Causes of excess cortisol levels during pregnancy
While cortisol levels rise as gestation progresses, there are events that may occur during the pregnancy that elevate cortisol further. Many of the listed prenatal risk factors for ASD have the potential to alter cortisol levels either directly through stimulating the adrenocortical cells, the HPA axis, or indirectly through modulating 11β-HSD1 expression. Conditions that increase cortisol production during gestation are listed below. For example, activation of cortisol production is important for a role in host response during acute or chronic stressful events such as sepsis and viral infections [217]. Also inflammatory cytokines, such as the interleukins (IL-1, IL-6) and TNF-α acting at the pituitary and adrenocortical levels, stimulate cortisol formation [217]. In patients with rheumatoid arthritis, the cytokines TNF-α, IL-6 and IL-1 cause inflammation of the synovial joints [218], which would alter cortisol production in this cohort. Adenovirus and cytomegalovirus have been shown to sequester into the adrenocortical cells to stimulate cortisol production [219,220]. Iron deficiency has been reported to elevate cortisol levels in pregnant women through increased synthesis of CRH, resulting in increased risk of preterm labour, hypertension and pre-eclampsia [221]. Additionally, haemoglobin levels are inversely correlated with IL-6 levels [222]. Uncontrolled asthma is associated with reduced placental 11β-HSD2 activity, which significantly increases fetal cortisol levels [223]. Glucocorticoids are now the consensus treatment for preterm labour occurring between gestational weeks 24 and 34 in nearly one in ten pregnancies in the USA, to prevent the adverse consequences of respiratory distress syndrome [224]. Prenatal depression and psychological stress are associated with elevated cortisol levels, prematurity and low birth weights [225,226]. Increased waist circumference associated with advancing age, even in the absence of weight gain [227] and obesity, are associated with increased cortisol production [228,229].