Updated February 2014
The Royal Infirmary, Edinburgh
Tommy’s third research centre, at the Royal Infirmary of Edinburgh, was opened in April 2008. Led by Professor Jane Norman, the focus of the team is on discovering ways to alleviate the risks and problems caused by maternal obesity. Other areas of research interest include blood vessel and tissue remodelling, fetal ‘programming’, inflammation, hypoxia and the process of labour and childbirth and maternal depression/stress.
Situated in the state-of-the-art buildings of the Queen’s Medical Research Institute, the centre is helping to make Tommy’s maternal and fetal research network a truly major force worldwide. It has 35 core staff and in 2011/2012 published 72 scientific papers in the pregnancy field in peer-reviewed medical journals. The centre has developed excellent collaborative links with the sister Tommy’s centres in London and Manchester, as well as with other relevant groups within Edinburgh and beyond. A major achievement has been the award of Centre status from the Medical Research Council (MRC), with the MRC Centre for Reproductive Health opening in April 2011. The Tommy’s centre is an integral part of the MRC Centre and is key to one of its main themes: ‘Developmental programming and reproductive resilience’.
The centre opened the Tommy’s Antenatal Metabolic Clinic in August 2008 and it is now providing specialised care to around 200 obese pregnant women per year. This clinic provides the infrastructure for most of the centre’s work on obesity in human pregnancy, and it has become a template for similar clinics around the UK.
Core funding from Tommy’s has allowed the Edinburgh centre to develop new research threads that are crucial for better understanding and treatment of complications associated with pregnancy.
Lecture from Professor Jane Norman on pregnancy research in Edinburgh
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Current research areas at Edinburgh
Do conditions in the womb ‘programme’ problems in later life?
Many studies have shown that the conditions experienced by the baby in the womb can increase the risk of various diseases in later life. Maternal obesity can also increase the risk of obesity, diabetes and heart disease in the offspring. We are investigating the mechanisms by which maternal obesity affects the long-term health of the offspring.
The effects of stress hormones in obese and non-obese women
Over-exposure of the developing baby to the steroid stress hormone cortisol results in low birthweight. The levels of this hormone increase during normal pregnancy and they are also altered in obesity, but we need to understand how they change in obese pregnant women. We are also using MRI scans to investigate whether maternal stress has a direct effect on fetal brain growth and development.
Understanding the link between obesity and pre-eclampsia
Obesity is now recognised as a major risk factor for pre-eclampsia. The mechanisms through which obesity increases the risk are unclear, but we believe it may affect the function of the blood vessels connecting mother and baby. We thus want to analyse this in the laboratory to see whether it can be treated.
Progesterone: could it prevent premature birth?
Although the main focus of the centre is on obesity, it is also handling a major clinical trial (the OPPTIMUM trial) to see whether giving high-risk women progesterone between 22 and 34 weeks of gestation will reduce the incidence of preterm birth. 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.
Can omega-3 fish oils reduce inflammation of the fetal membranes?
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. We have found that omega-3 fatty acids do 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.
Barriers to breastfeeding in obese women
Breastfeeding has significant benefits for maternal and offspring health but breastfeeding rates in the UK are low compared to the rest of Europe, and a number of factors are thought to contribute to this. We are studying the factors that influence breastfeeding behaviour in obese compared to a non-obese women, determining the barriers to successful breastfeeding, and investigating access to and provision of breastfeeding support.
Using MRI to study placental physiology and to detect intrauterine hypoxia
Many pregnancy complications such as pre-eclampsia, fetal growth restriction and diabetes are associated with poor placental function but there are no tests currently available which are able to assess placental function. A diagnosis of a ‘sick’ placenta is therefore only made relatively late in pregnancy. We have carried out a successful pilot study is to evaluate the feasibility of using magnetic resonance imaging (MRI) to investigate uteroplacental physiology during pregnancy. We are also using our powerful MRI scanners to investigate hypoxia (low oxygen levels) within the womb, with very encouraging results. In the longer term, we hope that novel imaging techniques will be able to provide information to help decide on the timing of delivery and thus improve outcome in pregnancies complicated by uteroplacental insufficiency.
Can the placenta be preconditioned to withstand low oxygen levels?
