Updated February 2015
Manchester research centre
Tommy’s research centre in Manchester is based at St Mary’s Hospital in the Central Manchester University Hospitals NHS Foundation Trust/University of Manchester partnership. It was opened in 2001 and now houses 88 clinicians and scientists (staff and students). In the last year the centre has published 60 scientific papers in peer-reviewed journals.
The centre’s focus is the baby’s life support machine, the placenta. Our scientists have recently made some important breakthroughs in understanding what can go wrong in that area and which chemical substances may tell us early on that there’s a problem, so that treatment can be targeted before it’s too late.
Fetal growth restriction is one of the main causes of stillbirth, and the centre opened the Manchester Placenta Clinic in January 2009 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.
It is estimated that over 4,000 women experience a stillbirth every year in the UK. In 2011, the Manchester centre launched a new Stillbirth Research Programme which 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.
Working in collaboration with the Tommy’s teams in London and Edinburgh as well as many overseas researchers, the Manchester centre is a vital part of the Tommy’s research network which is now a major force in the drive to improve pregnancy outcomes worldwide.
Current pregnancy research areas in Manchester
The research programme at our Manchester centre is funded by Tommy’s as well as other charities and government bodies such as the Medical Research Council.
The Stillbirth Research Programme
One in 200 women giving birth in the UK has a stillborn child, which equates to over 4,000 births per year. This rate of stillbirth is higher than that in comparable countries in northwest Europe and is unchanged from the late 1990s. Despite its frequency, there is little public perception of the frequency of stillbirth. There has also historically been a lack of funding for research into stillbirth. Our Stillbirth Research Programme, which launched in 2011, focusses on the following three areas:
Understanding the causes of stillbirth
Understanding the causes of stillbirth is important for two reasons. Firstly, the most frequently asked question by parents is ‘Why did my baby die?’; in many cases, understanding reasons for stillbirth helps parents with the grieving process. Secondly, women who have a stillbirth are between 2 and 10 times more likely than normal to have a stillbirth in their next pregnancy. Identifying causes which are likely to recur can prevent women from losing another baby. We are currently undertaking a study of placental structure in stillbirths from different causes. It is estimated that placental abnormalities occur in 60% of the cases of stillbirth. In a clinical study we have shown that examining the placenta after stillbirth reduces the proportion of stillbirths that are ‘unexplained’. Both these earlier studies have used very basic techniques to look at the placentas. However, using our biobank of over 300 placentas from stillbirths (with consent for research), we aim to understand how the placenta is damaged in conditions related to stillbirth by using more advanced techniques which allow us to look at specific cells in the placenta. We hope to find differences in stillbirths from different causes, such as fetal growth restriction, pre-eclampsia and infection in the womb. We will then look at placental samples from ‘unexplained’ stillbirths to see whether these new techniques can lead to better classification of stillbirths.
Preventing stillbirths by identifying babies at risk
Prevention of stillbirth represents a significant challenge as 85% of stillbirths occur in babies with no structural abnormalities, which explains why some of the advances in obstetric scanning have not led to a significant reduction in the stillbirth rate. One sign which identifies that a baby is at increased risk of stillbirth is a reduction in fetal movements, with pregnancies being 1.5 times more likely to have a stillbirth and 2.5 times more likely to have severe fetal growth restriction. Our recent FEMINA2 study recruited 300 women presenting with reduced fetal movements. 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 seven ultrasound features and blood tests that has the potential to detect 30% more babies with poor outcome than our current standard tests.
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.
Developing care for women who experience a stillbirth
We have carried out extensive surveys of midwives, obstetricians and pathologists to determine the knowledge and practice of professionals after parents experience a stillbirth. We have also surveyed parents about their experiences. These surveys have shown significant gaps in education and training for maternity healthcare professionals which have led to poorer care for parents. To address this, we are developing new national guidelines for staff caring for parents after a stillbirth which will include a specific care pathway to guide staff and an educational programme to train midwives and obstetricians to care for parents in this traumatic situation.
