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Due to the rapid developmental changes that occur during the fetal period, prenatal influences can affect the developing central nervous system with lifelong consequences for physical and mental health. Glucocorticoids are one of the proposed mechanisms by which fetal programing occurs. Glucocorticoids pass through the blood-brain barrier and target receptors throughout the central nervous system. Unlike endogenous glucocorticoids, synthetic glucocorticoids readily pass through the placental barrier to reach the developing fetus. The synthetic glucocorticoid, betamethasone, is routinely given prenatally to mothers at risk for preterm delivery. Over 25% of the fetuses exposed to betamethasone will be born at term. Few studies have examined the lasting consequences of antenatal treatment of betamethasone on the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. The purpose of this study is to examine whether antenatal exposure to betamethasone alters circadian cortisol regulation in children who were born full term. School-aged children prenatally treated with betamethasone and born at term (n=19, mean (SD)=8.1 (1.2) years old) were compared to children not treated with antenatal glucocorticoids (n=61, mean (SD)=8.2 (1.4) years old). To measure the circadian release of cortisol, saliva samples were collected at awakening; 30, 45, and 60min after awakening; and in the evening. Comparison children showed a typical diurnal cortisol pattern that peaked in the morning (the cortisol awakening response) and gradually decreased throughout the day. In contrast, children exposed to antenatal betamethasone lacked a cortisol awakening response and had a flatter diurnal slope (p's

Experimental animal models have demonstrated that one of the primary consequences of prenatal stress is increased fear and anxiety in the offspring. Few prospective human studies have evaluated the consequences of prenatal stress on anxiety during preadolescence. The purpose of this investigation is to determine the consequences of prenatal exposure to both maternal biological stress signals and psychological distress on anxiety in preadolescent children. Participants included 178 mother-child pairs. Maternal psychological distress (general anxiety, perceived stress, depression and pregnancy-specific anxiety) and biological stress signals were evaluated at 19, 25, and 31 gestational weeks. Anxiety was evaluated in the children at 6-9 years of age using the Child Behavior Checklist. Analyses revealed that prenatal exposure to elevated maternal cortisol, depression, perceived stress and pregnancy-specific anxiety was associated with increased anxiety in children. These associations remained after considering obstetric, sociodemographic and postnatal maternal psychological distress; factors that could influence child development. When all of the prenatal measures were considered together, cortisol and pregnancy-specific anxiety independently predicted child anxiety. Children exposed to elevated prenatal maternal cortisol and pregnancy-specific anxiety were at an increased risk for developing anxiety problems during the preadolescent period. This project identifies prenatal risk factors associated with lasting consequences for child mental health and raises the possibility that reducing maternal distress during the prenatal period will have long term benefits for child well-being.

Human life history schedules vary, partly, because of adaptive, plastic responses to early-life conditions. Little is known about how prenatal conditions relate to puberty timing. We hypothesized that fetal exposure to adversity may induce an adaptive response in offspring maturational tempo. In a longitudinal study of 253 mother-child dyads followed for 15 years, we investigated if fetal exposure to maternal psychological distress related to children's adrenarche and gonadarche schedules, assessed by maternal and child report and by dehydroepiandrosterone sulfate (DHEA-S), testosterone, and estradiol levels. We found fetal exposure to elevated maternal prenatal psychological distress predicted earlier adrenarche and higher DHEA-S levels in girls, especially first-born girls, and that associations remained after covarying indices of postnatal adversity. No associations were observed for boys or for gonadarche in girls. Adrenarche orchestrates the social-behavioral transition from juvenility to adulthood; therefore, significant findings for adrenarche, but not gonadarche, suggest that prenatal maternal distress instigates an adaptive strategy in which daughters have earlier social-behavioral maturation. The stronger effect in first-borns suggests that, in adverse conditions, it is in the mother's adaptive interest for her daughter to hasten social maturation, but not necessarily sexual maturation, because it would prolong the duration of the daughter allomothering younger siblings. We postulate a novel evolutionary framework that human mothers may calibrate the timing of first-born daughters' maturation in a way that optimizes their own reproductive success. • We assess how mothers' prenatal distress relates to their children's puberty timing. • Following 253 mother-child dyads for 15 years, we measured maturational processes. • Maternal prenatal distress predicted accelerated adrenal maturation in girls only. • Maternal distress may affect daughters' transition to an adult social-behavioral role. • We posit a new evolutionary framework for calibration of offspring maturational tempo. [ABSTRACT FROM AUTHOR]

