Updated February 2015

Research into stillbirth

When a baby dies after 24 weeks of gestation it is called a stillbirth. Incredibly, over 4,000 babies are stillborn every year in the UK and many of these deaths remain unexplained. Tommy’s research is dedicated to improving these shocking statistics.

Our research centre in Manchester is focusing on the main cause of stillbirth: fetal growth restriction due to problems with placental blood flow. We are undertaking a whole series of projects looking at this and you can see the ones most related to stillbirth below. This centre set up the Manchester Placenta Clinic in January 2009. The aim of this clinic, the first of its kind in the UK, is to combine specialised antenatal care for pregnancies affected by fetal growth restriction with frontline research into why the condition occurs and how it might be treated. By creating such a close link between clinical researchers and patients, we hope to increase the speed at which research advances can be made.

In 2011 the Manchester centre launched its Stillbirth Research Programme with new funding from Tommy's. The programme focuses on:

  • understanding the causes of stillbirth and developing new diagnostic tools
  • preventing stillbirths by identifying babies at risk
  • developing new national guidelines for health professionals.

Our Edinburgh centre is looking at the effects of obesity on pregnancy outcome. It has been shown that obese women are at higher risk of having a stillborn baby. We want to understand why that's the case so that we can develop treatments to reduce the number of stillbirths.

Individual stillbirth research projects

Viagra: assessing its effectiveness as a treatment for fetal growth restriction and pre-eclampsia

Investigators: Dr Elizabeth Cottrell, Dr Sarah Finn-Sell, kDr 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 three drugs, tempol, resveratrol and Viagra, all 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 then worked with a group of obstetricians in Canada to conduct a small human trial to determine whether babies with severe growth restriction would benefit from Viagra. This provided evidence, similar to the mouse work, that Viagra could indeed improve growth of such babies without causing harm. This evidence is so promising that the Medical Research Council has recently agreed to fund a £3m multicentre clinical trial of Viagra for treating fetal growth restriction. Our Manchester Placenta Clinic will play a major role in this exciting drug trial. We have also begun testing the therapeutic potential of foodstuffs such as beetroot juice and pomegranate juice. These both contain chemicals which could work similarly to tempol, resveratrol and Viagra but which, because they are naturally occurring, would be more acceptable to pregnant women.

Investigation of the causes of and potential treatments for unexplained stillbirth at term

 

Investigators: Professor Catherine Williamson, Dr Lucy Chappell, Dr Peter Dixon, Dr Victoria Geenes, Professor Jim Thornton (Nottingham), Dr Julia Gorelik (Imperial College)

 

Funding: Tommy’s part-funds this study

Summary: Women with the commonest liver disorder specific to pregnancy, called intrahepatic cholestasis of pregnancy (ICP), have a three-fold increased risk of stillbirth. These women have raised levels of bile acids in the blood and it is known that the stillbirth risk is greater in women with particularly high bile acids. They may affect the baby’s heart and make it beat irregularly (called arrhythmia). We have found in our laboratory texting that a drug called ursodeoxycholic acid (UDCA) can prevent arrhythmia caused by bile acids. This project will enable us to use a new portable heart monitor that can be worn by pregnant women to measure the rhythm of the unborn baby’s heart to measure the extent of the abnormal rhythms. We will also be performing a clinical trial of UDCA compared to placebo in women with ICP (the PITCHES trial). This project will recruit participants of this study with the aim of establishing whether we can prevent arrhythmia in unborn ICP babies using UDCA.

