英国利物浦热带医学院Feiko O ter Kuile团队研究了每月使用双氢青蒿素-哌喹联合和不联合阿奇霉素，与每月使用磺胺多辛-乙胺嘧啶间歇预防治疗对不良妊娠结局的影响。2023年3月10日，《柳叶刀》杂志发表了这一成果。

在东非恶性疟原虫对磺胺多辛-乙胺嘧啶高度耐药性的地区，使用双氢青蒿素-哌喹的妊娠期间歇性预防性治疗（IPTp）比使用磺胺多辛-乙胺嘧啶的IPTp可更有效地减少妊娠期疟疾感染。该研究旨在评估与使用磺胺多辛-乙胺嘧啶的IPTp相比，单独使用双氢青蒿素-哌喹或与阿奇霉素联合使用的IPTp是否可以减少不良妊娠结局。

研究组在肯尼亚、马拉维和坦桑尼亚的磺胺多辛-乙胺嘧啶高耐药性地区进行了一项单独随机、双盲、三组、部分安慰剂对照试验。通过计算机生成进行随机分组，按地点和妊娠程度分层，将单胎妊娠存活的HIV阴性妇女随机分配（1:1:1），每月接受磺胺多辛-乙胺嘧啶IPTp（500 mg磺胺多辛和25 mg乙胺嘧啶，为期1天），每月接受双氢青蒿素-哌喹IPTp（按体重给药；三至五片，含40 mg双氢青蒿素和320 mg哌喹，每天一次，连续三天）加一个疗程的安慰剂，或每月接受双氢青蒿素-哌喹IPTp，再加上单一疗程的阿奇霉素（两片，含500 mg，每天一次，连续两天）。

分娩单位的结果评估员与治疗组双盲。复合主要终点为不良妊娠结局，定义为胎儿丢失、不良新生儿结局（胎龄小、低出生体重或早产）或新生儿死亡。主要分析采用改良意向治疗，由所有具有主要终点数据的随机参与者组成。至少接受一剂研究药物的女性被纳入安全性分析。

2018年3月29日至2019年7月5日，4680名女性（平均年龄25.00岁）被纳入并随机分配：1561名（33%；平均年龄24.9岁）被分配至磺胺多辛-乙胺嘧啶组，1561名被分配至双氢青蒿素-哌喹组，1558名被分配到双氢青蒿素–哌喹加阿奇霉素组。与磺胺多辛-乙胺嘧啶组1435名女性中的335名（23.3%）相比，双氢青蒿素-哌喹组（1442例中403例[27.9%]；风险比1.20）和双氢青蒿素–哌喹加阿奇霉素组（1433例中396例[27.6%]；1.16）报告不良妊娠结局的主要复合终点的频率更高。

母亲（磺胺多辛-乙胺嘧啶组为17.7例/100人年，双氢青蒿素-哌喹组为14.8例/100人年，双氢青蒿素-哌喹加阿奇霉素组为16.9例/100人年）和婴儿（磺胺多辛-乙胺嘧啶组为49.2例/100人年，双氢青蒿素-哌喹组为42.4例/100人年，双氢青蒿素–哌喹加阿奇霉素组为47.8例/100人年）的严重不良事件发生率相似。磺胺多辛-乙胺嘧啶组6685个疗程中有12名（0.2%）在30分钟内呕吐，双氢青蒿素-哌喹组7014个疗程中有19个（0.3%），双氢青蒿素-哌喹加阿奇霉素组6849个疗程中有23名（3%）。

研究结果表明，双氢青蒿素-哌喹的每月IPTp不能改善妊娠结局，单疗程阿奇霉素的添加也不能增强双氢青蒿素/哌喹的每月IPTp的效果。应考虑将磺胺多辛-乙胺嘧啶和双氢青蒿素-哌喹联合用于IPTp的试验。

附：英文原文

Title: Effect of monthly intermittent preventive treatment with dihydroartemisinin–piperaquine with and without azithromycin versus monthly sulfadoxine–pyrimethamine on adverse pregnancy outcomes in Africa: a double-blind randomised, partly placebo-controlled trial

Author: Mwayiwawo Madanitsa, Hellen C Barsosio, Daniel T R Minja, George Mtove, Reginald A Kavishe, James Dodd, Queen Saidi, Eric D Onyango, Kephas Otieno, Duolao Wang, Ulla Ashorn, Jenny Hill, Crispin Mukerebe, Samwel Gesase, Omari A Msemo, Victor Mwapasa, Kamija S Phiri, Kenneth Maleta, Nigel Klein, Pascal Magnussen, John P A Lusingu, Simon Kariuki, Jacklin F Mosha, Michael Alifrangis, Helle Hansson, Christentze Schmiegelow, Julie R Gutman, R Matthew Chico, Feiko O ter Kuile

