Stress reactivity in preschool-aged children: Evaluation of a social stress paradigm and investigation of the impact of prenatal maternal stress.

Prenatal maternal stress is an established risk factor for somatic and psychological health of the offspring. A dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in offspring has been suggested as an important mechanism. However, the impact of prenatal stress on stress reactivity in preschool-aged children is not yet well understood. This is partly due to the fact that for this age group there is no stress test as well established as for older children and adults. In the present work a previously published stress test (Kryski et al., 2011) was evaluated in a large sample of 45-month-old children (n = 339). Furthermore, the relation between measures of prenatal maternal stress and cortisol reactivity was investigated. Prenatal stress was defined as psychopathology (self-report available for n = 339; expert-rating available for a subsample of n = 246) and perceived stress (n = 244) during pregnancy. The stress paradigm elicited significant increases in salivary cortisol 30 and 40 min after the test, and 60.8% of the children were classified as responders. Lower cortisol levels after the stress test were observed in the group of children with prenatal stress defined as maternal psychopathology (both self-reported and expert-rated). Maternal perceived stress as a continuous measure was not significantly associated with cortisol levels. However, when comparing children in the highest quartile of maternal perceived stress to all other children, significantly lower cortisol values were observed in the prenatally stressed group. The present study confirms the paradigm by Kryski et al. as an effective stress test for preschool-aged children. Moreover, it provides further evidence that prenatal stress impacts HPA axis reactivity. Future studies should target the timing, nature, and intensity of prenatal stressors and their effect on the stress response in offspring at different developmental stages.

Send TS ，Bardtke S ，Gilles M ，Wolf IAC ，Sütterlin MW ，Kirschbaum C ，Laucht M ，Witt SH ，Rietschel M ，Streit F ，Deuschle M ... -  《-》

Prenatal maternal stress is associated with lower cortisol and cortisone levels in the first morning urine of 45-month-old children.

Prenatal stress (PS) has been related to altered hypothalamic-pituitary-adrenal (HPA) axis activity later in life. So far, studies in children assessing HPA axis functioning have focused on salivary cortisol, reflecting daytime activity. The present work is part of a prospective study and aims to extend knowledge about the association between PS and HPA axis regulation in children. To do so, we investigated cortisol, cortisone, and the ratio cortisone/(cortisone + cortisol) in the first morning urine of 45-month-old children in relation to several measures of maternal stress during pregnancy. Urinary cortisol and cortisone were measured by online turbulent flow chromatography coupled with high performance liquid chromatography-tandem mass spectrometry. PS was defined as: perceived stress for aim 1 (Perceived Stress Scale; n = 280); presence of self-reported (n = 371) and expert-rated psychopathology for aim 2 (Mini International Neuropsychiatric Interview; n = 281); continuous measures of anxiety and depression for exploratory aim 3 (State-Trait Anxiety Inventory and Edinburgh Postnatal Depression Scale; n = 280). Aim 1: Perceived maternal PS showed negative associations with cortisol and cortisone levels. Aim 2: The presence of expert-rated maternal psychopathology was associated with reduced morning cortisone. Aim 3: Continuous measures of anxiety and depression showed negative associations with cortisol and cortisone levels. After correcting for multiple testing, perceived maternal PS (aim 1) and prenatal level of anxiety (aim 3) were significant predictors of children's urinary cortisol and cortisone in the morning (and, in the case of cortisone, also prenatal level of depression). The ratio cortisone/(cortisone + cortisol) as a global marker for the balance between the enzymes metabolizing cortisol to cortisone and vice versa (11β-hydroxysteroid dehydrogenases type 1 and 2; 11β-HSD1 and 2) was not associated with any measure of maternal PS (aims 1-3). The present study provides insight into possible programming effects of PS on nocturnal HPA axis activity and a proxy of 11β-HSD in a large sample. The results suggest that the nocturnal rate of cortisol production is lower in children exposed to PS, but do not support the hypothesis of divergent 11β-HSD activity.

Send TS ，Bardtke S ，Gilles M ，Wolf IAC ，Sütterlin MW ，Wudy SA ，Wang R ，Laucht M ，Witt SH ，Rietschel M ，Streit F ，Deuschle M ... -  《-》

Maternal hypothalamus-pituitary-adrenal (HPA) system activity and stress during pregnancy: Effects on gestational age and infant's anthropometric measures at birth.

Prenatal maternal stress might be a risk for the developing fetus and may have long-lasting effects on child and adult vulnerability to somatic and psychiatric disease. Over-exposure of the unborn to excess glucocorticoids and subsequent alteration of fetal development is hypothesized to be one of the key mechanisms linking prenatal stress with negative child outcome. In this prospective longitudinal study, mothers-to-be (n = 405) in late pregnancy (36.8 ± 1.9 weeks of gestational age) and their singleton neonates were studied. We investigated the impact of different prenatal stress indices derived from six stress variables (perceived stress, specific prenatal worries, negative life events, symptoms of depression, trait anxiety, neuroticism) and diurnal maternal saliva cortisol secretion on gestational age and anthropometric measures at birth. Maternal prenatal distress during late gestation was associated with significant reduction in birth weight (-217 g; p = .005), birth length (-1.2 cm; p = .005) and head circumference (-0.8 cm; p = .001). Prenatal stress was modestly but significantly associated with altered diurnal cortisol pattern (flattened cortisol decline and higher evening cortisol), which in turn was significantly related to reduced length of gestation. No evidence for a profound interaction between maternal cortisol level in late pregnancy and infant's anthropometric measures at birth (i.e., birth weight, length, head circumference) was found. Prenatal stress is associated with flattened circadian saliva cortisol profiles and reduced infant's anthropometric measures at birth. HPA system activity during pregnancy may be related to low gestational age. The effect of prenatal stress might be partly mediated by maternal-placental-fetal neuroendocrine mechanisms especially the dysregulation of diurnal cortisol profile.