Highlights • Maternal distress during pregnancy has been related to negative child outcomes. • Associations between maternal cortisol and psychological distress were examined. • Elevated maternal anxiety was associated with slightly lower awakening cortisol. • However, psychological variables explained no variance in diurnal cortisol levels. • The search for underlying mechanisms should be continued and extended. Abstract Background Maternal psychological distress during pregnancy is related to adverse child behavioral and emotional outcomes later in life, such as ADHD and anxiety/depression. The underlying mechanisms for this, however, are still largely unknown. The hypothalamic-pituitary-adrenal (HPA)-axis, with its most important effector hormone cortisol, has been proposed as a mechanism, but results have been inconsistent. The current study investigated the association between maternal psychological distress (i.e. anxiety and depressive symptoms) and maternal cortisol levels during pregnancy using a mixed models approach. Method During three pregnancy trimesters, mothers (N = 170) collected four salivary samples for two consecutive days. Mothers reported symptoms of anxiety and depression three times during pregnancy (at 13.3 ± 1.1, 20.2 ± 1.5, and 33.8 ± 1.5 weeks of pregnancy, respectively) using the anxiety subscale of the Symptom Checklist (SCL-90), the Spielberger State and Trait Anxiety Inventory (STAI), and the Edinburgh Postnatal Depression Scale (EPDS). Specific fears and worries during pregnancy were measured with the short version of the Pregnancy Related Anxiety Questionnaire (PRAQ-R). Results We found a significant effect of SCL-90 anxiety subscale on cortisol levels at awakening (p =.008), indicating that mothers with higher anxiety showed lower cortisol at awakening. Maternal psychological variables explained 10.5% of the variance at the person level in awakening cortisol level, but none in the overall diurnal cortisol model. Conclusion More research is necessary to unravel the underlying mechanisms of the association between maternal psychological distress and cortisol and the search for mechanisms other than the HPA-axis should be continued and extended. [ABSTRACT FROM AUTHOR]

Prenatal environment reportedly affects the programming of developmental trajectories in offspring and the modification of risks for later morbidity. Among the increasingly studied prenatal exposures are maternal psychological distress (PD) and altered maternal hypothalamus-pituitary-adrenal (HPA) axis functioning. Both prenatal PD and maternal short-term cortisol concentrations as markers for HPA axis activity have been linked to adverse child outcomes and it has been assumed that maternal PD affects the offspring partially via altered cortisol secretion patterns. Yet, the existing literature on the interrelations between these two measures is conflicting. The assessment of cortisol levels by using hair cortisol concentration (HCC) has gained interest, as it offers a way to assess long-term cortisol levels with a single non-invasive sampling. According to our review, 6 studies assessing the associations between maternal HCC during pregnancy and various types of maternal PD have been published so far. Measures of prenatal PD range from maternal symptoms of depression or anxiety to stress related to person’s life situation or pregnancy. The aim of this systematic review is to critically evaluate the potential of HCC as a biomarker for maternal PD during pregnancy. We conclude that HCC appears to be inconsistently associated with self-reported symptoms of prenatal PD, especially in the range of mild to moderate symptom levels. Self-reports on PD usually cover short time periods and they seem to depict partly different phenomena than HCC. Thus, methodological aspects are in a key role in future studies evaluating the interconnections across different types of prenatal PD and maternal HPA axis functioning. Further, studies including repetitive measurements of both HCC and PD during the prenatal period are needed, as timing of the assessments is one important source of variation among current studies. The significance of prenatal HCC in the context of offspring outcomes needs to be further investigated. [ABSTRACT FROM AUTHOR]

Purpose Fetal programming is the idea that environmental stimuli can alter the development of the fetus, which may have a long-term effect on the child. We have recently reported that maternal prenatal cortisol predicts infant negative emotionality in a sex-dependent manner: high prenatal cortisol was associated with increased negative emotionality in females, and decreased negative emotionality in males. This study aims to test for this sex-specific effect in a different cohort, and investigate whether sex differences in fetal programming may be specific to glucocorticoid mechanisms by also examining a maternal salivary alpha-amylase (sAA) by sex interaction. Methods 88 pregnant women (mean gestational age = 27.4 weeks, SD = 7.4) collected saliva samples at home over two working days to be assayed for the hormone cortisol (range = 0.13–88.22 nmol/l) and the enzyme alpha-amylase (range = 4.57–554.8 units/ml). Samples were collected at waking, 30-min post-waking and 12 h post-waking. Two months after birth participants reported infant negative emotionality using the distress to limits subscale of the Infant Behavior Questionnaire. Results The interaction between maternal prenatal cortisol and infant sex to predict distress to limits approached significance (p = 0.067). In line with our previous finding there was a positive association between prenatal cortisol and negative emotionality in females, and a negative association in males. The interaction between sAA and sex to predict distress was significant (p = 0.025), and the direction of effect was the same as for the cortisol data; high sAA associated with increased negative emotionality in females and reduced negative emotionality in males. Conclusions In line with our previous findings, this research adds to an emerging body of literature, which suggests that fetal programming mechanisms may be sex-dependent. This is the first study to demonstrate that maternal prenatal sAA may be an important biomarker for infant behavior, and the findings have implications for understanding sex differences in developmental psychopathology. [ABSTRACT FROM AUTHOR]

