Updated February 2015

Research into premature birth

Around 60,000 babies are born prematurely each year in the UK (Born too soon, The Global Action Report on Preterm Birth, WHO 2012)and many suffer lifelong consequences as a result. This is one of the highest rates in Europe and it's still rising, yet there is currently no accurate screening test available to identify women at risk. Tommy's believes creating a test must be an absolute priority and much of our current research is devoted to this.

Our London and Manchester centres are searching for biological markers identifying women likely to have preterm babies. Both centres are participating in the international SCOPE study, which is investigating ways to predict various pregnancy probjems, including preterm birth. We have previously found that fetal fibronectin is a reliable indicator of preterm birth and we are now investigating the cost-effectiveness of a screening test based on this. We have also discovered that lower than expected levels of progesterone in saliva are a predictor of spontaneous preterm labour.

Our research into preterm birth is also focusing on strategies to prevent or delay early labour. At our centre in Edinburgh, Tommy’s Professor Jane Norman is leading a major clinical trial (the OPPTIMUM trial) to see whether progesterone is effective in preventing preterm birth. We're also looking closely at ways to prevent the contractions that begin the labour process. There have been some exciting results in this area, as you'll see below.

Individual research projects

The international SCOPE study

Investigators: Manchester - Professor Philip Baker, Dr Jenny Myers; London - Annette Briley, Dr Lucy Chappell, Jenny Carter, Professor Lucilla Poston, Professor Andrew Shennan, Jenny Carter, Paul Seed

Funding: Part-funded by Tommy’s

Timescale: 2007 onwards

Summary: The SCOPE study is a huge international study looking at how to predict and prevent the major diseases of late pregnancy: pre-eclampsia, preterm birth and fetal growth restriction. The project completed recruitment in 2011, with a total of 5,690 women recruited in New Zealand, Australia, the UK and Ireland. The study has already led to identification of a useful way to predict pre-eclampsia, and also a healthy pregnancy, and has provided valuable information on a wide range of different problems in pregnancy, including miscarriage and the influence of smoking on the developing baby.

Progress report: All research teams have access to the samples and data and many papers have been published. The Tommy’s London and Manchester centres have contributed to several of these studies, one of which, recently reported in the British Medical Journal, suggested novel ways of finding out early in pregnancy which women were likely to have a completely healthy pregnancy.

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Is progesterone a cost-effective way to prevent preterm birth? (the OPPTIMUM trial)

Investigators: Professor Jane Norman with co-investigators from around the UK including Professor Andrew Shennan (Tommy’s centre in London) and Professor Dame Tina Lavender (Tommy’s centre in Manchester); Jane Brewin (Tommy’s Chief Executive) sits on the trial steering committee
Funding: Study taking place in all three Tommy’s-funded centres

Timescale: 2008–2015

Summary: Spontaneous preterm birth is a pervasive and expensive health problem, with around 60,000 babies being born preterm (before 37 weeks) in the UK every year. Two studies have now suggested that progesterone reduces preterm delivery in high-risk women. This project, called the OPPTIMUM trial, has recruited women 1,250 women from over 60 sites around the UK to test whether giving natural progesterone daily from 22 to 34 weeks of gestation is a cost-effective way to reduce the likelihood of preterm birth and the associated neonatal death and childhood disability that often accompanies it.

Progress report: Recruitment of women was completed in 2013 and this is now the largest trial of progesterone in the world, with over 1,200 women randomised to receive progesterone or placebo. We are now in the baby follow-up stage and results should be available in 2016. We had initial difficulties in persuading women to bring their children back for follow-up, but this is now improving, with 63% of all tests that are due having been done. If we show that progesterone prevents preterm birth and improves outcome in childhood, it could become a widely used treatment for the prevention of prematurity.

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PDE4 inhibitors: a treatment for mothers and babies at risk of premature delivery?

