Secondary efficacy 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).

为减轻妊娠疟疾带来的不良后果，世界卫生组织推荐采用磺胺多辛-乙胺嘧啶（sulfadoxine–pyrimethamine）实施妊娠期疟疾间歇性预防治疗（intermittent preventive treatment of malaria in pregnancy, IPTp）。然而，广泛存在的恶性疟原虫（Plasmodium falciparum）耐药性已对磺胺多辛-乙胺嘧啶的IPTp方案有效性构成威胁，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，能够获得更优异的妊娠结局。
方法与结果
本研究在疟疾寄生虫对磺胺多辛-乙胺嘧啶耐药现象普遍存在的乌干达开展，纳入2757名孕妇，实施双盲、随机对照试验。受试者按1:1:1的比例随机分组，每月分别接受磺胺多辛-乙胺嘧啶、双氢青蒿素哌喹，或双氢青蒿素哌喹联合磺胺多辛-乙胺嘧啶的IPTp方案。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。次要结局包括具体的单项不良妊娠结局、妊娠期疟疾相关指标，以及安全性/耐受性。
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降低（30.0%，相对风险（relative risk, RR）0.97 [95%置信区间（confidence interval, CI）0.84–1.12]；p=0.70）；相较于磺胺多辛-乙胺嘧啶组（26.4%），联合用药组的复合不良妊娠结局风险亦无显著改善（30.0%，RR 1.14 [95%CI 0.98–1.33]；p=0.10）。双氢青蒿素哌喹组的复合不良妊娠结局风险高于磺胺多辛-乙胺嘧啶组（30.9% vs 26.4%，RR 1.17 [95%CI 1.01–1.36]；p=0.04）。
针对单项不良妊娠结局分析显示，相较于磺胺多辛-乙胺嘧啶组，双氢青蒿素哌喹联合磺胺多辛-乙胺嘧啶组的小于胎龄儿风险更高（23.4% vs 18.7%，RR 1.25 [95%CI 1.04–1.51]；p=0.02），低出生体重风险亦更高（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，联合用药组的早产风险更高（5.3% vs 3.1%，RR 1.73 [95%CI 1.07–2.79]；p=0.03）。
妊娠期疟疾相关指标方面，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94%（每人年发病0.03 vs 0.46次，发病比（incidence rate ratio, IRR）0.06 [95%CI 0.03–0.12]；p<0.001），镜检疟原虫血症风险降低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-乙胺嘧啶方案相较于单一双氢青蒿素哌喹方案，并未进一步改善疟疾相关结局。三组间任何3~4级不良事件的发生率均无显著差异。由于本研究在疟疾高传播强度且磺胺多辛-乙胺嘧啶耐药普遍的地区开展，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备更优异的抗疟活性，但单一使用磺胺多辛-乙胺嘧啶的妊娠结局更佳。相较于单一使用磺胺多辛-乙胺嘧啶或双氢青蒿素哌喹，采用双氢青蒿素哌喹联合磺胺多辛-乙胺嘧啶的IPTp方案并未改善妊娠结局。
试验注册
ClinicalTrials.gov（NCT04336189；https://clinicaltrials.gov/study/NCT04336189）