Background Psychosocial stress during pregnancy has been proposed as a major contributor of glucocorticoid-mediated programming of the fetal hypothalamic-pituitary adrenal (HPA) axis, with later adverse health consequences. However, evidence linking maternal stress to maternal cortisol values during pregnancy is inconclusive. A possible explanation for this is that other maternal factors overshadow any potential effects of stress on cortisol levels. We studied a large cohort of pregnant women with extensive data on pregnancy characteristics to determine the respective contributions of biological, environmental and psychosocial stress factors to cortisol levels in pregnancy. Methods We used data from 3039 women from the Amsterdam Born Children and their Development-study cohort. Serum cortisol was measured in blood, collected at the first prenatal visit, at different gestational ages (median = 91 days, range = 40–256 days), and at various time points during the day (median = 11:45 h, range = 08:00–18:30 h). We assessed associations between maternal serum cortisol in pregnancy and biological factors, lifestyle factors and stress factors, including depression, anxiety, pregnancy-related anxiety, work stress, parenting stress and fatigue. Results In multivariable analysis, variables that were associated with higher cortisol levels in pregnancy were lower maternal age [1.5 nmol/l, 95%CI (0.6–2.4)], being nulliparous [21.5 nmol/l (15.9–27.1)], lower pre-pregnancy body mass index (BMI) [1.3 nmol/l (0.3–2.4)], higher C-reactive protein (CRP) [1.0 nmol/l (0.4–1.5)], carrying a female fetus [9.2 nmol/l (1.8–16.5)], non-smoking [14.2 nmol/l (0.6–27.7)], sufficient sleep [8.5 nmol/l (0.9–16.1)], and being unemployed [12.7 nmol/l (2.2–23.2)]. None of the psychosocial stressors was significantly associated with serum cortisol levels in pregnancy. A total of 32% of all variance in cortisol was explained by gestational age, maternal age, time of day, parity, pre-pregnancy BMI, CRP, fetal sex, smoking behavior, self-reported sleep sufficiency, and employment. Conclusions Our data suggest that maternal cortisol during pregnancy is mainly affected by biological and lifestyle factors, but not by psychosocial factors. We suggest that psychosocial stress in pregnancy might program the fetus through other mechanisms than through altering maternal cortisol levels. [ABSTRACT FROM AUTHOR]

Objective Fetal exposure to maternal prenatal stress hormones such as cortisol exerts influences on the developing nervous system that persist and include risk for internalizing symptoms later in life. Placental corticotropin-releasing hormone (pCRH) is a feto-placental stress signal that also shapes fetal neurodevelopment and may be a more direct indicator of the fetal experience than maternal stress hormones. The programming effects of pCRH on child development are unknown. The current investigation examined associations between prenatal maternal and placental stress hormone exposures (maternal cortisol and pCRH) and child self-reported internalizing symptoms at age 5. Method Maternal plasma cortisol and pCRH levels were measured at 15, 19, 25, 31, and 36 weeks’ gestation in a sample of 83 women and their 91 children (8 sibling pairs from separate pregnancies), who were born full-term. Child self-reported internalizing symptoms at age 5 were obtained using scales of the Berkeley Puppet Interview. Results Placental CRH profiles (including elevations in mid-gestation) were associated with higher levels of internalizing symptoms at age 5. This effect was not explained by critical prenatal or postnatal influences, including obstetric risk, concurrent maternal psychological state, and family socio-economic status. Prenatal maternal cortisol was not significantly associated with child self-reported internalizing symptoms. Conclusions Findings suggest that elevated exposures to the feto-placental stress signal pCRH exert programming effects on the developing fetal central nervous system, with lasting consequences for child mental health. [ABSTRACT FROM AUTHOR]

The long-term consequences of exposure to excess stress, particularly during sensitive developmental windows, on the initiation and progression of many complex, common physical and mental disorders that confer a major global burden of disease are well established. The period of intrauterine life represents among the most sensitive of these windows, at which time the effects of stress may be transmitted inter-generationally from a mother to her as-yet-unborn child. As explicated by the concept of fetal or developmental programming of health and disease susceptibility, a growing body of evidence supports the notion that health and disease susceptibility is determined by the dynamic interplay between genetic makeup and environment, particularly during intrauterine and early postnatal life. Except in extreme cases, an adverse intrauterine exposure may not, per se , ‘cause’ disease, but, instead, may determine propensity for disease(s) in later life (by shaping phenotypic responsivity to endogenous and exogenous disease-related risk conditions). Accumulating evidence suggests that maternal psychological and social stress during pregnancy represents one such condition that may adversely affect the developing child, with important implications for a diverse range of physical and mental health outcomes. In this paper we review primarily our own contributions to the field of maternal stress during pregnancy and child mental and physical health-related outcomes. We present findings on stress-related maternal-placental-fetal endocrine and immune/inflammatory processes that may mediate the effects of various adverse conditions during pregnancy on the developing human embryo and fetus. We enunciate conceptual and methodological issues related to the assessment of stress during pregnancy and discuss potential mechanisms of intergenerational transmission of the effects of stress. Lastly, we describe on-going research and some future directions of our program. [ABSTRACT FROM AUTHOR]

