Research into pre-eclampsia

Pre-eclampsia affects four million women around the world every year and results in about 70,000 maternal deaths. In developed countries, it complicates between 3% and 6% of all pregnancies. It thus remains a major cause of illness and death for both mother and baby. Furthermore, the incidence of the disease hasn’t decreased over the last 20 years and, because obesity seems to increase the risk, it could mean more women are developing the disorder than ever before.

At present, only women who had pre-eclampsia in previous pregnancies or who have symptoms associated with an increased risk receive targeted care. Tommy’s research is dedicated to developing a routine screening test for all women to identify those most likely to get pre-eclampsia.

A number of studies funded by Tommy’s are looking to identify markers at the molecular or genetic level that will predict pre-eclampsia. As you’ll see from the projects below, we have already made some exciting discoveries in this area, and a predictive test may not be too far away.

Of course, we’re also conducting projects aimed at treating those women identified as being at high risk. Our Manchester centre is looking at relaxing the blood vessels connecting mother and baby because when these are constricted it can lead to a variety of pregnancy problems, including pre-eclampsia. Excessive cell death in the placenta is another possible cause that we are looking at, as are elevated levels of damaging free radicals in the placenta.

Individual research projects

Predicting pre-eclampsia in normal and low-risk pregnancies
Investigators: Dr Lucy Chappell, Dr Hiten Mistry, Dr Kate Bramham, Professor Robyn Nirth, Professor Lucilla Poston
Funding: Current pilot work funded by Tommy’s
Timescale: 2008–2011
Summary: Diagnosing pre-eclampsia is difficult and being able to tell which women are most likely to develop the condition would reduce the number of unnecessary hospital visits and tests for those at low risk and allow care to be given appropriately to those at higher risk. We are planning to use a new technique called proteomics, which identifies proteins that may not have been found previously by older methods. We will analyse urine samples already given by pregnant women to a large international study (the SCOPE study, which is known as MAPS in the UK) which has already collected samples from 4,500 pregnant women. Once we know more about specific proteins in the urine of pregnant women, we can develop tests to predict and diagnose pre-eclampsia, which is then likely to help us to improve antenatal care for these women. It could also lead to future preventative treatments.

Improved pre-eclampsia detection
Investigators: Dr Lucy Chappell, Professor Andrew Shennan, Dr Pippa Kyle, Lynda Mulhair, Annette Briley, Jenny Carter
Funding: Tommy’s funds several of the doctors working on this project.
Timescale: 2009–2010
Summary: Screening for pre-eclampsia is currently done by checking urine for protein and measuring blood pressure, which is poor at identifying those women at high risk of the disease. This study is evaluating two new simple automated tests (ACR and PCR), which are likely to be signficantly more reliable. The tests can be done in the Antenatal Day Unit and give rapid results, avoiding unneccessary admissions of low-risk women.

The role of kisspeptin in placental function and pre-eclampsia
Investigators: Dr Rebecca Reynolds, DrThayalini Ramaesh, Dr Patrick Hadoke, Dr Simon Riley, Professor Brian Walker, Professor R Millar
Funding: Tommy’s funds several of the doctors working on this project.
Timescale: 2007–2010
Summary: Kisspeptin is a peptide (a short chain of amino acids) which has recently been identified in the placenta. We are investigating its role in the formation and constriction of placental blood vessels using various models.

Chronic hypertension in pregnancy
Investigators: Dr Kate Bramham, Dr Lucy Chappell, Dr Hiten Mistry, Professor Lucilla Poston
Funding: Tommy’s funds several of the doctors working on this project.
Timescale: 2010 onwards
Summary: Chronic hypertension affects as many as 33,000 pregnant women in the UK every year and is associated with significant complications for both mother and baby. Current methods of predicting adverse pregnancy outcomes are limited. This study will attempt to identify novel chemicals in the urine of women with hypertension which may be used to identify which of them are likely to have problems in their pregnancy. We will also investigate urinary biomarkers that may allow us to discriminate better between raised blood pressure and the more dangerous condition of pre-eclampsia.

An investigation of pre-eclampsia using a placental perfusion model
Investigators: Elizabeth Hutchinson, Dr Paul Brownbill, Dr Vikki Abrahams (Yale University), Professor Colin Sibley, Dr Ian Crocker
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2006–2009
Summary: This project developed a technique called placental perfusion, which replicates the abnormal placental conditions associated with pre-eclampsia, i.e. those of altered oxygen and turbulent blood flow over the placental surface. We have been investigating which factors issued from the placenta trigger the condition.
Progress report: Although several possible factors have been confirmed, we are currently in the process of characterising and identifying what these are. The identification of an active circulating factor in pre-eclampsia, produced by the placenta, would have an immediate impact on screening and therapeutic options. A recent significant finding is that abnormal levels of free fatty acids (palmitic, oleic and linoleic acid) in the mother’s blood can potentially trigger pre-eclampsia, and measuring them may also allow us to predict the condition.