Older mothers and the risk of stillbirth
Delaying childbearing is a growing trend among UK women. This is a major clinical and public health concern because advanced 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 are also collecting the placentas from both groups of women so that we can perform laboratory tests to study its development, growth and function. Recruitment of women to this 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.
Improving support in pregnancy following stillbirth or neonatal death (the IMPS study)
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 is exploring 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.
Treating the growth-restricted baby with Viagra: an example of translating research to benefit patients
Abnormal growth of the baby in the womb (fetal growth restriction) can cause stillbirth or, if detected, leave parents and obstetricians with the only option of delivering a baby very prematurely, when it may die anyway, or be left with lifelong handicap. The team in Manchester is trying to address both the problem of reliably detecting fetal growth restriction and, once identified, devise treatments that will improve the growth of the baby without resorting to delivery.
Sildenafil is a drug better known by its trade name Viagra. It works by increasing the diameter of specific blood vessels and thereby improving blood flow to an organ; it came on to the market around 1998. Work in Manchester, as well as other centres, has shown that one of the abnormalities in fetal growth restriction is poor blood flow to the placenta, the organ that transfers nutrients from mum to baby. Because we developed methods for studying placental blood vessels in the laboratory during the late 1990s we were able to show that one of the causes of this abnormal blood flow is that the vessels are unable to expand and contract normally. Once we became aware of the properties of Viagra, it was logical that we should investigate whether this drug could improve placental blood vessel function. Our experiments (around 2001–2005) showed that Viagra did indeed improve the ability of placental blood vessels, taken after delivery from pregnancies affected by fetal growth restriction, to expand.
While the blood vessel work was encouraging, it did not guarantee that the drug could be used effectively and safely in women; experiments in animals were needed as the next step. The Manchester centre had also been working, since about 2000, to develop mice with placental defects and fetal growth restriction similar to that found in human pregnancy. We have tested whether Viagra, when given to such mice, would improve the growth of the mouse fetuses and found that indeed it did, and without causing any obvious harm.
At the same time, we worked with a group of obstetricians in Canada to conduct a small human trial to determine whether Viagra might improve growth of severely growth-restricted babies. This provided evidence, similar to the mouse work, that Viagra could improve fetal growth without causing harm. All of this work, as well as other studies across the world, provided the evidence needed to justify a formal trial of whether Viagra can be used to treat fetal growth restriction. Because such a trial is very expensive and requires a large number of pregnancies to be studied, Tommy’s Manchester centre collaborated with a number of other groups across the UK and Ireland to seek funding from the Medical Research Council. We heard recently that the application was successful and the trial (costing around £3 million) will soon get under way. The Manchester Placenta Clinic will play a crucial role in this study. Although we cannot predict the outcome of the trial, it is exciting and demonstrates that our approach of long-term integration of laboratory work and clinical experience, with a focus on the placenta, can provide hope for new treatments for fetal growth restriction and stillbirth.
We've identified two proteins that could identify women at risk of pre-eclampsia
There is currently no screening test which can effectively predict pre-eclampsia. However, using a new mass spectrometry technique that we developed, we have identified 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.
Care of women experiencing reduced fetal movements (the AFFIRM trial)
The majority of stillbirths occur in normally formed infants, with (retrospective) evidence of placental insufficiency being the most common clinical finding. The mother’s perception of reduced fetal movements is an early marker both placental insufficiency and subsequent stillbirth. The AFFIRM study, which is a collaboration between Tommy’s Manchester and Edinburgh centres, is investigating 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. There has been 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.
The placenta is one of the two main organs of pregnancy along with the uterus, so understanding it is absolutely crucial if we’re to discover why things go wrong. Surprisingly, though, knowledge of the placenta is limited so several of the centre’s current projects are aimed at increasing our understanding of the way it works.