Summary Objective Childhood obesity affects nearly 17% of children and adolescents in the United States. Increasing evidence indicates that prenatal maternal stress signals influence fetal growth, child obesity, and metabolic risk. Children exhibiting catch-up growth, a rapid and dramatic increase in body size, within the first two years of life are also at an increased risk for developing metabolic disorder and obesity. We evaluate the potential role of the maternal hypothalamic-pituitary-adrenal (HPA) and placental axis in programming risk for child obesity. Method This prospective longitudinal study measured placental corticotropin-releasing hormone (pCRH) and maternal plasma cortisol at 15, 19, 25, 30, and 37 gestational weeks and collected child body mass index (BMI) at birth, 3, 6, 12, and 24 months. Participants included 246 mothers and their healthy children born full term. Each child's BMI percentile (BMIP) was determined using World Health Organization (WHO) standards based on age and sex. Child BMIP profiles from birth to two years of age were characterized using general growth mixture modeling (GGMM). We evaluated whether fetal exposure to placental CRH and maternal cortisol are associated with BMIP profiles. Results Placental CRH at 30 gestational weeks was highly associated with both BMIP ( p < .05) and weight ( p < .05) at birth when accounting for gestational age at birth and used as a predictor in modeling BMIP profiles. Maternal cortisol was not associated with child BMIP. GGMM analyses identified four distinct BMIP profiles: typical, rapid increase, delayed increase, and decreasing (See Fig. 2). The typical profile comprised the majority of the sample and maintained BMIP across the first two years. The rapid and delayed increase profiles each exhibit a period of reduced body size followed by BMI catch-up growth. The rapid increase profile exhibited catch-up within the first 12 months while the delayed group showed an initial decrease in BMIP at 3 months and a dramatic increase from 12 to 24 months. The decreasing profile exhibited normal birth weight and BMIP followed by persisting, low BMIP. The members of the rapid and delayed increase profiles were exposed to the highest concentrations of placental CRH at 30 gestational weeks compared to those in the typical profile group (Fig. 3). Conclusions Exposure to elevated placental CRH concentrations during the third trimester is associated with catch-up growth. An early period of small body size followed by rapid catch-up growth is a profile associated with increased metabolic risk and increased obesity risk. Our findings suggest that placental CRH exposure makes a unique contribution to fetal programming of obesity risk. [ABSTRACT FROM AUTHOR]

Glucocorticoid use is prevalent in pregnant women, but whether in utero exposure impacts mental health in the offspring has not been fully explored. The aim of this study was to investigate if in utero exposure to synthetic glucocorticoids increases the risk of anxiety and depression in childhood or adolescence. The study was conducted as a nationwide cohort study, including negative control exposure analyses and a sibling design to optimize control of confounding. The study population comprised 1,275,909 children born in 1996–2015 in Denmark (median follow-up of 13 years). Exposure was divided into systemic and local glucocorticoid exposure, levels of cumulative dose, generic type and according to trimester of exposure. The comparison cohort was children without exposure born to maternal never-users. Negative control exposures included children without glucocorticoid exposure born to: maternal users of non-steroidal anti-inflammatory drugs or immunotherapy during pregnancy, maternal former users of systemic glucocorticoids, maternal users of systemic glucocorticoids in the postnatal period, and fathers who were prescribed glucocorticoids. The sibling design compared siblings with and without exposure. 9307 (0.7%) children were exposed to systemic glucocorticoids and 116,389 (9.1%) children were exposed to local glucocorticoids. High-dose systemic glucocorticoids (≥500 mg prednisolone equivalents) increased the risk of anxiety compared to the comparison cohort [aIRR 1.79 (95% CI: 1.36–2.37), cumulative risk 16% vs. 7.8% by age 20]. A similar result was found for depression [aIRR 1.45 (95% CI: 0.80–2.63), cumulative risk 3.6% vs. 2.6% by age 20]. The association with anxiety was consistent in the sibling design [aIRR 1.83 (95% CI: 1.03–3.66), exposed siblings (≥ 500 mg) vs. unexposed]. Sex did not modify the associations. Negative control exposure analyses indicated robustness towards confounding from genetics and family environment. No association was found with low doses of systemic exposure or local use. In conclusion, potential adverse mental health effects of in utero exposure to high-dose glucocorticoids merit clinical attention. • In utero glucocorticoid environment might program the fetal hypothalamic-pituitary-adrenal axis. • Altered sensitivity of this endocrine axis is linked to anxiety and depression. • In utero exposure to high-dose systemic glucocorticoids increased the risk of later anxiety. • In utero exposure to local glucocorticoids and low systemic doses did not affect the risk. [ABSTRACT FROM AUTHOR]

