Antenatal maternal stress and long-term effects on child neurodevelopment: how and why?

Abstract

We review a significant body of evidence from independent prospective studies that if a mother is stressed while pregnant, her child is substantially more likely to have emotional or cognitive problems, including an increased risk of attentional deficit/hyperactivity, anxiety, and language delay. These findings are independent of effects due to maternal postnatal depression and anxiety. We still do not know what forms of anxiety or stress are most detrimental, but research suggests that the relationship with the partner can be important in this respect. The magnitude of these effects is clinically significant, as the attributable load of emotional/behavioral problems due to antenatal stress and/or anxiety is approximately 15%. Animal models suggest that activity of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis and its hormonal end-product cortisol are involved in these effects in both mother and offspring. The fetal environment can be altered if stress in the mother changes her hormonal profile, and in humans, there is a strong correlation between maternal and fetal cortisol levels. However, many problems remain in understanding the mechanisms involved in this interaction. For example, maternal cortisol responses to stress decline over the course of pregnancy, and earlier in pregnancy, the link between maternal and fetal cortisol is less robust. It is possible that the effects of maternal anxiety and stress on the developing fetus and child are moderated by other factors such as a maternal diet (e.g., protein load). It is suggested that extra vigilance or anxiety, readily distracted attention, or a hyper-responsive HPA axis may have been adaptive in a stressful environment during evolution, but exists today at the cost of vulnerability to neurodevelopmental disorders.

Figure 1

A model to show how antenatal stress may affect the function of the HPA axis, by a reduction in glucocorticoid receptors in the hippocampus, causing reduced negative feedback. The HPA axis is an elaborate system of checks and balances that, beyond the maintenance of a circadian rhythm, allows mammals to adapt to changes in their environment. The system is geared to respond rapidly to stressful stimuli, and then return to the baseline state of homeostasis. Under stimulatory conditions neurons in the paraventricular nucleus of the hypothalamus (PVN) secrete corticotropin releasing hormone (CRH) into the hypophyseal portal circulation. In the anterior pituitary, CRH induces production of adrenocorticotropin (ACTH), which is released into the systemic circulation to stimulate formation and release of glucocorticoids from the adrenal cortex (cortisol in human and corticosterone in rat). Elevated serum glucocorticoids provide the physiologic milieu required for an adaptive stress response, but also immediately begin to interact with corticoid receptors to inhibit the stress response via negative feedback. Deleterious consequences of chronic exposure to stress or high levels of glucocorticoids are well characterized, including structural damage to key brain regions such as the hippocampus. Therefore, the HPA axis needs to not only respond swiftly to stress, but to terminate the stress response equally rapidly. Two steroid receptors mediate HPA negative feedback in the brain. The glucocorticoid receptor (GR) demonstrates low affinity binding of glucocorticoids operates within the range of the stress response. The mineralocorticoid receptor (MR) has higher affinity to glucocorticoids and is vital in controlling basal HPA tone and the circadian rhythm. While the PVN expresses predominantly GR, both receptors are particularly enriched in hippocampus, which has been implicated in mediating the neuronal aspects of glucocorticoid feedback on the brain. Therefore, it is reasonable to assume that dysfunction in either receptor system could severely affect the ability of an animal to adapt to its environment. In the model of epigenetic effects of prenatal stress on the hippocampal glucocorticoid receptors in the child proposed in this review, prenatal stress causes increased methylation for the promoter region of the glucocorticoid receptor in the hippocampus. This results in less transcription, fewer receptors, less feedback control and a greater cortisol response to stress. These effects may be modified by maternal prenatal diet or immune status