Nutrient transfer from mother to baby
To prevent miscarriage and other pregnancy complications, it’s vital that nutrients are transported from mother to baby and that waste products go in the other direction. A group of studies looks at how this occurs and why it may go wrong.
In normal pregnancies, there is an orderly process of cell death and regeneration in the placenta. However, in cases of pre-eclampsia, cell death is often excessive so a number of projects are looking at why this occurs and how to treat it.
Using MRI to detect problems with the placenta during pregnancy
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. In a new study to address this, we are asking women to undergo two placental MRI scans during pregnancy, if possible before and after any treatment. The information obtained will contribute to the battery of tests we are developing to predict which pregnancies are at risk of stillbirth. Ethical permission has recently been obtained and we have now started recruiting women to this study
Improving pregnancy outcomes in women with chronic hypertension
In women with a history of hypertension, blood vessel function is altered and, in contrast to healthy pregnancies, the blood vessels do not relax as the pregnancy progresses. This failure of the blood vessels to adapt to pregnancy is associated with an increased risk of developing pre-eclampsia and/or fetal growth restriction. In this study we are measuring blood vessel relaxation using a highly sensitive blood pressure machine which measures the stiffness of blood vessels. This technique has been shown to be much more accurate than measuring blood pressure alone. In the first part of this study we will determine whether this technique helps to identify which women are at the highest risk of needing an early delivery. In the second part we will use these measurements to identify women at high risk of a preterm delivery and recruit them to a pilot randomised controlled trial of a commonly used blood pressure tablet (nifedipine). This pilot trial will assess the efficacy, safety and acceptability of targeted therapy. A specialist clinical research clinic, the Manchester Antenatal Vascular Service (MAViS), was established in April 2011 and more than 200 women have already been recruited to this trial.
Placental homing peptides and targeted drug delivery in pregnancy
Several potential therapies for pregnancy diseases have been shown to improve placental function in laboratory experiments, but there is no means of safely delivering them to the placentas of pregnant women. To address this need, we are developing a targeted drug delivery system suitable for use in pregnancy. By restricting the actions of suitable drugs to the placental surface, women will feel more confident that any treatment they receive during pregnancy will not harm their unborn child. It has recently been shown that every organ in the body expresses a unique combination of molecules on its surface, giving it a unique identity or molecular 'postcode'. By studying the molecular postcode of the placenta we have identified a series of 'placental homing peptides', which, when injected into the bloodstream of pregnant mice, bind only to the surface of the placenta and not to any other organ. By coating drugs with placental homing peptides, they can be targeted directly at the placenta. This idea is being tested using mouse models of pregnancy complications, to assess the ability of targeted drug delivery to improve placental function and enhance fetal growth. As all our homing peptides also bind to human placental tissue, this strategy may be used to treat pregnancy complications in women in the longer term.
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The Manchester suite of research clinics
For most women, pregnancy is a time of excitement that ultimately results in the birth of a healthy baby, with all the joy this brings. Unfortunately, for a minority (about 10%) of women, this is not the case and this normally happy event becomes complicated, sometimes with the loss of the child. The four main causes of such complications are fetal abnormality, pre-eclampsia, premature birth and fetal growth restriction (FGR). To try to tackle FGR, the Manchester Tommy’s centre decided to set up the Manchester Placenta Clinic. The aim of this clinic, the first of its kind in the UK, is to combine specialised antenatal care for pregnancies affected by FGR 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 the five years since the Manchester Placenta Clinic was set up by Dr Ed Johnstone, the portfolio of clinical research clinics held in Tommy’s Manchester centre has grown. While the Manchester Placenta Clinic remains the core clinical component of our strategy, we have expanded our research clinics to include:
- Rainbow Clinic, for parents who have experienced a stillbirth, run by Dr Alex Heazell
- Manchester Antenatal Vascular Service (MaVIS), a clinic for women at high risk of hypertension in pregnancy, run by Dr Jenny Myers
- Lupus in Pregnancy Study (LIPS) Clinic, run by Dr Clare Tower.
