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

Komentář v

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

Zobrazit více v PubMed

Moeller SL, Nyengaard JR, Larsen LG, et al. Malaria in early pregnancy and the development of the placental vasculature. J Infect Dis. 2019;220:1425–1434. PubMed

Griffin JB, Lokomba V, Landis SH, et al. Plasmodium falciparum parasitaemia in the first half of pregnancy, uterine and umbilical artery blood flow, and foetal growth: a longitudinal Doppler ultrasound study. Malar J. 2012;11:319. PubMed PMC

McClure EM, Meshnick SR, Lazebnik N, et al. A cohort study of Plasmodium falciparum malaria in pregnancy and associations with uteroplacental blood flow and fetal anthropometrics in Kenya. Int J Gynaecol Obstet. 2014;126:78–82. PubMed PMC

Schmiegelow C, Matondo S, Minja DTR, et al. Plasmodium falciparum infection early in pregnancy has profound consequences for fetal growth. J Infect Dis. 2017;216:1601–1610. PubMed

Huynh BT, Cottrell G, Cot M, Briand V. Burden of malaria in early pregnancy: a neglected problem? Clin Infect Dis. 2015;60:598–604. PubMed

Harrington WE, Moore KA, Min AM, et al. Falciparum but not vivax malaria increases the risk of hypertensive disorders of pregnancy in women followed prospectively from the first trimester. BMC Med. 2021;19:98. PubMed PMC

Accrombessi M, Yovo E, Fievet N, et al. Effects of malaria in the first trimester of pregnancy on poor maternal and birth outcomes in Benin. Clin Infect Dis. 2019;69:1385–1393. PubMed

Moore KA, Simpson JA, Wiladphaingern J, et al. Influence of the number and timing of malaria episodes during pregnancy on prematurity and small-for-gestational-age in an area of low transmission. BMC Med. 2017;15:117. PubMed PMC

Valea I, Tinto H, Drabo MK, et al. An analysis of timing and frequency of malaria infection during pregnancy in relation to the risk of low birth weight, anaemia and perinatal mortality in Burkina Faso. Malar J. 2012;11:71. PubMed PMC

Cottrell G, Mary JY, Barro D, Cot M. The importance of the period of malarial infection during pregnancy on birth weight in tropical Africa. Am J Trop Med Hyg. 2007;76:849–854. PubMed

Walker PGT, ter Kuile FO, Garske T, Menendez C, Ghani AC. Estimated risk of placental infection and low birthweight attributable to Plasmodium falciparum malaria in Africa in 2010: a modelling study. Lancet Glob Health. 2014;2:e460–e467. PubMed

Accrombessi M, Fievet N, Yovo E, et al. Prevalence and associated risk factors of malaria in the first trimester of pregnancy: a preconceptional cohort study in Benin. J Infect Dis. 2018;217:1309–1317. PubMed

Hounkonnou CPA, Briand V, Fievet N, et al. Dynamics of submicroscopic Plasmodium falciparum infections throughout pregnancy: a preconception cohort study in Benin. Clin Infect Dis. 2020;71:166–174. PubMed PMC

Tuikue Ndam N, Tornyigah B, Dossou AY, et al. Persistent Plasmodium falciparum infection in women with an intent to become pregnant as a risk factor for pregnancy-associated malaria. Clin Infect Dis. 2018;67:1890–1896. PubMed

Moller AB, Petzold M, Chou D, Say L. Early antenatal care visit: a systematic analysis of regional and global levels and trends of coverage from 1990 to 2013. Lancet Glob Health. 2017;5:e977–e983. PubMed PMC

WHO WHO guidelines for malaria. 2022. https://www.who.int/publications/i/item/guidelines-for-malaria PubMed

Saito M, Mansoor R, Kennon K, et al. Efficacy and tolerability of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: a systematic review and individual patient data meta-analysis. Lancet Infect Dis. 2020;20:943–952. PubMed PMC

Burger RJ, van Eijk AM, Bussink M, Hill J, ter Kuile FO. Artemisinin-based combination therapy versus quinine or other combinations for treatment of uncomplicated Plasmodium falciparum malaria in the second and third trimester of pregnancy: a systematic review and meta-analysis. Open Forum Infect Dis. 2015;3 PubMed PMC

