The association between malaria and iron status or supplementation in pregnancy: a systematic review and meta-analysis

Abstract

Introduction: Malaria prevention and iron supplementation are associated with improved maternal and infant outcomes. However, evidence from studies in children suggests iron may adversely modify the risk of malaria. We reviewed the evidence in pregnancy of the association between malaria and markers of iron status, iron supplementation or parenteral treatment.

Methods and findings: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Global Health Library, and the Malaria in Pregnancy library to identify studies that investigated the association between iron status, iron treatment or supplementation during pregnancy and malaria. Thirty one studies contributed to the analysis; 3 experimental and 28 observational studies. Iron supplementation was not associated with an increased risk of P. falciparum malaria during pregnancy or delivery in Africa (summary Relative Risk = 0.89, 95% Confidence Interval (CI) 0.66-1.20, I(2) = 78.8%, 5 studies). One study in Asia reported an increased risk of P. vivax within 30 days of iron supplementation (e.g. adjusted Hazard Ratio = 1.75, 95% CI 1.14-2.70 for 1-15 days), but not after 60 days. Iron deficiency (based on ferritin and C-reactive protein) was associated with lower odds for malaria infection (summary Odds Ratio = 0.35, 0.24-0.51, I(2) = 59.2%, 5 studies). With the exception of the acute phase protein ferritin, biomarkers of iron deficiency were generally not associated with malaria infection.

Conclusions: Iron supplementation was associated with a temporal increase in P vivax, but not with an increased risk of P. falciparum; however, data are insufficient to rule out the potential for an increased risk of P. falciparum. Iron deficiency was associated with a decreased malaria risk in pregnancy only when measured with ferritin. Until there is more evidence, it is prudent to provide iron in combination with malaria prevention during pregnancy.

Figure 1. Flow diagram of study selection.

Footnote: *1 study (Kapito-Tembo 2010) appears in categories of iron supplementation and iron status. **Iron status is further stratified into iron deficiency vs. malaria risk and iron biomarkers vs. malaria risk.

Figure 2. Plasmodium falciparum by blood smear among iron-supplemented and non-supplemented pregnant women by timing of malaria test.

Footnote: AM: antimalarials used (either IPTp or cotrimoxazole). CI: confidence interval. G1: primigravidae. G2+: Multigravidae. HIV(+): HIV-positive. IPTp2: intermittent preventive treatment with 2 doses of sulfadoxine-pyrimethamine. *Daily dose of elementary iron. Notes: At delivery: placental blood smear for Ndyomugyenyi 2000 and van Eijk 2007, and peripheral blood smear for Mwapasa 2004. The weight for each study is indicated as a grey block around the risk estimate. Subgroup analyses and additional data are included in eSupplement 3.

Figure 3. Malaria parasitemia by blood smear among iron deficient and non-deficient participants, by definition of iron deficiency during pregnancy.

Footnote: CI: confidence interval. CRP: C-Reactive Protein. EP: Erthyrocyte protoporphyrin. Hb: hemoglobin. *Use of adjusted odds ratios: Kapito-Tembo 2010: odds ratio adjusted for CD4 count, gravidity, and intestinal infections, Dreyfuss: odds ratio adjusted for hookworm infection, serum retinol and trimester of pregnancy. **Iron deficiency definition: Ferritin <30 ng/mL & CRP< = 8.2 ng/mL or ferritin <70 ng/mL & CRP>8.2 ng/mL. The weight for each study is indicated as a grey block around the risk estimate. For Dreyfuss 2000, malaria parasitemia was limited to P. vivax in Asia. All other studies were conducted in Africa where P. falciparum is the predominant species.

Figure 4. Malaria parasitemia among iron deficient and non-deficient participants, by definition of iron deficiency at the time of delivery.

Footnote: BS: bloodsmear. CI: confidence interval. CRP: C-reactive protein. EP: Erthyrocyte protoporphyrin. Hb: hemoglobin. sTfR: Soluble transferrin receptor. *Adjusted odds ratios used: Kabyemela 2008: odds ratio adjusted for gravidity. Senga 2011: odds ratio adjusted for gravidity, age, and blood group. Placental histology in Senga 2011: active infection defined by acute or chronic infection (parasites alone, or parasites in the presence of haemozoin). No placental infection defined by the absence of parasites and haemozoin. ** Ferritin 30/CRP 8.3: Ferritin <30 ng/mL & CRP< = 8.2 ng/mL or ferritin <70 ng/mL & CRP>8.2 ng/mL. The weight for each study is indicated as a grey block around the risk estimate.

Figure 5. Geometric mean difference in ferritin among pregnant women infected with malaria compared to pregnant women without malaria.

Footnote: CI: confidence interval. SD: standard deviation. *Van Santen 2011 and Massawe 2002: study population primigravidae. Abrams 2005 and Ouedraogo 2012: study population HIV(-) women. The weight for each study is indicated as a grey block around the risk estimate. For Dreyfuss 2000, the malaria parasitemia was limited to P. Vivax in Asia. All other studies were conducted in Africa where P. falciparum is the predominant species.

Figure 6. Mean difference in soluble transferring receptor and serum transferrin among pregnant women infected with malaria compared to pregnant women without malaria.

Footnote: CI: confidence interval. SD: standard deviation. *Van Santen 2011 and Massawe 2002: study population primigravidae. Abrams 2005: study population HIV(-) women. The weight for each study is indicated as a grey block around the risk estimate. Removal of the study of Eteng 2010, an outlier for Serum Transferrin, gives the following result: Pooled mean difference Serum Transferrin (g/L): −0.11, 95% CI −0.30 to 0.09, I² 14.8%.

Figure 7. Mean difference in transferrin saturation, serum iron and total iron binding capacity among pregnant women infected with malaria compared to pregnant women without malaria.

Footnote: CI: confidence interval. SD: standard deviation. *Van Santen 2011: study population primigravidae. The weight for each study is indicated as a grey block around the risk estimate. Removal of the study of Eteng 2010, an outlier for Serum Iron and Total Iron Binding Capacity, gives the following results: Pooled mean difference serum iron (μmol/L): −1.13, −2.57 to 0.31, I² 27.3%; Pooled mean difference Total Iron Binding Capacity (μmol/L): 0.13, −0.67 to 0.92, I-squared 0%.