UNDERSTANDING AND PREVENTING PREMATURE LABOUR

Project to discover how production and action of certain enzymes are controlled and how this affects premature rupture of the membranes that contain the baby

The commonest cause of premature birth is that the membranes that contain the baby and the fluid surrounding it are ruptured prematurely, ie a mother's waters break early.

Scientists have already discovered that membranes which have ruptured early show signs of changes in their structure which may have weakened them. In addition, the team has identified the enzymes which cause these changes.

The team is now investigating how the enzymes are produced by the body and what controls their numbers and actions. This could, in future, lead to drugs being developed which prevent these enzymes being produced or working, thereby preventing premature rupture and premature birth.

Project to discover if excessive stretch of the uterus helps to start labour

During a normal pregnancy, the womb expands to accommodate the growing baby and contractions are prevented. Conversely, during labour, the muscle cells in the womb contract helping to push the baby out. Excessive "stretch" of the womb may be important in causing premature labour particularly since we know that twin or triplet pregnancies - where the womb is overstretched - have a much greater likelihood of ending in prematurity.

The mechanism which causes contractions in the womb is probably very complex involving several different factors. However, there is evidence to suggest that a special group of proteins within the muscle cells of the womb may be involved in the triggering process. These proteins are called G-proteins. Our researcher believes the overstretching of the womb in multiple pregnancies may cause these G-proteins to switch to an active state causing the womb to contract.

Using a new model system which grows the muscles cells of the uterus in culture, researchers will be able to stretch the cells to mimic the way they would be stretched in the womb. The results will provide a better understanding of what happens to the G-proteins when they are stretched and of the cellular mechanism which controls these changes. They may provide an opportunity for drugs to be developed in the future to treat this problem.

A novel approach to finding an effective new drug to delay labour

This study aims to find a drug which can delay labour without incurring unwelcome side-effects in either the mother or baby. Researchers will focus on certain proteins found in the cells of the myometrium (muscle wall of the uterus) called potassium channels which are thought to be extremely important in controlling contractions. Researchers believe that careful characterisation of these channels may offer a novel approach to the development of drugs to stop early labour.

Project to investigate the role of the protein Tenascin in premature rupture of the membranes

Normally, the "waters" or amniotic fluid which surrounds the baby is held together by a skin or membrane until labour gets underway. This study will look at the role of Tenascin, a protein and how it may control vital cell changes in the membrane which could cause the waters to break early. If the waters break early, premature labour often follows. The research group investigating Tenascin already know that the changes that occur in the membrane are very similar to those that are seen in a wound. They hope their findings will lead to a preventative treatment for premature rupture of the membranes.

Studying the role of Rho proteins in preterm birth

The uterus is a remarkable organ which stretches enormously during pregnancy thanks to its muscles - the myometrium. These expand and relax until a signal is given for labour to start, which leads to a powerful combination of hormones (prostaglandins & oxytocin) causing strong contractions. We are interested in what this signal is.

The study will focus on the role of the Rho family of proteins. It will investigate the possibility that near the onset of labour, Rho proteins play an important part in tensing up the internal structure of the myometrium which makes the cells extra sensitive to the labour-inducing hormones. The complex way in which the Rho proteins act means that contractions will start even without the normal surge in calcium in the myometrial cells which precedes labour.

If preterm labour is the result of premature action by these Rho proteins, then it may be possible to develop better drugs to prevent preterm delivery.

The PREMET trial: Multi-centre clinical trial to test if metronidazole (an antibiotic) can cure suspected infection and prevent preterm delivery

For more information about this research, visit our PREMET trial page

Saliva progesterone levels in women who go into premature labour

This is a collaborative project with PREMET. The aim is to test progesterone levels in women who are at risk of going into premature labour in order to evaluate the hormone's importance in predicting labour. The theory, based on what happens in pregnant sheep, is that the onset of labour is preceded by a rise in oestrogen and a fall in progesterone. The researchers have already measured oestriol levels in the saliva specimens of pregnant women and found that levels rise before both normal and premature labour; they now intend to test the saliva of women who have taken part in PREMET for progesterone levels to see if their theory is correct.

