Investigation of the maternal immune phenotype in women with recurrent pregnancy loss due to chronic histiocytic intervillositis

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Principal subject of the research: My project aims to discover the cause of a rare but devastating disease of pregnancy that causes repeated miscarriage and stillbirth. Chronic histiocytic intervillositis (CHI) affects 1 in 10,000 pregnancies but carries a very high risk of recurrence, meaning that some affected couples have suffered several pregnancy losses. Only about half of all babies in CHI pregnancies survive, and over half of these will be born very premature, causing long-term consequences for their health. The emotional burden for parents enduring these repeated losses is immense. We have chosen to study this disease in the hope of improving the outlook for affected families.The cause of CHI is unknown and it can only be diagnosed after a pregnancy has ended, by analysing the placenta under a microscope. In a subsequent pregnancy, apart from recognising a very small baby on ultrasound scans, there are no proven warning signs of recurrence and no reliable test that can predict whether the pregnancy will succeed or fail. There is also no treatment that can consistently prevent CHI from recurring. The project's key aims:Current scientific evidence suggests that CHI is caused by an antibody from the mother that attacks the placenta during pregnancy. This prevents the placenta from developing and stops the unborn baby from growing normally. We aim to identify this antibody in order to improve our understanding of the cause of CHI. I will also study immune cells from the lining of the womb of women who have had CHI, to discover further clues as to the cause of recurrent pregnancy loss. Determining the cause of CHI is critical to the discovery of treatments that can prevent recurrence and offer affected women the hope of a healthy baby. The structure and setting of the research:The research will be divided into two components: firstly, the search for a maternal antibody that attacks the placenta in CHI; and secondly, an investigation into the function of immune cells from the endometrium (lining of the womb) in women with CHI. The first component will be undertaken at the UCL Institute for Women's Health, a vibrant community of doctors and scientists working to improve outcomes across the spectrum of women's health. The Institute hosts several high-profile related studies investigating problems such as severe fetal growth restriction and has an excellent track record in bringing innovative new maternal and fetal therapies to clinical trials. It therefore represents the perfect setting for this research. The second component will be undertaken in Sweden, thanks to an exciting collaboration with scientists at the Karolinska Institute in Stockholm. This will allow us to learn and implement pioneering new techniques for the study of endometrial immune cells and their role in placental health and disease. These cells have never been studied before in women with CHI and our findings could play a pivotal role in understanding why these women, and others, have recurrent pregnancy loss. Potential impact: This research is designed to benefit patients. Discovering the cause of CHI will bring us closer to being able to design and implement new treatments to prevent recurrent pregnancy loss. We hope that our findings could form the basis of a clinical trial for CHI in the future, and that they might also provide a useful model for the investigation of unexplained recurrent pregnancy loss. Our findings could also benefit doctors and scientists working to solve other antibody-driven diseases, such as lupus. We are committed to learning from affected patients and families about their priorities for research, their perceptions of perinatal bereavement care and their unique experience of living with a poorly understood condition that causes recurrent pregnancy loss. We want to raise the profile of this neglected disease to stimulate further research and improve outcomes for patients in the future.