Daily estimated physiologic requirements for iron – the amounts to be absorbed - are estimated to be ~ 0.8 mg/d during the first trimester, 4–5 mg/d in the second trimester and ~ 6 mg/d in the third trimester for an average weight woman (6, 7).

To maintain iron homeostasis during pregnancy, the efficiency of iron absorption increases. One early study using radioactive isotope showed that iron absorption increased from 1% in early pregnancy to 15% in late pregnancy (8). This increase of iron absorption is normally at least partially facilitated by hepcidin modulation. Hepcidin is the main regulatory hormone of iron homeostasis and its synthesis is regulated by circulating iron and iron stores, erythropoietic activity, and inflammation (9). When stimulated, it acts on ferroportin to inhibit intestinal iron absorption and iron release from macrophages and liver (10). During the second and third trimester, serum hepcidin concentrations normally are suppressed and allow greater iron flow into the circulation from both dietary and endogenous sources (11). However, conditions such as infection, inflammation, obesity and pre-eclampsia can stimulate hepcidin and thus counter the normal adaptation to enhance iron absorption in the latter half of pregnancy. Hence, despite these physiological adaptations, iron sufficiency through dietary sources often cannot be met due to the high demand, especially if dietary sources are primarily plant based and of limited bioavailability due to phytates, polyphenols, and other inhibitors of absorption. Furthermore, pre-pregnancy iron stores of ~ 300 mg are needed to augment absorption of dietary iron to meet maternal and fetal iron needs (6). A large proportion of women enter pregnancy with inadequate iron stores.

IRON SUPPLEMENTATION DURING PREGNANCY

Although anemia rates in pregnancy have reportedly declined from ~ 43% to ~38% during the period from 1995–2011, such prevalence estimates represent > 30 million women (12). Approximately half of the anemia during pregnancy is attributable to iron deficiency and is associated with multiple adverse outcomes affecting the woman and her fetus, such as increased risk of preterm birth and low birth weight. It is estimated that the global prevalence of iron deficiency anemia is 19% in pregnant women (13).

In countries where anemia prevalence is over 40%, daily iron supplementation of 60 mg is recommended for pregnant women by the WHO (2). In a Cochrane review, daily iron supplementation was estimated to reduce 70% of anemia during pregnancy (14) and, in some studies, to reduce adverse pregnancy outcomes (15). However, a recent large-scale preconception intervention trial in Vietnam using 60 mg/d iron and folate supplements found that the intervention modestly increased maternal and infant iron stores but did not affect anemia (16). This limited impact may have been due to the low anemia rate of 20% and to the low rate of depleted iron stores (14%) of the participants.

Although many well controlled trials showed the efficacy of iron supplementation (15), poor compliance and limited availability may affect the effectiveness of iron supplementation programs, especially in low resources settings. One study in rural Tanzania (17) showed only a 42% adherence rate to a conventional iron supplement over 12 weeks. Another study in Indonesia (18) found that only approximately 1/3 of women were 100% compliant during the two-month iron supplementation intervention. Strategies to reduce the side effects and increase compliance are under development, such as different forms of iron to improve bioavailability, intermittent iron supplementation therapy, and addition of prebiotics (6, 19).

MALARIA, PREGNANCY AND IRON HOMEOSTASIS

Another confounding factor that affects the effectiveness of iron supplementation is the regulation of hepcidin in settings of inflammation and infection, such as malaria. Malaria is a mosquito-borne infectious disease that causes an intense inflammatory response. It is endemic in sub-Saharan Africa and rural regions of South Asia. Pregnant women are at high risk of malaria infection which is associated with miscarriages, infant mortality, increased vulnerability to maternal infections (20) and sequestration of malaria-infected erythrocytes in the maternal blood spaces of the placenta (21). Approximately 35 million pregnant women are at risk of malaria infection every year (22). Besides these well-documented adverse effects, malaria infection during pregnancy also may lead to anemia of inflammation. The increase of inflammatory cytokine IL-6 by malaria stimulates production of hepcidin which then counteracts the iron homeostasis regulation during pregnancy, when hepcidin levels are normally low (9, 23). Another confounding factor is that the majority of the malaria endemic regions are also iron-deficiency-endemic regions, making it critical to implement safe and effective iron supplementation in these regions.

Iron supplementation in malaria endemic regions has been associated with increased occurrence of adverse events, such as other infectious diseases and inflammation, which was associated with increased morbidity in infants and young children, as discussed in subsequent sections. In pregnant women, observational studies have shown an association between iron status and risk of malaria. In northeastern Tanzania, where both malaria and iron deficiency are common, placental malaria was less prevalent and less severe among iron deficient women compared to those with sufficient iron storage (24). Similar results were found in southern Malawi (25), such that iron deficiency was associated with reduced prevalence of malaria infections. Also in Democratic Republic of the Congo, serum ferritin, a positive acute phase reactant, was significantly higher in malaria-infected pregnant women than in non-infected women (26). A plausible explanation for these findings is that iron deficiency may limit iron availability to the malaria parasite. Indeed, one in vitro study that examined red blood cells from pregnant women (27) found that the growth of malaria parasite Plasmodium falciparum was reduced in anemic pregnant women and was increased with iron supplementation. Overall, the increase of hepcidin with inflammation appears to be a physiological protective response to reduce iron availability for potential pathogen growth. Administration of iron supplements to pregnant women who are malaria infected could theoretically worsen the infection by providing additional iron to malaria parasites but strong evidence for such an effect is lacking.

