Obesity in pregnancy—Long‐term effects on offspring hypothalamic‐pituitary‐adrenal axis and associations with placental cortisol metabolism: A systematic review

Abstract

Obesity, affecting one in three pregnant women worldwide, is not only a major obstetric risk factor. The resulting low‐grade inflammation may have a long‐term impact on the offspring's HPA axis through dysregulation of maternal, placental and fetal corticosteroid metabolism, and children born of obese mothers have increased risk of diabetes and cardiovascular disease. The long‐term effects of maternal obesity on offspring neurodevelopment are, however, undetermined and could depend on the specific effects on placental and fetal cortisol metabolism. This systematic review evaluates how maternal obesity affects placental cortisol metabolism and the offspring's HPA axis. Pubmed, Embase and Scopus were searched for original studies on maternal BMI, obesity, and cortisol metabolism and transfer. Fifteen studies were included after the screening of 4556 identified records. Studies were small with heterogeneous exposures and outcomes. Two studies found that maternal obesity reduced placental HSD11β2 activity. In one study, umbilical cord blood cortisol levels were affected by maternal BMI. In three studies, an altered cortisol response was consistently seen among offspring in childhood (n = 2) or adulthood (n = 1). Maternal BMI was not associated with placental HSD11β1 or HSD11β2 mRNA expression, or placental HSD11β2 methylation. In conclusion, high maternal BMI is associated with reduced placental HSD11β2 activity and a dampened cortisol level among offspring, but the data is sparse. Further investigations are needed to clarify whether the HPA axis is affected by prenatal factors including maternal obesity and investigate if adverse effects can be ameliorated by optimising the intrauterine environment.

Pregestational Prediabetes Induces Maternal Hypothalamic–Pituitary–Adrenal (HPA) Axis Dysregulation and Results in Adverse Foetal Outcomes

“…After birth, the HPA axis is able to regulate responses to adverse conditions, acting on the metabolism of carbohydrates, proteins and lipids, and participating in anti-inflammatory effects and suppression of the immune response [138,139]. A study found that maternal diabetes with high cortisol levels is linked to changes in the development of the brain's cortical, neuroendocrine system by reducing the number of hippocampal neurons [140]. This is accompanied by disruptions in the foetal HPA axis, resulting in structural changes such as cortical thinning, enlarged amygdala, and impaired development of the foetal cerebellum [141,142].…”

“…This is accompanied by disruptions in the foetal HPA axis, resulting in structural changes such as cortical thinning, enlarged amygdala, and impaired development of the foetal cerebellum [141,142]. The modifications in brain structures caused by cortisol have been consistently linked to impairments in both cognitive and emotional development, as well as basal high cortisol levels in children [140][141][142]. However, the exact molecular and cellular mechanism by which diabetes during pregnancy affects the development of the brain is still unknown [143].…”

A Review of Fetal Development in Pregnancies with Maternal Type 2 Diabetes Mellitus (T2DM)‐ Associated Hypothalamic‐Pituitary‐Adrenal (HPA) Axis Dysregulation: Exploring Links to Pregestational Prediabetes

“…It metabolises active glucocorticoids (cortisol in humans and corticosterone in rats) into inactive glucocorticoids, thereby shielding the fetus against excessive glucocorticoid exposure from the mother [106][107][108]. Although the placenta metabolises a significant proportion of cortisol (80-90% during gestation), excess cortisol may reach the fetus and the ʹbarrierʹ can be further weakened by maternal high maternal glucocorticoid or placental dysfunction, which is commonly caused by increased oxidative stress resulting in hypoxia, allowing increased transfer of glucocorticoids from mother to fetus [19,65,109]. The HPA axis dysregulation with elevated basal glucocorticoid has been investigated in type 2 diabetes mellitus (T2DM) similarly to maternal stress and adverse fetal outcomes in pregnancy [9][10][11].…”

A Review of Fetal Development in Pregnancies with Maternal Type 2 Diabetes Mellitus (T2DM)-Associated Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysregulation: Possible Links to Pregestational Prediabetes

“…It metabolizes active glucocorticoids (cortisol in humans, and corticosterone in rats) into inactive glucocorticoids, thereby shielding the fetus against excessive glucocorticoid exposure from the mother, as shown in ( Figure 1 ) [ 85 , 86 ]. Although the placenta metabolizes a significant proportion of cortisol (80–90% during gestation), excess cortisol may reach the fetus, and the ‘barrier’ can be further weakened by maternal high maternal glucocorticoid or placental dysfunction, which is commonly caused by increased oxidative stress, resulting in hypoxia, allowing for the increased transfer of glucocorticoids from the mother to the fetus [ 16 , 54 , 87 ]. The following section describes T2DM, prevalences, pregestational consequences associated with fetal programming, and associated diseases in adulthood.…”