title: Intermittent preventive treatment of malaria in pregnancy with mefloquine in HIV-negative women: a multicentre randomized controlled trial.
abstract: BACKGROUND
  Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended by WHO to prevent malaria in African pregnant women. The spread of SP parasite resistance has raised concerns regarding long-term use for IPT. Mefloquine (MQ) is the most promising of available alternatives to SP based on safety profile, long half-life, and high efficacy in Africa. We evaluated the safety and efficacy of MQ for IPTp compared to those of SP in HIV-negative women.
  
  
  RESULTS
  A total of 4,749 pregnant women were enrolled in an open-label randomized clinical trial conducted in Benin, Gabon, Mozambique, and Tanzania comparing two-dose MQ or SP for IPTp and MQ tolerability of two different regimens. The study arms were: (1) SP, (2) single dose MQ (15 mg/kg), and (3) split-dose MQ in the context of long lasting insecticide treated nets. There was no difference on low birth weight prevalence (primary study outcome) between groups (360/2,778 [13.0%]) for MQ group and 177/1,398 (12.7%) for SP group; risk ratio [RR], 1.02 (95% CI 0.86-1.22; p=0.80 in the ITT analysis). Women receiving MQ had reduced risks of parasitemia (63/1,372 [4.6%] in the SP group and 88/2,737 [3.2%] in the MQ group; RR, 0.70 [95% CI 0.51-0.96]; p=0.03) and anemia at delivery (609/1,380 [44.1%] in the SP group and 1,110/2743 [40.5%] in the MQ group; RR, 0.92 [95% CI 0.85-0.99]; p=0.03), and reduced incidence of clinical malaria (96/551.8 malaria episodes person/year [PYAR] in the SP group and 130/1,103.2 episodes PYAR in the MQ group; RR, 0.67 [95% CI 0.52-0.88]; p=0.004) and all-cause outpatient attendances during pregnancy (850/557.8 outpatients visits PYAR in the SP group and 1,480/1,110.1 visits PYAR in the MQ group; RR, 0.86 [0.78-0.95]; p=0.003). There were no differences in the prevalence of placental infection and adverse pregnancy outcomes between groups. Tolerability was poorer in the two MQ groups compared to SP. The most frequently reported related adverse events were dizziness (ranging from 33.9% to 35.5% after dose 1; and 16.0% to 20.8% after dose 2) and vomiting (30.2% to 31.7%, after dose 1 and 15.3% to 17.4% after dose 2) with similar proportions in the full and split MQ arms. The open-label design is a limitation of the study that affects mainly the safety assessment.
  
  
  CONCLUSIONS
  Women taking MQ IPTp (15 mg/kg) in the context of long lasting insecticide treated nets had similar prevalence rates of low birth weight as those taking SP IPTp. MQ recipients had less clinical malaria than SP recipients, and the pregnancy outcomes and safety profile were similar. MQ had poorer tolerability even when splitting the dose over two days. These results do not support a change in the current IPTp policy.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT 00811421; Pan African Clinical Trials Registry PACTR 2010020001429343 Please see later in the article for the Editors' Summary.
authors.affiliation: Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain; Manhiça Health Research Center (CISM), Manhiça, Mozambique.
authors.forename: Raquel
authors.initials: R
authors.lastname: González
authors.affiliation: Centre de Recherches Médicales de Lambaréné (CERMEL), Albert Schweitzer Hospital, Lambaréné, Gabon; Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.
authors.forename: Ghyslain
authors.initials: G
authors.lastname: Mombo-Ngoma
authors.affiliation: Faculté des Sciences de la Santé (FSS), Université d'Aboméy Calavi, Cotonou, Benin; Institut de Recherche pour le Développement (IRD), Paris, France.
authors.forename: Smaïla
authors.initials: S
authors.lastname: Ouédraogo
authors.affiliation: Ifakara Health Institute (IHI), Dodoma, Tanzania.
authors.forename: Mwaka A
authors.initials: MA
authors.lastname: Kakolwa
authors.affiliation: Ifakara Health Institute (IHI), Dodoma, Tanzania.
authors.forename: Salim
authors.initials: S
authors.lastname: Abdulla
authors.affiliation: Faculté des Sciences de la Santé (FSS), Université d'Aboméy Calavi, Cotonou, Benin; Institut de Recherche pour le Développement (IRD), Paris, France.
authors.forename: Manfred
authors.initials: M
authors.lastname: Accrombessi
authors.affiliation: Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain; Manhiça Health Research Center (CISM), Manhiça, Mozambique.