This study will help improve our ability to predict premature labour. Ultimately, the aim is to develop treatments for the prevention of premature birth.

Project to study the role of inflammation, particularly the chemical IL-8 in premature labour

Labour resembles a large inflammatory response. In other words, the underlying processes which trigger contractions are very similar to those which occur when a part of the body becomes inflamed. So far, scientists have discovered that a family of important inflammatory substances - prostaglandins - are increased in labour. This study will examine another inflammatory chemical found in the uterus - IL-8 - which is responsible for the softening of the cervix at labour. By understanding how this chemical is controlled in the uterus, scientists believe they will have a much greater understanding of premature labour. The results of this research should lead to improvements in our ability to both predict and prevent preterm delivery.

Investigating the cause and prevention of Bacterial Vaginosis

Pregnant women with a condition called Bacterial Vaginosis are more likely to go into premature labour. The vagina contains many bacteria but in Bacterial Vaginosis, the bacteria are lost and replaced by abnormal ones. The reason for the death of these bacteria is not known but it is thought that viruses (phages) are to blame. This study will search out these viruses by examining vaginal swabs taken from pregnant women and if, as expected, they are found to be the cause of Bacterial Vaginosis, researchers will be able to develop longterm preventative treatments for the condition thereby cutting the rate of prematurity.

The role of the hormone CRH in premature labour

This study will investigate the role of the hormone CRH (corticotrophin releasing hormone) in triggering labour. Because CRH is high in women who give birth prematurely and low in women who are overdue, scientists believe that it could be an accurate marker of how long a pregnancy will last. The study will examine the afterbirth (placenta) closely to analyse if it is CRH hormones from the mother's blood stream that trigger the birth process or local hormones produced by the placenta. Whatever the source, it is likely that CRH is responsible for stimulating the production of womb-contracting substances. The project will provide essential information in our understanding of labour.

The role of ion channels in triggering premature labour

We know that the muscle of the womb needs to contract before a baby can be born. This project will test the theory that chemicals flowing in and out of special pores (ion channels) in the muscle of the womb are responsible for triggering contractions. The fact that some women do not go into labour when they should tells us that something may be wrong with these pores. Our study intends to examine the pores for detailed biological knowledge so that we can understand the processes of pregnancy and childbirth better and ascertain what causes premature labour.

Investigating the enzyme Sialidase as a predictor of premature labour

A team of researchers funded by Tommy's has studied an enzyme that is produced by bacteria in pregnant women that may be responsible for many premature births. The team has used their knowledge to develop a test, recently patented, which they hope will be able to predict who are at risk of going into premature labour.

The enzyme in question is Sialidase and the reseachers have discovered that it is often found in pregnant women who have the infection Bacterial Vaginosis (BV) which is associated with premature birth. Equally important, they have also shown it can be found in some women without BV as well, which might explain why preterm labour often occurs without detected vaginal infection.

Bacteria are thought to enter and inflame the uterus by using this enzyme to break through the defensive barrier - the mucus plug - which protects the baby in the uterus from the outside world. This increases the risk of premature birth.

400 pregnant women at risk of premature labour (for example if they have had a previous premature baby) will take the new test. The doctors will examine them for increased Sialidase activity using a simple vaginal swab at 20, 24 and 28 weeks of pregnancy and compare the result with the timing of delivery and infection in the uterus.

UNDERSTANDING AND PREVENTING MISCARRIAGE AND STILLBIRTH

Prevention of recurrent miscarriage by genetic diagnosis before embryo implantation

Genes are the blueprints of life. Each of our cells contains its genes carried on 23 pairs of chromosomes so that each gene is represented twice. Sometimes breaks can occur in chromosomes. If this happens to two chromosomes at the same time, the broken pieces can swap and rejoin in the wrong place. This is called translocation and usually causes no harm to the cell.

The translocation can be passed on to an embryo via the sperm and eggs. Again, the embryo will be normal but will have the translocation in each of its cells. Problems arise when the embryo is fully grown and the person, who is known as a translocation carrier, tries to have children. Their sperm or eggs may contain forms of the translocation which have extra copies of some genes or be missing others. Life cannot be successfully created from these faulty blueprints.

