Optimal chemopreventive regimens to prevent malaria and improve birth outcomes in Uganda

项目总结/摘要 妊娠期疟疾仍然是非洲的一个重大挑战，非洲约有5 000万妇女面临感染疟疾的风险。 P.每年在怀孕期间感染恶性疟原虫。在疟疾流行地区的孕妇中， 有症状的疾病并不常见，但疟疾寄生虫感染与母体贫血有关 和不良分娩结局，包括流产、死产、早产、低出生体重（LBW）和婴儿 mortality.世界卫生组织（世卫组织）建议使用长效驱虫蚊帐（长效蚊帐） 和用磺胺嘧啶-乙胺嘧啶进行间歇性预防性治疗， 在非洲流行地区怀孕。然而，人们担心这些干预措施的效力正在下降， 由于病媒对长效驱虫蚊帐中使用的拟除虫菊酯类杀虫剂的抗药性以及寄生虫对 SP.因此，迫切需要新的战略来预防怀孕期间的疟疾，并改善妇女的健康状况。 出生结果。以青蒿素为基础的联合疗法现在是疟疾的标准治疗方法， 非洲双氢青蒿素-哌喹（DP）是一种固定剂量的ACT，是治疗IPTp的一种有吸引力的SP替代品。DP 是非常有效的，哌喹的长半衰期提供了至少4周的后治疗 预防。我们小组和其他人最近的随机对照试验表明，与IPTp相比， 与SP相比，IPTp与DP联合使用显著降低了疟疾特异性结局的风险， SP组和DP组不良出生结局风险的差异。激励的关键问题是 这就是为什么IPTp联合SP或DP与不良出生结局的风险相似的原因 尽管DP的抗疟活性远为上级。可能的解释是，SP，一种广谱的 抗生素，防止非疟疾原因的LBW和早产。我们的中心假设是SP 改善出生结果，与其抗疟活性无关，IPTp与SP+DP的组合将 提供抗疟和非抗疟福利，从而为不良出生结果提供上级预防 与单独使用的药物相比。为了验证这一假设，我们将进行一项双盲随机 在疟疾传播强度非常高的乌干达农村地区进行的一项临床试验， 拥有完善的临床研究基础设施。我们的具体目标是（1）比较 随机接受每月一次的IPTp（SP vs. DP vs. SP+DP，（2）在随机分配至 接受每月一次的IPTp，SP vs. DP vs. SP+DP，以及（3）比较疟疾特异性和非疟疾的风险 随机接受每月一次的IPTp（SP vs. DP vs. SP+DP）的孕妇的结局。本研究 将是第一个评估一种新的经过充分研究的药物组合的有效性和安全性， 出生结果和我们的发现很可能具有重要的政策含义，标准做法会发生变化 为非洲数百万的孕妇提供服务。

PROJECT SUMMARY/ABSTRACT Malaria in pregnancy remains a major challenge in Africa, where approximately 50 million women are at risk for P. falciparum infection during pregnancy each year. Among pregnant women living in malaria endemic areas symptomatic disease is uncommon, but infection with malaria parasites is associated with maternal anemia and adverse birth outcomes including abortions, stillbirth, preterm birth, low birth weight (LBW), and infant mortality. The World Health Organization (WHO) recommends the use of long-lasting insecticidal nets (LLINs) and intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) for the prevention of malaria in pregnancy in endemic areas of Africa. However, there is concern for diminishing efficacy of these interventions due to the spread of vector resistance to the pyrethroid insecticides used in LLINs and parasite resistance to SP. Thus, there is an urgent need for new strategies for the prevention of malaria in pregnancy and improving birth outcomes. Artemisinin-based combination therapies (ACTs) are now the standard treatment for malaria in Africa. Dihydroartemisin-piperaquine (DP) is a fixed-dose ACT and an attractive alternative to SP for IPTp. DP is highly efficacious, and the long half-life of piperaquine provides at least 4 weeks of post-treatment prophylaxis. Recent randomized controlled trials from our group and others showed that, compared to IPTp with SP, IPTp with DP dramatically reduced risks of malaria-specific outcomes but there were minimal differences between the SP and DP groups in risks of adverse birth outcomes. The key question motivating this proposal is why IPTp with either SP or DP is associated with similar risks of adverse birth outcomes despite the far superior antimalarial activity of DP. The likely explanation is that SP, a broad-spectrum antibiotic, protects against non-malarial causes of LBW and preterm birth. Our central hypothesis is that SP improves birth outcomes independent of its antimalarial activity and that IPTp with a combination of SP+DP will offer antimalarial and non-antimalarial benefits, thus providing superior prevention of adverse birth outcomes compared to either drug used alone. To test this hypothesis we will conduct a double-blinded randomized clinical trial in a rural area of Uganda with very high malaria transmission intensity, where our group already has an established infrastructure for clinical research. Our specific aims will be (1) to compare the risk of adverse birth outcomes among pregnant women randomized to receive monthly IPTp with SP vs. DP vs. SP+DP, (2) To compare safety and tolerability of IPTp regimens among pregnant women randomized to receive monthly IPTp with SP vs. DP vs. SP+DP, and (3) to compare risks of malaria-specific and non-malarial outcomes among pregnant women randomized to receive monthly IPTp with SP vs. DP vs. SP+DP. This study will be the first to evaluate the efficacy and safety of a novel combination of well-studied drugs for improving birth outcomes and our findings may well have important policy implications, with a change in standard practice for millions of pregnant women in Africa.