It is widely assumed that glucocorticoids represent a primary mechanism through which exposure to adversity and maternal psychological distress shape prenatal developmental trajectories of both mother and fetus. However, despite repeated investigations and the fact that prenatal cortisol has been reliably linked to developmental outcomes, the empirical evidence supporting an association between prenatal cortisol and maternal distress is scarce. In this study, a novel approach to assessing links between maternal prenatal psychological distress and gestational cortisol profiles, general growth mixture modeling (GGMM), was applied. Method: Measures of pregnancy anxiety, perceived stress, and state anxiety and depressive symptoms as well as plasma samples (for determination of cortisol) were collected from 250 women 4 times during pregnancy. Results: Using GGMM, 3 cortisol trajectory groups were identified, including a typical group (n ϭ 199) that exhibited the expected steady increase in cortisol throughout gestation, a steep group (n ϭ 31) displaying an accelerated increase in cortisol over the course of pregnancy relative to the typical group, and a flat group (n ϭ 20) with relatively higher cortisol levels early in pregnancy that plateaued in midgestation. Women reporting the highest distress scores exhibited trajectories expected to be associated with the least optimal developmental outcomes (flatter trajectories characterized by relatively higher levels early in gestation and lower levels late in gestation). Conclusions: These findings suggest that psychological distress during pregnancy is associated with unique prenatal cortisol profiles and support further examination of this link, to enable continued evaluation of a plausible biological pathway by which maternal psychological distress programs fetal development.

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Introduction:The developmental origins of disease or fetal programming model predicts that intrauterine exposures have life-long consequences for physical and psychological health. Prenatal programming of the fetal hypothalamic-pituitary-adrenal (HPA) axis is proposed as a primary mechanism by which early experiences are linked to later disease risk.Areas covered: This review describes the development of the fetal HPA axis, which is determined by an intricately timed cascade of endocrine events during gestation and is regulated by an integrated maternal-placental-fetal steroidogenic unit. Mechanisms by which stress-induced elevations in hormones of maternal, fetal, or placental origin influence the structure and function of the emerging fetal HPA axis are discussed. Recent prospective studies documenting persisting associations between prenatal stress exposures and altered postnatal HPA axis function are summarized, with effects observed beginning in infancy into adulthood. Expert commentary:The results of these studies are synthesized, and potential moderating factors are discussed. Promising areas of further research highlighted include epigenetic mechanisms and interactions between pre and postnatal influences.CRH-producing neurons in paraventricular nucleus of the hypothalamus are innervated by afferent projections from multiple brain regions, including the brain stem, lamina terminalis, extra-PVN hypothalamic nuclei, and limbic structures, which respond to different physical and emotional stressors [29-31; see Figure 1]. CRH is secreted, along with argininevasopressin (AVP), into the hypophyseal portal blood, via axons projecting to the median eminence. CRH binds to its receptors on corticotropes of the anterior pituitary, stimulating production of the 31K dalton prohormone proopiomelanocortin (POMC). POMC is cleaved by enzymes into adrenocorticotrophic hormone (ACTH) and other bioactive peptides. ACTH enters the bloodstream and induces secretion of the glucocorticoid steroid hormone cortisol from the zona fasciculata of the adrenal cortex (see Figure 1). This cascade of hormone events mobilizes the body's physiological and psychological resources to cope with the stressor and maintain homeostasis.Circulating cortisol exerts its effects by binding to two types of receptors, the type I, highaffinity mineralocorticoid receptor (MR), and the type II, low-affinity glucocorticoid receptor (GR). Cortisol has a 10-fold higher affinity for MRs than for GRs, so at basal concentrations of cortisol, MRs are occupied and GRs remain largely unoccupied [32]. MRs are proposed to regulate the tonic actions of cortisol, including its normative diurnal rhythm and the sensitivity of the stress response, whereas GRs are increasingly occupied during periods of elevated cortisol in response to stress [10,[32][33][34]. The effects of stress-induced elevations in cortisol include activation and regulation of cardiovascular and immune systems, utilization of energy stores and gluconeogenesis, inhibition of feeding, reproductive, and...