Last updated: November 2013
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 84 clinicians and scientists (staff and students). In the last year the centre has published 57 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.
The centre opened the Manchester Placenta Clinic in January 2009 and over 1,000 examinations have already been performed in women at high risk of fetal growth restriction. Some of these women are now returning in subsequent pregnancies.
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 focusses on: (1) understanding the causes of stillbirth and developing new diagnostic tools; (2) preventing stillbirths by identifying babies at risk; and (3) 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. We are currently recruiting women presenting with reduced fetal movements to the FEMINA2 study. We have developed and validated novel two- and three-dimensional ultrasound techniques to measure the size, volume, vascularisation and blood flow of the placenta in utero. Maternal plasma and serum samples are being collected for later analysis. As the size of the cohort grows, all these measurements will be compared between pregnancies with good and poor outcome. We will then see whether any of these new tests can predict pregnancies that will have complications.
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 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. 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. Recruitment of women to this study is well underway and has been extended to six other sites in the UK.
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.
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.
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.
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 has cared for approximately 75 women to date.
Diabetes is the most common complication of pregnancy and may have severe consequences, including stillbirth. However, it is still largely unknown why diabetes affects pregnancy in this way so our team is trying to find the answers.
Preventing fetal overgrowth in diabetes
We previously discovered that the widely prescribed cholesterol-lowering drugs known as statins affect placental development and should thus only be given to pregnant women with great care. However, in a promising further development of this research, funded by Diabetes UK, we are now investigating whether these drugs might actually be of benefit in mothers with diabetes, where they can prevent abnormal placental growth and so help stop the babies getting too big.
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 discovered 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 will be 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.
Tempol and Viagra: assessing their effectiveness as treatments for pre-eclampsia and fetal growth restriction
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 are currently testing a number of existing drugs in mice to see whether they are useful for treating the symptoms of these diseases. 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.
Community exercise and lifestyle classes to improve the wellbeing of obese pregnant women and the life chances of their children
There has been a rise in the number of women who are obese when pregnant, which results in pregnancy complications for the mother and baby. We are developing and refining a programme of exercise and lifestyle classes, which these women can attend with their children if they choose to. The lifestyle part of the programme is multi-faceted, and includes physical activity, healthy eating, motivational techniques, personal care during pregnancy and social networking. To assess whether these programme are acceptable to women and has any impact on their weight, we are collecting information using various methods such as diaries, interviews, questionnaires and clinical records.
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The Manchester Placenta Clinic
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.
Progress in finding any treatments for FGR has been painfully slow, partly due to the frequently disjointed nature of care for this condition when it is antenatally diagnosed. This results in the loss of data on the pregnancies and their outcomes, as well as the loss of biological samples which might be used to further research.
The Manchester Placenta Clinic was launched in 2009 by obstetricians Dr Ed Johnstone and Dr Clare Tower and research midwives Dr Tracey Mills and Suzanne Moody and has now expanded to two clinical sessions. As well as providing improved diagnosis, based upon placental structure and function, the clinic enables patients to be recruited to studies involving MRI, placental science, ultrasound biomarkers and qualitative outcomes. In addition, all antenatal and outcome data is logged on a specially purchased database and tissue and blood is stored in a long-term biobank. The women are also entered into a registry facilitating our next aim of infant developmental follow-up. During the clinic’s first year a regional referral network and management protocols was established.
The clinic’s initial aim was to translate existing research knowledge on the predictive role of placental ultrasound scanning into clinical practice and this has now been achieved. 2,118 examinations in over 500 pregnant women have now been performed, with detection rates for FGR of 75%. This is a considerable success and we believe it is preventing some stillbirths from occurring at St. Mary’s, Manchester. However, these improvements come at considerable cost in terms of healthcare resource investment which would prevent their introduction within the wider NHS. To address this we are continuing to develop newer ultrasound parameters and in utero MRI to focus our resources on those who need it most. This will also aid us in our eventual aim, which is to develop drug treatments for FGR as accurate identification of affected patients is essential for this to succeed. Judging the success of such interventions will require follow-up of children after they are born and we are very pleased to welcome Dr Suresh Victor, Senior Lecturer in Neonatology, to our team. Dr Victor is leading a new paediatric clinic looking at the children whose mothers we have looked after in pregnancy at the age of 2 to see how they are developing. This will enable us to examine whether, once identified, we are managing babies with FGR in the most appropriate way.
Key past achievements
The Manchester Placenta Clinic
In January 2009 Tommy’s opened the UK’s first placenta clinic (see below) 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.
- 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.
- Treatments: We have also identified several candidates to help improve blood vessel widening to ensure miscarriages don’t occur.
- Genetic deficiencies: One of the functions of the placenta is to protect the fetus from drugs and toxic substances present in the mother’s blood. This is done by a class of transporter proteins called ABC transporters. We have identified genetic reasons why these may fail to work properly and are now looking at treatments.
- Implantation: A major cause of miscarriage is when the placenta fails to implant properly in the uterus. We have established a model that replicates the early stages of implantation and have identified a set of molecular markers involved in the attachment which should form the basis of treatment in high-risk women.
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.
- Diabetes: Diabetes is the most common complication of pregnancy and may have severe consequences, including pre-eclampsia and stillbirth. Our studies show that diabetes and the associated changes in glucose levels cause arteries to fail to relax properly, meaning the fetus may suffer restricted growth. This knowledge will allow us to improve the management of diabetes during pregnancy, leading to improvements in the long-term health of both mother and child.
- 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.
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.
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