Investigators: Professor Mark Johnson (Imperial College London), Dr Rachel Tribe, Dr Pei Lai

Funding: Study taking place in a Tommy’s funded centre

Summary: The most frequent cause of premature delivery is preterm labour but, despite an intensive research effort and various new treatments, we have advanced very little in effective prevention of preterm labour. More recently, the emphasis has shifted to the prevention of preterm labour in high-risk women who are identified by a combination of their history and the detection of a shortened cervix on ultrasound screening. The ability to identify women at high risk allows us to intervene with treatments not only to reduce the risk of preterm labour but also to protect the baby from the complications of premature delivery. Our preliminary data show that the messenger molecule cAMP suppresses the oxytocin receptor, a key component of the increase in uterine contractility seen with labour. PDE4 is an enzyme that breaks down cAMP and this study will investigate whether PDE4 inhibitors can be used to prevent preterm labour by increasing the levels of cAMP within cells.

Progress report: Out initial results suggest that cAMP can play different roles in the control of contractions within the myometrium, both being able to promote and prevent them depending on when its levels change. We are now directing our research towards understanding more about this effect of time on cAMP in the myometrium, as well as exploring the possibility of enhancing its pro-relaxatory effects by combining its use with progesterone, a drug commonly used to prevent preterm labour but only effective in 45% of singleton pregnancies.

Kv7 potassium channel activators – a possible new treatment for preterm labour

Investigators: Dr Rachel Tribe, Yosef Mansour, Dr Katharina Mahn, Dr Katrein Schaefer, Dr Paul Taylor, Dr Sarah England (USA), Dr Donna Slater (Canada)

Funding: Study taking place in a Tommy’s funded centre

Summary: Activation of contractions is involved in the initiation of both preterm and normal labour and we know that this is triggered by the amount of calcium entering the cell. This project examines whether the level of calcium may be limited by activating so-called ‘potassium channels’. These are small pores on the cell membranes that allow potassium in and out. It is hoped that opening these channels will keep uterine muscle in a relaxed, non-contractile state, thus preventing preterm labour.

Progress report: Our recent studies have identified a new ion channel target for the development of drugs that inhibit uterine contractions. We have shown that the Kv7 subclass of potassium channel activators can profoundly inhibit uterine contractions in the laboratory. The aim of this study is to demonstrate, in pregnant mice, that potassium channel activators can inhibit uterine contractile activity in vivo with limited maternal and fetal side effects. With drug companies very interested in potassium channels currently, this research could pave the way for a concrete treatment to help prevent preterm birth. [L209]

Care of women with threatened preterm labour (the PETRA study)

Investigators: Jenny Carter, Dr Rachel Tribe, Professor Jane Sandall, Professor Andrew Shennan, Dr Annette Briley, Paul Seed

Funding: Tommy’s part-funds this study

Summary: While preterm birth remains a major cause of infant mortality and morbidity, some interventions, e.g. steroids to improve the baby's lung function, and hospital admission, are known to reduce associated risks. Although these interventions are relatively safe, they still carry risk of side effects and incur cost, both for the woman and the NHS.  It is important that these interventions are offered in a timely manner, but labour is unpredictable and difficult to diagnose accurately in the earlier stages. The majority of women with symptoms of threatened preterm labour (TPTL) will not deliver early, but many are treated ‘just in case’, because the consequences of not treating could be devastating. This study aims to improve the management and experience of women with TPTL by ensuring that appropriate care is offered to those most at risk while reducing unnecessary intervention.

Blockade of decidual inflammation as a novel therapy for preterm labour

Investigators: Sylvia Lui, Gillian Stephen, Dr Rebecca Jones, Dr Lynda Harris, Dr Clare Tower