Women living at high altitude during pregnancy can often have low birthweight babies due to lower oxygen levels (hypoxia). This is a problem as low birthweight is correlated with perinatal death and disease, inhibited intellectual development, and chronic diseases, such as diabetes in adult life. The effects of hypoxia seem to be mediated through changes in the placenta, which carries nutrients and oxygen to developing babies. We have used placental cells to investigate the effects of hypoxia on cell function. This has shown that it inhibits their ability to produce proteins, but that this is restored when the cells are grown in normal oxygen levels. This ability to recover is useful, as it has been shown that some organs (e.g. the heart) are more able to cope with an insult such as low oxygen if the body has experienced it before. This is termed preconditioning, and it could be useful during pregnancy, for instance during labour when the placenta undergoes hypoxia but still needs to be able to function correctly, to support the baby. Ultimately, the results of this research could help protect babies from the adverse effect of reduced oxygen supplies in the womb.
The AFFIRM randomised trial for prevention of stillbirth
Rates of stillbirth in the UK are amongst the highest in resource-rich countries. The majority of stillbirths occur in normally formed infants, with (retrospective) evidence of placental insufficiency being the most common clinical finding. Maternal perception of reduced fetal movements is an early marker both placental insufficiency and subsequent stillbirth. The AFFIRM study will investigate whether the introduction of a package of care for women with reduced fetal movements reduces stillbirth. The package of care includes education to increase pregnant women’s awareness of fetal movements and prompt reporting of reduced fetal movements, followed by a standardised management plan for identification of placental insufficiency with timely delivery in confirmed cases. When a similar package was introduced in Norway, the frequency of stillbirth fell by 30% but the efficacy of this intervention has not been robustly tested in a randomised trial (the best form of evidence). Hospitals in Scotland, Ireland, England and Wales will be randomised to the timing of introduction of the care package. A smaller study will examine the acceptability of the intervention to patients and healthcare providers and identify any barriers to implementation.
The accuracy of ultrasound fetal weight estimation in obese women
In very severely obese pregnant women it can be difficult to assess the size of the fetus using standard measurements such as the size of the uterus. Ultrasound is often used as an alternative method of assessing fetal size and to provide an estimate of birthweight. The aim of this study is to compare measurements of fetal size and estimates of birthweight in very severely obese compared to lean women. We have completed recruitment to this study and are currently finalising the analysis of our results, which suggest that ultrasound is not very accurate in assessing fetal size in either lean or obese women. However, ultrasound is no less accurate in severely obese women and may therefore be useful to inform the clinical care of these women.
Weight gain during pregnancy
Weight gain during pregnancy may be associated with having a large baby, which may have short-term consequences for the mother and baby, including operative delivery problems, as well as longer term problems such obesity in later life. We are investigating the weight gain in pregnancies from booking to delivery in women in Midlothian who do not have access to antenatal clinics where dieticians could offer advice. We are also examining attitudes to diet and exercise in this cohort.
CRH receptor antagonists to prevent preterm labour
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 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 we are evaluating the role of the CRH/urocortin family of genes on the process of labour. We hope that this will ultimately lead to a drug that can prevent preterm labour.
Metformin for reducing excess birthweight in the babies of obese pregnant women (the EMPOWaR study)
In the EMPOWaR clinical trial, we are evaluating whether giving obese pregnant women the drug metformin (an agent that restores maternal blood glucose and insulin resistance towards normal) reduces excess birthweight in their babies. Such excess birthweight is a surrogate marker of future life risk of obesity and metabolic syndrome. The trial was initially scheduled to recruit women from Edinburgh and Liverpool only. However, we have had huge interest from other centres and we are currently recruiting from Edinburgh, Liverpool, Coventry, Sheffield and Nottingham. The study has received considerable press attention in the UK and overseas, including an interview with Professor Jane Norman on the Radio 4 ‘Today’ programme. We are also interested in the effect of metformin on the pregnant woman’s body composition and fat distribution over the course of pregnancy, as well as the distribution of body fat in the developing fetus. We are investigating this by using magnetic resonance imaging (MRI).
