Prenatal CRH: An integrating signal of fetal distress

Corticotropin-releasing hormone (CRH) is distributed throughout the brain and in peripheral sites but primarily is localized in the paraventricular nucleus of the hypothalamus. It is a "master" stress hormone that is responsible for the synthesis of proopiomelanocortin (POMC) in the anterior pituitary gland. Behaviorally active peptide hormones, including adrenocorticotropin hormone (ACTH) and B-endorphin, are liberated from POMC by enzymes to activate critical processes during stress. CRH is not detectable in the circulation even during extreme stress. However, during human pregnancy, the human placenta expresses the gene for CRH (pCRH) resulting in detectable levels in maternal plasma that increases 20- to 40-fold over the course of gestation. Placental CRH is identical to CRH of hypothalamic origin in size, structure, immunoreactivity, and bioactivity. However, unlike the negative feedback between adrenal cortisol and hypothalamic CRH, cortisol stimulates the synthesis and release of pCRH. The bidirectional release of pCRH into maternal and fetal compartments is associated with regulating the timing of delivery, remodeling the fetal nervous system, and influencing developmental trajectories. Fetal exposure to pCRH during early and late gestation is associated with unique patterns of cortical thinning in school-age children. Placental CRH is elevated in response to physical and behavioral stress and may be an integrative marker of early adversity

Developmental Origins of the Human Hypothalamic-Pituitary-Adrenal Axis

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

Prenatal Maternal Psychological Distress and Fetal Developmental Trajectories: Associations with Infant Temperament

Associations between prenatal maternal psychological distress and offspring developmental outcomes are well documented, yet relatively little research has examined links between maternal distress and development in utero, prior to postpartum influences. Fetal heart rate (FHR) parameters are established indices of central and autonomic nervous system maturation and function which demonstrate continuity with postnatal outcomes. This prospective, longitudinal study of 149 maternal–fetal pairs evaluated associations between prenatal maternal distress, FHR parameters, and dimensions of infant temperament. Women reported their symptoms of psychological distress at five prenatal visits, and FHR monitoring was conducted at the last three visits. Maternal report of infant temperament was collected at 3 and 6 months of age. Exposure to elevated prenatal maternal psychological distress was associated with higher late-gestation resting mean FHR (FHRM) among female but not male fetuses. Higher late-gestation FHRM was associated with lower infant orienting/regulation and with higher infant negative affectivity, and these associations did not differ by infant sex. A path analysis identified higher FHRM as one pathway by which elevated prenatal maternal distress was associated with lower orienting/regulation among female infants. Findings suggest that, for females, elevated maternal distress alters fetal development, with implications for postnatal function. Results also support the notion that, for both sexes, individual differences in regulation emerge prenatally and are maintained into infancy. Collectively, these findings underscore the utility of direct assessment of development in utero when examining if prenatal experiences are carried forward into postnatal life

Intra-Individual Consistency in Endocrine Profiles Across Successive Pregnancies

Context: It is yet unknown how similar women’s hormone levels are during successive pregnancies, and very little is known about the degree to which siblings experience similar prenatal environments. Given the importance of understanding how women’s reproductive life-histories exert cumulative effects on health via hormone exposure, and the importance of understanding how fetal programming via endocrine signaling affects sibling trait concordance, here we address this important lacuna in the literature. Objective: To investigate how consistent are women’s hormone profiles across two successive pregnancies. Design and Main Outcome Measures: This longitudinal, prospective study followed a cohort of 28 women across two pregnancies (PREG 1; PREG 2). Women’s circulating hormone levels were assessed from blood samples at 25, 31, and 37 weeks’ gestation for adrenocorticotropic hormone (ACTH), placental corticotropin-releasing hormone (pCRH), cortisol, estradiol, and progesterone. ACTH and cortisol levels were assessed 3-months postpartum. Research questions include: Are hormone levels in PREG 2 significantly different from levels in PREG 1?Whatproportion of variance in PREG 2 hormone levels is attributable to variance in PREG 1 levels? Are hormone levels more stable between PREG 1 and PREG 2 compared with postpartum phases following these pregnancies? Is pCRH, which is completely placentally derived, less similar than other hormones across successive pregnancies? Setting: Psychobiology laboratory. Participants: Pregnant women in California. Results and Conclusions: Comparisons of hormone concentrations across women’s successive pregnancies via paired t-test revealed substantial consistency from one pregnancy to another, with only significant differences between pregnancies for pCRH. Regressions revealed substantial predictability from one pregnancy to another, with between 17%–56% of PREG 2 variances accounted for by PREG 1 values. Women exhibited lower degrees of consistency and predictability in hormone levels across postpartum phases compared with gestational concentrations. This is the first study to describe maternal and placental hormone levels across successive pregnancies

