Updated February 2014

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 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 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.

Effects of prenatal inflammation on placental function and consequences for the baby

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.

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: 2011–2014

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: We have so far recruited 214 women presenting with reduced fetal movements to the FEMINA2 study, and we are on target to recruit our total of 300 women by March 2014. We will then use the validated placental measures and further analysis of maternal serum to determine the best tests to detect poor perinatal outcome in women attending with reduced fetal movements. We plan to use the best-performing tests in a multicentre pilot randomised controlled trial to see whether this reduces poor pregnancy outcome, including stillbirth. 

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Reduced fetal movements: exploring women’s and clinicians’ experiences

Investigators: Dr Rebecca Smyth, Wendy Taylor, Dr Melissa Whitworth, Dr Alex Heazell, Dr Christine Furber, Professor Dame Tina Lavender

Funding: Tommy’s funds this study

Timescale: 2012–2013

Summary: A mother’s perception of her baby’s movements has been used for many years as a method to evaluate fetal wellbeing on the premise that fetal movements are a confirmation of the baby’s wellbeing. Maternal perception of reduced fetal movements is associated with adverse fetal pregnancy outcome including stillbirth, growth restriction, preterm birth and fetal abnormality. A perception of reduced fetal movements is frequently reported by pregnant women and occurs in approximately 5% to 16% of pregnancies in the last three months of pregnancy, although the absence of perceived movements does not necessarily indicate fetal death or fetal compromise. A common cause of stillbirth is placental insufficiency, where the placenta cannot supply the baby with enough oxygen or nutrients to survive. When this happens, it is thought that a reduction in movements is a survival strategy to conserve energy. As many as 50% of women perceive a gradual reduction in movements several days before a stillbirth.We are unable to find any qualitative research that has focused on women’s accounts of experiencing reduced fetal movements, and our qualitative study of interviews with women will further our understanding of this situation. We will also interview clinicians to find out about the practical challenges of identifying and managing women with decreased movements.

Progress report: Twenty women and ten clinicians have been interviewed. The findings have confirmed that women are receiving conflicting advice from their clinicians about reduced fetal movements. In addition, the study identified clear knowledge deficits in respect of current clinical guidance amongst clinicians, with significant variations in the definition of what constitutes reduced fetal movements and uncertainty regarding management. We are now planning a UK-wide survey of midwives’ and obestricians’ practices for detecting and managing reduced fetal movements in pregnancy. 

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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. This new study will recruit women with a recent stillbirth or late miscarriage, or similar women returning with a subsequent ongoing pregnancy. To identify those women with signs of SLE, we will use both standard blood tests for autoantibodies and alternative measurements to account for their pregnancy loss. If successful, these results could lead to nationwide antenatal screening for SLE or related conditions as a means of highlighting women, early in their pregnancy, at risk of stillbirth or miscarriage.

Using MRI to detect problems with the placenta during pregnancy

Investigators: Dr Emma Ingram, Dr Ed Johnstone, Dr David Morris, Dr Jo Naish 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.

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 and our initial MRI studies demonstrate that the spectral output from placentas from pregnancies with suspected fetal compromise is very different from those from a normal pregnancy. We are currently recruiting a cohort of women whose babies are affected by less severe fetal compromise to see whether there is a gradation in this effect.

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Can the placenta be preconditioned to withstand low oxygen levels?

Investigators: Professor Jane Norman, Professor Nicola Gray, Jessica Scanlon (MSc student)

Funding: Tommy’s funds the MSc student and the consumables for this study

Timescale: 2013–2014

Summary: Women living at high altitude during pregnancy can often have low birthweight babies due to lower oxygen levels (hypoxia). This is a problem as low birthweight is correlated with perinatal death and disease, inhibited intellectual development, and chronic diseases, such as diabetes in adult life. The effects of hypoxia seem to be mediated through changes in the placenta, which carries nutrients and oxygen to developing babies. We have used placental cells to investigate the effects of hypoxia on cell function. This has shown that it inhibits their ability to produce proteins, but that this is restored when the cells are grown in normal oxygen levels. This ability to recover is useful, as it has been shown that some organs (eg the heart) are more able to cope with an insult such as low oxygen if the body has experienced it before. This is termed preconditioning, and it could be useful during pregnancy, for instance during labour when the placenta undergoes hypoxia but still needs to be able to function correctly, to support the baby. Ultimately, the results of this research could help protect babies from the adverse effect of reduced oxygen supplies in the womb. 

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. 

Maternal obesity and effects on placental and fetal development

Investigators: Dr Vicky King, Nanette Hibbert, Professor Jane Norman, Professor Jonathan Seckl, Dr Mandy Drake

Funding: Tommy’s funds Dr King and the consumables for this study

Timescale: 2010–2013

Summary: Obesity is associated with a significantly increased risk of pregnancy complications including stillbirth. There is also evidence that maternal obesity in pregnancy might ‘programme’ an increased risk of obesity and cardiovascular disease in the offspring. In this study we are using our mouse model of maternal obesity to determine how maternal obesity might impact on the growth and development of the placenta and the fetus.

Progress report: We have found effects on genes which regulate placental and fetal growth in early gestation but these effects were no longer present in late gestation. We propose that differences in maternal weight gain and/or specific dietary components may impact on fetal and placental growth and later disease risk. Our results have recently been published in the journal Placenta.

Understanding placental cell damage

Investigators: Dr Sarah Coleman, Dr Alex Heazell, Professor John Aplin, Professor Colin Sibley

Funding: Tommy’s part-funds the studentship for Ms Coleman

Timescale: 2009–2013

Summary: The pregnancy complications pre-eclampsia and fetal growth restriction (FGR) are important causes of preterm birth and stillbirth but we do not yet have effective treatments for these diseases. One reason for this is that we don’t understand the underlying causes of these diseases. We do know that the placenta is damaged in both pre-eclampsia and FGR, although we don’t know how this damage occurs. Syncytial knots, or syncytial nuclear aggregates (SNAs), are clusters of ageing cell components and they are gathered together in the placenta, and there are more of these in placentas of women with pre-eclampsia and FGR. We are investigating how and why these knots form, and whether compounds can stop their formation.

Progress report: One of the most active theories has been that these clusters represent exaggerated cell death, but we have now found that there is no more death in nuclear clusters than the rest of the outer cell layer of the placenta. This helps doctors studying placentas after stillbirth to better understand what is happening in the placenta in pregnancy complications.

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: 2011–2014

Summary: Delaying childbearing is a growing trend among UK women. This is a major clinical and public health concern because advanced maternal age 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: So far we have recruited 278 women to the MAMAs study, which has now been extended to six other sites in the UK. The target number of women is 450. Initial results from our placental analyses suggest that there is accelerated ageing in the placentas of older women. We have also found that placental nutrient transport - a marker of placental function – is markedly altered in these mothers.

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 confirmed that villitis of unknown aetiology was associated with fetal growth restriction. 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, A Patel, Kirstie Coxon

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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