title: Malaria illness mediated by anaemia lessens cognitive development in younger Ugandan children.
abstract: BACKGROUND
  Asymptomatic falciparum malaria is associated with poorer cognitive performance in African schoolchildren and intermittent preventive treatment of malaria improves cognitive outcomes. However, the developmental benefits of chemoprevention in early childhood are unknown. Early child development was evaluated as a major outcome in an open-label, randomized, clinical trial of anti-malarial chemoprevention in an area of intense, year-round transmission in Uganda.
  
  
  METHODS
  Infants were randomized to one of four treatment arms: no chemoprevention, daily trimethoprim-sulfamethoxazole, monthly sulfadoxine-pyrimethamine, or monthly dihydroartemisinin-piperaquine (DP), to be given between enrollment (4-6 mos) and 24 months of age. Number of malaria episodes, anaemia (Hb < 10) and neurodevelopment [Mullen Scales of Early Learning (MSEL)] were assessed at 2 years (N = 469) and at 3 years of age (N = 453); at enrollment 70 % were HIV-unexposed uninfected (HUU) and 30 % were HIV-exposed uninfected (HEU).
  
  
  RESULTS
  DP was highly protective against malaria and anaemia, although trial arm was not associated with MSEL outcomes. Across all treatment arms, episodes of malarial illness were negatively predictive of MSEL cognitive performance both at 2 and 3 years of age (P = 0.02). This relationship was mediated by episodes of anaemia. This regression model was stronger for the HEU than for the HUU cohort. Compared to HUU, HEU was significantly poorer on MSEL receptive language development irrespective of malaria and anaemia (P = 0.01).
  
  
  CONCLUSIONS
  Malaria with anaemia and HIV exposure are significant risk factors for poor early childhood neurodevelopment in malaria-endemic areas in rural Africa. Because of this, comprehensive and cost/effective intervention is needed for malaria prevention in very young children in these settings.
authors.affiliation: Department of Psychiatry, Michigan State University, 965 Fee Road, Room A227, East Fee Hall, East Lansing, MI, 48824, USA. boivin@msu.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Boivin
authors.affiliation: Department of Statistics and Probability, Michigan State University, East Lansing, MI, USA.
authors.forename: Alla
authors.initials: A
authors.lastname: Sikorskii
authors.affiliation: Department of Psychiatry, Michigan State University, 965 Fee Road, Room A227, East Fee Hall, East Lansing, MI, 48824, USA.
authors.forename: Itziar
authors.initials: I
authors.lastname: Familiar-Lopez
authors.affiliation: Department of Psychiatry, Michigan State University, 965 Fee Road, Room A227, East Fee Hall, East Lansing, MI, 48824, USA.
authors.forename: Horacio
authors.initials: H
authors.lastname: Ruiseñor-Escudero
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Mary
authors.initials: M
authors.lastname: Muhindo
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: James
authors.initials: J
authors.lastname: Kapisi
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Victor
authors.initials: V
authors.lastname: Bigira
authors.affiliation: Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: Judy K
authors.initials: JK
authors.lastname: Bass
authors.affiliation: Department of Paediatrics and Child Health, School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Robert O
authors.initials: RO
authors.lastname: Opoka
authors.affiliation: Department of Psychiatry, School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Noeline
authors.initials: N
authors.lastname: Nakasujja
authors.affiliation: School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Moses
authors.initials: M
authors.lastname: Kamya
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA, USA.
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
mesh_terms: D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D000367:Age Factors; D000740:Anemia / Q000150:complications / Q000453:epidemiology / Q000209:etiology; D000962:Antimalarials / Q000627:therapeutic use; D037621:Artemisinins / Q000627:therapeutic use; D003071:Cognition; D003072:Cognition Disorders / Q000209:etiology; D060085:Coinfection / Q000150:complications / Q000453:epidemiology / Q000209:etiology; D004338:Drug Combinations; D016778:Malaria, Falciparum / Q000150:complications / Q000188:drug therapy / Q000453:epidemiology / Q000469:parasitology; D011739:Pyrimethamine / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use; D012307:Risk Factors; D013413:Sulfadoxine / Q000627:therapeutic use; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000627:therapeutic use; D014454:Uganda / Q000453:epidemiology; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; C039060:artenimol; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; C034759:piperaquine; D011739:Pyrimethamine; D011804:Quinolines; D013413:Sulfadoxine; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D010879:Piperazines