DHEA: A Neglected Biological Signal That May Affect Fetal and Child Development

The stress-sensitive maternal hypothalamic–pituitary–adrenal (HPA) axis through the end-product cortisol, represents a primary pathway through which maternal experience shapes fetal development with long-term consequences for child neurodevelopment. However, there is another HPA axis end-product that has been widely ignored in the study of human pregnancy. The synthesis and release of dehydroepiandosterone (DHEA) is similar to cortisol, so it is a plausible, but neglected, biological signal that may influence fetal neurodevelopment. DHEA also may interact with cortisol to determine developmental outcomes. Surprisingly, there is virtually nothing known about human fetal exposure to prenatal maternal DHEA and offspring neurodevelopment. The current study examined, for the first time, the joint impact of fetal exposure to prenatal maternal DHEA and cortisol on infant emotional reactivity. Methods Participants were 124 mother–infant dyads. DHEA and cortisol were measured from maternal hair at 15 weeks (early gestation) and 35 weeks (late gestation). Observational assessments of positive and negative emotional reactivity were obtained in the laboratory when the infants were 6 months old. Pearson correlations were used to examine the associations between prenatal maternal cortisol, prenatal maternal DHEA, and infant positive and negative emotional reactivity. Moderation analyses were conducted to investigate whether DHEA might modify the association between cortisol and emotional reactivity. Results Higher levels of both early and late gestation maternal DHEA were linked to greater infant positive emotional reactivity. Elevated late gestation maternal cortisol was associated with greater negative emotional reactivity. Finally, the association between fetal cortisol exposure and infant emotional reactivity was only observed when DHEA was low. Conclusions These new observations indicate that DHEA is a potential maternal biological signal involved in prenatal programming. It appears to act both independently and jointly with cortisol to determine a child\u27s emotional reactivity. Its role as a primary end-product of the HPA axis, coupled with the newly documented associations with prenatal development shown here, strongly calls for the inclusion of DHEA in future investigations of fetal programming

A Longitudinal Study of Women’s Depression Symptom Profiles During and After the Postpartum Phase

Background An issue of critical importance for psychiatry and women\u27s health is whether postpartum depression (PPD) represents a unique condition. The Diagnostic and Statistical Manual of Mental Disorders asserts that major depressive disorder (MDD) may present with peripartum onset, without suggesting any other differences between MDD and PPD. The absence of any distinct features calls into question the nosologic validity of PPD as a diagnostic category. The present study investigates whether symptom profiles differ between PPD and depression occurring outside the postpartum phase. Methods In a prospective, longitudinal study of parturient women (N = 239), we examine the manifestation of depression symptoms. We assess factor structure of symptom profiles, and whether factors are differentially pronounced during and after the postpartum period. Results Factors were revealed representing: Worry, Emotional/Circadian/Energetic Dysregulation, Somatic/Cognitive, Appetite, Distress Display, and Anger symptoms. The factor structure was validated at postpartum and after‐postpartum timepoints. Interestingly, the Worry factor, comprising anxiety and guilt, was significantly more pronounced during the postpartum timepoint, and the Emotional/Circadian/Energetic Dysregulation factor, which contained sadness and anhedonia, was significantly less pronounced during the postpartum period. Conclusions These results suggest that PPD may be a unique syndrome, necessitating research, diagnosis, and treatment strategies distinct from those for MDD. Results indicate the possibility that Worry is an enhanced feature of PPD compared to depression outside the postpartum period, and the crucial role of sadness/anhedonia in MDD diagnosis may be less applicable to PPD diagnosis

Gestational Hormone Profiles Predict Human Maternal Behavior at 1-Year Postpartum

In many non-human species, including primates, gestational reproductive hormones play an essential role in the onset of maternal motivation and behaviors. We investigated the associations between prepartum estradiol and progesterone and maternal behavior at 1-year postpartum in 177 women. Blood was obtained at five gestational time points and an index of quality of maternal care was determined using a well-validated mother-child interaction protocol. Women who exhibited higher quality maternal care at 1-year postpartum were characterized by unique gestational profiles of estradiol, progesterone and the estrogen to progesterone ratio; specifically by slower accelerations and levels of these hormone trajectories beginning in midgestation. Further, it appeared that both fetal sex and parity moderated these findings, with first time mothers and mothers of females showing stronger associations. In sum, these data document persisting associations between prepartum hormone profiles and human maternal behavior. More broadly, these findings add to the growing literature highlighting the perinatal period as one of critical neurodevelopment in the lifespan of the human female