 

 

The placenta as a novel therapeutic target to prevent inflammatory-related stillbirth

 

Investigators: Dr Sylvie Girard, Dr Rebecca Jones, Dr Alex Heazell, Dr Vikki Abrahams (Yale) and Professor Colin Sibley

Funding: Study taking place in a Tommy’s funded centre

Timescale: 2012 onwards

Summary: The placenta is essential to the development of the baby whilst in the womb, as it is the sole supplier of oxygen and nutrients. Any alteration in the function of the placenta will have serious negative effects on the pregnancy with devastating impact on the newborn, including small babies, and can lead to stillbirth. We know from our previous studies that inflammation is a direct cause of placental malfunction subsequently leading to stillbirth. We have now been studying a group of women who report that their babies are moving less (reduced fetal movements) during the third trimester of pregnancy to investigate the connection between inflammation, placental malfunction and the risk of stillbirth. We have determined that a unique inflammatory profile is present in the placentas of these women. The changes in inflammatory mediators (members of the interleukin-1 family) that we have detected in the maternal serum prior to delivery have the potential to lead to new diagnostic tools and therapeutic targets in high-risk women.

The AFFIRM randomised trial for prevention of stillbirth

Investigators: Professor Jane Norman (Tommy’s Edinburgh centre), Dr Alexander Heazell (Tommy’s Manchester centre)

Funding: Study taking place jointly in Tommy’s Edinburgh and Manchester centres

Timescale: 2013–2017

Summary:  Rates of stillbirth in the UK are amongst the highest in resource-rich countries. The majority of stillbirths occur in normally formed infants, with (retrospective) evidence of placental insufficiency being the most common clinical finding. Maternal perception of reduced fetal movements is an early marker both placental insufficiency and subsequent stillbirth. The AFFIRM study will investigate whether the introduction of a package of care for women with reduced fetal movements reduces stillbirth. The package of care includes education to increase pregnant women’s awareness of fetal movements and prompt reporting of reduced fetal movements, followed by a standardised management plan for identification of placental insufficiency with timely delivery in confirmed cases. When a similar package was introduced in Norway, the frequency of stillbirth fell by 30% but the efficacy of this intervention has not been robustly tested in a randomised trial (the best form of evidence). Hospitals in Scotland, Ireland, England and Wales will be randomised to the timing of introduction of the care package. A smaller study will examine the acceptability of the intervention to patients and healthcare providers and identify any barriers to implementation.

Progress update: We have had huge interest in this study, with 29 sites and around 450,000 pregnant women scheduled to participate. Tommy’s Dr Alex Heazell, Professor Jane Norman and Dr Sarah Stock have been launching the trial in various centres. Recruitment of women started in May 2014, and the trial will be completed in Spring 2016. This study has the potential to directly improve stillbirth rates.

Assessing fetal health using novel biomarkers in women perceiving reduced fetal movements (the FEMINA2 study)

Investigators:Investigators: Dr Lucy Higgins, Dr Alex Heazell, Dr Edward Johnstone, Dr Melissa Whitworth, Dr Mark Wareing, Professor Dame Tina Lavender, Professor Colin Sibley

Funding: Tommy’s part-funds this study

Timescale: 2011–2015

Summary: A mother’s perception of her baby's movements has been used to confirm fetal wellbeing for many years. Conversely, a reduction in the baby's movements is associated with poor pregnancy outcome, including significantly increased risk of stillbirth. A reduction in fetal movements is thought to be a survival strategy to conserve energy when nutrients and/or oxygen are in short supply. Women are told in pregnancy to be aware of their babies’ movements and to present to their maternity unit if they notice a reduction. As a consequence, a reduction in fetal movements is a common reason for women to attend maternity services in the last 12 weeks of pregnancy. There is currently no accurate way to predict which of these women will have a normal pregnancy (the majority) and which will have a poor pregnancy outcome. A test is needed to inform obstetricians as to which women to deliver to prevent stillbirth. This study builds on earlier work in Manchester and is recruiting women who present with reduced fetal movements after 28 weeks of pregnancy.

Progress report: The FEMINA2 study reached its target recruitment of 300 women who presented with reduced fetal movements after 28 weeks of pregnancy. 56 had a bad outcome, including stillbirth, failure to grow, signs of stress before birth and admission to the neonatal intensive care unit. For each case we collected 181 different pieces of information. We were then able to see which of these predicted poor pregnancy outcome. We have made a combination of 7 ultrasound features and blood tests that has the potential to detect 30% more babies with poor outcome than our current standard tests. We will test this in a new group of women in the PAPPO study.