Gilles M ，Otto H ，Wolf IAC ，Scharnholz B ，Peus V ，Schredl M ，Sütterlin MW ，Witt SH ，Rietschel M ，Laucht M ，Deuschle M ... -  《-》

Prenatal programming of emotion regulation: neonatal reactivity as a differential susceptibility factor moderating the outcome of prenatal cortisol levels.

Hypothalamic-pituitary-adrenal (HPA) activation during pregnancy is linked to dysfunctional behavioral outcomes in the offspring. According to Belsky's differential susceptibility hypothesis, individuals vary regarding their developmental plasticity. Translating the differential susceptibility hypothesis to the field of fetal programming, we hypothesize that infants' temperament, as the constitutionally based reactivity to stimulation, moderates prenatal environmental effects on postnatal emotion regulation. Maternal HPA axis activity and stress-reactivity during pregnancy was estimated, by measuring cortisol concentrations in saliva, collected at 0, 30, 45 and 60 min after awakening and in blood, collected during a laboratory stress test (Trier Social Stress Test), respectively. Newborns reactivity to stimulation was evaluated between postnatal day 10 and 14 using the Neonatal Intensive Care Unit Network Neurobehavioral Scale. Infant's self-quieting-activities, as an indicator of emotion regulation, were evaluated at the age of six months during the still face paradigm. Maternal cortisol reactivity to stress during pregnancy was associated with infant's emotion regulation at the age of six months. Whereas cortisol levels after awakening in mid and late pregnancy were not associated with emotion regulation. Furthermore, regression analyses revealed that in interaction with neonatal reactivity, both, prenatal maternal HPA activity as well as prenatal maternal HPA reactivity to stress predicted emotion regulation. The findings indicate that newborns' reactivity to stimulation is moderating the association between prenatal exposure to maternal glucocorticoids and emotion regulation in infancy. Data suggests that temperamental characteristics of the newborn are a relevant differential susceptibility factor with regard to prenatal effects on emotion regulation.

Bolten M ，Nast I ，Skrundz M ，Stadler C ，Hellhammer DH ，Meinlschmidt G ... -  《-》

Prenatal maternal psychopathology and stress and offspring HPA axis function at 6 years.

Intrauterine exposures such as maternal psychopathology and stress are known to influence the physical and mental health of the offspring. One of the proposed pathways underlying these associations is dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity in the offspring. This study examined the relation of perinatal maternal symptoms of psychopathology and stress with offspring HPA axis activity at 6 years as measured by hair cortisol and cortisone concentrations. The study was part of the population-based Generation R Study, a prospective population-based cohort from fetal life onwards. 2546 children and their mothers formed the study population. Perinatal maternal psychopathology and stress were assessed by questionnaires in the second and third trimester. Principal components for both psychopathology and stress were created to reduce the number of explanatory variables. Child hair samples for cortisol and cortisone measurements were collected at the age of 6. Linear regression analysis, adjusted for covariates, was used to examine associations between maternal psychopathology and stress and child hair cortisol and cortisone levels. The maternal psychopathology principal component was associated with higher child hair cortisone (adjusted B = 0.24, 95%CI 0.08;0.40, p-value < 0.01). Effect estimates of the individual dimensions ranged from 0.97 (95%CI 0.21;1.73, p-value = 0.01) for interpersonal sensitivity to 1.67 (95%CI 0.86;2.47, p-value < 0.01) for paranoid ideation. In addition, children exposed to intrauterine stress, as measured by the principal component, had higher hair cortisone levels (adjusted B = 0.54, 95%CI 0.21;0.88, p-value < 0.01). Exposure to maternal psychopathology and stress was not associated with offspring hair cortisol. Stratification by child sex resulted in associations between maternal symptoms of psychopathology during pregnancy and child hair cortisone levels in boys and associations between maternal symptoms of stress during pregnancy and child hair cortisone levels in girls. Our results suggest that maternal psychopathology and stress during pregnancy are associated with long-term HPA axis activity of the offspring. The association of maternal psychopathology and stress during pregnancy with offspring hair cortisone levels is a novel finding. Future studies should examine whether these psychophysiological differences between exposed and non-exposed children underlie offspring morbidity associated with maternal psychopathology and stress during pregnancy.

Molenaar NM ，Tiemeier H ，van Rossum EFC ，Hillegers MHJ ，Bockting CLH ，Hoogendijk WJG ，van den Akker EL ，Lambregtse-van den Berg MP ，El Marroun H ... -  《-》