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.
FINDINGS: 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).
INTERPRETATION: 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.
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The pregnant refugee and migrant women and SMRU staff made this study possible. We thank Paul Agius for statistical advice and Campbell Aitken for technical assistance. The Shoklo Malaria Research Unit is part of the Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme supported by the Wellcome Trust of Great Britain (Major Overseas Programme–Thailand Unit Core Grant). KAM is supported by an Australian Postgraduate Award funded by the Commonwealth Government of Australia. FJIF is supported by a Future Fellowship funded by the Australian Research Council. KAM and FIJF are supported by an Operational Infrastructure Support grant awarded to the Burnet Institute and funded by the Victorian State Government. The data extraction and analysis was supported by a grant funded by the Bill & Melinda Gates Foundation (ID 46589).