Proteomics in pre-eclampsia
Investigators: Dr Richard Blankley, Dr Jenny Myers, Sitara Kuruvilla, Christal Fisher, Dr Sarah Hart, Professor Philip Baker
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2005–2011
Summary: There is currently no screening test which can effectively predict pre-eclampsia. This project uses proteomics – the study of proteins – to measure the differences in protein expression in a variety of biological and clinical samples to see whether markers associated with high pre-eclampsia risk can be identified.
Progress report: We have identified a substance called endoglin as an example of a protein found at elevated levels in the blood plasma of women who go on to develop pre-eclampsia. We have also discovered a number of possible proteins in urine that might be candidates for a predictive test.

Identifying biomarkers that predict pre-eclampsia
Investigators: Dr Marie Brown, Dr Louise Kenny (University of Cork), Professor Douglas Kell, Professor Philip Baker
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2005–2009
Summary: The aim of this project, which is an extension of a longstanding and successful collaboration between the Tommy’s group in Manchester and the Department of Chemistry at the University of Manchester, is to identify biomarkers that can be used in early pregnancy to predict which women are at increased risk of developing pre-eclampsia.
Progress report: This project has been highly successful so far, with the identification of a number of possible biomarkers. In particular, our scientists have developed a technique for detecting certain metabolites (metabolites are waste products produced by chemical reactions within our bodies) that predict pre-eclampsia. This discovery should bring a practical test to identify high-risk women much closer.

Screening and diagnosis of pre-eclampsia in high-risk pregnant women
Investigators: Catherine Chmiel, Alicia Requena, Professor Philip Baker, Dr Ian Crocker
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2008–2011
Summary: While past studies have identified predictive markers for pre-eclampsia in the maternal bloodstream, none of these markers have shown the necessary accuracy for establishing a clinical test. However, we are now measuring and combining these markers simultaneously in a single blood assay, thus greatly enhancing their predictive capabilities. This will provide a convenient tool for clinical use and allow fast and effective decision making.
Progress report: In the first instance, it is logical to test this predictive tool on a patient group at high risk of developing pre-eclampsia. We are therefore recruiting patients from high-risk antenatal clinics within St Mary’s Hospital in Manchester and following their biomarker profiles longitudinally. In due course, this will be expanded to a large-scale study of low-risk pregnancies.

The role of endothelial progenitor cells in placental blood flow
Investigators: Dr Peter Sipos, Dr Mark Wareing, Dr Carl Hubel (University of Pittsburgh), Professor Philip Baker, Professor Colin Sibley, Dr Ian Crocker
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2008–2011
Summary: Poor blood vessel development is one of the reasons why pregnancy problems such as miscarriage, fetal growth restriction and pre-eclampsia can occur. In adults, cells called endothelial progenitor cells are important for blood vessel development and repair. We have identified these cells in the placental circulation and in this study we are determining whether these cells play a similar role in the placenta.

Increased placental cell turnover in pre-eclampsia
Investigators: Dr Andrew Sharp, Dr Alex Heazell, Professor Gil Moore (Yale University), Professor Philip Baker, Dr Ian Crocker
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2007–2010
Summary: We have previously associated pre-eclampsia with increased cell death in the human placenta and we have also shown that low oxygen and fluctuations in oxygen are likely causes of this exaggerated placental cell death.
Progress report: In placental cells exposed to low or fluctuating oxygen, we have noted changes in internal cellular signals, particularly those associated with a protein called p53. We are now using a laboratory model to look at whether enhanced p53 activity is a key component in the regulation of cell death and, if so, whether we can reduce it so that cell death is minimised and the pregnancy can proceed normally.

Do free radicals hinder placental development?
Investigators: Paula Diaz, Professor Colin Sibley, Dr Sue Greenwood
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2009–2013
Summary: It is known that there are increased levels of highly damaging free radicals in the placentas of women with pre-eclampsia and fetal growth restriction. In this study we will investigate the possibility that these free radicals hinder placental development by inactivating potassium channels. Potassium channels are proteins in the cell membrane and we discovered that they are required for normal placental development. Free radicals inactivate potassium channels in many tissues of the body but it is not known whether this occurs in the placenta. If we discover that this is the case, we will devise therapies to regain potassium channel function and restore placental development in pre-eclampsia and fetal growth restriction.