Associations between maternal prenatal cortisol concentrations and child outcomes: A systematic review

A frequently proposed mechanism underlying the link between maternal prenatal stress/anxiety and child outcomes is heightened concentrations of maternal cortisol. In this systematic review, empirical findings on associations between maternal prenatal cortisol concentrations and child outcomes (physical/health, cognitive/motor, psychological/behavioral, and cortisol) are summarized. The number of empirical studies that find significant associations between maternal prenatal cortisol and child outcomes is small, but the majority of the studies that do find associations show that maternal cortisol is related to altered child outcomes (e.g. more physical/health problems, lower cognitive/motor development, more psychological/behavioral problems, and higher child cortisol concentrations). Inspection of the studies reveals possible critical gestational periods for maternal cortisol to affect different child outcomes.The heterogeneity in study designs and cortisol assessment methods makes drawing strong conclusions premature. However, the fact that most studies did not find significant associations suggests that maternal cortisol may not to be the sole or even main underlying mechanism in the relation between maternal prenatal stress/anxiety and child outcomes. Limitations of the reviewed studies are discussed, and directions for future research and reporting strategies are provided.     

Influence of low level maternal Pb exposure and prenatal stress on offspring stress challenge responsivity

We previously demonstrated potentiated effects of maternal Pb exposure producing blood Pb(PbB) levels averaging 39 μg/dl combined with prenatal restraint stress (PS) on stress challenge responsivity of female offspring as adults. The present study sought to determine if: (1) such interactions occurred at lower PbBs, (2) exhibited gender specificity, and (3) corticosterone and neurochemical changes contributed to behavioral outcomes. Rat dams were exposed to 0, 50 or 150 ppm Pb acetate drinking water solutions from 2 mos prior to breeding through lactation (pup exposure ended at weaning; mean PbBs of dams at weaning were <1, 11 and 31 μg/dl, respectively); a subset in each Pb group underwent prenatal restraint stress (PS) on gestational days 16–17. The effects of variable intermittent stress challenge (restraint, cold, novelty) on Fixed Interval (FI) schedule controlled behavior and corticosterone were examined in offspring when they were adults. Corticosterone changes were also measured in non-behaviorally tested (NFI) littermates. PS alone was associated with FI rate suppression in females and FI rate enhancement in males; Pb exposure blunted these effects in both genders, particularly following restraint stress. PS alone produced modest corticosterone elevation following restraint stress in adult females, but robust enhancements in males following all challenges. Pb exposure blunted these corticosterone changes in females, but further enhanced levels in males. Pb-associated changes showed linear concentration dependence in females, but non-linearity in males, with stronger or selective changes at 50 ppm. Statistically, FI performance was associated with corticosterone changes in females, but with frontal cortical dopaminergic and serotonergic changes in males. Corticosterone changes differed markedly in FI vs. NFI groups in both genders, demonstrating a critical role for behavioral history and raising caution about extrapolating biochemical markers across such conditions. These findings demonstrate that maternal Pb interacts with prenatal stress to further modify both behavioral and corticosterone responses to stress challenge, thereby suggesting that studies of Pb in isolation from other disease risk factors will not reveal the extent of its adverse effects. These findings also underscore the critical need to extend screening programs for elevated Pb exposure, now restricted to young children, to pregnant, at risk, women.     

Women's work stress and cortisol levels: a longitudinal study of the association between the psychosocial work environment and serum cortisol

OBJECTIVE: The aim of the present study was to investigate whether there is an association between serum cortisol and work-related stress, as defined by the demand-control model in a longitudinal design. METHODS: One hundred ten women aged 47-53 years completed a health questionnaire, including the Swedish version of the Job Content Scale, and participated in a psychological interview at baseline and in a follow-up session 2 years later. Morning blood samples were drawn for analyses of cortisol. RESULTS: Multiple stepwise regression analyses and logistic regression analyses showed that work demands and lack of social support were significantly associated with cortisol. CONCLUSIONS: The results of this study showed that negative work characteristics in terms of high demands and low social support contributed significantly to the biological stress levels in middle-aged women. Participation in the study may have served as an intervention, increasing the women's awareness and thus improving their health profiles on follow-up.     