González R, Pons-Duran C, Bardají A, Leke RGF, Clark R, Menendez C. Systematic review of artemisinin embryotoxicity in animals: implications for malaria control in human pregnancy. Toxicol Appl Pharmacol. 2020;402 PubMed

Clark RL. Safety of treating malaria with artemisinin-based combination therapy in the first trimester of pregnancy. Reprod Toxicol. 2022;111:204–210. PubMed

Clark RL. Embryotoxicity of the artemisinin antimalarials and potential consequences for use in women in the first trimester. Reprod Toxicol. 2009;28:285–296. PubMed

Gomes C, Boareto AC, Dalsenter PR. Clinical and non-clinical safety of artemisinin derivatives in pregnancy. Reprod Toxicol. 2016;65:194–203. PubMed

Dellicour S, Sevene E, McGready R, et al. First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: a meta-analysis of observational studies. PLoS Med. 2017;14 PubMed PMC

WHO Malaria Policy Advisory Committee and Secretariat Malaria Policy Advisory Committee to the WHO: conclusions and recommendations of eighth biannual meeting (September 2015) Malar J. 2016;15:117. PubMed PMC

McGready R, Nosten F, Barnes KI, Mokuolu O, White NJ. Why is WHO failing women with falciparum malaria in the first trimester of pregnancy? Lancet. 2020;395:779. PubMed

Rao VB, Jensen TO, Jimenez BC, et al. Malaria in pregnancy: a call for a safe, efficient, and patient-centred approach to first-trimester treatment. Lancet Glob Health. 2018;6:e607–e608. PubMed

Stewart LA, Clarke M, Rovers M, et al. Preferred reporting items for systematic review and meta-analyses of individual participant data: the PRISMA-IPD statement. JAMA. 2015;313:1657–1665. PubMed

WHO . World Health Organization; Geneva: 2006. Neonatal and perinatal mortality country, regional and global estimates.

VanderWeele TJ, Ding P. Sensitivity analysis in observational research: introducing the e-value. Ann Intern Med. 2017;167:268–274. PubMed

Tinto H, Sevene E, Dellicour S, et al. Assessment of the safety of antimalarial drug use during early pregnancy (ASAP): protocol for a multicenter prospective cohort study in Burkina Faso, Kenya and Mozambique. Reprod Health. 2015;12:112. PubMed PMC

Manyando C, Mkandawire R, Puma L, et al. Safety of artemether-lumefantrine in pregnant women with malaria: results of a prospective cohort study in Zambia. Malar J. 2010;9:249. PubMed PMC

Rulisa S, Kaligirwa N, Agaba S, Karema C, Mens PF, de Vries PJ. Pharmacovigilance of artemether-lumefantrine in pregnant women followed until delivery in Rwanda. Malar J. 2012;11:225. PubMed PMC

Mosha D, Mazuguni F, Mrema S, Sevene E, Abdulla S, Genton B. Safety of artemether-lumefantrine exposure in first trimester of pregnancy: an observational cohort. Malar J. 2014;13:197. PubMed PMC

Moore KA, Simpson JA, Paw MK, et al. Safety of artemisinins in first trimester of prospectively followed pregnancies: an observational study. Lancet Infect Dis. 2016;16:576–583. PubMed PMC

Saito M, Carrara VI, Gilder ME, et al. A randomized controlled trial of dihydroartemisinin-piperaquine, artesunate-mefloquine and extended artemether-lumefantrine treatments for malaria in pregnancy on the Thailand-Myanmar border. BMC Med. 2021;19:132. PubMed PMC

Rouamba T, Valea I, Bognini JD, et al. Safety profile of drug use during pregnancy at peripheral health centres in Burkina Faso: a prospective observational cohort study. Drugs Real World Outcomes. 2018;5:193–206. PubMed PMC

Mehta U, Clerk C, Allen E, et al. Protocol for a drugs exposure pregnancy registry for implementation in resource-limited settings. BMC Pregnancy Childbirth. 2012;12:89. PubMed PMC

European Concerted Action on Congenital Anomalies and Twins EUROCAT congenital anomalies prevalence charts and tables. 2022. https://eu-rd-platform.jrc.ec.europa.eu/eurocat/eurocat-data/prevalence_en

