Research into stillbirth

When a baby dies after 24 weeks of gestation it is called a stillbirth. Incredibly, over 3,000 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.

Tommy’s scientists are working on a number of projects that aim to identify women at high risk of losing a baby. If a reliable test could be developed to determine those at most risk, we could ensure that the women who really need it get targeted treatment.

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 research projects

Looking at whether fetal movement is a useful measure of baby health
Investigators: Dr Alexander Heazell, Giovanna Bernatavicius, Lynne Warrander
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2009–2010
Summary: In the UK over 1 in 200 pregnancies ends in stillbirth. A common cause of this is placental insufficiency, where the placenta cannot supply the fetus with enough oxygen or nutrients to survive. When this happens, it is thought that a reduction in fetal movement is a survival strategy to conserve energy. A mother’s perception of fetal movements has been used for many years as an indicator of the baby’s wellbeing. In about half the cases of stillbirth, the mother will have perceived reduced fetal movement for more than 24 hours before the stillbirth is diagnosed.
Progress report: We are currently recruiting 300 women who report reduced fetal movement to join a prospective cohort study that will test this theory. The women are assessed clinically, then a blood sample is taken and an ultrasound scan performed to measure fetal growth, the volume of water (liquor) around the baby and blood flow through the umbilical cord. This will allow us to evaluate whether fetal movement monitoring combined with any of these investigations could decrease stillbirths.

Investigating the link between air pollution and pregnancy problems
Investigators: Kim Hannam, Dr Roseanne McNamee (Health Methodology Research Group), Professor Philip Baker, Professor Colin Sibley, Professor Raymond Agius (Occupational and Environmental Health Research Group), Dr Bernice Dillon
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2009–2013
Summary: Studies from various countries have demonstrated a link between air pollution and poor pregnancy outcomes such as fetal growth restriction (FGR), preterm birth, stillbirth, miscarriage and congenital anomalies. There are particular health challenges in the northwest of England: a baby born in Manchester has a life expectancy 11 years lower than a baby born in the southeast. Rates of pregnancy complications such as FGR and preterm birth are increased in the northwest. The northwestern database of 55,000 deliveries per year is being used to explore the role of air pollution on pregnancy outcomes in the region.

Using MRI scanning to diagnose fetal growth restriction
Investigators: Dr Caroline Wright, Dr David Morris, Dr Ian Crocker, Professor Geoff Parker, Professor Penny Gowland (University of Nottingham), Professor Philip Baker, Professor Colin Sibley
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2008–2012
Summary: Fetal growth restriction (FGR) is a serious complication of pregnancy. Babies affected by the condition are more likely to be stillborn or die shortly after delivery. The placenta is very important in the growth of a baby as it supplies nutrients and oxygen that are essential for normal growth. Magnetic resonance imaging (MRI) is a technique that is safe to use in pregnancy and which can assess blood flow in the placenta. We are performing MRI scans to compare normal pregnancies with those affected by FGR to try to understand the differences that cause the condition.
Progress report: We have successfully developed MRI techniques for studying the placenta. The initial results have been promising and suggest that tissue fibrin (which is involved in tissue damage and repair processes) might be a useful marker for the condition. (Fibrin content is often high in FGR placentas.) Overall, we aim to determine whether MRI can be used to detect placentas that are not functioning normally, with the hope that it could be used as a tool for diagnosing or predicting FGR.

Creating a model to study fetal growth restriction
Investigators: Melissa Brereton, Dr Susan Greenwood, Dr Mark Wareing
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2008–2011
Summary: Fetal growth restriction is commonly associated with reduced blood flow in placental blood vessels. This project aims to develop a model of the smooth muscle cells within the blood vessel walls, so that the problem may be studied.

Understanding why some babies stop growing in the womb
Investigators: Dr Tracey Mills, Dr Mark Wareing, Dr Susan Greenwood
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2008 onwards
Summary: There are currently no effective treatments to prevent or improve abnormally slow growth of babies in the womb. We know that a possible cause is reduced blood flow between mother and baby via the placenta. This project will compare normal and problematic pregnancies to see whether ultrasound scans can pick up differences in blood vessel development that might cause this problem. It will also investigate whether altered potassium channels (pores that allow potassium into and out of cells) may cause the reduced blood flow.

Effects of steroid stress hormones on placental nutrient transfer and fetal growth restriction
Investigators: Dr Justine Nugent, Dr Rebecca Jones, Dr Mark Wareing, Professor Colin Sibley, Professor Philip Baker
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2006 onwards
Summary: The causes of fetal growth restriction (FGR) are unknown but there is increasing evidence that the stress hormones called glucocorticoids are involved. We have previously shown that women who experience severe stress during pregnancy are more likely to deliver a small baby. In normal pregnancies, an enzyme in the placenta, 11 beta-dehydrogenase type 2 (11β-HSD2), protects the baby from excessive levels of glucocorticoids. However, in pregnancies with FGR, there are lower levels of 11β-HSD2 in the placenta, which suggests that these placentas and babies are exposed to higher levels of glucocorticoids.
Progress report: We have recently shown that glucocorticoids cause abnormal behaviour of isolated placental blood vessels and this may cause the abnormal blood flow seen in FGR. We have also shown that glucocorticoids alter the balance between cell growth and cell death in early pregnancy tissue. This project is investigating whether altering the level of 11β-HSD2 in placental cells, to mimic what happens in FGR, alters the way nutrients are taken up by placental tissue. A better understanding of the links between glucocorticoids and FGR could lead to improved therapies for FGR.