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The Placental Assessment Predicting Pregnancy Outcome (PAPPO) study

Investigators: Dr Alexander Heazell, Dr Melissa Whitworth, Dr Clare Davenport (Birmingham), Professor Lelia Duley (Nottingham), Professor Jim Thornton (Nottingham), Professor Alan Montgomery (Nottingham), Professor Tracy Roberts (Birmingham)

Funding: Study taking place in a Tommy’s funded centre

Timescale: 2014–2019

Summary: In the UK, 1 in 200 pregnancies after 24 weeks ends in stillbirth. The majority of cases of stillbirth are associated with placental failure which may sometimes be associated with a reduction in the baby’s growth. If we could better identify these cases then, in combination with targeted delivery of the baby, this approach could reduce the number of stillbirths. We will initially combine studies that investigated whether using placental tests to determine delivery is effective, and to do this the outcome of pregnancy in women who had an additional placental test will be compared with those who did not. Then we will analyse results from all studies that measure how well the placenta works to see which of these tests best identifies babies at risk of stillbirth. We will then apply these tests to a group of women at high risk of stillbirth to see whether they accurately predict adverse pregnancy outcome. Finally, we will conduct a multi-centre pilot trial of placental tests to reduce stillbirth to see whether a larger trial to give a definitive answer would be possible and desirable. 

Understanding placental pathology in stillbirth

Investigators: Imogen Ptacek, Dr Alex Heazell, Dr  Paul Brownbill

Funding: Study taking place in a Tommy’s funded centre

Timescale: 2013

Summary: The role of the placenta in some stillbirths is well established and thus all international guidelines for the investigation of stillbirth recommend examination of the placenta. However, we have systematically reviewed the medical literature and found large variations in the estimated value of placental examination. In particular, the studies used 17 different classification systems, and of course the results differed depending on the classification system used. To address this, we have studied placental tissue from stillbirths due to fetal growth restriction to determine whether this differs from live births which were also growth restricted. We found that placental abnormalities are similar in both groups but that the abnormalities are more severe in stillbirths. This suggests that the magnitude of placental damage may be important in determining whether a baby is born alive or dead. A widely accepted classification system for stillbirths which includes relevant placental problems with explicit diagnostic criteria is essential to facilitate understanding of the role the placenta has in stillbirth.

Undiagnosed lupus and unexplained stillbirth

Investigators: Dr Ian Crocker, Dr Clare Tower, Dr Ian Bruce, Dr Ed Johnstone, Dr Alex Heazell

Funding: Study taking place in a Tommy’s funded centre

Timescale: 2014–2016

Summary: Women with the autoimmune condition systemic lupus erythematosus (SLE) have a 20% chance of their pregnancies ending in fetal loss (miscarriage or stillbirth). A study of 1.4 million Danish women has shown a clear relationship between ‘unexplained’ stillbirth/miscarriage and the subsequent onset of SLE, most notably in the first 5 years after pregnancy loss. Given that patients with SLE usually have a prolonged phase before diagnosis, we suspect that a significant number of unexplained fetal deaths may be attributed to undiagnosed SLE or lupus-like autoimmunity in a portion of pregnant women.

We have two approaches, firstly to recruit women with a recent stillbirth or late miscarriage, or similar women returning in a subsequent pregnancy, defining lupus-like features which may underscore their past fetal loss and assist their current antenatal care. Secondly, we are using nationwide clinical databases to ask population-based questions, such as the incidence of SLE following a previous stillbirth/miscarriage and timing of this onset. Combined, this information will identify the form and usefulness of early antenatal screening in defining women at greatest risk of miscarriage/stillbirth.

Progress report: In addition to these direct patient observations, we are extending the power of our study dramatically using local and national clinical databases. We have extracted anonymised clinical data from 4.5 million pregnancies over the last decade. We are now starting to investigate this wealth of patient information. The study began in January 2014, with population outcomes generated first from the North West of England and more recently the whole country, over the last decade. Recruitment is now complete for pregnant SLE patients for comparison, whilst recruitment and characterisation of women returning after stillbirth/miscarriage is underway. 