Epigenetic effects of maternal diabetes
We are studying whether exposure to maternal diabetes in the womb has a long-term adverse effect on the baby as it grows up. We are using Generation Scotland, a large cohort of families in Scotland who have already agreed to participate in medical research, which provides very detailed clinical information, measurements, blood tests and DNA. The processes by which the maternal intrauterine environment has long‐lasting effects on offspring are unknown, but epigenetic mechanisms may play a role. These are modifications of DNA, without changing its actual sequence, that can affect which genes are expressed in specific tissues.
Physical activity interventions in pregnancy and the postnatal period - what do women want?
Exercise in pregnancy is safe and has considerable benefits for both mother and baby. However, studies encouraging exercise in obese pregnant women have largely been unsuccessful. In this project we are exploring severely obese women’s knowledge, attitudes and behaviours, including the perceived benefits and barriers, with regard to participating in physical activity during pregnancy and the postnatal period. Our findings so far suggest that most obese pregnant women are aware of the health benefits of exercise in pregnancy but lack knowledge of what is safe to do. There is an urgent need to develop suitable interventions to help women in pregnancy to overcome barriers to carrying out physical activity. We have now designed a feasibility study for an exercise intervention in pregnancy and we are currently conducting this among women attending our Edinburgh Antenatal Metabolic Clinic.
Establishing a resource for the study of genetic associations with preterm labour
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.
A pilot study of the Arabin pessary for preventing preterm birth
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.
Home blood pressure monitoring in pregnancy using telemetry – the BLOSSOM study
Women with hypertensive disorders in pregnancy require more frequent monitoring of their blood pressure during the antenatal period. This results in more appointments with their community midwife or attendance at the hospital’s Day Assessment or Triage department for monitoring. We are investigating whether substituting these visits with home monitoring of blood pressure using telemetry is an acceptable method to women and what impact this has on the service.
Role of androgens in uterine contractions
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.
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The Edinburgh Antenatal Metabolic Clinic
The effects of maternal obesity
With around half the women of childbearing age in the UK now overweight or obese, the impact of obesity in pregnancy continues to be a major issue, both to the immediate outcome in pregnancy and to the long-term health of the child. Government projections for Scotland suggest that, without clear action, obesity figures will rise to almost nine in ten adults and two-thirds of children by 2050. This matters because of the severe impact being overweight or obese can have on an individual’s health - both are associated with an increased risk of diabetes, cancer, heart disease and massive complications during pregnancy. In addition, a report by CEMACH (Confidential Enquiry into Maternal Deaths) has shown that obese pregnant women are probably at four or five times greater risk of maternal death than a woman of normal weight - and the same for their babies dying.
The associated risks in pregnancy for obese women include increased chances of miscarriage, stillbirth, pre-eclampsia, gestational diabetes, neonatal obesity and preterm birth. These preterm babies are at much greater risk of blindness, deafness, cerebral palsy and developmental delay - disabilities which can bring a lifetime of suffering.
Emerging evidence also suggests that maternal obesity has long-term consequences for the baby, including childhood obesity and increased risk of developing heart disease and diabetes in later life. Studies have shown that part of the reason behind this is the poor diet of the mother while pregnant, which in turn makes the baby more likely to crave a similar diet themselves. The baby is, as such, ‘programmed’ in the womb by an adverse fetal environment during pregnancy.
Consequently, this is the first generation in human history where the health of the children will be worse than that of their parents and the cycle of disadvantage is passed from one generation to the next.
The importance of additional clinical care
There is very little help available for people who are obese and pregnant in Scotland. Health professionals rarely intervene, partly because there are very limited options available to help obese people and partly because it often impacts on the midwife or doctor/patient relationship, making individuals less likely to see their midwife or doctor. The situation is exacerbated during pregnancy as women tend to increase weight from one pregnancy to the next.
Tommy’s is determined to tackle the problems of maternal obesity, both through research and through providing high-quality clinical care. The first major achievement of the Edinburgh centre was to open a new Antenatal Metabolic Clinic, jointly funded by Tommy’s, Lothian Health Board and the University of Edinburgh, at which obese mothers are monitored throughout their pregnancy. In addition to providing valuable data for our research scientists, our clinic ensures that these women get a far higher standard of care than they would otherwise.
The clinic is going from strength to strength and sees around 200 obese pregnant women (with a body mass index (BMI) of 40 or more) per year. The clinic is multidisciplinary, with care being provided by obstetricians, endocrinologists, dieticians and a psychiatrist (where appropriate). Not only is this type of specialist treatment and care helping to reduce the prevalence of pregnancy complications in obese pregnant women who attend the clinic, but it is also crucial in facilitating research into mechanisms and treatment.