Funding: Tommy’s studentship to Ms Lui

Timescale: 2012–2015

Summary: Babies born prematurely have an increased risk of serious illness, disability or death, and those who survive are likely to have long-lasting health problems. Current treatments to stop preterm labour aim to prevent contractions of the muscular layer of the womb (the myometrium) and at best only delay labour by a few hours or days. It would be much better to target earlier events in the labour process as this is more likely to be effective. Our recent studies have shown that macrophages, a type of white blood cell from the mother’s immune system, enter the lining of the womb (the decidua) during labour at term and in preterm labour. These macrophages can produce a multitude of inflammatory factors which could trigger labour. Importantly, using a rat model, we found that these macrophages enter the decidua before the onset of labour, suggesting they play a key role in the early stages of labour. We have also identified the factors which we believe are causing the macrophages to enter the decidua: a family of inflammatory factors called chemokines which act to guide white blood cells into tissues. Drugs which specifically block chemokines are currently being developed to treat diseases such as arthritis and cancer, and they are already in clinical use for HIV treatment. They therefore have enormous potential for the treatment of preterm labour. The aim of this project is to study all of the different processes that occur around the time of labour, both in the decidua and the myometrium, to identify key factors that control the onset of very early labouring events. Once we have identified these candidate factors, we will test whether available drugs can inhibit their actions in human tissue and in animal models, and see whether these drugs might be suitable to treat preterm labour.

Progress report: This project has shown for the first time the full spectrum of genes and pathways that are involved in labour in the human decidua and which of these are also involved in labour in the human myometrium. The prominence of inflammatory pathways in both tissues reinforces anti-inflammatory therapy as a novel approach to prevent or block preterm labour. To understand how these interact and identify the most important regulators, we have performed in-depth network analyses using multiple bioinformatics software packages. These studies have revealed potential key regulators of labour in both tissue layers in the uterus. The effect of inhibiting these factors will now be tested in laboratory analyses using human tissues.

New ultrasound techniques to diagnose fetal infection

Investigators: Professor Sarah Stock, Basky Thilaganathan (St Georges University London), and Matt Kemp, John Newnham and Scott White (University of Western Australia)

Funding: Study taking place in a Tommy’s funded centre

Timescale: 2014-2015

Summary: Infection that occurs in the womb in pregnancy can harm the developing baby and result in preterm labour. Often these infections have no overt signs in the mother. A major problem is thus recognising pregnancies that are affected with infection, so that treatments can be targeted and delivery timed to optimise outcomes for babies. The aim of this study is to develop and validate a non-invasive ultrasound technique for monitoring a developing baby’s wellbeing and response to infection. We are determining the potential of these new techniques by a study in sheep, which will indicate whether clinical trials in humans are feasible.

Improving pregnancy outcomes in women with chronic hypertension

Investigators: Dr Jenny Myers, Dr Emma Shawkat, Dr Ruth Cockerill, Catherine Chmiel, Dr Ian Crocker, Dr Ed Johnstone

Funding: Study taking place in a Tommy’s funded centre

Timescale: 2012–2017

Summary: 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 are determining 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 has been set up which will facilitate this research project.

Progress report: We are now half-way through the first part of this programme of research, with more than 200 women recruited through our specialist research clinic, the Manchester Antenatal Vascular Service (MAViS). [M304]

Fetal fibronectin testing to predict preterm birth: the EQUIPP study

Investigators: Professor Andrew Shennan, Jenny Carter, Dr Rachel Tribe, Dr Natasha Hezelgrave, Annette Briley, Paul Seed

Funding: Study taking place in a Tommy’s funded centre

Summary: Tommy’s scientists have previously shown that fetal fibronectin, a special protein enabling the membranes around the baby to stick to the walls of the womb, should only appear at around 22 weeks and again at the end of pregnancy. If it appears between these dates it indicates that an early labour is imminent, which means that it is an excellent predictor for preterm birth. Our initial trial was highly encouraging and we are now evaluating a more accurate quantitative machine for analysing fetal fibronectin (the EQUIPP study). If this more accurate test proves to be cost-effective, there will be much wider use of this predictive test for preterm labour. This will help to prevent hospital admissions and unnecessary interventions for women at low risk, thereby reassuring them and saving precious healthcare resources.