Using MRI to detect problems with the placenta during pregnancy

Investigators: Dr Emma Ingram, Dr Ed Johnstone, Dr David Morris, Dr Jo Naish, Jenny Myers and Professor Colin Sibley at Tommy’s London centre, and Dr Fiona Denison  and Professor Jane Norman at Tommy’s Edinburgh centre

Funding: Tommy’s funds this project

Timescale: 2013–2017

Summary: Abnormalities in the development of the placenta are linked to many complications of pregnancy, including pre-eclampsia, fetal growth restriction, miscarriage and stillbirth. Significant progress has been made in determining some of the causes of placental disease by examining the placenta after it has been delivered at the end of pregnancy. However, obstetricians need to be able to detect these different placental characteristics whilst the placenta is still functioning in the womb, and this remains a challenge. However, we have developed placental magnetic resonance imaging (MRI) techniques over the last 4 years that are showing promise in attacking this problem. Our data has shown progressive changes in MRI placental appearance and function across pregnancy gestation and between normal and complicated pregnancies, but at present this data is only available at one time point during pregnancy. This new study will address this problem by asking women to undergo two placental MRI scans during pregnancy, if possible before and after any treatment. Placental MRI scans will follow our previous scan procedure protocols. The information obtained will contribute to the battery of tests we are developing to predict which pregnancies are at risk of stillbirth.

Progress report: Ethical permission has now been obtained and we have started recruiting women to this study.

Novel MRI techniques to detect intrauterine hypoxia

Investigators: Dr Fiona Denison, Dr Scott Semple, Professor Jane Norman, Dr Jane Walker, Professor Edwin van Beek

Funding: Study taking place in a Tommy’s funded centre

Timescale: 2011 onwards

Summary: Poor placental function causes hypoxia (low oxygen levels) within the womb. This is the leading cause of poor fetal growth and stillbirth. Unfortunately, none of the tests that doctors currently use are very good at telling how hypoxic babies are within the womb and predicting how well (or otherwise) they are. The aim of this research is to find out whether new magnetic resonance imaging (MRI) techniques can detect differences in oxygen tension between normal and at-risk pregnancies, and whether these measurements correlate with the current clinical methods of assessing intrauterine hypoxia. The longer term goals of this research are to assess whether information gained from novel imaging techniques can inform timing of delivery and thus improve outcome in pregnancies complicated by uteroplacental insufficiency.

Progress report: Recruitment is going well. Our initial analyses are exciting and suggest that there are differences in the metabolic footprint from placentas in women with a small baby compared to healthy gestation-matched controls.

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Managing obstetric cholestasis (the PITCHES trial)

Investigators: Dr Lucy Chappell, Paul Seed, Professor Catherine Williamson (Imperial College Healthcare), Professor Jim Thornton (University of Nottingham)

Funding: Study taking place in a Tommy’s funded centre

Summary: Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease in pregnancy. Affected women itch and have abnormal liver blood tests. It is important to diagnose ICP because it is associated with risks for the unborn baby. Blood tests in the mother may show high levels of bile acids, which can increase the risk of the baby being born early and, in severe cases, being stillborn. At present the main drug used to treat ICP is ursodeoxycholic acid (UDCA). Our recently published pilot trial showed that women with ICP are willing to take part in a trial comparing UDCA with a placebo (an identical tablet not containing the drug). The trial also suggested that UDCA may protect the unborn baby from poor outcomes, but the study was not large enough to be certain. Our larger PITCHES clinical trial will address this problem. If it shows that UDCA protects babies, the current UK clinical guidelines can be updated to be clearer about its recommendations. This research will give vital information to help doctors understand and try to prevent the poor outcomes for the baby in ICP pregnancies. The trial will start in early 2015 once all approvals have been granted.

