Safety outcomes.

Background
To mitigate adverse consequences of malaria in pregnancy, the World Health Organization recommends intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine–pyrimethamine. However, the effectiveness of IPTp with sulfadoxine–pyrimethamine has been threatened by widespread Plasmodium falciparum resistance, especially in East and Southern Africa. For IPTp, dihydroartemisinin–piperaquine has shown superior antimalarial effects compared to sulfadoxine–pyrimethamine, but sulfadoxine–pyrimethamine has been associated with improved birth outcomes compared to dihydroartemisinin–piperaquine. We hypothesized that a combination of both dihydroartemisinin–piperaquine and sulfadoxine–pyrimethamine would provide superior birth outcomes compared to either drug alone.
Methods and findings
We conducted a double-blinded, randomized, controlled trial of 2,757 pregnant women in Uganda, where resistance of malaria parasites to sulfadoxine–pyrimethamine is widespread. Women were randomly assigned (1:1:1) to monthly IPTp with sulfadoxine–pyrimethamine, dihydroartemisinin–piperaquine, or dihydroartemisinin–piperaquine plus sulfadoxine–pyrimethamine. The primary outcome was the risk of a composite adverse birth outcome defined as any of the following: spontaneous abortion, stillbirth, low birthweight (LBW, < 2,500 g), preterm delivery (<37 weeks), small-for-gestational age, or neonatal death. Secondary outcomes included specific individual adverse birth outcomes, measures of malaria during pregnancy, and safety/tolerability. Combining dihydroartemisinin–piperaquine plus sulfadoxine–pyrimethamine did not reduce the risk of a composite adverse birth outcome compared to dihydroartemisinin–piperaquine (30.0% versus 30.9%, relative risk (RR) 0.97 [95% CI 0.84–1.12]; p = 0.70) or sulfadoxine–pyrimethamine (30.0% versus 26.4%, RR 1.14 [95% CI 0.98–1.33]; p = 0.10). The risk of a composite adverse birth outcome was higher with dihydroartemisinin–piperaquine compared to sulfadoxine–pyrimethamine (30.9% versus 26.4%, RR 1.17 [95% CI 1.01–1.36]; p = 0.04). Considering individual adverse birth outcomes, combining dihydroartemisinin–piperaquine plus sulfadoxine–pyrimethamine was associated with a higher risk of small-for-gestational age (23.4% versus 18.7%, RR 1.25 [95% CI 1.04–1.51]; p = 0.02) and low birthweight (8.6% versus 5.8%, RR 1.48 [95 CI 1.04–2.12]; p = 0.03) compared to sulfadoxine–pyrimethamine and a higher risk of preterm delivery (5.3% versus 3.1%, RR 1.73 [95% CI 1.07–2.79]; p = 0.03) compared to dihydroartemisinin–piperaquine. During pregnancy, compared to sulfadoxine–pyrimethamine, dihydroartemisinin–piperaquine was associated with a 94% reduction in the incidence of symptomatic malaria (0.46 versus 0.03 episodes per person-year, incidence rate ratio 0.06 [95% CI 0.03–0.12]; p < 0.001) and a 97% reduction in the risk of microscopic parasitemia (17.7% versus 0.6%, RR 0.03 [95% CI 0.02–0.05]; p < 0.001), but dihydroartemisinin–piperaquine plus sulfadoxine–pyrimethamine was not associated with improved malaria outcomes over dihydroartemisinin–piperaquine alone. There were no significant differences in the incidence of any grade 3–4 adverse events between the treatment arms. As this study was conducted in an area of high transmission intensity with widespread resistance to sulfadoxine–pyrimethamine, findings may not be generalizable to other settings.
Conclusions
Despite the superior antimalarial activity of dihydroartemisinin–piperaquine, sulfadoxine–pyrimethamine alone was associated with improved birth outcomes. Combining dihydroartemisinin–piperaquine plus sulfadoxine–pyrimethamine for IPTp did not improve birth outcomes compared to either sulfadoxine–pyrimethamine or dihydroartemisinin–piperaquine alone.
Trial registration
ClinicalTrials.gov (NCT04336189; https://clinicaltrials.gov/study/NCT04336189).

