title: Safety of artemisinins in first trimester of prospectively followed pregnancies: an observational study.
abstract: BACKGROUND
  Artemisinins, the most effective antimalarials available, are not recommended for falciparum malaria during the first trimester of pregnancy because of safety concerns. Therefore, quinine is used despite its poor effectiveness. Assessing artemisinin safety requires weighing the risks of malaria and its treatment. We aimed to assess the effect of first-trimester malaria and artemisinin treatment on miscarriage and major congenital malformations.
  
  
  METHODS
  In this observational study, we assessed data from antenatal clinics on the Thai-Myanmar border between Jan 1, 1994, and Dec 31, 2013. We included women who presented to antenatal clinics during their first trimester with a viable fetus. Women were screened for malaria, and data on malaria, antimalarial treatment, and birth outcomes were collected. The relationship between artemisinin treatments (artesunate, dihydroartemisinin, or artemether) and miscarriage or malformation was assessed using Cox regression with left-truncation and time-varying exposures.
  
  
  RESULTS
  Of 55 636 pregnancies registered between 1994 and 2013, 25 485 pregnancies were analysed for first-trimester malaria and miscarriage, in which 2558 (10%) had first-trimester malaria. The hazard of miscarriage increased 1·61-fold after an initial first-trimester falciparum episode (95% CI 1·32-1·97; p<0·0001), 3·24-fold following falciparum recurrence (2·24-4·68; p<0·0001), and 2·44-fold (1·01-5·88; p=0·0473) following recurrent symptomatic vivax malaria. No difference was noted in miscarriage in first-line falciparum treatments with artemisinin (n=183) versus quinine (n=842; HR 0·78 [95% CI 0·45-1·34]; p=0·3645) or in risk of major congenital malformations (two [2%] of 109 [95% CI 0·22-6·47] versus eight (1%) of 641 [0·54-2·44], respectively).
  
  
  CONCLUSIONS
  First-trimester falciparum and vivax malaria both increase the risk of miscarriage. We noted no evidence of an increased risk of miscarriage or of major congenital malformations associated with first-line treatment with an artemisinin derivative compared with quinine. In view of the low efficacy of quinine and wide availability of highly effective artemisinin-based combination therapies, it is time to reconsider first-trimester antimalarial treatment recommendations.
  
  
  BACKGROUND
  The Wellcome Trust and The Bill & Melinda Gates Foundation.
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia; Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, VIC, Australia. Electronic address: kerrynmoore.kam@burnet.edu.au.
authors: Kerryn A
authors: KA
authors: Moore
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
authors: Julie A
authors: JA
authors: Simpson
authors: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors: Moo Kho
authors: MK
authors: Paw
authors: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors: MuPawJay
authors: M
authors: Pimanpanarak
authors: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors: Jacher
authors: J
authors: Wiladphaingern
authors: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors: Marcus J
authors: MJ
authors: Rijken
authors: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors: Podjanee
authors: P
authors: Jittamala
authors: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors: Nicholas J
authors: NJ
authors: White
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia; Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, VIC, Australia; Department of Epidemiology and Preventive Medicine and Department of Infectious Diseases, Monash University, Melbourne, VIC, Australia.
authors: Freya J I
authors: FJI
authors: Fowkes
authors: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors: François
authors: F
authors: Nosten
authors: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors: Rose
authors: R
authors: McGready
mesh_terms: D000022:Abortion, Spontaneous / Q000139:chemically induced / Q000453:epidemiology; D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000453:epidemiology; D016780:Malaria, Vivax / Q000188:drug therapy; D011247:Pregnancy; D011248:Pregnancy Complications; D011261:Pregnancy Trimester, First; D011803:Quinine / Q000627:therapeutic use; D013785:Thailand / Q000453:epidemiology
chemical_list: D000962:Antimalarials; D037621:Artemisinins; C039060:artenimol; C031327:artemisinin; D011803:Quinine