Gamble C, Ekwaru JP, ter Kuile FO. Insecticide-treated nets for preventing malaria in pregnancy. Cochrane Database Syst Rev. 2006;2 PubMed PMC

Moore KA, Simpson JA, Scoullar MJL, McGready R, Fowkes FJI. Quantification of the association between malaria in pregnancy and stillbirth: a systematic review and meta-analysis. Lancet Glob Health. 2017;5:e1101–e1112. PubMed

D'Alessandro S, Menegola E, Parapini S, Taramelli D, Basilico N. Safety of artemisinin derivatives in the first trimester of pregnancy: a controversial story. Molecules. 2020;25 PubMed PMC

Clark RL. Teratogen update: malaria in pregnancy and the use of antimalarial drugs in the first trimester. Birth Defects Res. 2020;112:1403–1449. PubMed

Clark RL, Arima A, Makori N, et al. Artesunate: developmental toxicity and toxicokinetics in monkeys. Birth Defects Res B Dev Reprod Toxicol. 2008;83:418–434. PubMed

Brent RL. Utilization of animal studies to determine the effects and human risks of environmental toxicants (drugs, chemicals, and physical agents) Pediatrics. 2004;113(suppl):984–995. PubMed

Dolk H, Loane M, Garne E. The prevalence of congenital anomalies in Europe. Adv Exp Med Biol. 2010;686:349–364. PubMed

Bower C, Rudy E, Callaghan A, Quick J, Nassar N. Age at diagnosis of birth defects. Birth Defects Res A Clin Mol Teratol. 2010;88:251–255. PubMed

Holmes LB, Nasri HZ, Hunt AT, Zash R, Shapiro RL. Limited surface examination to evaluate potential teratogens in a resource-limited setting. Birth Defects Res. 2021;113:702–707. PubMed PMC

Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;39:1890–1900. PubMed

Saito M, Gilder ME, Nosten F, McGready R, Guérin PJ. Systematic literature review and meta-analysis of the efficacy of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: methodological challenges. Malar J. 2017;16:488. PubMed PMC

WHO . 3rd edn. WHO Press; Geneva: 2015. Guidelines for the treatment of malaria.

Bretscher MT, Dahal P, Griffin J, et al. The duration of chemoprophylaxis against malaria after treatment with artesunate-amodiaquine and artemether-lumefantrine and the effects of PFMDR1 86Y and PFCRT 76T: a meta-analysis of individual patient data. BMC Med. 2020;18:47. PubMed PMC

Achan J, Talisuna AO, Erhart A, et al. Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malar J. 2011;10:144. PubMed PMC

Hill J, D'Mello-Guyett L, Hoyt J, van Eijk AM, ter Kuile FO, Webster J. Women's access and provider practices for the case management of malaria during pregnancy: a systematic review and meta-analysis. PLoS Med. 2014;11 PubMed PMC

Dellicour S, Desai M, Aol G, et al. Risks of miscarriage and inadvertent exposure to artemisinin derivatives in the first trimester of pregnancy: a prospective cohort study in western Kenya. Malar J. 2015;14:461. PubMed PMC

Mosha D, Mazuguni F, Mrema S, Sevene E, Abdulla S, Genton B. Safety of artemether-lumefantrine exposure in first trimester of pregnancy: an observational cohort. Malar J. 2014;13:197. PubMed PMC

Webster J, Hoyt J, Diarra S, et al. Adoption of evidence-based global policies at the national level: intermittent preventive treatment for malaria in pregnancy and first trimester treatment in Kenya, Malawi, Mali and The Gambia. Health Policy Plan. 2021;35:1364–1375. PubMed PMC

Sangaré LR, Weiss NS, Brentlinger PE, et al. Patterns of anti-malarial drug treatment among pregnant women in Uganda. Malar J. 2011;10:152. PubMed PMC

Clark RL. Animal embryotoxicity studies of key non-artemisinin antimalarials and use in women in the first trimester. Birth Defects Res. 2017;109:1075–1126. PubMed

WHO 22nd meeting of the Malaria Policy Advisory Group (MPAG) 2022. https://www.who.int/news-room/events/detail/2022/10/11/default-calendar/22nd-meeting-of-the-malaria-policy-advisory-group