Investigating diabetes and fetal growth disorders
Investigators: Dr Alexandra Solomon, Dr Melissa Westwood, Professor Martin Gibson, Professor John Aplin, Professor Philip Baker
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2007–2010
Summary: Babies born to mothers with diabetes can be smaller or bigger than normal; both abnormalities can cause health problems for the infant. This research is investigating the molecular mechanisms responsible for the fetal growth disorders associated with diabetic pregnancies, with the long-term aim of developing new therapeutic approaches for normalising fetal growth in affected pregnancies.

Looking at how calcium is transferred to the developing baby
Investigators: Dr Mark Dilworth, Laura Kusinski, Dr Stuart Ward, Professor Sir Robert Boyd, Professor Colin Sibley, Dr Jo Glazier, Dr Shahid Husain (QMC, London), Dr Miguel Constância (Cambridge)
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2005–2009
Summary: Growth-restricted babies are far more likely to be stillborn or have other problems. One way this can occur is if the baby doesn’t get enough calcium, a process that is controlled by the placenta. This project is investigating the genetic background to calcium transport by examining mice that have specific genes deleted.
Progress report: Using the mouse models we have been able to show that when there is a specific genetic deficiency the calcium concentration in the baby’s blood is lower than in the mother’s, when it should be the other way around. The mouse models have proven to be excellent models with which to assess placental calcium transport in human fetal growth restriction. They will allow us to develop and test therapeutic strategies for growth-restricted babies in the future.

Investigating how genes may cause the placenta not to work properly
Investigators: Laura Kusinski, Dr Jo Glazier, Dr Mark Wareing, Professor Philip Baker, Professor Colin Sibley
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2007–2011
Summary: This project aims to discover the causes of fetal growth restriction, one of the main causes of stillbirth. It will look at deactivating certain genes in mice to see which genes affect placental function so that a possible genetic cause for growth restriction might be discovered. It is hoped that treatments could then be developed for humans.

The effects of binge drinking on early placental development
Investigators: Dr Clare Tower, Dr Melissa Whitworth
Funding: Study taking place in Tommy’s funded centre
Timescale: 2009–2011
Summary: Alcohol consumption among young women is rarely out of the news headlines. Levels of alcohol use are higher than they have ever been, and the health education message to pregnant women has been confusing over recent years. One reason for this is a lack of scientific evidence upon which to base advice. It is known that very high levels of alcohol consumption over a prolonged period of time causes problems in the baby. However, the effects of different patterns of drinking, such as binge drinking, and lower levels of consumption, are unknown. This study is investigating how alcohol affects the early development of the human placenta and the way that nutrients are carried across the placenta from mother to baby.

The role of homocysteine in pregnancy problems
Investigators: Dr Nita Solanky, Jane Guarino, Alicia Jimenez Requena, Dr Eleni Tsitsiou, Dr Stephen D’Souza, Professor Michael Taggart (University of Newcastle), Professor Colin Sibley, Dr Jo Glazier
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2006–2009
Summary: 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. This project aims to discover why.
Progress report: We have shown that homocysteine can decrease the transport of essential amino acids between mother and baby. We have also found that folate and vitamin B12 are important in recycling homocysteine in the placenta. We are now studying how homocysteine can affect blood vessel function, placental function and metabolism, and fetal development.

Reducing the effects of lupus on pregnancy
Investigators: Dr Debora Chirico, Dr Clare Tower, Dr Ian Crocker, Professor Philip Baker, Dr Ian Bruce
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2007–2010
Summary: Systemic lupus erythematosus (SLE) is a serious disorder affecting many organs in the body and is caused by the body ‘attacking itself’ in the same way as it would an infective organism. It occurs most often in women of childbearing age and is associated with poor outcomes of pregnancy such as miscarriage, stillbirth, pre-eclampsia and poor growth of the baby. As we do not understand why women with SLE suffer these problems, the possibilities for treatments are currently limited. This study is looking at two factors called Treg cells and transforming growth factor beta 1 (TGFβ1) that are involved in immune responses in the body to see whether they are different in women with SLE compared to healthy women.
Progress report: We think that low levels of Treg cells and of TGFβ1 might prevent the placenta forming properly in women with SLE. Our early results have suggested that these women do indeed have lower levels of these cells. If we confirm our initial findings, we will apply for further funding so that we can expand the study to more women, and look at the factors in more detail.

Managing obstetric cholestasis: the PITCH trial
Investigators: Dr Lucy Chappell, Annette Briley, Jenny Carter, Professor Jim Thornton (University of Nottingham), Professor Catherine Williamson (Imperial College Healthcare)
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2008–2011
Summary: Obstetric cholestasis is a serious problem in pregnancy, affecting about 1 in 150 pregnancies, or about 4,500 women a year in the UK. These women develop severe itching and sometimes jaundice. More importantly, the condition is associated with preterm birth, and is also believed to be an important cause of stillbirth. However, there is no clear evidence as to whether the most popular treatment, a drug called ursodeoxycholic acid (UDCA), is beneficial to the baby, or even whether it is safe in pregnancy. Nor do we know whether planned early delivery of the baby at 37–¬38 weeks, another common treatment, does more harm than good. We plan some preliminary studies to design a larger randomised trial (Pregnancy Intervention Trial in Cholestasis; PITCH) and see whether it is feasible.

Studying the effects of obesity in pregnancy
Investigators: Dr Mandy Drake, Vicky King
Funding: Tommy's completely funds this project.
Timescale: 2008 onwards
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. This project aims to develop a mouse model to enable us to better understand why obesity in pregnancy is associated with this increased risk of complications affecting both mother and baby and how we might intervene to reduce this risk.

Understanding placental cell damage
Investigators: Sarah Coleman, Dr Alexander Heazell, Professor John Aplin, Professor Colin Sibley
Funding: Study taking place in a Tommy’s funded centre
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 are groups 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.