MICA: The role of placental infection in adverse pregnancy outcome.

这项研究的背景是，欧盟有500万新生儿，美国有400万新生儿，严重的怀孕不良后果相对常见。例如，仅在英国，每年就有4000名婴儿死产。大多数不良后果发生在缺乏已知风险因素的妇女身上。胎盘功能不良被认为是大多数死产的原因(胎盘是“胎盘”，对正常妊娠至关重要)。导致死产的并发症还与婴儿死亡、残疾以及由于不良的产前环境而导致晚年健康不良有关。然而，导致这些并发症的胎盘功能障碍的根本原因仍然不清楚。在考虑器官功能障碍的可能原因时，感染显然是主要的可能解释之一。多项研究已报道妊娠合并不良结局的胎盘炎症率较高。其他人报告了怀孕期间母亲血液中存在的传染病抗体与先兆子痫(妊娠期高血压和肾功能异常)等结局风险之间的联系。其他研究表明，胎盘细胞在含有某些细菌或病毒的培养中感染会损害它们的功能。然而，关于胎盘炎和胎盘感染的证据质量普遍较差。此外，遗传物质分析的最新进展产生了强大的新工具来识别组织中是否存在感染源，这些工具以前从未被用于研究胎盘感染在导致先兆子痫和胎儿生长不良中的可能作用。自2008年1月以来，我们一直在进行一项研究(由NIHR剑桥综合生物医学研究中心资助)。我们招募了在第一次扫描时首次怀孕的女性。我们在怀孕12周、20周、28周和36周左右采集血液样本。我们还获得了出生后胎盘的样本。我们进行额外的研究扫描，这样我们就有了关于经历并发症的女性和将与她们进行比较的对照组的详细信息。到这个项目开始时，我们将拥有来自4000多名完成研究的妇女的数据和样本，这为确定胎盘感染是否是常见妊娠并发症(先兆子痫和婴儿发育不良)的决定因素提供了一个独特而强大的资源。我们的方法是(1)检测胎盘中感染源的遗传物质(DNA或RNA)的存在，(2)测量储存的血液样本中的感染和炎症标志物，以及(3)确定胎盘中的炎症是否在复杂妊娠中更常见。关键的是，我们还聘请了国际公认的专家(来自著名的惠康信托桑格研究所)，在检测组织样本中的传染病病原体(细菌、病毒等)的技术方面。该项目可能会发现目前已识别的感染源的这种作用，甚至可以确定这些并发症是否是由目前尚未识别的细菌或病毒引起的。在过去的30年里，识别以前未被认识到的传染病的原因在医学上一直是至关重要的。对细菌(幽门螺杆菌)的作用的认识改变了消化性溃疡疾病的治疗，对病毒(人乳头瘤病毒)在宫颈癌中的作用的认识导致了接种疫苗作为一种预防性方法。如果不良妊娠结局的谜团部分可以通过感染来解释，这可能会导致理解上的类似戏剧性变化，并产生改善母婴健康的新方法。

The context for this study is that there are >5 million births in the EU and >4 million births in the USA and severe adverse outcome of pregnancy is relatively common. For example, in the UK alone, >4000 infants are stillborn per year. The majority of adverse outcomes occur to women who lack known risk factors. Poor placental function is thought to be responsible for the majority of stillbirths (the placenta is the "afterbirth" and is critically important for normal pregnancy). The complications which lead to stillbirth are also associated with infant mortality, disability and, through a poor prenatal environment, ill health in later life. However, the underlying cause of placental dysfunction leading to these complications remains obscure. Infection is clearly one of the major possible explanations when considering possible causes of dysfunction of an organ. Multiple studies have reported high rates of placental inflammation in pregnancies with adverse outcome. Others have reported associations between the presence of antibodies to infectious agents in the mother's blood during pregnancy and the risk of outcomes such as pre-eclampsia (high blood pressure and abnormal kidney function during pregnancy). Others have shown that infection of placental cells in culture with certain bacteria or viruses impairs their function. However, the quality of the evidence around both placental inflammation and placental infection is generally poor. Furthermore, recent developments in the analysis of genetic material have generated powerful new tools to identify the presence of infectious agents in tissue and these have not previously been applied to studying the possible role of placental infection in causing pre-eclampsia and poor fetal growth.We have been conducting a study since January 2008 (funded by the NIHR Cambridge Comprehensive Biomedical Research Centre). We have recruited women having first pregnancies at the time of their first scan. We obtain blood samples at around 12, 20, 28 and 36 weeks of pregnancy. We also obtain samples of the placenta following birth. We perform extra research scans so that we have detailed information on both the women experiencing complications and the controls with whom they will be compared. By the start of this project, we will have data and samples from more than 4,000 women who have completed the study and this provides a unique and powerful resource to identify whether infection of the placenta is a determinant of common pregnancy complications (pre-eclampsia and poor growth of the baby). Our approach is (1) to detect the presence of genetic material (DNA or RNA) for infectious agents in the placenta, (2) to measure markers of infection and inflammation in the stored blood samples, and (3) to determine whether inflammation in the placenta is more common in complicated pregnancies. Critically, we have also enlisted internationally recognised experts (from the renowned Wellcome Trust Sanger Institute) in the technology of detecting infectious agents (bacteria, viruses etc) in tissue samples. This project could uncover such a role for a currently recognised infectious agent, or it could even identify if these complications are being caused by some currently unrecognised bacterium or virus. Identification of previously unrecognised infectious causes of disease has been critical in medicine in the last 30 years. Recognition of the role of a bacterium (Helicobacter pylori) transformed the management of peptic ulcer disease and recognition of the role of a virus (human papilloma virus) in cervical cancer has led to vaccination as a preventative approach. If the mystery of adverse pregnancy outcome is partly explained by infection, this could lead to similarly dramatic changes in understanding and generate new approaches to improving the health of mothers and babies.