Obesity and co-morbid hypertensive and diabetic disorders in pregnancy and early manifestations of neurodevelopmental adverity in the offspring: prediction and prevention of pre-eclampsia and intrauterine growth restriction (predo) study

The prevalence of women entering pregnancy with overweight and obesity is growing worldwide reaching epidemic proportions. Apart from the risks of maternal and fetal morbidity associated with overweight and obesity, excessive weight is also an essential risk factor for diabetic and hypertensive disorders occurring before and during pregnancy. Maternal obesity and co-morbid hypertensive and diabetic disorders affect fetal development and have been linked with compromised neurodevelopment of the offspring; however, previous findings are not entirely consistent. Further, due to high co-morbidity between maternal overweight/obesity and hypertensive and diabetic disorders, it is difficult to disentangle their individual effects on child neurodevelopment. In addition, the mechanisms underlying associations between maternal overweight/obesity and co-morbid disorders and child neurodevelopment remain elusive. This thesis examines the effects of maternal overweight/obesity and co-morbid hypertensive and diabetic disorders on early manifestations of neurodevelopmental adversity and on developmental delay in early childhood. It also examines whether DNA methylation (DNAm) biomarker of gestational age (GA) at birth reflects prenatal exposure to maternal overweight/obesity and co-morbid hypertensive and diabetic disorders, and hence, has a potential to identify individuals at risk for neurodevelopmental adversity already at birth. This thesis capitalizes on the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) birth cohort comprising 4777 women and their singleton children born in Finland between 2006 and 2010. Data on maternal early pregnancy BMI, pre-pregnancy and gestational hypertension, pre-eclampsia, type 1 diabetes and gestational diabetes mellitus (GDM) were derived from the Finnish Medical Birth Register (MBR). DNAm gestational age (DNAm GA) was calculated using the method based on the methylation profile of 148 selected cytosine-phosphate-guanine (CpG) sites on DNA. Regulatory behavior problems in infancy were measured using Neonatal Perception Inventory (NPI) at the infant’s mean age of 16.9 (SD=7.6) days. Developmental milestones were measured using Ages and Stages Questionnaire (ASQ) Third edition at the child’s mean age of 42.1 (SD=8.2) months. In comparison to the infants born to normal weight mothers, infants born to overweight/obese mothers displayed more regulatory behavior problems and were more likely to display regulatory behavior problems in multiple areas of self-regulation. These effects were independent of the co-morbid hypertensive and diabetic disorders (Study II). Children of overweight and obese mothers were more likely to display more severe and pervasive developmental delay in comparison to the children on normal weight mothers. The effects of maternal overweight and obesity on severity and pervasiveness of developmental delay in early childhood were also independent of the co-morbid hypertensive and diabetic disorders (Study III). Infant regulatory behavior problems partially mediated the association between maternal overweight/obesity and child neurodevelopmental milestones (Study II). Maternal pre-eclampsia was marginally associated with infant regulatory problems in multiple areas of self-regulation in normal weight non-diabetic women, but its effect was not significant in overweight/obese women and/or women with GDM (Study II). Maternal pre-eclampsia increased the odds of more severe and pervasive developmental delay in early childhood, and these effects were lower in the presence of overweight/obesity and diabetic disorders (Study III). GDM was not associated with infant regulatory behavior problems (Study II). The effect of GDM on severity and pervasiveness of developmental delay in early childhood was partially driven by maternal overweight/obesity and/or pre-eclampsia (Study III). Gestational and chronic hypertension were not associated with infant regulatory behavior problems and developmental delay(Studies II and III). Maternal BMI was not associated with variation in DNAm GA (Study IV). Maternal pre-eclampsia was associated with DNAm GA acceleration (Study IV). GDM in index pregnancy was not associated with variation in DNAm GA, however, insulin treated GDM in previous pregnancy was associated with DNAm GA deceleration (Study IV). These study findings suggest that maternal overweight and obesity affect child neurodevelopment independently of the co-morbid hypertensive and diabetic disorders, and that the trajectory of this effect can partially be traced from infant regulatory behavior problems to developmental delay in early childhood. Hence, infant regulatory behavior problems may represent an early manifestation of neurodevelopmental adversity due to prenatal exposure to maternal overweight/obesity. Pre-eclampsia increases the risk of developmental delay in early childhood independently of maternal overweight, obesity and diabetic disorders and its adverse effects on child neurodevelopment have a potential to be detected already at birth by assessing DNAm GA. Adverse effects of gestational diabetes on child neurodevelopment can be partially accounted for by highly co-morbid maternal overweight/ obesity and pre-eclampsia. Efforts aimed at weight management among women of reproductive age and prevention of pre-eclampsia during pregnancy are likely to reduce the burden of neurological morbidity in the future.