Updated February 2014

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, Professor Robyn North, 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 has completed recruitment, with a total of 5,690 women recruited in New Zealand, Australia, the UK and Ireland. The study is now testing whether certain clinical and molecular markers (certain proteins, fats and small molecules in blood) can predict these complications. We already know that none of the candidate markers will work on their own, but combinations of markers are likely to result in clinically useful screening tests. The Tommy’s London and Manchester centres are participating in this major study.

Progress report: All research teams have access to the samples and data and after several years of recruitment the immense effort to establish the SCOPE cohort is now being rewarded and many papers have been published. The Tommy’s London and Manchester centres have contributed to several 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. 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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Anti-inflammatory signals to prevent preterm labour

Investigators: Professor Jane Norman, Professor Adriano Rossi, Sara Rinaldi

Funding: Tommy’s fund the PhD student and the consumables for this study

Timescale: 2009–2013

Summary: In this study we are looking at the role of signals made naturally in the body that stop inflammation. We believe that by increasing these signals we could stop the inflammation that occurs in preterm labour, and thus prevent both preterm birth and the damage to babies’ brains that can occur as a result of the inflammation in the womb in preterm labour.

Progress report: We have investigated various anti‐inflammatory agents in our mouse model of preterm labour. While the treatments tested did not delay preterm labour, we found that one of them, epi-lipoxin, reduced mortality in pups born preterm, suggesting that this anti-inflammatory agent may be useful in protecting the fetus from the adverse effects of infection-induced preterm birth. Using models such as the one described here is vital to improving our understanding of the events regulating the induction of preterm labour and will ultimately aid the search for novel therapeutic options. We calculated that, if the effects of mortality reduction in mouse pups could be translated to human babies, it would save the lives of 750 babies per year. Further mouse work is necessary before human studies, but these data show promise for future development.

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Understanding the role of cervical antimicrobial peptides in pregnancy

Investigators: Dr Sarah Stock, Professor Jane Norman, Donald Davidson, Lorraine Frew

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

Timescale: 2010–2013

Summary: Antimicrobial peptides are small proteins which are important in infectious and inflammatory conditions. This project is focusing on one called human cathelicidin, which is produced by the epithelial cells lining the lower genital tract. Levels of cathelicidin change with changes in bacterial flora, and it also promotes inflammation in these cells. We believe that cathelicidin may be important in the pathophysiology of preterm rupture of the fetal membranes and spontaneous preterm labour. It is thus an attractive target for possible treatments to prevent preterm birth.

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The efficacy of CRH receptor antagonists to treat preterm labour

Investigators: Professor Jane Norman, Dr Sharon Battersby, Dr Chiara Voltolini (Siena), Professor Felice Petraglia (Siena)

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

Timescale: 2011–2013

Summary: Preterm labour leading to premature birth is the single biggest cause of neonatal mortality and morbidity. Recent work has highlighted the role of inflammation/infection in both the aetiology and adverse outcomes associated with preterm labour. Effective treatment is likely to involve both inhibition of uterine contractions and inhibition of intrauterine pro-inflammatory events. Corticotrophin-releasing hormone (CRH) has been strongly implicated in the initiation of labour and this project seeks to evaluate the role of the CRH/urocortin family of genes on the process of labour, and (ultimately) to investigate their antagonists as therapeutic agents to prevent preterm labour.

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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.

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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 vitro. 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.

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Blockade of decidual chemokines as a novel therapy for preterm labour

Investigators: Sylvia Lui, 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: To obtain a complete picture of the inflammatory changes taking place in the human uterus during term labour, we are performing gene array analyses, which screen 45,000 genes simultaneously, to determine whether their expression is upregulated or downregulated during labour. We have collected samples of decidua from women who had undergone normal labour at term, and compared them to those who had delivered their babies by caesarean section at term, without any signs of labour. We have also collected samples of their myometrium which we have analysed in parallel. As expected, the pathways that are most highly stimulated during labour are inflammatory pathways.

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Investigating the link between air pollution and pregnancy problems

Investigators: Dr Kimberley Hannam, Dr Roseanne McNamee, Professor Raymond Agius, Professor Colin Sibley, Dr Bernice Dillon, Professor Philip Baker

Funding: Tommy’s part-funds the studentship for Ms Hannam

Timescale: 2009–2013

Summary: Recent epidemiological studies have found associations between exposure to high levels of air pollution and an increased risk of preterm birth and low birthweight. Air quality in the UK, particularly in the urban areas of the North West of England, still regularly breaches air quality standards set to protect health. This study is using records from the North West Perinatal Survey Unit (NWPSU) to look at the relationship between air pollutants and birth outcomes in this population during the period 2004-2008.

