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

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.