Effects of metronidazole plus intermittent preventive treatment of malaria in pregnancy on birth outcomes: a randomised controlled trial in Zambia

在东部和南部非洲地区，孕期感染疟疾以及可治愈的性传播和生殖道感染(性传播感染/生殖道感染)非常普遍。该次区域约三分之一的妇女在怀孕期间感染疟疾寄生虫，其中一半患有细菌性阴道病(BV)，四分之一感染阴道毛滴虫(TV)。所有这些都会导致不良的生育结果。疟疾寄生虫在胎盘中隔离，因此，常规的血液测试可能无法检测到感染。因此，世界卫生组织建议居住在疟疾流行地区的妇女在怀孕第二和第三个三个月期间使用磺胺二甲胺间歇预防性治疗。然而，疟疾寄生虫已经对SP产生了抗药性。双氢青蒿素-哌喹(DP)是SP的一种替代品，已被证明比SP更好地清除孕妇的疟疾寄生虫。然而，SP似乎也提供了一些保护，防止非疟疾原因造成不良的出生结果，包括可治愈的性传播感染/生殖道感染。因此，从SP切换到DP可能不是最好的选择。如果与针对BV和TV甲硝唑(MTZ)的治疗相结合，SP或DP--一种在怀孕中期和晚期也可以安全使用的药物--可能比提供SP--目前的护理标准--更好。为了检验这一点，我们提议进行一项三臂试验，部分由安慰剂控制，将在赞比亚东北部的一个地理区域比较SP+MTZ安慰剂与SP+MTZ与DP+MTZ，那里疟疾传播率高，疟疾寄生虫对SP的抵抗力高，孕妇中BV和TV的流行率也很高。作为主要试验的一部分，我们还将利用离散选择试验对试验干预措施的建立成本、增量成本-效果以及三种研究处理的可接受性进行全面的经济评估。我们将询问潜在参与者是否会提供阴道拭子和大便样本，我们将使用这些样本来描述跨试验手臂治疗对阴道和肠道微生物群落、阴道和肠道细菌负荷的影响，并确定与炎症有关的潜在早产诱因。最后，我们还将测试与阴道分泌物、下腹痛或生殖器溃疡有关的几种病原体的药物敏感性。

In areas of East and Southern Africa, malaria infection during pregnancy and curable sexually transmitted and reproductive tract infections (STIs/RTIs) are very common. About one-third of women in the sub-region are infected with malaria parasites during pregnancy, one-half of them have bacterial vaginosis (BV) and one-quarter are infected with trichomonas vaginalis (TV). All of these cause adverse birth outcomes. Malaria parasites sequester in the placenta and, therefore, taking conventional blood test may not detect the infection. Thus, the World Health Organization recommends that women who live in malaria-endemic areas receive intermittent preventive treatment (IPTp) using sulphadoxine-pyrimethamine (SP) during their second and third trimesters of pregnancy. However, malaria parasites have developed resistance against SP. An alternative to SP, dihydroartemisinin-piperaquine (DP), has been shown to clear malaria parasites from pregnant women better than SP. However, SP appears also to confer some protection against non-malaria causes of adverse birth outcomes including curable STIs/RTIs. So a switch from SP to DP might not be best. It is possible that SP or DP - if combined with treatment against BV and TV metronidazole (MTZ), a medicine that is also safe to administer in the second and third trimesters of pregnancy - may be better than providing SP, the current standard of care. To examine this, we are proposing a three-arm trial, partially placebo-controlled, that will compare SP plus MTZ placebo versus SP plus MTZ versus DP plus MTZ in a geographic area of north-east Zambia where malaria transmission is high, malaria parasite-resistance to SP is high, and the prevalence of BV and TV in pregnant women is also high. As part of the main trial, we will also conduct a full economic evaluation of trial interventions establish costs, the incremental cost-effectiveness, and acceptability of the three study treatments using discrete choice experiments. We will ask prospective participants if they will provide vaginal swabs and stool samples which we will use to characterise the effect of treatment across trial arms on the vaginal and intestinal microbiota communities, vaginal and intestinal bacterial loads and identify potential triggers of preterm birth that are related to inflammation. Finally, we will also measure the drug sensitivity of several pathogens implicated with vaginal discharge, lower abdominal pain, or genital ulcers.