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

本研究的背景是，欧盟有> 500万例出生，美国有> 400万例出生，妊娠的严重不良结局相对常见。例如，仅在英国，每年就有超过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女性身上。胎盘功能不佳被认为是造成大多数死胎的原因（胎盘是“胞衣”，对正常妊娠至关重要）。导致死产的并发症还与婴儿死亡、残疾有关，并由于产前环境差，导致晚年健康不良。然而，胎盘功能障碍导致这些并发症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中胎盘炎症的高发生率，并伴有不良结局。其他人报道了怀孕期间母亲血液中感染因子抗体的存在与先兆子痫（怀孕期间高血压和肾功能异常）等结局风险之间的关联。其他研究表明，培养中的胎盘细胞被某些细菌或病毒感染会损害其功能。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产生了强有力的新工具来识别组织中感染因子的存在，这些工具以前没有应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。我们自2008年1月以来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妇女。我们在怀孕12周、20周、28周和36周左右采集血样。我们还在出生后采集胎盘样本。我们进行额外的研究扫描，以便我们有详细的信息，无论是妇女经历的并发症和控制，他们将与谁进行比较。到该项目开始时，我们将获得来自4,000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强大的资源。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）测量储存的血液样本中的感染和炎症标志物，（3）确定胎盘中的炎症是否在复杂妊娠中更常见。重要的是，我们还聘请了国际公认的专家（来自著名的Wellcome Trust桑格研究所）在检测组织样本中的传染性病原体（细菌，病毒等）的技术。该项目可以揭示目前公认的感染因子的这种作用，或者它甚至可以确定这些并发症是否由一些目前尚未认识到的细菌或病毒引起。在过去的30年里，识别以前未被认识到的疾病的传染性原因在医学上一直是至关重要的。认识到细菌（幽门螺杆菌）的作用改变了消化性溃疡疾病的管理，认识到病毒（人乳头瘤病毒）在宫颈癌中的作用，导致疫苗接种作为一种预防方法。如果不良妊娠结局的神秘性部分可以用感染来解释，这可能会导致理解上的类似巨大变化，并产生改善母亲和婴儿健康的新方法。

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.