If the majority of sperm or eggs produced by the translocation carrier are normal, they can have healthy children but they have a higher than average risk of a miscarriage. Others, sadly, produce a majority of abnormal eggs and sperm and this person or their partner is likely to experience repeated miscarriages.

Researchers have been working for five years to help translocation carriers have a healthy baby by uniting the parents' sperm and eggs outside of the womb (IVF) and creating a way to spot the embryos which have normal chromosomes and can grow. However, the method they have developed is costly and slow. This project aims to develop a faster and more efficient way of testing embryos to discover which can develop into a healthy baby.

A project to investigate the failure of the placenta in miscarriage

During a normal pregnancy, cells from the placenta called trophoblast migrate out of the placenta and into the wall of the womb and then grow into the mother's blood vessels in the womb. The result of this is that these blood vessels increase the blood supply to the placenta and to the baby enabling it to grow. In some cases of miscarriage, it is thought that the movement of the trophoblast does not occur and the baby is not able to grow. The question is how often does this happen and why?

The study will examine whether the movement of the trophoblast is controlled by the transforming growth factor Beta (TGFBeta). It will also look at whether miscarriage is caused by a failure of the molecules found on the surface of the trophoblast cells to stick to the placenta. These molecules are called 'adhesion molecules' because they normally help cells to attach to other cells or tissues.

The researchers have devised a safe method of taking samples of the wall of the uterus immediately after the miscarriage. Their work should provide a clearer picture of the factors responsible for miscarriage. It is only by understanding why the placental trophoblast does not migrate properly into the wall of the womb that we will be able to consider more rational therapies in the future.

Study to assess the prevalence and cause of Obstetric Cholestasis

Many babies may be dying at birth or being born prematurely because of a condition called Obstetric Cholestasis which often goes unrecognised. This major new project aims to assess how prevalent Obstetric Cholestasis is and what causes it.

The condition, characterised by excessive itching all over the body in the last trimester of pregnancy may account for as many as five per cent of stillbirths in the UK. Because itching is common in pregnancy, many women are not aware they may have the condition and are therefore missing out on life-saving treatment.

Mr Andrew Shennan, Senior Lecturer for Tommy's, is co-ordinating the research. He believes it is likely that many more pregnant women are suffering from the condition than first thought. The problem is that doctors don't know how many women are at risk, as blood tests are not routinely carried out on women who itch. This project will help establish who needs blood tests and ultimately how we can identify women at risk and prevent them from losing their babies.

Obstetric Cholestasis is a disease of the liver. Although its exact cause is not yet known, Mr Shennan and his team believe it may be linked to raised bile acids. The project will therefore examine the relationship between liver function tests, bile acid tests and itching. There also appears to be a strong genetic predisposition to the disease as well as an underlying susceptibility to the hormone oestrogen. The latter may explain why the condition surfaces in pregnancy and why women who have had cholestatic symptoms on the pill are more likely to suffer.

Study to show that too much oyxgen in the placenta too soon may cause early miscarriage

Oxygen is the essence of life, except, it seems, in early pregnancy where it may be the cause of miscarriage. Our new project predicts that too much oxygen rather than too little may react on the growing baby in a similar way that food goes stale or fats turn rancid.

Our researcher believes that in the first three months of pregnancy the concentration of oxygen in the uterus is very low. Why this is the case is unclear but it may be protecting the delicate developing embryo from the harmful effects of oxygen.

His team have used new imaging techniques to examine early pregnancy and these have shown that in miscarriage, it seems there is an abnormally early blood flow in the uterus to the placenta. This could lead to too much oxygen being present too soon which could damage the placenta and lead to the loss of the baby. The long-term aim of the study is to discover a treatment which may prevent some early miscarriages.

Abnormality of the mother's small blood vessels and subsequent impairment of the placenta

There is a growing amount of evidence to suggest that many pregnancy problems are caused by abnormalities of the mother's blood vessels. One group of women who we know suffer recurrent complications such as miscarriage and pre-eclampsia are those with high levels of the antiphospholipid antibody in the blood which can lead, indirectly, to blood vessel damage.