Summary During gestation, development proceeds at a pace that is unmatched by any other stage of the life cycle. For these reasons the human fetus is particularly susceptible not only to organizing influences, but also to pathogenic disorganizing influences. Growing evidence suggests that exposure to prenatal adversity leads to neurological changes that underlie lifetime risks for mental illness. Beginning early in gestation, males and females show differential developmental trajectories and responses to stress. It is likely that sex-dependent organization of neural circuits during the fetal period influences differential vulnerability to mental health problems. We consider in this review evidence that sexually dimorphic responses to early life stress are linked to two developmental disorders: affective problems (greater female prevalence) and autism spectrum disorder (greater male prevalence). Recent prospective studies illustrating the neurodevelopmental consequences of fetal exposure to stress and stress hormones for males and females are considered here. Plausible biological mechanisms including the role of the sexually differentiated placenta are discussed. [ABSTRACT FROM AUTHOR]

The etiology of child and adolescent anxiety remains poorly understood. Although several previous studies have examined associations between prenatal maternal psychological functioning and infant and child health outcomes, less is known about the impact of maternal anxiety specific to pregnancy and cortisol during pregnancy on childhood anxiety outcomes. Participants included 496 mother-child pairs from the PROGRESS longitudinal birth cohort in Mexico City. Anxiety symptoms were assessed at age 8–11 years during 2018–2019 using the Revised Children's Manifest Anxiety Scale. Pregnancy-specific anxiety was assessed using an expanded version of the Pregnancy Anxiety Scale. Maternal biological stress response during pregnancy was assessed using salivary cortisol measures (area under the curve, cortisol awakening response, and diurnal slope). Linear regression models were used to estimate associations between maternal anxiety and cortisol in relation to continuous child anxiety symptom T-scores. Models were adjusted for maternal age, socioeconomic status, child sex and age, and gestational age at saliva collection. We found that higher levels of pregnancy-specific anxiety in the mother were associated with higher anxiety symptoms in the child (β: 1.30, 95% CI: 0.19, 2.41). We additionally observed an association between higher maternal total cortisol output during pregnancy and higher anxiety symptoms in the child (β: 1.13, 95% CI: 0.25, 2.01). These findings highlight the importance of screening for maternal pregnancy-specific anxiety and the need to identify interventions and support for mothers during pregnancy in order to promote healthy outcomes for mothers and their children. • The etiology of child and adolescent anxiety remains poorly understood. • We studied impacts of maternal cortisol and anxiety on offspring anxiety symptoms. • Maternal pregnancy-specific anxiety was associated with anxiety in the child. • Higher maternal prenatal cortisol was related to greater childhood anxiety symptoms. • These findings highlight the importance of screening for pregnancy-specific anxiety. [ABSTRACT FROM AUTHOR]

Summary: Maternal stress during pregnancy has pervasive effects on the offspring''s physiology and behavior, including the development of anxious, reactive temperament and increased stress responsivity. These outcomes can be seen as the result of adaptive developmental plasticity: maternal stress hormones carry useful information about the state of the external world, which can be used by the developing fetus to match its phenotype to the predicted environment. This account, however, neglects the inherent conflict of interest between mother and fetus about the outcomes of fetal programming. The aim of this paper is to extend the adaptive model of prenatal stress by framing mother-fetus interactions in an evolutionary conflict perspective. In the paper, I show how a conflict perspective provides many new insights in the functions and mechanisms of fetal programming, with particular emphasis on human pregnancy. I then take advantage of those insights to make sense of some puzzling features of maternal and fetal physiology and generate novel empirical predictions. [Copyright &y& Elsevier]