authors.forename: John J
authors.initials: JJ
authors.lastname: Aponte
authors.affiliation: Centre de Recherches Médicales de Lambaréné (CERMEL), Albert Schweitzer Hospital, Lambaréné, Gabon; Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.
authors.forename: Daisy
authors.initials: D
authors.lastname: Akerey-Diop
authors.affiliation: Centre de Recherches Médicales de Lambaréné (CERMEL), Albert Schweitzer Hospital, Lambaréné, Gabon; Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.
authors.forename: Arti
authors.initials: A
authors.lastname: Basra
authors.affiliation: Institut de Recherche pour le Développement (IRD), Paris, France; Université René Descartes, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Briand
authors.affiliation: Centre de Recherches Médicales de Lambaréné (CERMEL), Albert Schweitzer Hospital, Lambaréné, Gabon; Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.
authors.forename: Meskure
authors.initials: M
authors.lastname: Capan
authors.affiliation: Institut de Recherche pour le Développement (IRD), Paris, France; Université René Descartes, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Cot
authors.affiliation: Ifakara Health Institute (IHI), Dodoma, Tanzania.
authors.forename: Abdunoor M
authors.initials: AM
authors.lastname: Kabanywanyi
authors.affiliation: Centre de Recherches Médicales de Lambaréné (CERMEL), Albert Schweitzer Hospital, Lambaréné, Gabon; Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kleine
authors.affiliation: Centre de Recherches Médicales de Lambaréné (CERMEL), Albert Schweitzer Hospital, Lambaréné, Gabon; Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kremsner
authors.affiliation: Manhiça Health Research Center (CISM), Manhiça, Mozambique.
authors.forename: Eusebio
authors.initials: E
authors.lastname: Macete
authors.affiliation: Centre de Recherches Médicales de Lambaréné (CERMEL), Albert Schweitzer Hospital, Lambaréné, Gabon; Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.
authors.forename: Jean-Rodolphe
authors.initials: JR
authors.lastname: Mackanga
authors.affiliation: Faculté des Sciences de la Santé (FSS), Université d'Aboméy Calavi, Cotonou, Benin.
authors.forename: Achille
authors.initials: A
authors.lastname: Massougbodgi
authors.affiliation: Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain; Manhiça Health Research Center (CISM), Manhiça, Mozambique.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Mayor
authors.affiliation: Manhiça Health Research Center (CISM), Manhiça, Mozambique.
authors.forename: Arsenio
authors.initials: A
authors.lastname: Nhacolo
authors.affiliation: Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain.
authors.forename: Golbahar
authors.initials: G
authors.lastname: Pahlavan
authors.affiliation: Centre de Recherches Médicales de Lambaréné (CERMEL), Albert Schweitzer Hospital, Lambaréné, Gabon; Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany; Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Ramharter
authors.affiliation: Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain; Manhiça Health Research Center (CISM), Manhiça, Mozambique.
authors.forename: María
authors.initials: M
authors.lastname: Rupérez
authors.affiliation: Manhiça Health Research Center (CISM), Manhiça, Mozambique.
authors.forename: Esperança
authors.initials: E
authors.lastname: Sevene
authors.affiliation: Manhiça Health Research Center (CISM), Manhiça, Mozambique.
authors.forename: Anifa
authors.initials: A
authors.lastname: Vala
authors.affiliation: Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany; Ngounie Medical Research Centre, Fougamou, Gabon.
authors.forename: Rella
authors.initials: R
authors.lastname: Zoleko-Manego
authors.affiliation: Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain; Manhiça Health Research Center (CISM), Manhiça, Mozambique.
authors.forename: Clara
authors.initials: C
authors.lastname: Menéndez
mesh_terms: D000293:Adolescent; D000328:Adult; D017954:Africa South of the Sahara / Q000453:epidemiology; D000962:Antimalarials / Q000008:administration & dosage*; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections; D006801:Humans; D007230:Infant, Low Birth Weight; D057148:Insecticide-Treated Bednets / Q000706:statistics & numerical data*; D008288:Malaria / Q000175:diagnosis / Q000453:epidemiology / Q000517:prevention & control*; D015767:Mefloquine / Q000008:administration & dosage*; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000175:diagnosis / Q000453:epidemiology / Q000517:prevention & control*; D011314:Preventive Health Services / Q000706:statistics & numerical data; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000962:Antimalarials; D015767:Mefloquine