Progress report: The EQUIPP study recruited 1,572 eligible women and the results have recently been analysed. The data have validated the important concept that higher fetal fibronectin concentrations are directly associated with a higher risk of spontaneous preterm birth.  The next stage for this work is to evaluate how these findings can influence the management of high-risk women to optimise outcome. 

Natural antimicrobial defences in women at high risk of preterm labour (the INSIGHT study)

Investigators: Dr Rachel Tribe, Dr Evonne Chin Smith, Mr Paul Seed, Dr Natasha Hezelgrave, Professor Andrew Shennan

Funding: Tommy’s part-funds this this project

Timescale: 2014 onwards

Summary: There is a need to identify women most at risk of spontaneous preterm birth early in pregnancy and to understand the mechanisms promoting cervical shortening in response to infection and inflammation. In another recent project, we identified elafin, a molecule belonging to a ‘family’ of natural ‘defence’ molecules known as antimicrobial peptides, as a useful early pregnancy biomarker that can identify women at most risk of spontaneous preterm birth. Laboratory-based studies also provided important data regarding the mechanisms by which cells of the cervix regulate these antimicrobial peptides. For example, we demonstrated that vitamin D supplementation can boost the production of another member of the antimicrobial peptide family, cathelicidin, whereas elafin is only induced by stimuli which cause inflammation. These exciting results have led us to develop a large programme of work to validate the use of cervico-vaginal fluid measurements of elafin as a predictor of spontaneous preterm birth and to further investigate the cellular regulation of antimicrobial peptides in cells from the cervix. We will also extend the studies to determine whether we can measure elafin in saliva obtained from women in the POPPY study.

Measuring progesterone in saliva to predict preterm labour: the POPPY study

Investigators: Professor Lucilla Poston, Jenny Carter, Ruth Cate, Joy Kemp, Judith Filmer, Dr Rachel Tribe, Dr Natasha Hezelgrave, Dr Carolyn Gill, Annette Briley, Paul Seed

Funding: Tommy’s part-funds this project

Summary: In a recent preliminary study, we discovered that low levels of progesterone in saliva were a predictor of spontaneous preterm labour. If validated in a larger study, this simple test could be used to predict which women may go into labour very early, allowing for greater surveillance and early intervention. We are investigating: (1) whether the test can help to predict which women at risk for preterm labour and delivery are likely to respond to treatment with progesterone; and (2) whether a combination of progesterone and fetal fibronectin testing will provide more accurate prediction of preterm labour then either test alone.

Progress report: Recruitment of over 1200 women was completed during 2013, and statistical analysis is now underway. Our results support our initial finding that women most at risk of preterm labour have reduced saliva progesterone concentrations, but the data is less clear-cut than in the previous study and we are now working on a more sensitive test with collaborators at King’s College Hospital in London. Additional studies planned include the measurement of unfolded proteins, which have been associated with pre-eclampsia and preterm birth, in association with Professor Susan Fisher (University of California at San Francisco). 

Role of androgens in uterine contractions

Investigators: Professor Jane Norman, Philippa Saunders, Sofia Makieva

Funding: Study taking place in a Tommy’s funded centre

Timescale: 2013–2015

Summary: Preterm birth is a major cause of neonatal morbidity and mortality. It is important that spontaneous uterine contractions prior to term be avoided. Some androgens, including testosterone and its metabolite dihydrotestosterone, increase as pregnancy progresses but we don’t yet understand their role in myometrial (uterine muscle) contractility. We have been examining the action of androgens on spontaneous myometrial contractility on tissue samples obtained from pregnant women at term undergoing caesarean delivery. We have found that exposure to either of these androgens rapidly inhibits spontaneous contractions. Further understanding of how androgens reduce myometrial contractions will help us to understand what causes new preterm labour and to develop new treatments. 