Summary: Background: Raised maternal anxiety during pregnancy is associated with increased risk of adverse neurodevelopmental outcomes for her child. The mechanisms underlying this are not known but animal studies suggest prenatal stress may alter the function of the placenta. Here we determined whether maternal prenatal anxiety was associated with a downregulation of placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), the enzyme which metabolises cortisol. Methods: We recruited mothers the day before delivery by elective caesarean, and gave them the Spielberger Trait and State anxiety and Edinburgh Depression self-rating scales. Placentae were collected and aliquots stored for later analysis. Results: Prenatal Trait anxiety was negatively correlated with placental 11β-HSD2 mRNA expression (r =−0.40, p <0.01, n =56). Results were similar with male and female fetuses (r =−0.39, p =0.04, n =28; r =−0.40, p =0.03, n =28) respectively. Results were also significant with State anxiety (r =−0.27, p =0.05, n =56) but somewhat weaker for depression (r =−0.20, p =0.13, n =56). Preliminary analyses on a subset of cases (n =25) suggested parallel results for enzyme activity. Conclusions: These findings provide evidence for an association between prenatal maternal mood and downregulation of placental 11β-HSD2. Results are consistent with raised maternal anxiety being associated with increased fetal exposure to maternal cortisol, and support the hypothesis that this may be one mechanism underlying fetal programming by prenatal stress. [Copyright &y& Elsevier]

One of the key proposed agents of fetal programming is exposure to maternal glucocorticoids. Experimental animal studies provide evidence that prenatal exposure to elevated maternal glucocorticoids has consequences for hypothalamic–pituitary–adrenal (HPA) axis functioning in the offspring. There are very few direct tests of maternal glucocorticoids, such as cortisol, during human pregnancy and associations with infant cortisol reactivity. The current study examined the link between maternal prenatal cortisol trajectories and infant cortisol reactivity to the pain of inoculation in a sample of 152 mother-infant (47.4% girls) pairs. The results from the current study provide insight into fetal programming of the infant HPA axis, demonstrating that elevated prenatal maternal cortisol is associated with a larger infant cortisol response to challenge at both 6 and 12 months of age. • Prenatal maternal salivary cortisol increases from 15 to 37 weeks' gestation. • Infant inoculation at 6 and 12 months elicits a cortisol response. • Maternal prenatal cortisol was linked to greater infant cortisol response to pain. [ABSTRACT FROM AUTHOR]

• Maternal prenatal distress associated with infant cortisol stress response differently by sex. • Both saliva cortisol reactivity and recovery during an acute stressor were analyzed. • Maternal prenatal distress linked with decreased reactivity and recovery in females. • The combined depressive and anxiety symptom score provided the most robust findings. Previous research suggests that maternal prenatal psychological distress (PPD) is related to altered cortisol reactivity in the exposed child. There are indications for the sex differences in vulnerability for prenatal adversities that depend on the exposure and child outcome. Still, it is not known whether the association between maternal PPD and infant cortisol stress response is moderated by sex. In addition, the recovery phase of the cortisol stress response has not been given as much attention as reactivity. Our aim was to study the sex differences in the associations between self-reported maternal prenatal depressive-, anxiety- and pregnancy-related anxiety symptoms through gestational weeks 14, 24 and 34 and the saliva cortisol reactivity to and recovery from the acute stress among 10-week-old infants. The study population comprised of 363 mother-infant pairs from the FinnBrain Birth Cohort Study. We found evidence for sex-dependent associations between PPD exposure and infant cortisol response. A less steep recovery slope (-10 % per one SD increase in PPD [95 % CI = -18 to -2 %] and -8 % [-16 to 0 %] depending on the exposure) and a possibly less steep reactivity slope (-14 % [95 % CI = -25 to 0 %] and -10 % [-21 to 3 %]) were associated with higher PPD exposure in females. Of the PPD measures, the strongly intercorrelated, and thus combined, depressive and anxiety symptom score provided the most robust prediction of infant cortisol recovery. Our results demonstrate sexually dimorphic alterations in the functioning of the infant hypothalamus-pituitary-adrenal axis and especially in the functioning of the negative feedback loop of the axis after prenatal PPD exposure among healthy babies. [ABSTRACT FROM AUTHOR]

• Alcohol around conception increased immobility in offspring in the forced swim test. • Female offspring exposed to alcohol around conception increased affiliative behavior. • Alcohol around conception caused hyperactivity of the hypothalamic-pituitary-adrenal axis. • Periconceptional alcohol may contribute to depression and mental illness. Alcohol consumption throughout pregnancy has been associated with mental illness, hyperactivity and social difficulties in offspring. This may be due in part to programmed disruption of the hypothalamic-pituitary-adrenal axis (HPA) activity and responsiveness. However, it is unknown if the HPA is affected and similar behavioural outcomes occur following alcohol exposure limited to the time around conception, the periconceptional (PC) period. Female Sprague-Dawley rats were treated with PC:EtOH (12.5 % v/v EtOH liquid diet) or a control diet from four days before conception, until embryonic day 4. Offspring at 3-months of age underwent the forced swim test (FST) and social interaction test. HPA reactivity tests (combined dexamethasone suppression test (DST) and corticotropin-releasing hormone test (CST), 30-minute restraint stress) were performed at 5 months of age and then pituitary and adrenal glands were collected for expression of genes involved in HPA regulation. PC:EtOH exposure significantly increased immobility (p < 0.05) in both sexes in the FST. PC:EtOH also increased the duration of affiliative behaviour (p < 0.05) within the social interaction test in female offspring. PC:EtOH programmed HPA hyperactivity in both sexes during the DST/CST test (p < 0.05); however, there was no impact of PC:EtOH on plasma corticosterone concentration in response to restraint stress. There was no significant impact of PC:EtOH on mRNA expression in glucocorticoid signalling genes in the pituitary gland or the steroidogenic pathway in the adrenal gland. This study suggests that alcohol exposure, even when limited to a short period around conception, can program mental illness-like phenotypes, and this was associated with alterations in HPA responsiveness. This study further highlights that consumption of alcohol even prior to implantation may impact the long-term health of offspring. [ABSTRACT FROM AUTHOR]

