title: Developmental origins of disease: Intra-uterine programming of offspring metabolic function and long-term markers of health
Creators: name: Simpson, Joy
Publisher: name: University of Glasgow
Year: 2021
Subjects: subject: cord blood, leptin, adiponectin, lipids, offspring, childhood, adolescent; adiposity, cardiometabolic disease, nonalcoholic fatty liver disease, tracking, diabetes; pre-eclampsia.

description: It is widely acknowledged that maternal obesity and metabolic disorder during pregnancy may trigger long-lasting cardiovascular dysfunction in the mother. In obese pregnancy, there is progressive insulin resistance and a systemic inflammatory end-organ structure and function. Emerging evidence suggests that the offspring may also be subject to these metabolic changes and endure these long-lasting effects. The ‘Developmental Origins of Health and Disease’ (DOHaD) model suggests that exposure to an abnormal environment in utero, such as in obese or diabetic pregnancy, may set a trajectory of greater offspring adiposity throughout the life-course. This is demonstrated by the fact that exposure to maternal adiposity during pregnancy is associated with higher offspring birthweight and greater adiposity through childhood and into adulthood. Offspring of mothers with diabetes or hypertensive disorders of pregnancy (HDP), such as pre-eclampsia (PE), may also adopt a greater risk of cardiovascular disease in later life. This cycle is then perpetuated when the affected offspring become pregnant and extend this exponential risk profile onto the next generation. Epigenetic modification has been proposed in the pathogenesis of disease but shared familial lifestyle and behaviours may also be causal. With the increasing prevalence of childhood obesity and metabolic disorders, such as non-alcoholic fatty liver disease (NAFLD), there is a greater need to examine these causal relationships and determinants of the fetal origins of disease. Adipokines have both endocrine and paracrine function and are secreted by adipose tissue, as well as the placenta. Leptin is required for the regulation of maternal appetite and despite high levels during pregnancy, pregnancy induces a state of leptin resistance. Leptin is also a valid biomarker of neonatal fat mass and may be used as a proxy for neonatal anthropometry. Adiponectin has an opposing function to leptin during pregnancy and correlates with fasting insulin levels. Low adiponectin amongst obese adults is associated with metabolic dysfunction and systemic insulin resistance. Using data from the large prospective cohort, The Avon Longitudinal Study of Parents and Children (ALSPAC), analysis of 5011 cord blood samples was performed for the purpose of this thesis. Offspring biomarkers and birthweight were examined in relation to obese, diabetic and hypertensive disordered pregnancy. Since biomarkers have shown evidence of tracking in later life, repeat measures at serial time points from birth (referred to as ‘like for like’ measures), using data available from the offspring at later time points, were also examined. Lastly, cord blood adipokines and birthweight were examined in relation to later obesity or development of NAFLD amongst the offspring to determine the impact of fetal over-nutrition, as demonstrated by higher cord blood leptin for example, on the long-term metabolic function of the offspring. This study has demonstrated that maternal body mass index (BMI), rather than appropriate GWG, was more consistently associated with a wider range of offspring cardio-metabolic markers at birth. Whilst there was limited evidence of GDM influencing cord blood at birth, offspring of mothers with pre-eclampsia displayed higher cord blood leptin and lipids. There was limited evidence of tracking of cord blood measures from birth into adolescence, however. Specifically, gamma-glutamyl transferase (GGT) and adiponectin correlated with repeat measures taken at birth and age 9. Whilst the association with adiponectin was lost in later childhood, this study has shown that GGT may track from birth to age 17. Lastly, this study has demonstrated that cord blood leptin was weakly, and adiponectin strongly related to adiposity in childhood and adolescence respectively. As cord blood leptin may be used as a reflection of fetal fat mass, the positive association with adiposity in later life demonstrates that the offspring may be ‘programmed’ at birth and set on a trajectory of enhanced adiposity in later life. Neither birthweight, nor adiposity at birth were related to offspring markers of liver structure or function in adolescence, however. This suggested that behavioural and environmental factors may have contributed to the pathogenesis of NAFLD, and similar disorders, rather than exposure to an adverse perinatal environment itself. In conclusion, this study has demonstrated a limited association between disordered metabolism in pregnancy and offspring metabolic markers at birth. Whilst cord blood biomarkers being used as clinical predictors of disease may be the focus of future research, they are already established biomarkers of neonatal anthropometry. Given the direction of the association between cord blood leptin and birthweight with later offspring adiposity, exposure to over-nutrition in pregnancy may therefore have a long-lasting impact on the offspring’s phenotype rather than the metabolic function itself.