Issue&Volume: 2023-03-10

Abstract:

Background

Intermittent preventive treatment in pregnancy (IPTp) with dihydroartemisinin–piperaquine is more effective than IPTp with sulfadoxine–pyrimethamine at reducing malaria infection during pregnancy in areas with high-grade resistance to sulfadoxine–pyrimethamine by Plasmodium falciparum in east Africa. We aimed to assess whether IPTp with dihydroartemisinin–piperaquine, alone or combined with azithromycin, can reduce adverse pregnancy outcomes compared with IPTp with sulfadoxine–pyrimethamine.

Methods

We did an individually randomised, double-blind, three-arm, partly placebo-controlled trial in areas of high sulfadoxine–pyrimethamine resistance in Kenya, Malawi, and Tanzania. HIV-negative women with a viable singleton pregnancy were randomly assigned (1:1:1) by computer-generated block randomisation, stratified by site and gravidity, to receive monthly IPTp with sulfadoxine–pyrimethamine (500 mg of sulfadoxine and 25 mg of pyrimethamine for 1 day), monthly IPTp with dihydroartemisinin–piperaquine (dosed by weight; three to five tablets containing 40 mg of dihydroartemisinin and 320 mg of piperaquine once daily for 3 consecutive days) plus a single treatment course of placebo, or monthly IPTp with dihydroartemisinin–piperaquine plus a single treatment course of azithromycin (two tablets containing 500 mg once daily for 2 consecutive days). Outcome assessors in the delivery units were masked to treatment group. The composite primary endpoint was adverse pregnancy outcome, defined as fetal loss, adverse newborn baby outcomes (small for gestational age, low birthweight, or preterm), or neonatal death. The primary analysis was by modified intention to treat, consisting of all randomised participants with primary endpoint data. Women who received at least one dose of study drug were included in the safety analyses. This trial is registered with ClinicalTrials.gov, NCT03208179.

Findings

From March-29, 2018, to July 5, 2019, 4680 women (mean age 25·0 years [SD 6·0]) were enrolled and randomly assigned: 1561 (33%; mean age 24·9 years [SD 6·1]) to the sulfadoxine–pyrimethamine group, 1561 (33%; mean age 25·1 years [6·1]) to the dihydroartemisinin–piperaquine group, and 1558 (33%; mean age 24·9 years [6.0]) to the dihydroartemisinin–piperaquine plus azithromycin group. Compared with 335 (23·3%) of 1435 women in the sulfadoxine–pyrimethamine group, the primary composite endpoint of adverse pregnancy outcomes was reported more frequently in the dihydroartemisinin–piperaquine group (403 [27·9%] of 1442; risk ratio 1·20, 95% CI 1·06–1·36; p=0·0040) and in the dihydroartemisinin–piperaquine plus azithromycin group (396 [27·6%] of 1433; 1·16, 1·03–1·32; p=0·017). The incidence of serious adverse events was similar in mothers (sulfadoxine–pyrimethamine group 17·7 per 100 person-years, dihydroartemisinin–piperaquine group 14·8 per 100 person-years, and dihydroartemisinin–piperaquine plus azithromycin group 16·9 per 100 person-years) and infants (sulfadoxine–pyrimethamine group 49·2 per 100 person-years, dihydroartemisinin–piperaquine group 42·4 per 100 person-years, and dihydroartemisinin–piperaquine plus azithromycin group 47·8 per 100 person-years) across treatment groups. 12 (0·2%) of 6685 sulfadoxine–pyrimethamine, 19 (0·3%) of 7014 dihydroartemisinin–piperaquine, and 23 (0·3%) of 6849 dihydroartemisinin–piperaquine plus azithromycin treatment courses were vomited within 30 min.

Interpretation

Monthly IPTp with dihydroartemisinin–piperaquine did not improve pregnancy outcomes, and the addition of a single course of azithromycin did not enhance the effect of monthly IPTp with dihydroartemisinin–piperaquine. Trials that combine sulfadoxine–pyrimethamine and dihydroartemisinin–piperaquine for IPTp should be considered.

DOI: 10.1016/S0140-6736(22)02535-1

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02535-1/fulltext