A pilot study of the Arabin pessary for preventing preterm birth

Principal investigator: Professor Jane Norman

Funding: Tommy’s is providing the funding for the set-up for this study

Timescale: 2013–2014

Summary: A recent randomised trial suggests that the Arabin pessary, applied in unselected women with a cervical length of less than 25mm, is highly effective in reducing preterm birth. Although this trial was published in the Lancet, concerns have been expressed about the higher than expected incidence of preterm birth in the ‘placebo’ group (27%) and that the final sample size was less than half that originally planned. Many authorities have suggested that the findings should be replicated before the pessary is introduced into clinical practice. The Arabin pessary is inexpensive and easy to use. If it is effective in preventing preterm labour in women with a short cervix then it has the potential to be used in both developed and developing countries. This will have major benefits, particularly for developing countries, where neonatal death rates following preterm delivery are very high because specialised neonatal care is either not available or very limited.

Progress report: We have obtained ethics approval, and will start recruiting shortly.

Establishing a resource for the study of genetic associations with preterm labour

Investigators: Dr Sarah Stock, Professor Jane Norman

Funding: Study taking place in a Tommy’s funded centre

Timescale: 2013–2014

Summary: Both genetic and environmental factors contribute to a woman’s risk of spontaneous preterm birth. Advances in genetic and bioinformatic technologies now provide potential for these complicated interactions to start to be understood and for an individual’s chance of delivering early to be determined. We want to establish a biobank of samples for studies of genetic associations with preterm birth. However, uncertainty about the best way to involve pregnant women and the most efficient way to collect and analyse samples and data means that a pilot study is needed. We are recruiting woman who are participating in another trial (the OPPTIMUM trial – a randomised trial of progesterone pessaries to prevent preterm labour) to pilot the recruitment and sample collection methods. This pilot study will provide valuable information for future preterm birth research. [E401]

CLAHRC South London: ‘Birth and Beyond’ and ‘Supporting Women at Risk of Preterm Birth’

Investigators: Professor Jane Sandall, Professor Debra Bick, Dr Annette Briley, Professor Andrew Shennan, Professor Lucilla Poston, Professor Graham Thornicroft (CLAHRC South London Lead)

Funding: Tommy’s part-funds this study

Summary: Jane Sandall leads a theme in the ‘Collaboration for Leadership in Applied Health Research and Care’ (CLAHRC) South London, which comprises researchers, health professionals and NHS managers working at universities and NHS organisations south of the River Thames. The aim of this collaboration is to enable NHS services to offer excellent, evidence-based care to everyone, wherever they live and whatever their background. Socio-demographic factors, ethnicity, clinical and social risk, and poor quality of care result in inequitable distribution of maternal and infant health outcomes which persist over the life-course of the mother and the child. Compared with the national average, some of the boroughs in South London have higher levels of socio-economic deprivation, ethnic diversity and poor health.

Pregnancy is an optimal time to help promote a healthy lifestyle and introduce preventative measures. A life-course approach for women’s health care will maximise every opportunity that the health service has to support a woman to improve her lifestyle and general health, and ultimately to improve outcomes irrespective of her situation in society.

Two CLAHRC studies are currently underway. The first of these is ‘Birth and Beyond’. Work to date includes scoping of existing service provision for women who have high-risk pregnancies in South London, an ongoing review of evidence of what works to support postnatal health for women with pre-existing diabetes and women who develop pre-eclampsia/eclampsia in pregnancy and find the best way of identifying those most likely to benefit from multidisciplinary team follow-up. The pilot study will be tested in one South London maternity unit with a view to seeking substantive external funding for a future larger study to test the effectiveness of the intervention.

The second study is entitled ‘Supporting Women at Risk of Preterm Birth’. In 40% of cases of preterm birth, the cause is not known and our ability to identify those at risk is poor. Screening women at risk in a preterm surveillance clinic is now considered to be the best way to prevent hospital admissions and unnecessary interventions. However these methods are rarely used for management of high-risk women in the UK, and women often end up with very fragmented care. We aim to develop and test a novel model of care in Lewisham that includes a preterm surveillance clinic within a care pathway that provides continuity of midwifery care for women at high risk of preterm birth from the beginning of pregnancy through to the postnatal period. We will evaluate the implementation and impact on outcomes and experiences for women and their families.

 

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