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

本研究的背景是，欧盟和美国分别有150万新生儿和400万新生儿，严重的妊娠不良后果相对普遍。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危险因素的妇女身上。胎盘功能不佳被认为是大多数死产的原因（胎盘是“胎生物”，对正常妊娠至关重要）。导致死产的并发症还与婴儿死亡率、残疾以及由于产前环境恶劣而导致的晚年健康状况不佳有关。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。多项研究报告了妊娠期胎盘炎症的高发率和不良后果。其他研究报告称，怀孕期间母亲血液中存在的传染性病原体抗体与子痫前期（怀孕期间高血压和肾功能异常）等后果的风险之间存在关联。其他研究表明，培养的胎盘细胞受到某些细菌或病毒的感染会损害其功能。然而，关于胎盘炎症和胎盘感染的证据质量通常很差。此外，遗传物质分析的最新发展已经产生了强大的新工具来识别组织中感染因子的存在，这些工具以前没有被应用于研究胎盘感染在引起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）。我们招募了第一次怀孕的妇女进行第一次扫描。我们在怀孕12周、20周、28周和36周左右采集血液样本。我们还在出生后获取胎盘样本。我们会进行额外的研究扫描，这样我们就能得到有并发症的女性和对照组的详细信息。在这个项目开始时，我们将有来自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（先兆子痫和婴儿生长不良）的决定因素提供了独特而有力的资源。我们的方法是(1)检测胎盘中感染因子的遗传物质（DNA或RNA）的存在，(2)测量储存血液样本中感染和炎症的标志物，(3)确定胎盘炎症是否在复杂妊娠中更常见。至关重要的是，我们还聘请了国际公认的专家（来自著名的威康信托桑格研究所）在组织样本中检测感染因子（细菌，病毒等）的技术。这个项目可以揭示目前已知的感染因子的作用，或者它甚至可以确定这些并发症是否是由一些目前未被识别的细菌或病毒引起的。在过去的30年里，鉴定以前未被认识到的疾病的传染性原因在医学上是至关重要的。认识到一种细菌（幽门螺杆菌）的作用改变了消化性溃疡疾病的管理，认识到一种病毒（人乳头瘤病毒）在宫颈癌中的作用，导致接种疫苗作为一种预防方法。如果不良妊娠结局的奥秘部分是由感染解释的，这可能会导致人们对感染的理解发生类似的巨大变化，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.