Effect of maternal very severe obesity on maternal and offspring wellbeing and the influence of maternal glucocorticoids

Abstract

Globally one in five women are obese at antenatal booking, implying that many unborn infants are exposed to an obesogenic environment from very early in life. Obesity in pregnancy negatively affects both maternal and fetal health in the short and long-term, and remains a major public health burden. A meta-analysis demonstrated pregnant women with obesity are more likely to suffer from psychological distress, including symptoms of anxiety and depression, at prenatal and postpartum. This is of concern as prenatal exposure to psychological distress also has negative consequences on infant's future wellbeing. However, the interplay of psychological distress in very severely obese (SO, BMI > 40 kg/m2) pregnancies, and how both stressors interact in influencing the wellbeing of offspring, remains poorly characterised. Psychological distress is thought to dysregulate the maternal 'stress' axis, the hypothalamic-pituitaryadrenal (HPA) axis, during pregnancy, however less is known on how maternal obesity during pregnancy influence stress axis. Furthermore, it remains unclear how the biological changes induced by both maternal obesity and psychological distress are propagated by the placenta, which is the main conduit between mother and foetus during pregnancy. The work in this thesis tested the hypothesis that maternal obesity and psychological distress affect offspring wellbeing through increased maternal HPA axis activity and altered placental function, which increase the extent of glucocorticoid exposure to the developing foetus. The hypothesis was tested using a prospective casecontrol study cohort of 357 pregnancies with SO and lean controls (BMI < 25 kg/m2) in whom symptoms of anxiety and depression were evaluated during the antenatal and postnatal period, circulating glucocorticoid (serum Cortisol) were quantified across trimesters, placenta tissues were collected and stored for subsequent analyses, and children were followed up at 3 months and 3-5 years old. The key findings were that mothers with SO had higher symptoms of psychological distress both prenatal and postpartum than lean, and that the distress symptoms had adverse effects on their gestational weight gain and postpartum weight retention. This was not mediated by maternal Cortisol. Upon characterising the mRNA level profiles of genes constituting the placental glucocorticoid barrier, placentas of SO pregnancies were found to have an adaptive-protective profile towards excess maternal glucocorticoids. Further female fetuses appeared more vulnerable to psychological distress with potentially greater fetal glucocorticoid exposure. At 3-month follow-up, the levels of maternal psychological distress symptoms were associated with infants' higher weight and weight gain independent of maternal SO, implying that prenatal exposure to higher levels of psychological distress predispose infants to developing a risk factor for childhood obesity. At 3-5-year follow-up of 116 children (62 lean and 54 SO), there were significantly higher neuropsychiatric symptoms and poorer neurodevelopment in children born to SO pregnancies compared with lean, including higher symptoms of Attention Deficit and Hyperactivity Disorders (ADHD) and overall conduct, peerproblem and social difficulties, externalising behaviour, lower developmental milestones in problem-solving and lower executive functioning. Many of these associations, particularly externalising behaviour, were independent of maternal symptoms of psychological distress. Maternal prenatal metabolic markers (glucose, triglycerides, total cholesterol and Cortisol) were also linked to child's Cortisol profiles, and reduced circulating maternal Cortisol levels were associated with increased externalising behaviours independent of maternal SO. In conclusion, prenatal exposure to maternal obesity and psychological distress predispose offspring to higher risk of childhood obesity, neuropsychiatric and neurocognitive developmental problems.

Prenatal exposure to the adverse metabolic milieu associated with SO is likely to be one of the key in utero programming mechanisms of these predispositions, achieved either through the direct dysregulation of the child's HPA axis during development or indirectly through the adaptation of the placental glucocorticoid barrier.