• Maternal prenatal stress during individual points not related to offspring hair cortisol. • Maternal stress increases from second to third trimester then decreases. • Increases in maternal prenatal stress predicts higher child hair cortisol. • Girls and children of African American mothers exhibit higher hair cortisol. Maternal stress during pregnancy can influence the trajectory of fetal development, shaping offspring physiology and health in enduring ways. Some research implicates fetal programming of the hypothalamic-pituitary-adrenocortical (HPA) axis as a mediator of these effects. The present study is the first to examine child hair cortisol concentration (HCC) and maternal stress during pregnancy in a diverse, low-income sample. The sample consisted of 77 healthy, low-income (M annual income: $13,321), mother-children pairs (M child age = 3.81 years, SD = 0.43). The children were 57 % girls, 43 % boys. Mothers were 65 % Latina/Hispanic, 28 % Non-Hispanic White, 7% Black/African American. Maternal prenatal stress was measured with the Perceived Stress Scale administered by interview in the second and third trimesters, and again approximately four years later when child hair samples for assaying HCC were collected. On average maternal perceived stress increased significantly across pregnancy, then returned to lower levels 4 years after birth. Regression analysis revealed that child HCC was not significantly predicted by maternal perceived stress at either single prenatal time point. Exploratory analysis revealed evidence of a relation between increases in maternal prenatal stress from second to third trimester and child HCC four years later (r =.37, p =.04). These results suggest that measures of prenatal maternal stress at any one time point may not be predictive of offspring long-term HPA output in low-income child samples, but that increases in stress levels across pregnancy may provide important information undetected by individual time point measures. [ABSTRACT FROM AUTHOR]

• Propensity for childhood obesity may be programmed in utero via gestational biology. • Maternal preconception states/conditions can influence fetal programming pathways. • Childhood maltreatment (CM) exposure is estimated to affect up to 40 % of adult women. • CM exposure adversely affects maternal behavior, physiology, psychology and biology. • Intergenerational transmission of CM sequelae may influence child obesity risk. Childhood obesity constitutes a major global public health challenge. A substantial body of evidence suggests that conditions and states experienced by the embryo/fetus in utero can result in structural and functional changes in cells, tissues, organ systems and homeostatic set points related to obesity. Furthermore, growing evidence suggests that maternal conditions and states experienced prior to conception, such as stress, obesity and metabolic dysfunction, may spill over into pregnancy and influence those key aspects of gestational biology that program offspring obesity risk. In this narrative review, we advance a novel hypothesis and life-span framework to propose that maternal exposure to childhood maltreatment may constitute an important and as-yet-underappreciated risk factor implicated in developmental programming of offspring obesity risk via the long-term psychological, biological and behavioral sequelae of childhood maltreatment exposure. In this context, our framework considers the key role of maternal-placental-fetal endocrine, immune and metabolic pathways and also other processes including epigenetics, oocyte mitochondrial biology, and the maternal and infant microbiomes. Finally, our paper discusses future research directions required to elucidate the nature and mechanisms of the intergenerational transmission of the effects of maternal childhood maltreatment on offspring obesity risk. [ABSTRACT FROM AUTHOR]

