Delaying Iron Therapy until 28 Days after Antimalarial Treatment Is Associated with Greater Iron Incorporation and Equivalent Hematologic Recovery after 56 Days in Children: A Randomized Controlled Trial

Abstract

Background: Iron therapy begun concurrently with antimalarial treatment may not be well absorbed because of malaria-induced inflammation. Delaying the start of iron therapy may permit better iron absorption and distribution.

Objective: We compared erythrocyte iron incorporation in children who started iron supplementation concurrently with antimalarial treatment or 28 d later. We hypothesized that delayed iron supplementation would be associated with greater incorporation and better hematologic recovery.

Methods: We enrolled 100 children aged 6-59 mo with malaria and hemoglobin concentrations of 50.0-99.9 g/L who presented to Mulago Hospital, Kampala, into a randomized trial of iron therapy. All children were administered antimalarial treatment. Children with zinc protoporphyrin (ZPP) ≥80 μmol/mol heme were randomly assigned to start iron supplementation concurrently with the antimalarial treatment [immediate iron (I) group] or 28 d later [delayed iron (D) group]. All children were administered iron-stable isotope (57)Fe on day 0 and (58)Fe on day 28. We compared the percentage of iron incorporation at the start of supplementation (I group at day 0 compared with D group at day 28, aim 1) and hematologic recovery at day 56 (aim 2).

Results: The percentage of iron incorporation (mean ± SE) was greater at day 28 in the D group (16.5% ± 1.7%) than at day 0 in the I group (7.9% ± 0.5%; P < 0.001). On day 56, concentrations of hemoglobin and ZPP and plasma ferritin, soluble transferrin receptor (sTfR), hepcidin, and C-reactive protein did not differ between the groups. On day 28, the hemoglobin (mean ± SD) and plasma iron markers (geometric mean; 95% CI) reflected poorer iron status in the D group than in the I group at this intervening time as follows: hemoglobin (105 ± 15.9 compared with 112 ± 12.4 g/L; P = 0.04), ferritin (39.3 μg/L; 23.5, 65.7 μg/L compared with 79.9 μg/L; 58.3, 110 μg/L; P = 0.02), sTfR (8.9 mg/L; 7.4, 10.7 mg/L compared with 6.7 mg/L; 6.1, 7.5 mg/L; P = 0.01), and hepcidin (13.3 ng/mL; 8.3, 21.2 ng/mL compared with 38.8 ng/mL; 28.3, 53.3 ng/mL; P < 0.001).

Conclusions: Delaying the start of iron improves incorporation but leads to equivalent hematologic recovery at day 56 in Ugandan children with malaria and anemia. These results do not demonstrate a clear, short-term benefit of delaying iron. This trial was registered at clinicaltrials.gov as NCT01754701.

Keywords: Uganda; iron; iron-stable isotopes; malaria; timing of iron therapy.

FIGURE 1

Consort flow diagram. The circled R indicates random assignment.

FIGURE 2

Plasma iron and inflammatory markers at day 0, day 28, and day 56 in 100 Ugandan children aged 6–59 mo with malaria and anemia who started iron therapy concurrently with antimalarial treatment (immediate, I) or 28 d after antimalarial treatment (delayed, D). Error bars reflect SD for arithmetic mean and 95% CI for geometric means. Sample size for indicators (day 0, day 28, day 56) were as follows: hemoglobin (I group: 50, 43, 42; D group: 49, 41, 42), zinc protoporphyrin (I group: 50, 46, 45; D group: 49, 43, 42), plasma ferritin (I group: 50, 45, 43; D group: 48, 40, 43), plasma sTfR (I group: 50, 45, 43; D group: 48, 41, 43), plasma hepcidin (I group: 48, 45, 42; D group: 47, 39, 43), and plasma CRP (I group: 48, 45, 43; D group: 47, 41, 41). CRP, C-reactive protein; sTfR, soluble transferrin receptor.