Older mothers and the risk of stillbirth

Investigators: Samantha Lean, Jane Boscolo-Ryan, Linda Peacock, Dr Rebecca Jones, Dr Alex Heazell, Dr Tracey Mills, Jessica Thomas, Mark Dilworth

Funding: Tommy’s studentship to Ms Lean and funding for the research midwives

Timescale: 2011–2015

Summary: Delaying childbearing is a growing trend among UK women. This is a major clinical and public health concern because maternal age over 35 has consistently been associated with poor pregnancy outcome, particularly stillbirth. Although these complications are related to abnormalities in the way the placenta grows and works, there have been no studies to find out why and how advanced maternal age increases pregnancy risk. In this study, known as the Manchester Advanced Maternal Age Study (MAMAs), we are measuring the levels of hormones and markers of inflammation and oxidative stress in the blood of women of advanced maternal age (35 years and older) and comparing them to the levels in women of optimal childbearing age (20–30 years). We will also collect the placentas from both groups of women and perform laboratory tests to study its development, growth and function. This study will identify potential links between advanced maternal age and stillbirth. Understanding these links will allow women at high risk to be identified, enabling targeted intervention of clinical care to prevent stillbirth.

Progress report: The MAMAs study was extended to six other sites in the UK and recruited a total of 562 women. We have demonstrated for the first time that advanced maternal age is related to abnormalities in the placenta. We found microscopic features of accelerated ageing and lower rates of cell growth in the placentas of older women. The placentas also produced lower levels of the important hormone hCG. However, placental nutrient uptake flow was enhanced in women aged over 40 years, and the blood vessels in these placentas also relaxed more, which would lead to increased blood supply to the baby. These may be responses to promote the growth of the baby in reaction to an adverse environment. The study will conclude in early 2015 after all women have completed two study visits (at 28 and 36 weeks’ gestation) and have delivered. This is the largest prospective study of advanced maternal age and will enable detailed analysis of maternal risk factors for poor pregnancy outcome.

Villitis of unknown aetiology as a cause of stillbirth

Investigators: Hayley Derricott, Dr Rebecca Jones, Dr Alex Heazell, Dr Gauri Batra, Dr Sue Greenwood

Funding: Tommy’s studentship to Ms Derricott

Timescale: 2012–2015

Summary: Stillbirth is very closely related to problems in the placenta; how these problems arise and what effects they have are not fully understood. One abnormality seen in stillbirths is inflammation in the placenta (known as villitis). Other investigations have not found a cause for this inflammation such as a bacterium or virus. We are interested in this inflammation and how it relates to problems in the placenta; to investigate this we will look closely at how inflammation changes the structure of the placenta and whether it changes how effectively the placenta works. We will do this in samples from a well-characterised biobank of placental samples from pregnancies where the baby was stillborn. Our preliminary work has shown that the number of white blood cells, which indicate inflammation, is increased in placental tissue in cases where there were reduced fetal movements, particularly those ending in poor pregnancy outcome.

Progress report: We have completed a systematic review of previously completed studies which showed that inflammation, specifically villitis of unknown aetiology was present in 15% of apparently normal pregnancies and confirmed that it was about twice as common in babies that had failed to grow adequately. However, there have not been studies of enough patients to definitely associate it with stillbirth. We are continuing our laboratory analyses of placental samples from stillbirths and we will develop these observations to provide quantitative descriptions of the cell types involved. We hope that our results will enable a sufficiently large study to be carried out to determine whether villitis of unknown aetiology is indeed linked to stillbirth.