This study will be testing the theory that the antiphospholipid antibody 'attacks' the lining of the blood vessels (the endothelium) that supply blood to the placenta. This would lead to a reduced blood flow which would impair the development of the placenta and the baby.

Researchers will be measuring 'markers' of damage to the lining of the blood vessels in certain pregnant women. This will help them understand better the reasons why the placenta fails to work properly and the baby suffers.

UNDERSTANDING AND PREVENTING PRE-ECLAMPSIA

Investigating the hormone Activin A and its role in pre-eclampsia

The placenta produces many hormones which are essential for its normal functions and which let the mother's systems know what is needed for pregnancy to develop. One such hormone is Activin A. Researchers have discovered that levels of this hormone are raised in the blood stream of women with pre-eclampsia. These raised levels may appear before other symptoms.

The team is investigating if Activin A may be the cause of some of the symptoms of pre-eclampsia such as the breakdown of the surface of the placenta and the inflammation in the blood stream.

It is hoped that this project will shed light on the cause of pre-eclampsia and ways to treat and prevent it.

This grant is fully funded by the Freemasons' Grand Charity.

The VIP Trial: A study to test if vitamin C and E supplements can improve the clinical outcome of women at high risk of pre-eclampsia

For more information about this research, please visit our VIP trial page.

Examining the role of the placenta in pre-eclampsia

This study will test the theory that pre-eclampsia and small babies are the result of an abnormal development of the placenta.

Researchers will take a small biopsy from the inside of a mother's womb when she is having a caesarean section. The biopsy will be obtained from women having normal pregnancies as well as those suffering from pre-eclampsia or having small babies. The blood vessels from the biopsy will be examined under the microscope and researchers will investigate the difference in molecular activity between tissues which served the placenta well and those which did not.

The data from the study is expected to shed light on the vital changes that take place in the mother's blood vessels during pregnancy and help scientists develop a screening test to predict pre-eclampsia or the development of small babies long before the clinical symptoms become apparent.

Investigating the causes of raised blood pressure in women with pre -eclampsia

Preliminary studies by our researcher provided evidence that pre-eclampsia induces changes in the handling of calcium and other ions within cells of the blood vessel wall, which could result in elevated blood pressure. It is aimed to characterise the damaging effects of placental oxidation in endothelial and smooth muscle cells isolated from blood vessels derived from the maternal and fetal circulations of normal and pre-eclamptic pregnancies. Restoration of normal calcium levels and inhibition of select ion channels may provide an effective therapy to reduce maternal blood pressure in pre-eclampsia.

PREVENTING HEALTH PROBLEMS IN SMALL OR PRETERM BABIES

Investigating the effects of different methods of delivery of steroid treatment which may improve the unborn baby's ability to withstand periods of reduced oxygen supply during birth.

This is a continuation of work previously funded by Tommy's which is looking at how drugs, used to help a premature baby cope with breathing outside the womb, might also help it during the stress of delivery itself.

Woman who are at immediate risk of going into labour early are often given steroids to improve their baby's chance of survival should delivery occur prematurely. These drugs speed up the development of the unborn child, reducing the risk of potentially fatal health problems which occur because its lungs are not ready.

We already know that during labour and delivery, babies experience times when oxygen supply is reduced and that they cope with these stressful periods by making changes in their circulation so that blood is carried towards vulnerable organs, such as the brain, rather than their limbs. Previous research by this team indicated that steroids would also help an unborn baby cope better with periods of short oxygen supply by making this redistribution of blood much more efficient and better protecting the unborn baby's brain from short oxygen supply.

The team is continuing its work in the laboratory investigating if how the drug is administered makes a difference to its effectiveness in controlling such redistribution of blood flow. Their findings may lead to doctors administering drugs directly to the baby inside the womb rather than to its mother.

The study of fetal brain activity and the potential of preventing cerebral palsy and other problems in low birth-weight babies

Every year in the UK around 1,000 babies are born with severe cerebral palsy and this is commonly the result of low birth weight or premature birth. The aim of this study is to examine the activity and development of a baby's brain in the womb and to use this knowledge to find preventative treatments for cerebral palsy as well as other developmental problems associated with low birth weight.