Effects of maternal immobilization stress on birth weight and glucose homeostasis in the offspring

Recent epidemiological studies have shown strong associations between low birth weight and the incidence of diabetes in the adult offspring. It has been hypothesized that exposure to maternal glucocorticoids programs cellular changes in the fetus which increases the susceptibility of the offspring to diabetes. Stressors produces large increases in maternal glucocorticoids. The present study determined the effects of immobilization stress during weeks one, two or three of pregnancy on offspring birth weight, glucose homeostasis, and the ability of the offspring to cope with metabolic stress. Immobilization stress produced large increases in maternal levels of ACTH and corticosterone, but did not affect birth weight of the pups. Chronic administration of high fructose diet, a metabolic stressor, to 60 days old control and prenatally stressed offspring produced large increases in plasma levels of triglyceride and insulin. However, there were no differences between the groups either in peak levels, or in the rates of increase and decrease (upon discontinuation of the diet) of plasma triglyceride and insulin concentrations. Basal levels of glucose and insulin, and areas under the glucose and insulin plasma concentration-time curves after an i.p. glucose dose were similar between 120 days old control and prenatally stressed offspring. These results suggest that in young adult rats prenatal immobilization stress did not affect glucose homeostasis or the ability of these rats to cope with chronic metabolic stress.     

Duloxetine prevents the effects of prenatal stress on depressive-like and anxiety-like behavior and hippocampal expression of pro-inflammatory cytokines in adult male offspring rats

Stress during pregnancy may cause neurodevelopmental and psychiatric disorders. However, the mechanisms are largely unknown. Currently, pro-inflammatory cytokines have been identified as a risk factor for depression and anxiety disorder. Unfortunately, there is very little research on the long-term effects of prenatal stress on the neuroinflammatory system of offspring. Moreover, the relationship between antidepressant treatment and cytokines in the central nervous system, especially in the hippocampus, an important emotion modulation center, is unclear. Therefore, the aim of this study was to determine the effects of prenatal chronic mild stress during development on affective-like behaviors and hippocampal cytokines in adult offspring, and to verify whether antidepressant (duloxetine) administration from early adulthood could prevent the harmful consequences. To do so, prenatally stressed and non-stressed Sprague-Dawley rats were treated with either duloxetine (10 mg/kg/day) or vehicle from postnatal day 60 for 21 days. Adult offspring were divided into four groups: 1) prenatal stress + duloxetine treatment, 2) prenatal stress + vehicle, 3) duloxetine treatment alone, and 4) vehicle alone. Adult offspring were assessed for anxiety-like behavior using the open field test and depression-like behavior using the forced swim test. Brains were analyzed for pro-inflammatory cytokine markers in the hippocampus via real-time PCR. Results demonstrate that prenatal stress-induced anxiety- and depression-like behaviors are associated with an increase in hippocampal inflammatory mediators, and duloxetine administration prevents the increased hippocampal pro-inflammatory cytokine interleukin-6 and anxiety- and depression-like behavior in prenatally stressed adult offspring. This research provides important evidence on the long-term effect of PNS exposure during development in a model of maternal adversity to study the pathogenesis of depression and its therapeutic interventions.     

Effect of prenatal stress on memory,nicotine withdrawal and 5HT1A expression in raphe nuclei of adult rats

Maternal distress has often been associated with cognitive deficiencies and drug abuse in rats. This study examined these behavioral effects in offspring of mothers stressed during gestation. To this end, pregnant dams were subjected to daily electric foot shocks during the last 10 days of pregnancy. We measured litter parameters and body weights of the descendants after weaning (21 days) and at adulthood (80 days). Afterwards, prenatally stressed and control rats’ performances in the novel object recognition test were compared in order to evaluate their memory while others underwent the Water consumption test to assess the nicotine withdrawal intensity after perinatal manipulations. Meanwhile, another set of rats were sacrificed and 5HT_1A receptors’ mRNA expression was measured in the raphe nuclei by quantitative Real Time PCR. We noticed no significant influence of maternal stress on litter size and body weight right after weaning. However, control rats were heavier than the stressed rats in adulthood. The results also showed a significant decrease in the recognition score in rats stressed in utero compared to the controls. Moreover, a heightened anxiety symptom was observed in the prenatally stressed offspring following nicotine withdrawal. Additionally, the Real Time PCR method revealed that prenatal stress induced a significant decrease in 5HT_1A receptors’ levels in the raphe nuclei. Nicotine had a similar effect on these receptors’ expression in both nicotine-treated control and prenatally stressed groups. Taken together, these findings suggest that the cognitive functions and drug dependence can be triggered by early adverse events in rats.     