Data from randomized trials on the impact of iron supplementation during pregnancy in the presence of malaria infections is less clear. One recent trial in pregnant women from rural Malawi showed that, compared to a lipid-based nutrient supplement containing 20 mg iron plus multiple micronutrients or to a multiple micronutrient capsulated supplement containing 20 mg/d iron, a 60 mg/d iron + folic acid supplement during pregnancy was associated with better iron status at 36 weeks of gestation (28). Additionally, among those with malaria at enrollment, the probability of low hemoglobin at 36 weeks was lower in both the iron+folate and the multiple micronutrient capsule groups compared to the lipid-based nutrient supplement group, possibly due to lower bioavailability of the iron in the lipid-based supplement (28). Another trial of similar design in semi-urban setting of Ghana had similar findings on hemoglobin and iron status (29). Biomarkers of inflammation (CRP, AGP) were elevated at 36 weeks of pregnancy and were not affected by types of supplements. Malaria infection rate was approximately 10% at enrollment (12 weeks of pregnancy) and didn’t appear to associate with inflammation (29). There are other intervention trials that also showed no adverse effects of iron supplementation during pregnancy on risk of malaria in Gambia (30) and Kenya (31). One study in Thailand found that the development of Plasmodium vivax malaria was associated with iron supplementation during pregnancy (32). A 2015 systematic review and meta-analysis on the association between malaria and iron supplementation during pregnancy concluded that iron supplementation was associated with a temporal increase in Plasmodium vivax infections without a clear effect on Plasmodium falciparum risk (33). A 2018 Lancet review also concluded that in clinical trials, iron supplementation does not increase the risk of malaria in pregnancy (34)

Although majority of current literature showed no adverse impact of iron supplementation on maternal risk of malaria, treatment of malaria infections should be considered before or together with iron supplementation because some studies showed that it may improve birth outcomes. One study in urban Tanzania (35) randomized iron-replete pregnant women to an iron supplementation group (60 mg/d) or placebo, with malaria screening and treatment for all participants. Results showed that the risk of placental malaria was not increased by maternal iron supplementation. Compared with placebo, iron supplementation significantly decreased the risk of anemia at delivery and maternal iron deficiency, although iron supplementation did not affect birth weight. Another randomized controlled trial in pregnant women from rural Kenya (36) had a similar design of 60 mg/d iron supplementation or placebo, with intermittent preventive treatment of malaria. This study also found no significant differences in overall maternal Plasmodium infection risk between the two arms and iron supplementation increased birth weight. Another study in Mumbai, India (moderate risk of malaria) also showed that a daily dose of energy and nutrients, including iron (10–35% WHO Reference Nutrient Intakes) from >90 d before pregnancy until delivery resulted in increase of birth weight in mothers who were not under weight and consumed the supplement ≥ 3 months prior to pregnancy (37). Note that the iron supplementation in this trial was relatively low at ~6 mg/d and malaria status of the participants were not reported. A 2010 analysis of demographic and health surveys from 19 malaria-endemic countries demonstrated that there was a significant protective effect for neonatal death in mothers who received both iron supplementation and intermittent treatment of malaria. This protective effect did not exist in mothers who received either the iron supplementation or malaria treatment alone (38). Overall, it appears that with adequate measures to prevent and treat malaria infections, iron supplementation can be safe and effective to benefit both the mothers and the newborns. It is recommended to treat malaria intermittently and preventively during pregnancy in areas with medium and high malaria prevalence (39).

The current WHO recommendation on iron supplementation in non-pregnant females of reproductive age (menstruating adult women and adolescent girls) is 30–60 mg/d iron for three consecutive months in a year (2). Whether this recommended dose is safe and effective specifically in malaria-endemic settings is not clear. One recent trial in a malaria-endemic setting in rural Burkina Faso gave young women weekly supplementation of 60 mg iron with folic acid for up to 18 months preconception found that weekly iron supplementation did not increase malaria risk, improve iron status or reduce anemia either before or during early pregnancy (40). Although the mean hepcidin concentration was higher in individuals with malaria infection, this difference did not affect iron status (40). Safe and effective dosage of preconception iron supplementation needs further investigation.

