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 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. 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. 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 84 [9·2%] of 915; aHR 0·58, 0·36–0·92). 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 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. Medicines for Malaria Venture, WHO, and the Worldwide Antimalarial Resistance Network funded by the Bill & Melinda Gates Foundation.

中文翻译：

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青蒿素衍生物与非青蒿素抗疟药在妊娠早期治疗后的妊娠结局：系统评价和个体患者数据荟萃分析

妊娠前三个月的疟疾与不良妊娠结局有关。基于青蒿素的联合疗法 (ACT) 是治疗无并发症疟疾的高效一线疗法，但在妊娠前三个月除外，由于担心青蒿素潜在的胚胎毒性，建议使用奎宁和克林霉素。我们比较了妊娠前三个月接受青蒿素治疗 (ABT) 与非 ABT 后的不良妊娠结局。为了进行这项系统评价和个体患者数据 (IPD) 荟萃分析，我们检索了 MEDLINE、Embase 和妊娠疟疾图书馆，以查找 2015 年 11 月 1 日至 2021 年 12 月 21 日期间发表的前瞻性队列研究，其中包含有关妊娠结果的数据在妊娠早期接触 ABT 和非 ABT。此次检索的结果已添加到之前的系统评价中，其中包括截至 2015 年 11 月发表的出版物。我们纳入了在妊娠结果已知之前登记的妊娠。我们排除了缺少估计孕龄或暴露信息的妊娠、多胎妊娠以及在抗疟治疗前确认胎儿无法存活的妊娠。主要终点是不良妊娠结局，定义为流产、死产或主要先天异常的综合结果。使用共享脆弱性 Cox 模型进行了一阶段 IPD 荟萃分析。本研究已在 PROSPERO 注册，编号 CRD42015032371。我们确定了 7 项符合条件的研究，其中包括 12 个队列。所有 12 个队列均贡献了 IPD，其中包括 34 178 例妊娠、737 例经确认在妊娠早期接触过 ABT 的孕妇以及 1076 例经确认在妊娠早期接触过非 ABT 的孕妇。妊娠早期，736 例 ABT 暴露妊娠中，有 42 例 (5·7%) 发生不良妊娠结局，而 1074 例非 ABT 妊娠中，有 96 例 (8·9%) 发生不良妊娠结局（调整后风险比 [aHR] 0·71， 95% CI 0·49–1·03)。流产（aHR=0·74、0·47–1·17）、死产（aHR=0·71、0·32–1·57）和主要先天性异常（aHR= 0·60、0·13–2·87）。在妊娠前三个月，蒿甲醚-本芴醇的不良妊娠结局风险低于口服奎宁（524 中的 25 [4·8%] 915 中的 84 [9·2%]；aHR 0·58、0·36） –0·92)。我们没有发现基于妊娠前三个月与 ABT 相关的流产、死产或重大先天异常风险的胚胎毒性或致畸性证据。鉴于与奎宁相比，蒿甲醚-本芴醇治疗与不良妊娠结局相关较少，并且由于 ACT 已知具有优异的耐受性和抗疟功效，因此蒿甲醚-本芴醇应被视为妊娠早期单纯性疟疾的首选治疗方法。如果没有蒿甲醚-苯芴醇，则应首选其他 ACT（青蒿琥酯-磺胺多辛-乙胺嘧啶除外）而不是奎宁。持续积极的药物警戒是有必要的。Medicines for Malaria Venture、世界卫生组织和由比尔及梅琳达·盖茨基金会资助的全球抗疟疾网络。