Strain-dependent effects of prenatal maternal immune activation on anxiety- and depression-like behaviors in offspring

There is converging evidence that prenatal maternal infection can increase the risk of occurrence of neuropsychiatric disorders like schizophrenia, autism, anxiety and depression in later life. Experimental studies have shown conflicting effects of prenatal maternal immune activation on anxiety-like behavior and hypothalamic–pituitary–adrenal (HPA) axis development in offspring. We investigated the effects of maternal immune activation during pregnancy on anxiety- and depression-like behaviors in pregnant mice and their offspring to determine whether these effects are dependent on strain. NMRI and C57BL/6 pregnant mice were treated with either saline or lipopolysaccharide on gestational day 17 and then interleukin (IL)-6 and corticosterone (COR) levels; anxiety or depression in the pregnant mice and their offspring were evaluated. The results indicate that maternal inflammation increased the levels of COR and anxiety-like behavior in NMRI pregnant mice, but not in C57BL/6 dams. Our data also demonstrate that maternal inflammation elevated the levels of anxiety-and depression-like behaviors in NMRI offspring on the elevated plus-maze, elevated zero-maze, tail suspension test and forced swimming test respectively, but not in the open field and light–dark box. In addition, we did not find any significant change in anxiety- and depression-like behaviors of adult C57BL/6 offspring. Our findings suggest that prenatal maternal immune activation can alter the HPA axis activity, anxiety- and depression-like behaviors in a strain- and task-dependent manner in offspring and further comprehensive studies are needed to prove the causal relationship between the findings found here and to validate their relevance to neuropsychiatric disorders in humans.     

Prenatal maternal stress in relation to the effects of prenatal lead exposure on toddler cognitive development

ObjectiveTo evaluate the effects of maternal lead exposure during pregnancy on toddler cognitive development and the potential effect modification by maternal stress.MethodsWe conducted a prospective birth-cohort study in Shanghai from 2010 to 2012 and investigated 225 mother-infant pairs. The mothers were recruited in mid-to-late pregnancy and children were followed up until 24–36 months old. A self-administered Symptom Checklist-90-Revised Scale (SCL-90-R) was used to assess maternal emotional stress during pregnancy. Maternal whole blood lead levels were measured during gestational weeks 28–36. The toddlers’ cognitive levels were assessed using the Gesell Development Scale. Multiple linear regression models were established to explore the main effects of prenatal lead exposure on toddlers’ cognitive abilities and the modifying effects of maternal stress. Covariate information was collected through interviews, questionnaires and medical records.ResultsThe mean maternal blood lead concentration was 3.30 (95%CI: 3.05, 3.57) μg/dL. After adjusting for relevant confounders, no significant associations of maternal blood lead concentrations with toddlers' cognitive levels were observed in all five domains of the Gesell scale (P > 0.05). However, the interaction between prenatal maternal blood lead and stress was significant in the domains of adaptive behavior, language and social behavior. When stratified by maternal stress levels, compared with non-significant associations (P > 0.05) among low (P1-P75) prenatal stress group, adverse associations between maternal blood lead concentrations (log10-transformed) and toddlers’ cognitive levels were observed among high (P75-P100) prenatal stress group in the domains of language (β = −33.82, 95%CI: −60.04, −7.59), social behavior (β = −41.00, 95%CI: −63.11, −18.89) and adaptive behavior (β = −17.93, 95%CI: −35.83, −0.03).ConclusionPrenatal maternal stress may exacerbate the deleterious effects of prenatal exposure to lead on toddler cognitive development.     

Epigenetic programming of the stress response in male and female rats by prenatal restraint stress

Exposure to hostile conditions results in a series of coordinated responses aimed at enhancing the probability of survival. The activation of the hypothalamo-pituitary-adrenocortical (HPA) axis plays a pivotal role in the stress response. While the short-term activation of the HPA axis allows adaptive responses to the challenge, in the long run this can be devastating for the organism. In particular, life events occurring during the perinatal period have strong long-term effects on the behavioral and neuroendocrine response to stressors. In male and female rats exposed to prenatal restraint stress (PRS), these effects include a long-lasting hyperactivation of the HPA response associated with an altered circadian rhythm of corticosterone secretion. Furthermore, male animals exhibit sleep disturbances. In males, these HPA dysfunctions have been reported in infant, young, adult and aged animals, thus suggesting a permanent effect of early stress. Interestingly, after exposure to an intense inescapable footshock, female PRS rats durably exhibit a blunted corticosterone secretion response to stress. In male PRS rats exposed to an alcohol challenge, the HPA axis is similarly hyporesponsive. Rats exposed to PRS also show behavioral disturbances. Both male and female PRS rats show high anxiety levels and depression-like behavior during adulthood, although some studies suggest that female PRS rats present low anxiety levels. With ageing, male and female PRS rats exhibit memory impairments in hippocampus-dependent tasks, while female PRS rats improve their memory performance during adulthood. The gender effect on behavior seems to be related to a reduction in hippocampal plasticity in male PRS rats, and an increase in female PRS rats. Despite the permanent imprinting induced by early stress, the dysfunctions observed after PRS can be reversed by environmental or pharmacological strategies such as environmental enrichment or antidepressive and neurotrophic treatments. Mechanisms underlying the effects of PRS on the offspring remain largely unknown. However, previous studies have demonstrated that maternal glucocorticoids during pregnancy play an important role in the HPA disturbances reported in male offspring. Finally, gestational stress has long-lasting effects on the HPA axis and on behavior in the dams. Alterations in maternal behavior could thus also make a strong contribution to the long-term effects of PRS, through epigenetic mechanisms.     

