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Embryonic origins of cardiovascular health in later life: disentangling early causal pathways in a lifecourse perspective

Periodic Reporting for period 3 - EMBRYOandLATERHEALTH (Embryonic origins of cardiovascular health in later life: disentangling early causal pathways in a lifecourse perspective)

Reporting period: 2018-09-01 to 2020-02-29

Children born preterm or with a small size at birth have increased risks of cardiovascular disease and type 2 diabetes in adulthood. These intriguing associations strongly suggest that common diseases have at least part of their origins in early fetal life. From both an etiological and preventive perspective, it is important to disentangle the early fetal critical periods and causal pathways. An accumulating body of evidence suggests that early pregnancy, or even the preconception period, may influence the risk of cardiovascular and metabolic disease throughout the life course.

The main hypothesis for this project is that adverse exposures before or very early in pregnancy induce embryonic and placental developmental adaptations, which permanently affect cardiovascular and metabolic development and predispose individuals to both adverse outcomes at birth and cardiovascular and metabolic dysfunction and diseases in later life. The key objectives are: (1) To identify embryonic and early placentation developmental adaptations in response to preconception or early pregnancy exposures, and their associations with cardiovascular and metabolic adaptations in childhood; (2) To study cardiovascular and metabolic development and dysfunction from early fetal life to late childhood; (3) To identify persistent DNA-methylation changes in response to preconception or early pregnancy exposures, and their associations with cardiovascular and metabolic outcomes in childhood and adulthood.

This study will provide a new horizon for research into the Developmental Origins of Health and Disease. A specific focus on preconception period and early pregnancy exposures, with detailed repeated embryonic and early placentation measures, has not yet been perviously performed in population-based cohorts design. Ultimately, results will contribute to development of preventive strategies focused on future parents and children, to improve cardiovascular and metabolic health throughout the life course.

To increase societal impact and enable translation of findings to public health strategies, we have set up the Center for Pregnancy & Childhood. In this center, we discuss results with several scientists, public health workers, and policy makers. Also, the project coordinator is chair of the 10th World Congress of Developmental Origins of Health and Disease in Rotterdam the Netherlands (October 15-18th, 2017). Various results forthcoming from this project will be presented at this meeting.
Although the action is still in the first phase, it has already led to 40 scientific peer reviewed publications, including papers in Nature, JAMA, PLOS Medicine, Nature Genetics, and Nature Communications.

The new preconception cohort study, now referred to as the Generation R Next Study, has been approved by the Institutional Ethical Review Board. We have also set up the complex logistics in the city of Rotterdam, and developed the full study protocol. The start date of the study is now May/ June 2017. We have anticipated on a delay in starting by (1) enlarging the study area, which increases the number of eligible pregnant women by 50% and (2) including not only women before their conception but also in early pregnancy (< 8 weeks of gestation). These changes in recruitment (later start, larger area, wider gestational age period range) will NOT affect the total project, main expected results or needed overall budget.

We have completed the MRI scanning in children participating in the Generation R Study. In total, we were able to scan 3,000 children, more than expected. This larger group enables detection of smaller differences and more variation in relation to adverse exposures. Of these children, 1,100 children were born to mothers enrolled in first trimester of pregnancy. These measurements include right and left ventricular end-diastolic volume (RVEDV and LVEDV), right and left ventricular ejection fraction (RVEF and LVEF), left ventricular mass (LVM) and left ventricular mass-to-volume ratio (LMVR), pericardial fat, liver steatosis, and visceral abdominal fat. We have now related fetal and childhood socio-demographic, growth, nutritional factors (e.g. maternal obesity, breastfeeding) and genetic factors with these MRI outcomes (manuscripts submitted). We have also related these various exposures with growth and cardio-metabolic outcomes throughout childhood. Blood samples have been collected and are currently analyzed for metabolomics measurements, and insulin, glucose and lipid concentrations.

We have established successful collaborations with several cohorts to increase power for the main analyses. This collaboration, now established in the Pregnancy and Childhood Epigenetics (PACE) Consortium brings together 29 pregnancy and childhood cohorts, with in total more than 25,000 mothers and their children and measured DNA methylation at over 450,000 methylation sites (CpGs). We have started to analyze the associations of several adverse maternal and fetal exposures, including maternal smoking during pregnancy, folic acid supplement use and stress in relation to DNA-methylation changes. Current analyses are focused on the identification of DNA-methylation variants in relation to cardiovascular outcomes in children.
We have identified several common genetic and epigenetic variants that may explain part of the previously associations of fetal exposure and growth with diseases in adulthood. These findings include identification of 60 common genetic variants related to birth weight, suggesting a genetic basis for the associations of low birth weight with diseases in adulthood. We have also identified hundreds of CpGs methylation sites at birth that are associated with adverse fetal exposures. These findings give biological evidence of the epigenetic consequences of common adverse exposures in fetal life. The societal impact of these findings is great, because they underline the importance of strategies to improve health for pregnant women in order to give their offspring a better health throughout the life course.