BACKGROUND: Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns about the potential embryotoxicity of artemisinins. We compared adverse pregnancy outcomes after artemisinin-based treatment (ABT) versus non-ABTs in the first trimester of pregnancy. METHODS: For this systematic review and individual patient data (IPD) meta-analysis, we searched MEDLINE, Embase, and the Malaria in Pregnancy Library for prospective cohort studies published between Nov 1, 2015, and Dec 21, 2021, containing data on outcomes of pregnancies exposed to ABT and non-ABT in the first trimester. The results of this search were added to those of a previous systematic review that included publications published up until November, 2015. We included pregnancies enrolled before the pregnancy outcome was known. We excluded pregnancies with missing estimated gestational age or exposure information, multiple gestation pregnancies, and if the fetus was confirmed to be unviable before antimalarial treatment. The primary endpoint was adverse pregnancy outcome, defined as a composite of either miscarriage, stillbirth, or major congenital anomalies. A one-stage IPD meta-analysis was done by use of shared-frailty Cox models. This study is registered with PROSPERO, number CRD42015032371. FINDINGS: We identified seven eligible studies that included 12 cohorts. All 12 cohorts contributed IPD, including 34 178 pregnancies, 737 with confirmed first-trimester exposure to ABTs and 1076 with confirmed first-trimester exposure to non-ABTs. Adverse pregnancy outcomes occurred in 42 (5·7%) of 736 ABT-exposed pregnancies compared with 96 (8·9%) of 1074 non-ABT-exposed pregnancies in the first trimester (adjusted hazard ratio [aHR] 0·71, 95% CI 0·49-1·03). Similar results were seen for the individual components of miscarriage (aHR=0·74, 0·47-1·17), stillbirth (aHR=0·71, 0·32-1·57), and major congenital anomalies (aHR=0·60, 0·13-2·87). The risk of adverse pregnancy outcomes was lower with artemether-lumefantrine than with oral quinine in the first trimester of pregnancy (25 [4·8%] of 524 vs 84 [9·2%] of 915; aHR 0·58, 0·36-0·92). INTERPRETATION: We found no evidence of embryotoxicity or teratogenicity based on the risk of miscarriage, stillbirth, or major congenital anomalies associated with ABT during the first trimester of pregnancy. Given that treatment with artemether-lumefantrine was associated with fewer adverse pregnancy outcomes than quinine, and because of the known superior tolerability and antimalarial effectiveness of ACTs, artemether-lumefantrine should be considered the preferred treatment for uncomplicated P falciparum malaria in the first trimester. If artemether-lumefantrine is unavailable, other ACTs (except artesunate-sulfadoxine-pyrimethamine) should be preferred to quinine. Continued active pharmacovigilance is warranted. FUNDING: Medicines for Malaria Venture, WHO, and the Worldwide Antimalarial Resistance Network funded by the Bill & Melinda Gates Foundation.

Centers for Disease Control and Prevention Atlanta GA USA

Centre for Infectious Disease Epidemiology and Research University of Cape Town Cape Town South Africa

Centre for Tropical Medicine and Global Health Nuffield Department of Medicine University of Oxford Oxford UK; Shoklo Malaria Research Unit Faculty of Tropical Medicine Mahidol University Mae Sot Thailand

Centro de Investigação em Saúde de Manhiça Manhiça Mozambique

Clinical Research Unit of Nanoro Institut de Recherche en Sciences de la Santé Nanoro Burkina Faso

Department of Basic Sciences Copperbelt University Ndola Zambia

Department of Clinical Sciences Liverpool School of Tropical Medicine Liverpool UK

Department of Obstetrics and Gynaecology Makerere University Kampala Uganda

Department of Pharmacy School of Pharmacy and Department of Global Health School of Public Health University of Washington Seattle WA USA

Department of Reproductive Health Moi University Eldoret Kenya

Faculty of Medicine Eduardo Mondlane University Maputo Mozambique; Centro de Investigação em Saúde de Manhiça Manhiça Mozambique

Icon Prague Czech Republic

Ifakara Health Institute Rufiji Tanzania

Kenya Medical Research Institute Centre for Global Health Research Kisumu Kenya

National Institute of Medical Research Amani Medical Research Centre Muheza Tanzania

School of Medicine and Pharmacy University Teaching Hospital of Kigali University of Rwanda Kigali Rwanda

School of Public Health University of Ghana Dodowa Ghana

Tropical Diseases Research Centre Ndola Zambia

UNICEF UNDP World Bank WHO Special Programme for Research and Training in Tropical Diseases Geneva Switzerland; School of Public Health and Community Medicine Institute of Medicine University of Gothenburg Gothenburg Sweden

VA Los Angeles and University of California Los Angeles National Clinician Scholars Program VA Greater Los Angeles Healthcare System Health Services Research and Development Service Center of Innovation Los Angeles CA USA

WorldWide Antimalarial Resistance Network Oxford UK; Infectious Diseases Data Observatory Oxford UK; Centre for Tropical Medicine and Global Health Nuffield Department of Medicine University of Oxford Oxford UK

WorldWide Antimalarial Resistance Network Oxford UK; Infectious Diseases Data Observatory Oxford UK; Centre for Tropical Medicine and Global Health Nuffield Department of Medicine University of Oxford Oxford UK; Division of Infectious Diseases Advanced Clinical Research Center Institute of Medical Science University of Tokyo Tokyo Japan

WorldWide Antimalarial Resistance Network Oxford UK; Infectious Diseases Data Observatory Oxford UK; Department of Clinical Sciences Liverpool School of Tropical Medicine Liverpool UK

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Lancet. 2023 Jan 14;401(10371):81-83. doi: 10.1016/S0140-6736(22)02166-3. PubMed

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