Improving support in pregnancy following stillbirth or neonatal death (the IMPS study)

Investigators: Dr Tracey Mills, Dr Alexander Heazell, Dr Melissa Whitworth, Catherine Ricklesford, Professor Dame Tina Lavender

Funding: Tommy’s funds this study

Timescale: 2011–2014

Summary: The death of a baby before or shortly after birth is a profoundly devastating experience for parents. Many bereaved parents embark on another pregnancy, often within a relatively short time after their loss. Pregnancy after a stillbirth or neonatal death is often a time of emotional turmoil for women, and heightened worry and anxiety are common. This is important as excessive stress in pregnancy is increasingly recognised as contributing to problems before and after birth, and may impact on long-term health of mothers and babies. Women who have had a previous stillbirth or neonatal death are sometimes offered extra appointments or tests in pregnancy to give reassurance about their own and the baby’s wellbeing. However, the care provided may not be the same in different hospitals or areas of the country. We currently know very little about women’s experiences of care and what extra support they would find helpful, when it should be provided and by whom. This study will explore the views and experiences of women and health professionals and the findings will be used to improve current care and support the development of new and better ways to care for bereaved parents.

Progress report: We have completed a systematic review of the existing medical literature and this has identified a number of significant issues with current care provision and confirmed a lack of UK research exploring the parents’ or professionals’ experiences. Analysis of the responses of more than 500 women who completed our online questionnaire and of over 130 UK maternity units is nearing completion. Preliminary findings highlight many examples of excellent care and support within UK maternity services. However, positive experiences were not universal, and many women reported inadequate emotional and psychological support. We have also completed interviews with 12 fathers exploring their experiences of supporting their partners.

Targeting maternal RNA-binding protein defects to prevent stillbirth

Investigators: Professor Nicola Gray, Matt Brook, Lenka Habrakova

Funding: Study taking place in a Tommy’s funded centre

Timescale: 2012–2015

Summary: Stillbirth affects about 1 in 200 pregnancies. The causes are ill-defined, and progress has been severely limited by the lack of an animal model. In this project, we are exploring a mouse model that displays all the symptoms and signs of stillbirth in women. We hope this will help us understand what causes stillbirth, and that in the future this may lead to screening strategies to identify those women at highest risk of stillbirth and adverse pregnancy outcomes.

Improving maternal and perinatal outcomes through engaging women and families in their own safety (the REACH-UK study)

Investigators: Professor Jane Sandall, Professor Debra Bick and Nicola Mackintosh, Wendy Carter

Funding: Study taking place in a Tommy’s funded centre

Summary: Almost one in every 100 births in the UK results in the stillbirth or death of a baby in the early weeks of life. Stillbirths and neonatal deaths are also more common among some groups of mothers, principally women who smoke, who are obese and who are over 35 years old. Women from areas of social deprivation and those from some minority ethnic groups are also at increased risk. Various reports have found that a significant percentage could have been avoided with better care. The REACH-UK study will draw on the REACH programme developed in Australia which builds on the life-saving analogy for recognition and appropriate care of ‘deteriorating’ patients by encouraging patients and family to ‘put their hands in the air’ to signal they are ‘drowning’ and reach out for help. This project will explore the potential of providing women and their families with personalised information about key warning signs and what action to take, and develop provider response programmes and assess impact.

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Developing non-invasive long-term fetal monitoring – The Fetal Heart and Movement (FeHeMo) Vest

Investigators: Dr Alexander Heazell, Dr Ed Johnstone, Dr Anura Fernando and Dr Jayawan Wijekoon

Funding: Study taking place in a Tommy’s funded centre

Timescale: 2012 onwards

Summary: Current methods to check the wellbeing of babies in the womb include intermittently monitoring babies’ heart rate, but this approach has little or no effect on reduction of stillbirth, even in mothers at high risk of adverse pregnancy outcomes. However, these techniques are often used as little else is available. One suggestion to improve monitoring for babies is to develop technologies that can monitor babies for longer periods of time. These devices include longer term monitoring of babies’ heart rate or movements. To achieve this we cannot use current monitoring techniques which rely on ultrasound as this cannot be used for extended periods and mothers need to be relatively still. We have developed a device that can measure fetal heart rate and movements by sensors held in a fabric vest. We have worked with Manchester Integrating Medicine and Innovative Technology (MIMIT) to put together a team to develop this device. The final working version is currently under development and we hope to start initial clinical trials in January 2015. This device could make a major improvement in the detection of babies who have reduced movements, improving management and decreasing the risk of stillbirth.

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