Last updated: December 2012
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 (part of the SCOPE/MAPS study)
Investigators: Dr Lucy Chappell, Dr Kate Bramham, Dr Hiten Mistry, Paul Seed, Professor Lucilla Poston
Funding: Tommy’s funds the laboratory consumables and some of the doctors on this study
Timescale: 2008 onwards
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 using a new technique called proteomics, which identifies proteins that may not have been found previously by older methods. We are analysing 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 5,500 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.
Progress report: We have developed and validated a workflow for evaluating the urinary proteomic profile. Initial results showed that 981 proteins were identified using proteomics-specific software. Six proteins were present only in urine samples from women with pre-eclampsia; an additional single protein was present in control samples and absent from pre-eclamptic samples. We are currently undertaking validation in a set of time-of-disease samples (36 women with pre-eclampsia and 36 controls). Should validation prove successful, these results will form our final panel of biomarkers for development of a diagnostic test for pre-eclampsia.
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Placental growth factor as a marker of subsequent pre-eclampsia (the PELICAN study)
Investigators: Professor Andrew Shennan, Paul Seed
Funding: Study taking place in a Tommy’s-funded centre
Summary: Pre-eclampsia is a complex disease related to free radical damage and widespread oxidative stress and consequent damage of all blood vessels. Current tests mainly rely on detecting kidney and liver damage. An improving understanding of the underlying disease process has meant a number of tests have been identified that might discriminate between those with pre-eclampsia and those without. In particular, we are evaluating placental growth factor (PlGF) as a marker of subsequent disease and harm, in women with suspected pre-eclampsia.
Progress report: We have recruited 640 women who have presented with suspected pre-eclampsia. Earlier identification of true disease may result in significant differences in management involving admission, surveillance and timely delivery, while normal women could be promptly discharged. Our exciting results have shown that the PlGF blood test is very good at predicting when women will need to be delivered with pre-eclampsia. We are planning a trial of comparing management of women with knowledge of PlGF to those where this knowledge is not available, to determine whether pre-eclampsia can be diagnosed earlier and whether those women managed with this earlier identification have fewer problems.
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Proteomics in pre-eclampsia
Investigators: Christal Fisher, Dr Richard Blankley, Dr Jenny Myers, Melissa Westwood
Funding: Tommy’s part-funds a studentship to Ms Fisher
Timescale: 2008 onwards
Summary: Our current knowledge of pre-eclampsia suggests that any effective treatment would have to be started in the first half of pregnancy in order to have any chance of preventing or delaying the onset of the disease. However, 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: As part of the SCOPE consortium (known as the MAPS study in the UK), we have access to an unrivalled biobank of samples, taken at 15 weeks of gestation, from women who subsequently developed pre-eclampsia. We have so far identified over 500 plasma proteins and we have developed a novel mass spectrometry method to simultaneously measure up to 30 proteins in a single sample. This new technique has allowed us to identify two pregnancy-specific glycoproteins (PSG 5 and PSG 9) that are significantly elevated in women who subsequently develop pre-eclampsia. In combination with measurements of placental growth factor (PlGF) and clinical risk factors, these proteins could become an important component of a predictive test for pre-eclampsia.
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Screening and diagnosis of pre-eclampsia in high-risk pregnant women
Investigators: Dr Ian Crocker, Professor Philip Baker, Stephen Hopkins, David Broadhurst
Funding: Study taking place in a Tommy’s-funded centre
Timescale: 2008-2012
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.
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Predicting pre-eclampsia in first-time mothers (part of the SCOPE/MAPS study)
Investigators: Professor Robyn North, Professor Lucilla Poston, SCOPE Principal Investigators at Universities of Manchester, Leeds, Auckland, Adelaide and University College Cork
Funding: Tommy’s part-funds this study
Summary: First-time mothers have a one in 20 chance of developing pre-eclampsia, which can have life-threatening complications. There is currently no way to predict which first-time mothers will develop pre-eclampsia and, therefore, which women should be offered intervention and be monitored more closely during their pregnancy. We have recently identified a number of blood biomarkers associated with subsequent pre-eclampsia and clinical risk factors that identify some, but not all, women who will develop pre-eclampsia. Our new collaboration with Alere builds on this research. Over 40 biomarkers are being evaluated in samples collected from 5,500 first-time mothers in the SCOPE study (known as MAPS in the UK), with the objective being to develop a high-performance screening test for pre-eclampsia and, in particular, pre-eclampsia resulting in the birth of a premature baby.
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Community blood pressure monitoring for pregnancy hypertension in rural Africa: the CRADLE (formerly COBRA) project
Investigators: Professor Andrew Shennan, Dr Natasha Hezelgrave, Dr Kate Duhig, Paul Seed
Funding: Study taking place in a Tommy’s-funded centre
Summary: It is estimated that over half a million women die in pregnancy or childbirth each year, with 99% of these deaths occurring in the developing world. A large proportion of these are preventable, often with low-cost and simple interventions. 10-15% of these deaths are thought to be related to pre-eclampsia. Pre-eclampsia can be easily and cheaply detected in clinics by measuring blood pressure and testing urine. In the developing world, however, blood pressure monitoring is often not available. This study is investigating whether the introduction of simple to use, cheap automatic blood pressure monitoring devices in healthcare clinics in rural Africa (Zambia, Ethiopia and Tanzania) will affect the detection rates of high blood pressure in pregnancy, referrals to hospital, diagnosis of pre-eclampsia and ultimately the outcomes for the mother and baby.