Each of these specialist clinics focuses on disease processes that affect the placenta, and the information obtained in one group of high-risk patients helps us continue to develop new means to identify pregnancies at greatest risk of complications. In addition to the “placenta-focused” research clinics, we also provide a Preterm Labour Clinic (PTLC).
The expansion of our clinical research portfolio is evident in the number of patients seen and scans performed in our research clinics, with the latter increasing from 436 in 2009–10 to over 2,720 in 2013–14. This activity is also evident in the numbers of participants recruited to clinical trials: over the last year, another 1,034 women have been recruited to studies based in Tommy’s Manchester research centre.
These active research clinics are having a positive effect on care for patients in St Mary’s Hospital. Introduction of Rainbow Clinic, which cares for parents after a stillbirth, has improved the uptake of investigations to find the cause of stillbirth. Examination of the placenta has increased from 78% in 2010 to 88% of cases in 2013 and genetic analysis from 51% to 90% of cases in the same time frame. Our post-mortem rate after stillbirth has also increased from 29% to 39%. These investigations form the basis for care in subsequent pregnancy in Rainbow Clinic. In common with most UK hospitals, the most frequent cause of stillbirth at St Mary’s Hospital is fetal growth restriction, which is found in 43% of cases and an up to five-fold risk of recurrence. This emphasises the importance of the Manchester Placenta Clinic and Rainbow Clinic to find better ways to identify babies with placental dysfunction and fetal growth restriction who are at risk of stillbirth.
At St Mary’s Hospital, women who are at high risk of their babies having fetal growth restriction (failure to grow properly in the womb) are seen in the Manchester Placenta Clinic, where a variety of novel tests are performed to determine whether the placenta is abnormal. This then enables us to determine which patients are at highest risk of a growth-restricted baby and so give them increased attention during the rest of their pregnancy. We anticipate that by identifying cases of fetal growth restriction we will be able to reduce stillbirths by better timing of birth. This is borne out by data showing that since 2010 the stillbirth rate at St Mary’s Hospital has fallen from 6.9 per 1,000 live births to 5.7 per 1,000 in 2013. This translates to eight fewer stillbirths per year. If this reduction in stillbirths were translated to the North West region, we would reduce stillbirths by 40 per year. The process of implementing what we have learnt in our hospital to others in the North West region and beyond has begun: Dr Ed Johnstone and Dr Alex Heazell have co-chaired separate Task and Finish groups for the Department of Health looking at opportunities to reduce stillbirth by better detection of fetal growth restriction and better management of women who come with reduced fetal movements.
Our research clinics collect a lot of information on the placenta and baby while still in the womb. By following women through to birth we can then study the placentas in the laboratory and make connections with what we found before birth, and understand how this relates to placental function and pregnancy outcome. Consequently, our research clinics, particularly the Manchester Placenta Clinic, sit at the heart of our placental research programme. They also provide an important way for us to translate our research into better care, such as introducing measurement of placental growth factor (PlGF) to better diagnose pre-eclampsia, and using the findings of the IMPS study to structure the care given in Rainbow Clinic.
This programme of clinical research on the placenta translates a 30–40 year history of laboratory work in Manchester on this organ. We are almost certainly the largest placenta-focused research group in the world: according to data from the publishers Elsevier, in 2011/12 Manchester published more papers in the key international journal in the field – Placenta – than any other university in the world.
Key past achievements
The Manchester Placenta Clinic
In January 2009 Tommy’s opened the UK’s first placenta clinic at our research centre in Manchester, treating local women with placental complications. This has the dual benefit of ensuring that the women get the best standard of care and giving our scientists a chance to study placental function. The Manchester Placenta Clinic has now finished its first 5 year cycle and is achieving approximately 1,500 patient episodes per year. The Clinic has recently also seen the integration of Rainbow Clinic, which focuses on the care of women with a previous stillbirth. Sadly as fetal growth restriction is strongly associated with stillbirth, many of the patients will have had a stillbirth previously. This new Clinic formalises the care of these women and provides additional services to them.