Midwifery support underpins the success of the clinic. The midwife liaises with the women, engaging their support to attend the clinic. The care package is arranged by the midwife and tailored to the individual needs of the women. We also have support from the community midwives and the majority of referrals to the clinic come from them.
The enhanced care package includes additional detailed scans and growth scans, glucose tolerance tests (a test for gestational diabetes), post-dates monitoring, a thorough anaesthetist’s assessment, and the prescribing of drugs to prevent deep vein thrombosis.
We have set up postnatal follow-up clinics for mothers and babies who attended the Antenatal Metabolic Clinic. During these consultations we discuss any problems which occurred during pregnancy, reinforce healthy lifestyle advice for both mother and baby, and discuss issues for future pregnancy. So far we have followed up the babies of 192 of our very severely obese women and 119 of the normal-weight controls at 3 and/or six months of age.
During the initial clinic set-up we sought informal feedback from the women who attended the clinic. This was very positive, with women appreciating the care and additional support provided for them by the clinic. We have now begun to see a number women coming back to the clinic for their second pregnancy.
Key recent achievements at the Edinburgh research centre
We’ve shown that elective induction of labour at term in older women reduces the risk of stillbirth
By analysing Scottish birth records for more than 1 million women from 1981 to 2007, we were able to show that elective induction of labour from 37 weeks of gestation onwards reduces perinatal mortality. We also showed that it does not increase the risk of needing a caesarean section delivery. Our published results have been widely cited and, importantly, they stimulated new guidelines from the Royal College of Obstetricians and Gynaecologists that women at high risk (older women) should be offered routine induction of labour from 39 weeks of gestation. Implementation of this recommendation is likely to prevent the stillbirths of 17 babies per year in the UK.
We’ve confirmed that maternal obesity has long-term health risks for the child
In a study of people born in the Aberdeen area since the 1950s, we found that maternal obesity was associated with a 35% increase in premature death in the adult offspring, and a 29% increase in the risk of hospital admission for a cardiovascular event. The results were published in the BMJ in August 2013 and attracted considerable media interest. At current rates, maternal obesity will be associated with the premature deaths (before age 50) of 7,000 people per year in the UK.
We’ve shown that maternal obesity has consequences for the second-generation offspring
We explored the effects of maternal diet-induced obesity on the offspring in a mouse model. Surprisingly, there were few effects on the first-generation offspring. However, we found clear evidence of fetal growth restriction and persistent metabolic changes in the second-generation offspring. Effects on birthweight, insulin levels and gene expression in the liver were transmitted through both maternal and paternal lines. This suggests that the consequences of the current dietary obesity epidemic may also have an impact on the descendants of obese individuals, even when the first generation appears to be largely unaffected.
We’ve shown that omega-3 fatty acids can reduce inflammation in fetal membranes which is associated with preterm labour
We’ve shown 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.
We’ve found a potential treatment to prevent brain injury in premature babies
There is increasing evidence of a link between inflammation in the womb and preterm labour. In our studies of the mechanisms responsible for inflammation‐induced preterm labour in a mouse model, we have identified a previously unrecognised role for complement activation in several pregnancy complications, including miscarriage, fetal growth restriction and pre-eclampsia. (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 recently also demonstrated that complement activation plays a crucial role in changes in the cervix during preterm labour. This work has suggested that complement inhibitors and/or statins might be an effective treatment to prevent preterm labour and neonatal brain injury.
We’ve found that progesterone does not reduce preterm birth in twins
Although progesterone reduces preterm birth in women with one baby, we found that it did not reduce preterm birth (if anything, it increased it) in women with a twin pregnancy. This study is important in preventing women with twin pregnancy getting an ineffective treatment. Accordingly, the results were published on a ‘fast track’ basis in the Lancet medical journal and were accompanied by an editorial.
We’ve discovered that the hormone kisspeptin inhibits placental blood vessel growth
In a series of experiments in the test tube, we showed that the hormone kisspeptin influences the way blood vessels develop. We then tested this in the placenta and showed that kisspeptin reduces the amount of new blood vessel formation. This exciting finding may be important for diseases in pregnancy which result from poor placental development, such as pre-eclampsia and low birthweight.
