英国利物浦热带医学院Stephanie Dellicour团队研究了使用青蒿素衍生物与非青蒿素抗疟药物治疗妊娠早期疟疾的结局。相关论文于2022年11月25日发表在《柳叶刀》杂志上。

妊娠早期的疟疾与不良妊娠结局相关。基于青蒿素的联合疗法（ACTs）是治疗无并发症恶性疟原虫疟疾的高效一线治疗方法，但在妊娠早期，由于担心青蒿素的潜在胚胎毒性，建议使用奎宁和克林霉素。研究组比较了基于青蒿素的治疗（ABT）与非ABT在妊娠早期的不良妊娠结局。

为了进行系统回顾和个体患者数据（IPD）荟萃分析，研究组搜索了2015年11月1日至2021年12月21日发表在MEDLINE、Embase和《妊娠期疟疾图书馆》的前瞻性队列研究，其中包含有关妊娠早期暴露于ABT和非ABT的妊娠结局的数据。这项搜索的结果被添加到之前的系统综述中，其中包括截至2015年11月出版的论文。

研究组纳入了在妊娠结局已知之前登记的妊娠。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、死产或重大先天性畸形的综合。通过使用共享脆弱性Cox模型进行了一期IPD荟萃分析。

研究组确定了包括12个队列的7项合格研究。所有12个队列都贡献了IPD，包括34178例妊娠，737例妊娠早期暴露于ABT，1076例妊娠早期暴露于非ABT。736例ABT暴露孕妇中有42例（5.7%）出现不良妊娠结局，而在妊娠早期1074例非ABT暴露妊娠中有96例（8.9%），校正后的风险比（aHR）为0.71。

流产（aHR=0.74）、死产（aHR=0.71）和重大先天性畸形（aHR=0.60）的各个组成部分也出现了类似的结果。在妊娠的前三个月，蒿甲醚-本芴醇的不良妊娠结局风险低于口服奎宁（分别为524例中有25例[4.8%]，915例中有84例[9.2%]；aHR 0.58）。

研究结果表明，基于怀孕前三个月的流产、死胎或与ABT相关的重大先天性异常的风险，研究组未发现胚胎毒性或致畸性的证据。鉴于与奎宁相比，蒿甲醚-本芴醇治疗与较少的不良妊娠结局相关，且由于已知ACTs具有较高的耐受性和抗疟效果，因此蒿甲醚-本芴醇应被视为妊娠早期无并发症恶性疟原虫疟疾的首选治疗方法。如果无法获得蒿甲醚-本芴醇，其他ACTs（青蒿琥酯-磺胺多辛-乙胺嘧啶除外）应优先于奎宁。仍需要继续积极的药物警戒。

附：英文原文

Title: Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: a systematic review and individual patient data meta-analysis

Author: Makoto Saito, Rose McGready, Halidou Tinto, Toussaint Rouamba, Dominic Mosha, Stephen Rulisa, Simon Kariuki, Meghna Desai, Christine Manyando, Eric M Njunju, Esperanca Sevene, Anifa Vala, Orvalho Augusto, Christine Clerk, Edwin Were, Sigilbert Mrema, William Kisinza, Josaphat Byamugisha, Mike Kagawa, Jan Singlovic, Mackensie Yore, Anna Maria van Eijk, Ushma Mehta, Andy Stergachis, Jenny Hill, Kasia Stepniewska, Melba Gomes, Philippe J Guérin, Francois Nosten, Feiko O ter Kuile, Stephanie Dellicour

Issue&Volume: 2022-11-25

Abstract:

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 34178 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.

DOI: 10.1016/S0140-6736(22)01881-5

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01881-5/fulltext