• Consistently elevated depressive symptoms associate with higher end-of-pregnancy HCC. • Cumulative mean of worries about relationships is related to higher mid-pregnancy HCC. • The observed associations between distress measures and HCC are generally weak. • HCC and self-reports of distress represent partially distinct phenomena. • Cumulative distress vs short-term symptoms should be measured in the context of HCC. Maternal prenatal cortisol levels have been inconsistently associated with self-reports of prenatal psychological distress (PD). Previous research has linked hair cortisol concentration (HCC) evaluating cumulatively the previous months with cross-sectional PD measures that usually cover the past week(s), which may lead to misleading conclusions on their relations. We aimed to investigate how maternal HCC relates to cumulative PD measures across pregnancy. Subjects (N = 595) were drawn from the FinnBrain Birth Cohort Study. Maternal HCC was measured from hair samples collected at gestational week (gwk) 24 (HCC1, n = 467) and at delivery (HCC2, n = 222). As HCC1 and HCC2 comprised mostly of different subjects, they were considered as independent populations. Maternal PD assessments at gwks 14, 24, and 34 were the Edinburgh Postnatal Depression Scale (EPDS), the anxiety subscale of the Symptom Checklist (SCL-90), the Pregnancy-Related Anxiety Questionnaire -Revised2 (PRAQ-R2), and a daily hassles scale. Cumulative PD comprised of the mean scores of two consecutive assessments (mean1 = gwks 14 and 24; mean2 = gwks 24 and 34). In addition, EPDS and SCL scores were modelled by using growth mixture modelling to identify symptom trajectory categories. Regression models were adjusted for age, body mass index, education and use of selective serotonin/serotonin-norepinephrine reuptake inhibitor medication. In the adjusted regression model, higher HCC2 was related to the "consistently elevated" prenatal depressive symptoms trajectory in comparison to "consistently low" (β =.71, p =.021) and "low and increasing" (β =.82, p =.011) symptom trajectories. Additionally, the cumulative mean (mean 1) of daily hassles in relationships was associated with HCC1 (β = 0.25, p =.004). General or pregnancy-related anxiety symptoms were unrelated to HCC after adjustment for the covariates. The assessment of cumulative or trajectory measures of PD can reveal important associations with maternal prenatal HCC, even though the associations are generally weak. Of the different dimensions of PD, prenatal trajectories of depressive symptoms were most consistently linked with end-pregnancy HCC levels. [ABSTRACT FROM AUTHOR]

Background: Prenatal exposure to maternal psychological distress and glucocorticoids result in neurobiological adaptations within the fetus that increase risk for developing exaggerated emotional, behavioral, and stress responses to novelty and challenges in childhood. The current study investigated the influence of maternal depressed mood and cortisol during pregnancy on infant cardiac vagal control (CVC) to standardized laboratory challenge tasks., Methods: The sample comprised 194 women and their infants. Maternal reports of depressed mood and salivary cortisol were assessed at 14 and 32 weeks gestational age. Linear regression was used to examine associations between maternal measures during early and late pregnancy, and infant CVC indexed via respiratory sinus arrhythmia (RSA) at rest and in response to laboratory tasks designed to elicit frustration when infants were 6 months of age. It was hypothesized that maternal depressed mood and cortisol would be associated with lower basal RSA and smaller decreases in RSA from baseline to challenge., Results: A significant decrease in infant RSA from baseline to frustration tasks indicated that laboratory tasks elicited a reliable decrease in RSA from baseline to frustration among infants which is characterized by reduction in vagal efferent activity on the heart in response to challenge. Higher maternal cortisol, but not depressed mood, was associated with lower basal RSA and greater decrease in RSA from baseline to frustration. Associations between maternal cortisol and infant basal RSA were observed for both early and late pregnancy whereas the associations between prenatal cortisol and decrease in RSA from baseline to frustration were observed for early, but not late, pregnancy., Conclusions: Maternal cortisol during pregnancy was associated with infant CVC at 6-months of age. Such influences may have enduring impacts on the child and important implications for the development of physical and mental health outcomes., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Summary: Epidemiological and experimental studies have demonstrated that perinatal alterations such as maternal undernutrition are frequently associated with the onset of several chronic adult diseases. Although the physiological mechanisms involved in this “fetal programming” remain largely unknown, it has been shown that early exposure to undernutrition programs hypothalamic–pituitary–adrenal (HPA) axis throughout lifespan. However, the wide spectrum of experimental paradigms used (species, sex, age of the animals, and duration and severity of undernutrition exposure) has given rise to variable results that are difficult to interpret. To circumvent this problem, we used the same experimental protocol of maternal food restriction to study the effects of a severe maternal undernutrition on the HPA axis activity in the male rat offspring throughout the life, namely from fetal stage to adulthood. Mothers exposed to food restriction received 50% (FR50) of the daily intake of pregnant dams during the last week of gestation and lactation. In FR50 fetuses, HPA axis function was reduced and associated with a decreased placental 11β-HSD2 activity and a greater transplacental transfer of glucocorticoids. At weaning, maternal food restriction reduced HPA axis activity in response to an ether inhalation stress. In young adults (4-month-old), only fine HPA axis alterations were observed, whereas in older ones (8-month-old), maternal undernutrition was associated with chronic hyperactivity of this neuroendocrine axis. Interestingly, excessive glucocorticoids production is observed in a growing number of pathologies such as metabolic, cognitive, immune and inflammatory diseases, suggesting that they could, at least in part, result from fetal undernutrition and thus have a neurodevelopmental origin. [Copyright &y& Elsevier]