By using functional magnetic resonance imaging (fMRI) antenatally, our researchers will be able to map the response of the brain to a variety of stimuli in the important areas of sight, hearing and fetal learning. Magnetic resonance imaging is a medical imaging technique which does not involve any harmful radiation.

Project to analyse the effects of steroids on the unborn baby and its ability to withstand periods of reduced oxygen supply

A new grant has now been given to develop the work of this project (see above) Women in threatened early labour are often given drugs to improve their babies' chances of survival should delivery actually occur prematurely. These steroids speed up development of the unborn child and prepare it for life outside the womb. The aim of this study is to discover what effect steroid treatment might have on the unborn baby's response to the periods of reduced oxygen supply it experiences during birth. The study aims to identify some of the mechanisms by which the steroids act on the fetal cardiovascular system. It will also establish how long the protective effects of steroids last.

The overproduction of nitric-oxide in the brain and its possible role in causing brain damage

A lack of oxygen to the brain at around the time of birth is responsible for brain damage or death in thousands of babies. This project aims to understand the processes at work in controlling the flow of oxygen to the brain and devise new methods for predicting how severe brain damage will be if it is likely to occur. By assessing the risk for these babies, it may one day be possible to prevent brain damage or death occurring.

The study will focus on the molecule nitric oxide. This gas was originally thought to be an environmental pollutant (from car exhausts for example) but has recently been demonstrated to be a vital molecule in the body, acting as a messenger to trigger a number of important physiological processes such as blood flow and memory. However, too much nitric oxide in the wrong place can be toxic and studies have shown that nitric oxide levels increase during and after the brain is denied oxygen. This overproduction may play a role in brain damage; it may also be a marker of how severe the brain damage will be. Researchers will use a technique called electron paramagnetic resonance to measure the levels of nitric oxide in the unborn baby after a lack of oxygen to the brain. They will then take blood samples from the umbilical cord after birth to see if the levels of nitric oxide correlate with those from animals which are known to have suffered previous brain damage. This study may also shed light on the differences in the mechanism of brain damage in premature infants and babies born at term.

Fat utilisation and energy metabolism in newborn premature babies suffering from severe infection

The aim of this study is to understand how the body and particularly the liver of premature babies responds to serious infection. The theory is that these babies rely on a very special balance of nutrients for their energy. Our researchers will measure the composition of the air breathed in and out by these babies which will help them assess what they need to fight infection. In addition, they will investigate how the babies' livers use fat as an energy source. The longterm aim of the study is to improve the care of neonates with severe infections.

OTHER

Fetal Health Research Group - core funding

Lucilla Poston, Tommy's's Professor of Fetal Health has set up a dedicated Fetal Health Research Group at St Thomas' Hospital, which is fast becoming a significant force in the medical research world. Her projects focus on premature birth and include extensive investigation of the blood vessels in women with pre-eclampsia, the mechanisms of premature contraction of the uterus and clinical trials designed to prolong the pregnancies of women at risk of premature birth.

Information Series

Tommy's has received money from the National Lotteries Charities Board for the production and distribution nationwide of two leaflets on the care of women at risk of delivering their babies prematurely.

These leaflets will be produced in collaboration with the Royal College of Midwives and will be distributed nationally via the RCOM.

Research and development of a training mannequin for the management of shoulder dystocia

Shoulder dystocia is a dangerous complication of childbirth, where the fetal shoulders become lodged behind the pelvic inlet of the mother. The condition presents itself during the second stage of labour and requires expert clinical management in order to avoid fractures to the baby's clavicle or humerus. In severe cases the baby may die.

In a recent government report into stillbirths and deaths in infancy, the management of shoulder dystocia was identified as an area of particular concern. The report recommended that multidisciplinary training should be a priority.

The researchers will develop an accurate simulation of the bone, musculature and fat of the birth canal as well as a fetal model with sensors that will monitor where excessive force is applied. This will enable obstetricians and midwives to gain the most lifelike example of this complication during birth and the best way of securing a successful outcome.