Iron deficiency protects against severe Plasmodium falciparum malaria and death in young children

Abstract

Background: Iron supplementation may increase malaria morbidity and mortality, but the effect of naturally occurring variation in iron status on malaria risk is not well studied.

Methods: A total of 785 Tanzanian children living in an area of intense malaria transmission were enrolled at birth, and intensively monitored for parasitemia and illness including malaria for up to 3 years, with an average of 47 blood smears. We assayed plasma samples collected at routine healthy-child visits, and evaluated the impact of iron deficiency (ID) on future malaria outcomes and mortality.

Results: ID at routine, well-child visits significantly decreased the odds of subsequent parasitemia (23% decrease, P < .001) and subsequent severe malaria (38% decrease, P = .04). ID was also associated with 60% lower all-cause mortality (P = .04) and 66% lower malaria-associated mortality (P = .11). When sick visits as well as routine healthy-child visits are included in analyses (average of 3 iron status assays/child), ID reduced the prevalence of parasitemia (6.6-fold), hyperparasitemia (24.0-fold), and severe malaria (4.0-fold) at the time of sample collection (all P < .001).

Conclusions: Malaria risk is influenced by physiologic iron status, and therefore iron supplementation may have adverse effects even among children with ID. Future interventional studies should assess whether treatment for ID coupled with effective malaria control can mitigate the risks of iron supplementation for children in areas of malaria transmission.

Figure 1.

The prevalence of iron deficiency (ID) (circles), hemoglobin <10 g/dL (triangles), and hemoglobin <8 g/dL (squares) in children by age group. ID and hemoglobin were determined on samples obtained at routine, aparasitemic visits. The sample size was n = 1696 for ID measures and n = 1327 for hemoglobin measures. Age-specific sample sizes reflect ID measures on top row and hemoglobin measures on bottom row.

Figure 2.

Iron deficiency (ID) is associated with lower proportion of visits with parasitemia (A) and lower parasite density (B) in all age groups. Iron status measures were obtained at routine visits. (A) Percentage of visits with parasitemia in children at different age groups stratified by iron status. (B) Mean parasite count/200 white blood cells in parasitemic children at different age groups stratified by iron status. Children with ID had 6.6-fold lower odds of malaria parasitemia (odds ratio [95% confidence interval; CI] = 0.15 [0.12, 0.19], P < .001) and 3.9-fold lower parasite count (P < .001) compared with children with normal iron stores, even after accounting for potential confounders. Visits with normal iron stores (black bars) and ID (white bars) are shown. Samples sizes for visits with normal iron stores are given above samples sizes with ID. Error bars represent 95% CIs. WBC, white blood cells.

Figure 3.

Iron deficiency (ID) is associated with lower proportion of visits with hyperparasitemia (A) and severe malaria (B). Iron status measures were obtained at both routine and hospital visits. (A) Percentage of visits with hyperparasitemia in different age groups stratified by iron status. (B) Percentage of visits with severe malaria in different age groups stratified by iron status. Children with ID had a 24.0-fold lower odds of hyperparasitemia (odds ratio [OR; 95% confidence interval; CI] = 0.04 [0.02, 0.07], P < .001) and a 4.0-fold lower odds of severe malaria (OR [95% CI] 0.25 [0.14, 0.46], P < .001) than children with normal iron status, even after adjusting for potential confounders. Visits with normal iron stores (black bars) and ID (white bars) are shown. Samples sizes for visits with normal iron stores are given above samples sizes with ID. Error bars represent 95% CIs.

Figure 4.

Iron deficiency (ID) predicts decreased incidence of subsequent malaria events. Iron status, measures were obtained at routine, aparasitemic visits. For each iron status determination, we examined the relationship between iron status and the proportion of future visits with (A) parasitemia, (B) hyperparasitemia, or (C) severe malaria after adjusting for potential confounders and the number of iron status measures per child, the average age of the child at their iron status measurements, and the follow-up time interval. The time interval examined extended until the child had a subsequent iron status determination or completed the study. Children who were ID at routine aparasitemic visits had an 18% decreased mean incidence of parasitemia (P < .001), a 10% decreased mean incidence of hyperparasitemia (P = not significant), and a 38% decreased mean incidence of severe malaria (P = .07) during the subsequent months compared with children without ID. Error bars represent 95% confidence intervals.

Figure 5.

Iron deficiency (ID) predicts decreased risk of subsequent (A) all-cause mortality and (B) malaria-associated mortality. We evaluated the relationship between iron status measured at well-child, aparasitemic visits and mortality in Cox proportional hazards models. ID status was coded as a time-varying covariate. We assessed Hemoglobin S, village, bed net use, low birth weight, and hemoglobin level as potential confounders; however, none of these variables was associated with mortality at P < .1 and were therefore not included in the model. In each graph, dashed lines indicate normal iron status (totaling 42 135 person weeks) and solid lines indicate iron-deficient status (totaling 45 483 person weeks). During periods of ID, children had 60% reduced all-cause mortality (hazards ratio [HR; 95% confidence interval; CI] = 0.40 [0.16, 0.96], P = .04) and 66% reduced malaria-associated mortality (HR [95% CI] = 0.34 [0.09, 1.3], P = .11) over the 3 years of follow-up compared with iron-replete periods.