Last updated: December 2012
Premature birth
More than 50,000 babies are born prematurely each year in the UK 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
Making Pregnancy Safer (MAPS) – the UK arm of the international SCOPE study
Investigators: Manchester: Professor Philip Baker, Dr Jenny Myers, Suzanne Moody, Sarah Lawson; London: Annette Briley, Dr Lucy Chappell, Jenny Carter, Beth Steff, 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 (known as MAPS in the UK) 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 already recruited 4,000 women in New Zealand and Australia and will recruit a total of 3,000 in the UK and Ireland. The study will test 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 centres in both Manchester and London are participating in this major study.
Progress report: The MAPS study is part of a consortium made up of researchers in Manchester, London, Leeds, Cork, Auckland, Adelaide and, hopefully, the USA. Recruitment of the UK MAPS cohort is now complete. 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. The Tommy’s London and Manchester centres are initiating several further projects which utilise the SCOPE database and samples.
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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 over 40,000 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, is recruiting 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: Over 1,000 of the planned 1,250 women have been recruited to the study. 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 are investigating various anti‐inflammatory agents in our mouse model of preterm labour. Understanding the mechanisms involved will help to identify appropriate targets in the search for novel therapeutic agents to delay infection‐induced preterm labour. Drug efficacy in the mouse model could be rapidly followed by interventional clinical trials, which we are well set up to conduct.
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Can omega-3 fish oils reduce inflammation of the fetal membranes?
Investigators: Dr Sarah Stock, Lorraine Frew, Rose Leask, Dr Simon Riley, Professor Jane Norman
Funding: Study taking place in a Tommy’s-funded centre
Timescale: 2009 onwards
Summary: Preterm labour affects around 6% of pregnancies in Scotland and, despite great advances in neonatal care, prematurity remains the leading cause of death and disability in newborn babies. There are currently no effective treatments to prevent premature delivery, and factors controlling the onset of labour remain poorly understood. Dietary supplementation with omega-3 oils (such as those found in oily fish) may decrease the incidence of preterm labour, but it is unclear how this effect is mediated. Omega-3 oils have well-described anti-inflammatory effects in conditions such as arthritis and, as preterm labour is associated with excessive inflammation, similar mechanisms may be important in pregnancy. We are investigating the anti-inflammatory effects of fish oils on the fetal membranes, which surround the developing baby and produce inflammatory proteins crucial for the onset of labour. We anticipate that this study will increase understanding of the processes involved in preterm birth, and may help development of effective treatments for the prevention of this important pregnancy complication.
Progress report: We have found that omega-3 fatty acids, which are found in dietary fish oil supplements, have a direct anti-inflammatory effect on fetal membranes. This may be one mechanism through which fish oil supplements can prolong gestation. We have now extended this work to look at other anti-inflammatory/antimicrobial peptides present in the lower genital tract.
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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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The role of complement activation in preterm labour and fetal brain damage
Investigators: Guillermina Girardi (UoE), Juan M Gonzalez (UCSF, USA)
Funding: Study taking place in a Tommy’s-funded centre
Timescale: 2012–2013
Summary: There is increasing evidence of a link between inflammation in the womb and preterm labour. We are studying the mechanisms responsible for inflammation‐induced preterm labour in a mouse model that closely resembles the most common clinical scenario. The complement system consists of over 25 proteins that circulate in the blood and it is part of the body’s immune system. We have identified a previously unrecognised role for complement activation in several pregnancy complications including miscarriage, intrauterine growth restriction and pre-eclampsia and we recently demonstrated that complement activation also plays a crucial role in the cervical remodeling process during preterm labour. Ultimately, we hope that complement inhibitors and/or statins might be an effective treatment to prevent preterm labour and neonatal brain injury.
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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. Blocking macrophage entry to the decidua may therefore work to stop preterm 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. Our studies aim to test chemokine blockers in the rat to find out whether they can stop movement of these cells into the womb and could therefore stop preterm labour.
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Investigating the link between air pollution and pregnancy problems
Investigators: 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 of NOx and NO₂ 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 200m from a major road increased the risk of having a small for gestational age baby by 14% compared to living further away. We are continuing to analyse the relationship between air pollution and risk of preterm delivery and small for gestational age taking account of other factors that may confound the relationship, e.g. social status and maternal age.
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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 will measure blood vessel relaxation using a highly sensitive blood pressure machine which measures the stiffness of blood vessels. This technique has been shown to be much more accurate than measuring blood pressure alone. In the first part of this study we will determine whether this technique helps to identify which women are at the highest risk of needing an early delivery. In the second part we will use these measurements to identify women at high risk of a preterm delivery and recruit them to a pilot randomised controlled trial of a commonly used blood pressure tablet (nifedipine). This pilot trial will assess the efficacy, safety and acceptability of targeted therapy. A specialist clinical research clinic has been set up which will facilitate this research project.
Progress report: The Manchester Antenatal Vascular Service (MAViS) was established in April 2011 and has cared for approximately 75 women to date.
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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
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 reached our target of recruiting 300 symptomatic women to the study and we have already determined the optimal timing of the vaginal swabs.
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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, Professor Susan Fisher (UCSF, USA)
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: (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: The study protocol has been developed and the required regulatory approvals have been obtained. Women are being recruited at the KCL site and at 11 other UK centres. The target recruitment is 1,000 women. Additional studies planned include high-throughput screening of bacteria in cervico-vaginal fluid and in saliva, and collaboration with the University of California, San Francisco (UCSF) to undertake proteomic screening for novel predictors of premature birth.
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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
Funding: Tommy’s provided pilot funding for 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/MAPS 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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