Effects of PhD examination stress on allopregnanolone and cortisol plasma levels and peripheral benzodiazepine receptor density

Peripheral benzodiazepine receptor (PBR) density in blood platelets and plasma allopregnanolone concentration in humans were determined following acute stress as represented by PhD examination. Fifteen healthy PhD students participated. Heart rate, blood pressure, plasma allopregnanolone, plasma cortisol, and PBR density were measured at different time points.

Allopregnanolone and cortisol concentration and PBR density were significantly increased during examination. A positive correlation between allopregnanolone and PBR density was found.     

Effects of prenatal binge-like ethanol exposure and maternal stress on postnatal morphological development of hippocampal neurons in rats

BackgroundAlcohol is one of the most commonly used drugs of abuse negatively affecting human health and it is known as a potent teratogen responsible for fetal alcohol syndrome (FAS), which is characterized by cognitive deficits especially pronounced in juveniles but ameliorating in adults. Searching for the potential morphological correlates of these effects, in this study, we compared the course of developmental changes in the morphology of principal hippocampal neurons in fetal-alcohol (A group), intubated control (IC group), and intact control male rats (C group) over a protracted period of the first two postnatal months.MethodsEthanol was administered to the pregnant Wistar dams intragastrically, throughout gestation days (GD) 7–20, at a total dose of 6 g/kg/day resulting in the mean blood alcohol concentration (BAC) of 246.6 ± 40.9 mg/dl. Ten morphometric parameters of Golgi-stained hippocampal neurons (pyramidal and granule) from CA1, CA3, and DG areas were examined at critical postnatal days (PD): at birth (PD1), at the end of the brain growth spurt period (PD10), in juveniles (PD30), and in young adults (PD60).ResultsDuring postnatal development, the temporal pattern of morphometric changes was shown to be region-dependent with most significant alterations observed between PD1-30 in the CA region and between PD10-30 in the DG region. It was also parameter-dependent with the soma size (except for CA3 pyramids), number of primary dendrites, dendrite diameter, dendritic tortuosity and the branch angle demonstrating little changes, while the total dendritic field area, dendritic length, number of dendritic bifurcations, and spine density being highly increased in all hippocampal regions during the first postnatal month. Moderate ethanol intoxication and the maternal intubation stress during gestation, showed similar, transient effects on the neuron development manifested as a smaller soma size in granule cells, reduced dendritic parameters and lower spine density in pyramidal neurons at PD1. Full recovery from these effects took place within the first 10 postnatal days.ConclusionsThis study showed regional and temporal differences in the development of different morphometric features of principal hippocampal neurons in intact subjects over a protracted 2-months postnatal period. It also demonstrated an overlap in the effects of a moderate fetal ethanol intoxication and a mild maternal stress produced by the intragastric intubation, a commonly used method of ethanol administration to the pregnant dams. Fast recovery from the adverse effects on the soma size, dendritic arborization and spines density observed at birth indicates towards the fetal ethanol/stress induced developmental retardation.     

Sex and region difference of the expression of ERK in prenatal stress offspring hippocampus

Prenatal stress is known to cause neuronal loss and oxidative damage in the hippocampus of offspring rats. The underlying molecular mechanism has not been fully understood. The extracellularsignal-regulated kinase (ERK1/2) is recruited when the brain undergoes synaptic plasticity and remodeling. In the present study, we used Western blotting and immunohistochemistry techniques to examine the effects of prenatal restraint stress (PNS) on the expression of phosphorylated ERK (p-ERK) and total ERK. Pregnant rats in the PNS group were exposed to restraint stress on day 14-20 of pregnancy three times daily for 45min. One-month-old offspring rats were used in this experiment. PNS treatment increased the expression of p-ERK2 compared to that in the control female offspring rats and total ERK2 in female offspring hippocampus compared with that of control group. No significant changes in the amounts of total ERK1 of prenatally offspring hippocampus were observed in both genders compared with control animals. ERK immunodensity was significantly increased in PNS groups in CA3 field in male offspring hippocampus compared with control animals. ERK optical density was significantly increased in PNS female offspring hippocampus CA1, CA3 and CA4 region. However, ERK optical density was not significantly different between male control and PNS groups in CA1, CA4 fields and DG in offspring hippocampus. These findings suggest the sex and region-dependent effects of prenatal stress on the expression of ERK in offspring hippocampus. ERK expression changes induced by prenatal stress may contribute to hippocampus synaptic plasticity changes of the offspring.     