Progress report: The blood pressure device has been validated for use and negotiations have been entered into with a number of companies about developing their products to suit this environment. All four sites are currently in the post-intervention phase of data collection. Qualitative research is also underway to assess the referral process, the acceptability of the device and its accommodation into the health system.
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Control of hypertension in pregnancy (the CHIPS study)
Investigators: Professor Catherine Nelson-Piercy, M Ching Soh, Annette Briley, Jenny Carter, Professor Laura Magee (Vancouver), Hayley Tarft
Funding: Tommy’s funds Annette Briley
Summary: High blood pressure in pregnancy is associated with risks for mother and baby. However, there is no agreement about whether antihypertensives should be given for non-severe hypertension in pregnancy. Some clinicians treat mild to moderate hypertension whereas others only give medication once persistent severe hypertension develops. The CHIPS trial will randomise women with mild to moderate hypertension to ‘tight’ blood pressure control or ‘less tight’ control. The pregnancy outcomes for mother and baby will be examined to assess whether ‘tight’ or ‘less tight’ control has an influence.
Progress report: This international study has now finished recruitment and data analysis is underway.
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Repeated and automated blood pressure measurements for predicting pre-eclampsia (part of the SCOPE/MAPS study)
Investigators: Professor Andrew Shennan, Dr Dharmintra Pasupathy, Paul Seed, SCOPE study collaborators
Funding: Study taking place in a Tommy’s-funded centre
Summary: In pregnancy, blood pressure is measured routinely to identify women who develop raised blood pressure or pre-eclampsia, a disorder which complicates pregnancy and can cause significant adverse maternal and fetal outcomes. However, previous studies have shown that blood pressure measurements can be a poor predictor of pre-eclampsia. This is most likely due to the poor techniques used for measuring blood pressure. There is also limited evidence on the value of repeated versus single blood pressure measurements and the performance of automated devices for measuring blood pressure. The aim of this study is to determine the value of repeated and automated blood pressure measurement in the prediction of pre-eclampsia using data from the international SCOPE cohort (known as MAPS in the UK). Analysis is continuing but the preliminary results are encouraging.
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Chronic hypertension in pregnancy
Investigators: Dr Kate Bramham, Dr Lucy Chappell, Dr Hiten Mistry, Funsio Adegoke, Hayley Tarft, Ruth Cate, Professor Fiona Broughton Pipkin (Nottingham University), Professor Hannele Laivouri (Finland)
Funding: Study taking place in a Tommy’s-funded centre
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.
Progress report: We have access to a unique set of blood and urine samples obtained longitudinally during pregnancy from 81 White European women with known chronic hypertension (including 11 women who subsequently developed pre-eclampsia) and 81 carefully matched controls. A case-control study of 12 women with superimposed pre-eclampsia, 12 women with chronic hypertension, 12 women with chronic kidney disease and 12 healthy women is also ongoing.
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Pre-eclampsia in association with chronic hypertension, kidney disease and lupus (the PEACHES study)
Investigators: Dr Kate Bramham, Paul Seed, Professor Lucilla Poston, Funsio Adegoke, Hayley Tarft, Ruth Cate
Funding: Study taking place in a Tommy’s-funded centre
Summary: Pre-eclampsia poses considerable risks to both mother and fetus. Diagnosis can be difficult and relies on the detection of a rise in blood pressure, protein in the urine and blood tests. There are currently no simple tests that can make the diagnosis immediately or that can predict which women are likely to develop pre-eclampsia. Women with pre-existing medical conditions, including high blood pressure, kidney disease or connective tissue disease such as lupus, are at higher risk of developing pre-eclampsia and in these women the diagnosis is even more challenging. The aim of this study is to develop a test which will confirm or predict the diagnosis of pre-eclampsia in high-risk women.
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Tempol and Viagra: assessing their effectiveness as treatments for pre-eclampsia and fetal growth restriction
Investigators: Dr Jo Stanley, Dr Mark Dilworth, Dr Sue Greenwood, Dr Mark Wareing, Professor Philip Baker (Auckland), Professor Sandy Davidge (Edmonton), Professor Colin Sibley
Funding: Study taking place in a Tommy’s-funded centre
Timescale: 2010–2015
Summary: Despite the fact that pre-eclampsia and fetal growth restriction are responsible for the death and handicap of many women and their babies, no drugs have been designed specifically to treat these diseases. However, there are a number of drugs that are used to treat other illnesses, and are safe in people who are not pregnant, that have the potential to treat pre-eclampsia and fetal growth restriction. These drugs cannot be tested on pregnant women without first establishing whether they are effective and safe in treating similar diseases in pregnant animals. We have therefore developed the tools to study mice which have been specially bred to show symptoms like those found in women with pre-eclampsia and fetal growth restriction. Using these mice, we are currently testing a number of existing drugs to see whether they are useful for treating the symptoms of these diseases.
Progress report: So far we have tested two drugs, tempol and Viagra, both of which have been shown to improve blood flow in the placenta. We have also tested Viagra on blood vessels taken from human placentas and found that the drug improves their function. We are thus now taking part in an international clinical trial to test whether Viagra can improve the growth of babies suffering from fetal growth restriction in the womb.
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