Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - ObesityDevelop (Effects of maternal gestational adiposity on fetal development and perinatal, postnatal and next generation health.)

Teaser

What is the problem / issue being addressed?The obesity epidemic affects all people, consequently the prevalence of pregnant women who are overweight or obese has increased and there are concerns that this will result in increased pregnancy and perinatal complications and have...

Summary

What is the problem / issue being addressed?

The obesity epidemic affects all people, consequently the prevalence of pregnant women who are overweight or obese has increased and there are concerns that this will result in increased pregnancy and perinatal complications and have long-term adverse effects on the women\'s offspring and even grandchildren\'s future risk of obesity and adverse cardiometabolic health. Whilst maternal pregnancy adiposity is associated with adverse pregnancy, perinatal and offspring health, whether these associations are causal, and if they are the underlying (modifiable) mechanisms are unknown. Animal studies suggest that there might be transgenerational effects, such that maternal greater gestation adiposity adversely affects not just their immediate offspring but future generations; no studies to date have been able to explore this in humans. This proposal addresses these important gaps in current knowledge. That is, it addresses the issue of whether greater maternal gestational adiposity in humans causes adverse outcomes in pregnancy and \'programmes\' offspring, and future generations, to have poorer cardiometabolic health.

Why is it important for society?
A healthy pregnancy and birth of a live healthy infants are fundamental to human existence and to healthy societies. Up to 40% of pregnant women experience one or more pregnancy / perinatal complication (miscarriage, stillbirth, hypertensive disorder of pregnancy, gestational diabetes, preterm delivery, small or large for gestational age). The key causes underlying these, and hence how to prevent them, are poorly understood. Greater pre- or early-pregnancy adiposity are associated with many of these outcomes but whether these associations are causal, and if so their underlying mechanisms are unclear.

The obesity epidemic, and its impact on pregnant women, has also led to concerns that this could have adverse impacts on the whole of society through intrauterine mechanisms that \'programme\' offspring to be at risk of being more obese and having adverse cardiometabolic health throughout their lifecourse. If that is true it is further hypothesised that this will have transgenerational effects (offspring of more adipose pregnant women will have a greater risk of their children, importantly their daughters, being more adipose and have poor cardiometabolic health; those daughters will go into their pregnancies with greater adiposity and poor cardiometabolic health and hence similarly programme their offspring). If this is true then the obesity epidemic, and its adverse effects would take generations to halt and reverse. Whilst there is some animal model support for this developmental overnutrition hypothesis, whether it is causal in human populations and if so what the underlying mechanisms (that might be modifiable) are is currently unknown.

It is not possible to randomise pregnant women to being more or less adipose, and without good knowledge of the underlying metabolic consequences of greater adiposiy in pregnancy and their potential effects on outcomes, we cannot develop effective and safe interventions that might address the potential problems of greater adiposity in pregnancy.

What are the overall objectives?

The overall objectives of this project are to data from up to 100,000 participants from nine cohorts and two consortia to determine the effects of maternal pregnancy levels of adiposity and associated circulating nutrients on levels of adiposity and cardiometabolic health at three periods of the lifecourse:
(i) pregnancy and fetal development;
ii) infancy to adulthood and
(iii) in the next generation.

My proposed research is important because of how many women start pregnancy overweight/obese. It will provide a step-change in knowledge of how to prevent adverse outcomes across generations.

Work performed

So far we have shown the extent to which becoming pregnancy results in widespread metabolic change in unselected (health) pregnant women, that these changes in obese pregnant women are much more marked, but are modifiable by a lifestyle intervention that also resulted in less adiposity in infants at 6-months. We have also shown that maternal greater pregnancy BMI across the whole distribution causes greater birth weight and fatness, but does not appear to cause offspring later in life to be fatter or to have disrupted metabolism. We have also shown that fetuses of women who are diagnosed with gestational diabetes are already growing faster in early pregnancy; that is before the time in pregnancy when diagnostic tests are used to identify women with gestational diabetes. In on-going work we are looking at effects of more extreme exposures that mean BMI (such as gestational diabetes and metabolic disruption) and of ‘favourable adiposity’ with pregnancy and later offspring outcomes. We are also exploring the potential of continuous glucose monitoring in early pregnancy to identify early accelerated fetal growth, and have started to analyse next generation (grandchild) data.

Final results

We have made progress beyond the state of the art in the following areas:

First study to characterise the impact of pregnancy on widespread metabolomic change and how this is influenced by obesity in pregnancy in large scale human epidemiological studies. This has been made possible by the development of high throughput metabolomic profiling technologies, the University of Bristol (Host Institution) investment in these technologies and collaboration with an industry partner (Nightingale PLC).

Using repeat ultrasound scan assessments to model fetal growth from early pregnancy to delivery and explore the impact of maternal adiposity related phenotypes on this. Specifically, we have shown that maternal gestational diabetes and fasting and postload glucose on continuous scales influence fetal growth from early pregnancy (i.e. before the time - 26-28 weeks of gestation - when diagnostic tests for gestational diabetes are undertaken). This work highlights the importance of identifying methods for diagnosis hyperglycaemia / gestational diabetes earlier in pregnancy and has resulted in us establishing two successful industry partnerships; one (with Medtronic Ltd) to explore the potential for continuous glucose monitoring in early pregnancy to identify gestational glycaemia related fetal overgrowth and the second (with Roche Diagnostics) to explore a novel biomarker of theirs that has shown some validity with type 2 diabetes to predict gestational diabetes and fetal overgrowth.

Development of a framework for integrating evidence from several state-of-the-art novel causal methods (many of which we have developed) to address complex questions in humans using epidemiological data. These methods are essential to the applied questions that we are addressing in this proposal and to date have enabled us to identify that incremental differences in maternal BMI across its distribution have adverse effects on pregnancy and perinatal outcomes, but more extreme phenotypes (such as severe obesity, diabetes, or more widespread metabolic disruption) may be important for longer term offspring outcomes. These methodological developments are also transferable to other areas of research.

Expected results until the end of the project

We will use our state-of-the art methodologies to complete comprehensive assessments of the impact of maternal adiposity and associated metabolic disruptions on all pregnancy and perinatal outcomes. For this objective we have now extended our collaboration and have sufficient data to be able to explore relatively rare or difficult to determine but extremely important pregnancy loss outcomes (miscarriage and stillbirth).

Similarly, we will complete comprehensive assessment of the impact of maternal adiposity, associated metabolic disruptions and pregnancy and perinatal health on offspring adiposity and cardiometabolic risk factors and outcomes up to early adulthood. This work will be supported by very new and novel methods for using genetic instrumental variables (Mendelian randomization) to determine causal effects of intrauterine/pregnancy exposures in women on outcomes in their offspring. These methods have been developed by our collaborators at the University of Queensland, Australia (Dr Nicole Warrington and Prof David Evans).

For the third objective - determining effects of maternal adiposity, associated metabolic disruptions and pregnancy and perinatal health on the next generation (grandchildren), we have access to the unique Avon Longitudinal Study of Parents and Children - next generation study (ALSPAC-G2). This study is led by the PI of this ERC Advanced Grant. Recruitment and assessment of ALSPAC-G2 is not funded from this ERC grant but the data from it are essential to addressing this key objective. To date we have recruited 800 next generation and by the end of this ERC grant will have > 1000 on whom we will be able to assess the impact of their grandmother\'s pregnancy adiposity on their fetal and earl