The UPBEAT RCT mother-child study. Stratifying and treating obese pregnant women to prevent adverse pregnancy, perinatal and longer term outcomes.

In the UK almost one in five women are obese when they become pregnant. Whilst many of these women will have quite normal pregnancies there is a greater than average risk that the mother and her baby will develop complications. Diabetes is the most common, and even when treated it can make the baby grow too large which leads to problems at delivery. Obese women are also more prone to a disorder known as pre-eclampsia which can be very serious, and often leads to doctors having to deliver the baby before its due date. At present we do not have a complete picture of what causes these and other problems. In this study we are going to measure some specific chemicals in the blood of obese pregnant women, which our previous studies suggest may be important for causing these complications. We are also going to use a new and very accurate laboratory technique, known as metabolomics, which provides an overview of 216 different measures, to try to identify other novel chemicals that are responsible. We shall find out how the levels of these chemicals in the blood are related to development of the different complications. When we understand more about these relationships we hope we shall be able to develop better tests and treatments. In this study, one of our aims is to develop tests in early pregnancy that will be accurate enough to tell us which obese women will not have any problems in pregnancy and which women doctors and midwives will need to give more attention to in order to ensure they have the best possible chance of a healthy pregnancy.

This research will be made possible by a large study of more than 1500 women, called UPBEAT. The aim of UPBEAT it to find out whether fewer complications occur when obese mothers are helped to improve their diet and engage in more physical activity. UPBEAT is taking place in more than ten hospitals in the UK and will finish in 2014. Half of the pregnant women get special dietary and physical activity advice from health trainers from early on in their pregnancy, and the other half have normal antenatal care. The participants are providing blood samples at different times during their pregnancy which we will use for this study; not only will these help us to find out about the causes of the complications but it will be very interesting to see whether the blood chemical profile in women who have been helped to change their lifestyle is better than women who have had normal care.

Lastly, it is currently thought that babies born to obese mothers are more likely to become obese in childhood than babies born to thinner mothers. This is because if babies are exposed in the very earliest stage of life, i.e. in the womb, to the altered blood chemical levels of their mothers, that they are permanently affected. They are then likely to put on more weight and become obese children and adults. We have been funded to measure the fatness of the three year old children of the UPBEAT mothers, as well as their diet and physical activity. This is called the UPBEAT TEMPO study. By combining UPBEAT and UPBEAT TEMPO we will have a unique opportunity to determine whether the levels of the chemicals in the mother's blood in pregnancy are related to the levels of fatness in the children. Even more important is that we will also be able to determine whether the children of the mothers who changed their lifestyle during pregnancy are thinner. If we find out that there are chemical links between obesity in the mother and the development of obesity in her child that will be a major step in helping us work out new ways of helping to prevent obesity in children.

The challenge of maternal pregnancy obesity and its associated complications of gestational diabetes (GDM), pre-eclampsia and fetal macrosomia dominates clinical obstetrics worldwide. Insulin resistance, dyslipidaemia, adipocyte and inflammatory mediated processes and vascular endothelial dysfunction are all implicated but in the absence of definitive causal pathways, development of targeted and validated interventions which improve clinical outcomes has yet to be achieved. Emerging evidence also suggests that fetal development is compromised, leading to persistently positive energy balance and childhood obesity.This study attempts to characterise the metabolic pathways leading to GDM, pre-eclampsia, small for gestational age and large for gestational age deliveries in obese pregnant women. We shall also interrogate associations between the metabolic environment in fetal life and childhood obesity. Our strategy includes measuring a portfolio of metabolic markers, previously implicated, as well as NMR metabolic profiling, a validated fast throughput technology (and suitable for NHS labs in due course) with state of the art computational bioinformatics facilitating reliable identification and quantification of molecular species.Once identified, metabolic markers associated with specific outcomes will be combined with clinical risk factors in early pregnancy to model predictive tools for these adverse outcomes which will be validated in an Australian cohort. Associations between maternal metabolic markers and offspring BMI and fat mass at 6 months and 3 years will also be evaluated.

This study is facilitated by samples and the database from UPBEAT study, a RCT of a complex intervention in 1546 obese pregnant women which combines dietary and physical activity advice to reduce GDM and fetal macrosomia. Follow up of the children at 3yrs is being undertaken in UPBEAT TEMPO, an EU funded study. These existing studies provide important added value to this project.

Beneficiaries other than the applicants' immediate professional circle

1. Pregnant women and their children
The ultimate beneficiaries will be obese pregnant women and their children. Through anticipated improvement in risk assessment and in intervention strategies, these women and their infants should benefit from improved health. Better understanding of the influence of obesity in the mother and the risk of obesity in the child could also lead to improved health of the child in later life. Since the risk assessment tools will be developed and validated within the third year of the project some of these impacts could be realised as little as one or two years after the end of the grant.

2. The NHS
Development of risk assessment tools in pregnancy is likely to reduce NHS costs. Following introduction into antenatal care, fewer women would attend high risk clinics (diabetes, maternal medicine, obesity clinics) and receive expensive and unnecessary interventions. If the tools lead to earlier and better targeted intervention health care costs related to adverse pregnancy outcomes e.g. fewer inpatient days for mother and infant could be achieved.

3. The Commercial Sector
The PIs have established links with commercial companies working in the global women's health sector. The KCL group work with Alere, a global health company with a focus on women's health, notably in biomarker studies for prediction and better diagnosis of pre-eclampsia, and also Hologic, in relation to biomarkers for preterm labour. Professor Poston collaborates, through the EU EarlyNutrition programme with Abbott Nutrition, and also with Danone. Professor Sattar advises SureSensor, a company with an interest in gestational diabetes. We will approach these and other companies during the early stages of the study, to facilitate rapid IP licensing and development of relevant platforms.

3. Policy makers
We shall continue to engage with policy makers. NHS local commissioners in South London, and NICE Public Health guideline teams are interested in the UPBEAT trial. Professor Nelson and Sattar work with the Scottish Government and Dr Catherine Calderwood, Senior Medical Officer for the Scottish Government is aware of UPBEAT and will be using the findings to inform devolved health policy in Scotland. All the applicants anticipate continued involvement in guideline development. To date these have included the NICE 2010 Pregnancy weight management Guideline, the NICE Fertility Guideline and NICE considerations of ethnic-specific BMI cut-offs, the UK consensus on HbA1c for diagnosis of diabetes and diabetes screening documents in Scotland.

Through our roles in the RCOG (Academic Committee, Research Committee, Chair of the Maternal Medicine Clinical Study Group, President of the Blair Bell Research Society, Chair Scientific Advisory Committee), we anticipate that the RCOG position will quickly reflect any new evidence produced.

3. The Charitable Sector and the Lay Public.
Professor Poston, the Tommy's Charity Professor in London, will work with the Charity to disseminate information to the general public through press releases and via their publications and midwifery phone help line. Professor Sattar will promote diabetes-related research from the project through Diabetes UK. We shall also disseminate information through APEC, a national charity with whom we work closely which supports women with, or who have had, pre-eclampsia.

4. The staff
This project presents a valuable training opportunity for the staff. These include the KCL post doctoral fellow who will benefit from skills acquisition through working with a large and unique dataset, and with excellent mentors and the statistician in Glasgow will be trained by Professor Ala-Korpela in state of the art NMR spectral analysis. All staff will benefit from working in a multidisciplinary team, including members of the EarlyNutrition programme and our collaborators.