We’ve demonstrated that measuring arterial stiffness in obese pregnant women can identify those at risk of blood pressure complications
We have recently demonstrated that using the Vicorder device is a valid and reliable method for routine measurement of arterial blood vessel stiffness in obese pregnant women. Given that arterial stiffness increases before blood pressure does, this technique could be a useful screening tool to identify mothers who have an increased risk of developing blood pressure complications in later pregnancy.
We’ve confirmed that a mother’s diet during pregnancy can have long-term effects on her child
A group of men and women born in the late 1960s in Motherwell whose mothers’ food intakes in pregnancy were recorded took part in this study. We examined the effects of an ‘Atkins-type’ high-protein, low-carbohydrate diet during pregnancy on how regulation of key genes in the offspring is altered. Our study was the first to show that regulation of a number of genes which may be important in increasing the risk of diseases such as adult obesity and high blood pressure was related to the size of the baby at birth and, importantly, was altered by the diet eaten by the mother in pregnancy. This highlights the importance of the early life environment for future health.
We’ve found that pregnant women are often unaware of the risks of obesity to them and their babies
In a study of women’s perceptions of the risks of their obesity for their general health and for their pregnancy, we found that all of the women in the study claimed that before they were pregnant they had been largely unaware of the risks that obesity posed to them and their babies. The majority felt that inadequate reference had been made to obesity and the associated risks both before and during pregnancy. In some cases, this had caused concern or confusion.
We’ve developed liver function tests for obese pregnant women that can identify those most at risk of gestational diabetes
We have found that obese women display a unique pattern of liver function tests as their pregnancy progresses, compared with women with normal weight at their booking visit. In particular, the liver enzyme GGT was found to be an independent risk factor for subsequent gestational diabetes in our high-risk pregnant women, raising potential clinical interest in this test as a predictor of subsequent gestational diabetes at 24–28 weeks.
We’ve improved our understanding of the link between gestational diabetes and non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) is the most common liver condition in the Western world and Iit is known to be associated with type 2 diabetes; however, it is not known whether NAFLD predates the development of type 2 diabetes. In a study of 223 women, we found that those women who had had previous gestational diabetes were at significantly higher risk of developing NAFLD.
We’ve shown that MRI can be used non-invasively to detect placental insufficiency and fetal hypoxia
Currently, we are not able to directly measure placental function and fetal health within the womb. However, we have recently demonstrated for the first time that MRI can be used non-invasively to measure placental metabolism. This has real potential to reduce stillbirths by identifying those babies at greatest risk of coming to harm within the womb and by enabling doctors to time their delivery appropriately.
We’ve shown that the differences in insulin sensitivity between obese and lean pregnant women are greatest in early pregnancy
In our AMPOP metabolic study we found that differences in insulin sensitivity between obese and lean pregnant women are greatest in early pregnancy and that the maternal liver is spared from the adverse effects of maternal obesity. However, the resulting increased circulating lipids could have adverse effects on both the baby and the mother’s health, and interventions to prevent these effects of obesity should be delivered as early as possible in the pregnancy. These results provide further support for the rationale for the EMPOWaR study, in which we will determine whether improving insulin sensitivity in obese pregnant women improves outcomes.
We’ve quantified the clinical and short-term NHS costs of maternal obesity for maternity services in Scotland
Half of all Scottish women of reproductive age are overweight or obese and maternal obesity has significant implications for the health of mothers and their babies. Using the Scottish maternity database, we analysed the effect of maternal obesity on clinical outcomes in Scotland and also estimated the associated costs to the NHS. Women who are overweight are more likely to have maternal complications, require additional hospital care and incur higher medical costs for the NHS. The increased costs to the NHS per pregnancy for antenatal admissions alone for women who were overweight, obese or severely obese were £60, £202 and £351, respectively. The results were published in January 2014 and have gained considerable press interest. Locally, strategies and guidelines should be developed to minimise risk and optimise perinatal outcome. Nationally, the impact of maternal obesity should be considered when redesigning services. We are also using the results of this study to improve the care we provide for the women who attend the Edinburgh Antenatal Metabolic Clinic.
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