Severe anemia in Malawian children

Abstract

Background: Severe anemia is a major cause of sickness and death in African children, yet the causes of anemia in this population have been inadequately studied.

Methods: We conducted a case-control study of 381 preschool children with severe anemia (hemoglobin concentration, <5.0 g per deciliter) and 757 preschool children without severe anemia in urban and rural settings in Malawi. Causal factors previously associated with severe anemia were studied. The data were examined by multivariate analysis and structural equation modeling.

Results: Bacteremia (adjusted odds ratio, 5.3; 95% confidence interval [CI], 2.6 to 10.9), malaria (adjusted odds ratio, 2.3; 95% CI, 1.6 to 3.3), hookworm (adjusted odds ratio, 4.8; 95% CI, 2.0 to 11.8), human immunodeficiency virus infection (adjusted odds ratio, 2.0; 95% CI, 1.0 to 3.8), the G6PD^-202/-376 genetic disorder (adjusted odds ratio, 2.4; 95% CI, 1.3 to 4.4), vitamin A deficiency (adjusted odds ratio, 2.8; 95% CI, 1.3 to 5.8), and vitamin B₁₂ deficiency (adjusted odds ratio, 2.2; 95% CI, 1.4 to 3.6) were associated with severe anemia. Folate deficiency, sickle cell disease, and laboratory signs of an abnormal inflammatory response were uncommon. Iron deficiency was not prevalent in case patients (adjusted odds ratio, 0.37; 95% CI, 0.22 to 0.60) and was negatively associated with bacteremia. Malaria was associated with severe anemia in the urban site (with seasonal transmission) but not in the rural site (where malaria was holoendemic). Seventy-six percent of hookworm infections were found in children under 2 years of age.

Conclusions: There are multiple causes of severe anemia in Malawian preschool children, but folate and iron deficiencies are not prominent among them. Even in the presence of malaria parasites, additional or alternative causes of severe anemia should be considered.

Figure 1

Adjusted Odds Ratios and 95% Confidence Intervals for Factors Associated with Severe Anemia, According to Study Group and Recruitment Site. The model was corrected for the possible confounders of age, sex, recent antimalarial treatment (within the previous 8 weeks), recent hematinic treatment (within the previous 8 weeks), a history of transfusion (before the previous 4 weeks), and death of a parent. The goodness of fit of the model was evaluated by the Hosmer-Lemeshow test (P = 0.65). In the combined model, interaction existed between malaria and site (P<0.001). Limited maternal education indicates mothers who did not attend secondary school. Wasting is defined as a weight-for-height z score of less than −2. Concentrations of vitamin B₁₂ of less than 20 ng per deciliter (148 pmol per liter) and of vitamin A of less than 20 µg per deciliter (0.7 µmol per liter) are considered to indicate deficiency. Iron deficiency is defined as a ratio of soluble transferrin receptor to log ferritin (TfR-F index) of more than 5.6 (unpublished data). Cultures to detect bacteremia were performed only in case patients and hospital controls. Hookworm infection was not entered in the urban model because the prevalence was less than 5%. The reference single-nucleotide polymorphism (rs) classification for IL10 +4949 is rs3024500. Because of the high correlation among the three interleukin-10 polymorphisms, only one (most strongly associated with severe anemia) was included in the multivariate model. HIV denotes human immunodeficiency virus, and G6PD^{−202/−376} denotes boys who are hemizygous and girls who are homozygous for both the G6PD202A and the G6PD376G alleles.

Figure 2

Structural Equation Model for Severe Anemia, Iron Deficiency, and Malaria. In this exploratory model of the factors associated with severe anemia, the sizes of the associations are indicated by the standardized regression coefficients (range, −1.0 to +1.0). Inverse (protective) associations are indicated by red lines. This model was created containing all possible associations between the displayed variables, after which all nonsignificant arrows (P≥0.05) were removed. The model also contained all other variables entered in the multivariate model (omitted for clarity). The displayed variables were all adjusted for age; in addition, malaria was adjusted for previous use of antimalarial agents, and iron deficiency was adjusted for a history of transfusions (before the previous 4 weeks) or use of hematinic agents (within the previous 8 weeks) (both omitted for clarity). Replacement of severe anemia by continuous hemoglobin levels and iron deficiency (ratio of soluble transferrin receptor to log ferritin, >5.6) resulted in a virtually identical model. The overall model fit was valid (root mean square area of approximation, 0.043; 95% confidence interval, 0.039 to 0.048).