背景
为减轻妊娠疟疾带来的不良后果，世界卫生组织推荐使用磺胺多辛-乙胺嘧啶（sulfadoxine–pyrimethamine）开展妊娠期疟疾间歇性预防治疗（intermittent preventive treatment of malaria in pregnancy, IPTp）。然而，磺胺多辛-乙胺嘧啶IPTp方案的有效性正受到广泛存在的恶性疟原虫（Plasmodium falciparum）耐药性的威胁，这一问题在东非与南非尤为突出。相较于磺胺多辛-乙胺嘧啶，双氢青蒿素哌喹（dihydroartemisinin–piperaquine）在IPTp中展现出更优的抗疟效果，但有研究显示，相较于双氢青蒿素哌喹，磺胺多辛-乙胺嘧啶可改善妊娠结局。本研究假设，联合使用双氢青蒿素哌喹与磺胺多辛-乙胺嘧啶，相较于单一使用任一药物，可获得更优的妊娠结局。

方法与研究结果
本研究在乌干达开展了一项双盲、随机对照试验，共纳入2757名孕妇，该地区疟原虫对磺胺多辛-乙胺嘧啶的耐药性广泛存在。研究对象按1:1:1的比例随机分配至三组：每月接受磺胺多辛-乙胺嘧啶IPTp、双氢青蒿素哌喹IPTp，或双氢青蒿素哌喹联合磺胺多辛-乙胺嘧啶IPTp。本研究的主要结局为复合不良妊娠结局风险，复合不良妊娠结局定义为以下任意一种情况：自然流产、死胎、低出生体重（low birthweight, LBW，<2500g）、早产（<37周）、小于胎龄儿，或新生儿死亡。次要结局包括特定的单项不良妊娠结局、妊娠期疟疾相关指标，以及安全性与耐受性。
结果显示，相较于双氢青蒿素哌喹组（30.9%），双氢青蒿素哌喹联合磺胺多辛-乙胺嘧啶组的复合不良妊娠结局风险并未出现显著降低（30.0%，相对风险[RR] 0.97，95%置信区间[CI] 0.84~1.12；p=0.70）；相较于磺胺多辛-乙胺嘧啶组（26.4%），联合治疗组的复合不良妊娠结局风险同样无显著改善（30.0%，RR 1.14，95%CI 0.98~1.33；p=0.10）。相较于磺胺多辛-乙胺嘧啶组（26.4%），双氢青蒿素哌喹组的复合不良妊娠结局风险更高（30.9%，RR 1.17，95%CI 1.01~1.36；p=0.04）。
针对单项不良妊娠结局进行分析，相较于磺胺多辛-乙胺嘧啶组，联合治疗组的小于胎龄儿发生率更高（23.4% vs 18.7%，RR 1.25，95%CI 1.04~1.51；p=0.02），低出生体重发生率也更高（8.6% vs 5.8%，RR 1.48，95%CI 1.04~2.12；p=0.03）；相较于双氢青蒿素哌喹组，联合治疗组的早产发生率更高（5.3% vs 3.1%，RR 1.73，95%CI 1.07~2.79；p=0.03）。
妊娠期相关指标方面，相较于磺胺多辛-乙胺嘧啶组，双氢青蒿素哌喹组的症状性疟疾发病率降低了94%（每人人年发病0.03 vs 0.46例，发病率比0.06，95%CI 0.03~0.12；p<0.001），显微镜检检出疟原虫血症的风险降低了97%（17.7% vs 0.6%，RR 0.03，95%CI 0.02~0.05；p<0.001），但双氢青蒿素哌喹联合磺胺多辛-乙胺嘧啶组相较于单独使用双氢青蒿素哌喹组，并未在疟疾相关结局上获得进一步改善。三组间任何3~4级不良事件的发生率均无显著差异。由于本研究在磺胺多辛-乙胺嘧啶耐药广泛、疟疾传播强度高的地区开展，研究结果可能无法推广至其他场景。

结论
尽管双氢青蒿素哌喹具有更优的抗疟活性，但单独使用磺胺多辛-乙胺嘧啶可获得更好的妊娠结局。相较于单独使用磺胺多辛-乙胺嘧啶或双氢青蒿素哌喹，联合使用双氢青蒿素哌喹与磺胺多辛-乙胺嘧啶进行IPTp，并未改善妊娠结局。

试验注册
ClinicalTrials.gov（NCT04336189；https://clinicaltrials.gov/study/NCT04336189）