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

在东非和南部非洲地区，怀孕期间感染疟疾以及可治愈的性传播和生殖道感染（性病/生殖道感染）非常普遍。该次区域约有三分之一的妇女在怀孕期间感染了疟原虫，其中一半患有细菌性阴道病，四分之一感染了阴道毛滴虫。所有这些都会导致不良的分娩结果。疟疾寄生虫在胎盘中被隔离，因此，采用传统的血液检查可能无法检测到感染。因此，世界卫生组织建议生活在疟疾流行地区的妇女在妊娠中期和晚期接受磺胺嘧啶-乙胺嘧啶（SP）的间歇性预防治疗。然而，疟疾寄生虫已经对SP产生了耐药性。SP的替代品二氢青蒿素-哌喹（DP）已被证明比SP更能清除孕妇体内的疟疾寄生虫。然而，SP似乎也能提供一些保护，防止非疟疾原因导致的不良分娩结果，包括可治愈的性传播感染/呼吸道感染。因此，从SP转向DP可能不是最好的选择。SP或DP——如果与BV治疗和TV甲硝唑（MTZ）（一种在妊娠中期和晚期也安全使用的药物）联合使用——可能比提供SP（目前的标准护理）更好。为了检验这一点，我们提出了一项部分安慰剂对照的三组试验，将在赞比亚东北部的一个地理区域比较SP加MTZ安慰剂与SP加MTZ与DP加MTZ，该区域疟疾传播率高，疟疾寄生虫对SP的耐药性高，孕妇中BV和TV的患病率也高。作为主要试验的一部分，我们还将使用离散选择实验对试验干预措施的建立成本、增量成本效益和三种研究治疗的可接受性进行全面的经济评估。我们将询问潜在的参与者是否愿意提供阴道拭子和粪便样本，我们将使用这些样本来描述试验各组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，并确定与炎症相关的早产的潜在触发因素。最后，我们还将测量几种与阴道分泌物、下腹痛或生殖器溃疡有关的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.