Stillbirth and fetal growth restriction
- Fetal movement: Our research has shown that reduced fetal movement might be a reliable predictor of pregnancy complications. Previous practice in this area was found to be chaotic and non-evidence-based so our research has helped create a much more robust guideline for pregnant women to become aware of their own baby's activity levels.
- Studying the placenta with MRI: One of the main causes of stillbirth is fetal growth restriction due to problems with placental blood flow. We have developed new magnetic resonance imaging (MRI) techniques that might detect abnormalities in the placenta. We hope that MRI, which is safe to use during pregnancy, could soon be used as a tool for diagnosing or predicting fetal growth restriction.
- Identification: We provided the first demonstration that a screening test for pre-eclampsia is possible because certain factors predicting the disease begin circulating in the body well before the recognised symptoms occur.
- Predictors: We have identified 15 biological markers associated with pre-eclampsia that predict the condition. The metabolite markers (see above) are particularly exciting and should hopefully form the basis of a predictive screening test.
- Causes: During pregnancy, blood vessels in the uterus should widen to increase the flow of blood to the baby. If this doesn’t happen properly, miscarriage may result. We have identified the factors behind this process and are now considering strategies to improve blood vessel widening in pregnancies where this is impaired.
General pregnancy health
- Homocysteine: Evidence suggests a connection between the amino acid homocysteine and a range of pregnancy complications, including recurrent miscarriage, pre-eclampsia, spina bifida, neural tube, heart and limb defects, fetal growth restriction and stillbirth. We have shown that homocysteine can decrease the placental transport of other essential amino acids between mother and baby. We have also found that nutritional deficiencies in folate and vitamin B12 can lead to a build-up of homocysteine within cells.
- Stress and pregnancy: Our research shows a clear link between extreme stress (as defined by the loss of a close relative) in early pregnancy and a tendency for schizophrenia in the offspring.
- Pregnancy outcomes in younger women: About Teenage Eating (ATE), a joint study by our centres in London and Manchester, found that insufficient weight gain, poor diet and smoking in pregnancy may cause teenagers to deliver low-birthweight babies. We also identified nutrients that tend to be missing in younger women’s diets, which has crucial implications for improved management of teenage pregnancies by dietary supplements. We have also recently found that placentas from teenagers who are themselves still growing have a higher ability to transport amino acids than those from non-growing teenagers. This is consistent with growing teenagers delivering higher birthweight babies.
- Yoga and maternal anxiety: Previous Tommy’s research has shown conclusively that maternal anxiety can have an adverse effect on pregnancy outcome. Anxiety and fear of delivery usually increase as pregnancy progresses. We have now found that an eight-week course of yoga significantly reduces women’s anxiety scores as well as their levels of the stress hormone cortisol.
- Developing resources for women experiencing distress and mental health problems in pregnancy: It is known that stress resulting from living conditions, life events and related pressures can adversely affect mother and baby during pregnancy. A tool (the ‘Whooley questions’) which was recently introduced into routine clinical practice for detecting women at risk of depression was found to miss many possible cases. A number of factors which influence women’s willingness to disclose stress were uncovered. This research was the first study to validate the use of the Whooley questions in UK clinical practice. Zoe Darwin won the Society of Reproductive and Infant Psychology (SRIP) Annual Doctoral Thesis Award 2013 for this work. She was invited to contribute to a workshop on Measuring Psychological Health in the Perinatal Period and this workshop hsd led to a recently published national consensus statement. Zoe has become a member of the Tommy's Expert panel on Maternal Mental Health resources, and is working with Beckie Lang, the Health Campaigns Manager at Tommy's, to develop resources for women experiencing distress and mental health problems in pregnancy.
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