Impact of a prenatal cognitive-behavioral stress management intervention on salivary cortisol levels in low-income mothers and their infants

Recent findings suggest that elevated stress levels during the pre- and postpartum period are related to poor maternal and infant health outcomes; yet, few studies have prospectively examined the efficacy of stress management interventions on regulating stress levels among mothers and their infants. The current study examined whether a prenatal cognitive behavioral stress management (CBSM) intervention would be effective in regulating salivary cortisol (a biological marker of stress) and self-reported stress levels among mothers and their infants at six and 18 months postpartum, relative to two control groups. Our sample was comprised of predominantly Spanish-speaking, low-income women (80%; mean age=25±5 years) who were screened for depression during their second trimester of pregnancy (M=16±5 weeks of gestation). Women at high risk for depression [i.e., having either a past history of major depression or current elevated symptoms of depression (≥16 on CES-D)] were randomized to either a CBSM group (n=24) or a usual care (UC) group (n=33), while a low risk comparison (LRC) group (n=29) was comprised of women not meeting either depression criteria. ANCOVA analyses demonstrated that: (1) infants of women in the CBSM and LRC groups had significantly lower cortisol levels than infants of women in the UC group at six months postpartum (p<.001); and (2) women in the CBSM group had lower cortisol levels than women in the UC group at 18 months postpartum (p<.01). These results suggest that prenatal CBSM interventions may be efficacious in regulating biological markers of stress among mothers and their infants, thereby decreasing their risk for developing health complications over time.     

The association between perceived emotional support,maternal mood,salivary cortisol,salivary cortisone,and the ratio between the two compounds in response to acute stress in second trimester pregnant women

Objective

Little is known about the effect of social support on the reactivity of the hypothalamic–pituitary–adrenal (HPA) axis during pregnancy. Moreover, when investigating the HPA axis most studies do not consider the activity of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), an enzyme within the salivary glands that inactivates cortisol to cortisone. This study explores the association between perceived emotional support and the maternal psychobiological stress response to a standardized naturalistic stressor by assessing maternal mood and the reactivity of salivary cortisol (SalF), salivary cortisone (SalE), and the SalE/(E + F) ratio as a marker of 11β-HSD2 activity.

Methods

Repeated saliva samples and measures of maternal mood were obtained from 34 healthy second trimester pregnant women undergoing amniocentesis which served as a psychological stressor. The pregnant women additionally responded to a questionnaire of perceived emotional support and provided sociodemographic (e.g., maternal educational degree) and pregnancy-specific data (e.g., planned versus unplanned pregnancy).

Results

Perceived emotional support neither showed a significant effect on mood nor on the SalF or SalE response to stress. However, a moderately strong positive association was found between perceived emotional support and SalE/(E + F) (r = .49). Additionally, the final regression analysis revealed a significant negative relationship between educational degree, planned/unplanned pregnancy and SalE/(E + F).

Conclusion

Findings suggest a higher metabolization of cortisol to cortisone in pregnant women with higher emotional support. In contrast, higher maternal education and unplanned pregnancy appear to be associated with decreased salivary 11β-HSD2 activity. The current study emphasizes the importance of taking the activity of 11β-HSD2 into account when examining SalF.     

Effects of prenatal stress on sexually dimorphic asymmetries in the cerebral cortex of the male rat

Diamond and collaborators have reported sexual dimorphic right greater than left thickness asymmetries in the cerebral cortices of male Long-Evans rats. In the present work we report that normal Sprague-Dawley males show a similar cortical asymmetry. On the other hand, Sprague-Dawley males whose mothers were subjected to treatments of prenatal stress three times daily during the third trimester of gestation showed a nonsignificant left greater than right pattern in the same cortical areas--a pattern characteristic of the female cortex. These results are consistent with other findings from our laboratory wherein we have recently shown that prenatal stress during the third trimester of gestation demasculinizes sexually dimorphic regions of the preoptic hypothalamus in male rats. It is concluded that stress mediated changes in the prenatal environment can have a profound effect on the developmental processes which shape the morphology of sexually dimorphic regions of the brain in male offspring. Normal male anatomy is biased in the direction of a feminine structure. Such an anatomical picture is consistent with demasculinized and feminized behavior patterns exhibited by male offspring of prenatally stressed dams.