Progress report: Preliminary analysis has investigated the potential confounding effect of seasonality. The NWPSU data shows significant seasonal variation in the frequency of births and the rates of preterm birth and low birthweight. Air pollutants have traditionally been measured using stationary monitors but an individual’s exposure may be quite different owing to where they live, their individual characteristics and their activity patterns throughout the day. In a validation study, 85 participants over three seasons were recruited and participants measured their personal exposure to nitrogen oxides along with a time-activity log during early pregnancy. We found that personal exposure measurements correlated moderately with stationary monitor data. The agreement was stronger during the summer season, most likely due to the participants spending more time outside. Time-activity patterns showed women in early pregnancy were spending an average of 60% of their time in the home, 12.5% at a work location and 10% travelling. The strongest predictors of personal air pollution exposure were found to be season, mode of travel, cooking with gas and deprivation level. Using the large NWPSU database, we have linked women’s postcodes to the major road network in North West England, and we found that living less than 200 metres from a major road does not increase the risk of an adverse perinatal outcome, but there may be an increased risk living in much closer proximities (around 25 meters). We also found that women exposed to high air pollution concentrations, particularly in the later stages of pregnancy, are at an increased risk of a small for gestational age birth but not for preterm birth. No increased risk of an adverse perinatal outcome was found air pollution levels below the air quality standards that are currently in place in the UK; however, based on the estimates made in this study, a substantial number of women are exposed to levels above these standards.
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Improving pregnancy outcomes in women with chronic hypertension

Investigators: Dr Jenny Myers, Dr Ruth Cockerill, Catherine Chmiel, Dr Ian Crocker

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 100 women recruited through our specialist research clinic, the Manchester Antenatal Vascular Service (MAViS).

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Fetal fibronectin testing to predict preterm birth: the EQUIPP study

Investigators: Professor Andrew Shennan, Joy Kemp, Jenny Carter, Paul Seed, Dr Rachel Tribe, Dr Natasha Hezelgrave, Annette Briley, Dr Danelle Abbott, 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: We have completed recruiting 300 women who are showing symptoms of preterm labour and have already demonstrated that the new test is better than the previous test at determining who is in labour or not. Because an interim analysis in women without symptoms also looked very promising, the study has been extended to include women with twin pregnancy, those who have had previous cervical surgery and those have had measurement earlier in pregnancy. 

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

Investigators: Professor Lucilla Poston, Jenny Carter, Ruth Cate, Joy Kemp, Judith Filmer, Paul Seed, 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 will now investigate:

  • whether the test can help to predict which women at risk for preterm labour and delivery are likely to respond to treatment with progesterone
  • 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. Preliminary 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 also need to refine the sensitivity of the laboratory analyses. Additional studies planned include high-throughput screening of bacteria in cervico-vaginal fluid and in saliva, collaboration with the University of California, San Francisco (UCSF) to undertake proteomic screening for novel predictors of premature birth, and exploration of other saliva biomarkers.

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Are natural antimicrobial defences altered in women at high risk of preterm labour?

Investigators: Dr Rachel Tribe, Dr Danielle Abbott, Paul Seed, Professor Andrew Shennan, Evonne Chin Smith, Paul Seed

Funding: Tommy’s part-funds this this project 

Timescale: 2009 onwards

Summary: In order to develop treatments to prevent or stop preterm labour, we have to understand more about the processes causing it. One potential cause is infection that spreads from the vagina into the uterus (womb), but why some women are more at risk/less able to mount an appropriate immune response to combat this is unknown. This project, an extension of a clinical study already successfully undertaken at KCL, aims to understand how a woman's body may protect itself from risk of preterm labour by producing natural antimicrobial substances (nature's antibiotics), and whether vitamin D supplementation can enhance this process.
Progress report: We have identified elafin, a natural antimicrobial peptide, as a potentially useful indicator of women most at risk of preterm birth. An initial patent application has been submitted and commercial partnerships are being explored to pursue potential development of a bedside test using elafin as an ‘early pregnancy’ biomarker of preterm birth. An early pregnancy test based on elafin would add to the current use of fetal fibronectin for prediction of preterm birth at gestations later in pregnancy. The study has been expanded to include assessment of samples from low-risk women in the SCOPE cohort. We have also demonstrated that vitamin D enhances natural antimicrobial peptide production and we are thus now studying vitamin supplementation in women at high risk of preterm labour.

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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.

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 plan to recruit woman who have participated 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.

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