IRON NEEDS, MALARIA AND POSTNATAL IRON SUPPLEMENTATION

Newborns in most high-resource settings are at a low risk for iron deficiency due to a substantial iron endowment at birth (41), which provides adequate iron from birth to approximately 4–6 months of life. However, newborns in low-resource settings are at higher risk of anemia due to low maternal supply and infections which result in less placental iron transfer. Older infants and young children in malaria-endemic regions are also at high risk of iron-deficiency and iron-deficiency anemia, which may have long-term impact on growth, neuro- and motor- development (42). In sub-Saharan Africa (malaria-endemic regions), iron-deficiency anemia is estimated to be around 60% overall, with 40–50% in children under 5 years (43). Malaria infections may increase the risk of anemia in infants and young children, and there appears to be a direct relationship between malaria and iron status in infants and young children. One longitudinal observation study from birth to 3 years in Tanzania showed that iron deficiency reduced the odds of subsequent severe malaria and reduced the prevalence of severe malaria (44). A recent observational study in Benin also showed that high iron levels in infants were positively associated with malaria (Plasmodium falciparum) infections (45).

In intervention studies, a 2006 large-scale intervention trial conducted in Pemba, Zanzibar (46) found that iron supplementation (12.5 mg/d) was associated with more death and hospitalization in infants and young children compared with the placebo group. The adverse effects of the iron supplementation were observed primarily in participants who were iron replete. This trial led to the 2007 WHO recommendation not to use iron-containing micronutrient powders in high malaria transmission areas except for children who were documented to be iron deficient (47). A later statement of the WHO in 2011 indicated “In malaria-endemic areas, the provision of iron should be implemented in conjunction with measures to prevent, diagnose and treat malaria” in infants and young children 6 to 23 months (48).

Another later trial of older infants and toddlers in Pakistan also found that iron supplementation in the form of micronutrient powders resulted in an increased proportion of days with diarrhea and increased incidence of bloody diarrhea (49). A 2013 double-blind, randomized trial of children 6 to 35 months in Ghana showed that with appropriate malaria treatment, a daily micronutrient powder with 12.5 mg of iron did not increase the incidence of malaria (50). Another study of children in Uganda found that delaying iron supplementation 28 days after treatment of malaria did not have additional benefits comparing to beginning iron supplementation concurrently with malaria treatment (51). In a 2016 Cochrane review of 35 trials on iron supplementation in children with malaria (52), the overall conclusion was that iron supplementation did not increase the risk of clinical malaria when regular malaria prevention or management services were provided, and that iron can be administered without testing for iron deficiency if malaria prevention or management services can be provided efficiently.

IRON SUPPLEMENTATION AND THE GUT MICROBIOTA

Besides a direct impact on malaria parasite growth, iron may foster the growth of other pathogens in the gut. For example, iron is an indispensable nutrient for Salmonella spp, Shigella spp., and pathogenic E. coli (53). Because the iron absorption rate is relatively low, the majority of iron from supplementation will be unabsorbed and available for the growth of certain pathogenic strains in the gut (54). Studies of iron supplementation on the gut microbiota have mainly focused on infants and young children. A randomized controlled trial in Cote d’Ivoire (Ivory Coast) reported that iron fortification (providing ~20 mg/d) was associated with an unfavorable gut microbiome profile and increased gut inflammation in anemic African children (6–14 years old) (55). In anemic 6–9 month old Kenyan infants (56), iron supplementation was associated with increased Escherichia/Shigella and Clostridium, accompanied by elevated intestinal inflammation status. Similar findings were reported in non-anemic Kenyan infants as well (57).

Studies on the effects of iron supplementation on the enteric microbiome in pregnant women are limited. One recent study (58) compared the gut microbiota in overweight and obese pregnant women receiving <60 mg/d or >60 mg/d of iron in Australia and found that the low iron supplementation group had higher abundances of the potential beneficial short-chain fatty acid producing strains, compared with the high iron supplementation group. These findings, although limited and heterogeneous in design, suggested that the iron supplementation may adversely affect the gut microbial composition and metabolites which, in turn, may impact inflammatory status and other health indicators of the host. Future studies are needed to systematically evaluate iron supplementation on the gut microbiota in pregnant women from malaria endemic regions, who are already prone to infections and inflammation.

CONCLUSIONS

Given the well-documented adverse effects of iron deficiency on the pregnant woman and her fetus, it is critical to supplement iron to pregnant women who are iron deficient. However, iron supplements can potentially foster the growth of malaria parasites and other potential pathogens in the gut and may worsen inflammation. Although research on the impact of iron supplementation in pregnant women with malaria is still an active area of investigation, most of the current literature does not suggest an adverse effect of iron supplementation during pregnancy on risk of malaria. Malaria treatment and prevention during pregnancy with iron supplementation may improve birth outcomes, and in malaria-endemic regions, prevention and treatment of malaria infections along with iron supplementation are recommended. In pregnant women who are iron replete, there appears to be little or no known benefits of iron supplementation. When possible, testing iron status before prescribing iron supplementation to pregnant women is necessary to ensure safe and effective interventions. Postnatal iron supplementation in older infants and young children who are iron deficient is clearly warranted for the benefits on development and growth. Adverse effects of supplementation in children who are iron replete have been demonstrated and could potentially worsen malaria infections. If global screening for iron deficiency is not possible, iron supplementation should then be combined with malaria prevention and treatment in infants and young children.