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Effects of maternal gestational adiposity on fetal development and perinatal, postnatal and next generation health.

Periodic Reporting for period 4 - ObesityDevelop (Effects of maternal gestational adiposity on fetal development and perinatal, postnatal and next generation health.)

Reporting period: 2020-05-01 to 2021-07-31

The prevalence of pregnant women who are overweight or obese has increased and continues to do so. There are concerns that this will result in fetal over-nutrition and hence increased birth size, as well as greater adiposity across the life-course and potentially into the next generation. Whether observed associations are causal is unclear. This proposal addresses the issue of whether greater maternal gestational adiposity, and its associated exaggerated maternal gestational metabolomic responses causes increased offspring adiposity and cardio-metabolic risk from birth to early adulthood, and across two generations.

A healthy pregnancy and birth of a live healthy infants are fundamental to human existence and healthy societies. The obesity epidemic, and its impact on pregnant women, has led to higher body mass index (BMI) and more women being overweight and obese during pregnancy. It has been hypothesized that women who have higher BMI during pregnancy 'overfeed' the developing fetus, via exposure to higher levels of glucose, lipids and fatty acids, and that this fetal overgrowth will result in adverse perinatal outcomes and also higher risk levels of adiposity and cardiometabolic and cardiovascular risk in offspring throughout their lives. If this is true then it would result in a substantial health burden for individuals and society, with pressure on health services and the health of children and adult workers and greater care needed in older age. This would continue across generations as more adipose women will, via intrauterine mechanisms, have more adipose daughters, who will in turn go into their pregnancies with higher levels of adiposity. Establishing the likelihood of this is important for societal planning and prevention.

Our objective was to develop novel methods and compare results from different types of studies and different analytical methods to determine the effects of maternal pregnancy levels of adiposity and associated circulating nutrients on levels of adiposity and cardiometabolic health in offspring from birth through to early adulthood, and into the next generation.
We have shown widespread metabolomic change on becoming pregnant that returns to pre-pregnancy status after delivery. This is more extreme in obese pregnant women. Using RCT evidence we show that a lifestyle intervention can ameliorate adverse atherogenic lipid changes in obese pregnancy. We also find that South Asian women have a more marked glycaemia response to pregnancy than White European women, whilst White European women have a more dyslipidemia response.
By comparing results from different studies and analytical methods we have robustly demonstrated that higher maternal pregnancy BMI, circulating glucose, inflammatory markers and some amino acids increase fetal growth and birthweight. Traditional clinical chemistry measured lipids (total cholesterol, LDLc, HDLc, and triglycerides) did not appear t to influence birthweight, but exploratory results using a novel analysis method suggest that maternal total lipids in VLDL particles and in medium LDL particles causally increase birthweight. Using genetic variants related to metabolically favorable adiposity we demonstrate that in the absence of metabolic disruption, higher maternal adiposity does not result in fetal overgrowth, and indeed is related to lower mean birthweight.
Beyond the effects seen in infancy we did not find evidence of an effect of higher maternal BMI on offspring adiposity and cardiometabolic outcomes across childhood and into early adulthood. Whilst RCT evidence suggested randomized change to a healthier diet and physical activity, and consequent reduced maternal gestational weight gain, resulted in lower offspring birthweight and adiposity at 6-months, this was attenuated to the null by age 3-years.
In offspring whose mothers experienced gestational diabetes (GD) and those born large for gestational age, we have observed disrupted metabolism, with a more atherogenic profile, in childhood, adolescence and early adulthood. To explore this further, we have recently conducted the largest genome-wide association study to date (a trans-ethnic GWAS of 5,485 women with GD and 347,856 without), and identified Multiple lines of evidence pointed to genetic contributions to the shared pathophysiology of GD and type 2 diabetes. We are now under taking Mendelian randomization (MR) analyses of the effects of in utero exposure to GD on offspring future cardiovascular health.
In a UK three generation cohort, we have shown that the current generation of pregnant women have higher mean BMI and are more likely to be obese, than their mothers’ generation. We have further shown that the effect of maternal higher gestational BMI on offspring birthweight extends across generations, such that higher maternal grandmother BMI is related to higher offspring birthweight and length. Other transgenerational outcomes including of grandmaternal pregnancy BMI on lipids, fatty acids and blood pressure in infancy and early childhood are being explored .
We have engaged participants and the public in disseminating our findings. For example, through social and conventional media, running community scientific fairs, contributing to ‘a pint of science’, the Cheltenham Science festival and Einstein garden at the Greenman Festival
We have made progress beyond the state of the art in the following areas:

First study to characterize the impact of pregnancy on widespread metabolomic change and how this is influenced by obesity in pregnancy in large scale human epidemiological studies.
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. This work has highlighted the importance of identifying markers for early diagnosis of GD and has resulted in establishing two successful industry partnerships; one (Medtronic Ltd) to explore the potential for continuous glucose monitoring to screen for GD related fetal overgrowth, and the second (Roche Diagnostics) to explore the predictive ability of a novel biomarker.
Development of a framework for integrating evidence from several state-of-the-art novel causal methods (many of which we have developed) to answer complex causal questions. These methodological developments are transferable to other areas of research and relevant code and details are widely disseminated.
The integration of expertise and methods from social science, biology, epidemiology and clinical practice has moved the filed significantly beyond the state of the art. This has enabled causality to be clearly established for maternal adiposity and related metabolomic changes influencing fetal growth and birthweight, key outcomes for perinatal health.
We had anticipated that we would also find lasting causal effects into early adulthood. That our evidence to date does not suggest maternal higher pregnancy adiposity has a lasting effect on offspring cardio-metabolic or cardiovascular health is reassuring for parents and society. In on-going work we are cla
Graphic showing Maternal Gestational Favourable Adiposity does not result in fetal overgrowth