title: 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: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, MN; scusick@umn.edu.
authors.forename: Sarah E
authors.identifier: 0000-0002-0592-1867
authors.initials: SE
authors.lastname: Cusick
authors.affiliation: Departament of Paediatrics and Child Health, College of Health Sciences, Makerere University, Kampala, Uganda;
authors.forename: Robert O
authors.identifier: 0000-0003-3240-2058
authors.initials: RO
authors.lastname: Opoka
authors.affiliation: Department of Pediatrics, University of Texas at Austin Dell Medical School, Austin, TX; and.
authors.forename: Steven A
authors.identifier: 0000-0003-4972-9233
authors.initials: SA
authors.lastname: Abrams
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Chandy C
authors.identifier: 0000-0002-1634-1411
authors.initials: CC
authors.lastname: John
authors.affiliation: Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, MN;
authors.forename: Michael K
authors.identifier: 0000-0003-0844-6907
authors.initials: MK
authors.lastname: Georgieff
authors.affiliation: Departament of Paediatrics and Child Health, College of Health Sciences, Makerere University, Kampala, Uganda;
authors.forename: Ezekiel
authors.initials: E
authors.lastname: Mupere
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000097:blood / Q000188:drug therapy*; D000962:Antimalarials / Q000008:administration & dosage*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D002675:Child, Preschool; D019587:Dietary Supplements; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005293:Ferritins / Q000097:blood; D005500:Follow-Up Studies; D006454:Hemoglobins / Q000378:metabolism; D064451:Hepcidins / Q000097:blood; D006801:Humans; D007223:Infant; D007249:Inflammation / Q000097:blood / Q000209:etiology; D007501:Iron / Q000008:administration & dosage* / Q000097:blood; D007503:Iron Isotopes / Q000008:administration & dosage / Q000097:blood; D008288:Malaria / Q000150:complications / Q000188:drug therapy*; D008297:Male; D011524:Protoporphyrins / Q000097:blood; D011990:Receptors, Transferrin / Q000097:blood
chemical_list: D000962:Antimalarials; D015415:Biomarkers; D006454:Hemoglobins; D064451:Hepcidins; D007503:Iron Isotopes; D011524:Protoporphyrins; D011990:Receptors, Transferrin; C017803:zinc protoporphyrin; D002097:C-Reactive Protein; D005293:Ferritins; D007501:Iron
keywords: Uganda; iron; iron-stable isotopes; malaria; timing of iron therapy