Prenatal stress and vagal tone in infancy

Background: The fetal origins hypothesis poses that adverse intrauterine conditions predispose to cardiovascular and metabolic diseases in adulthood. Evidence is accumulating that similar mechanisms to those identified for physical disorders may also apply to psychiatric disorders. Focusing on the activity of neurophysiological systems thought to regulate emotions from very early in life may be key to understanding how maternal stress in pregnancy impacts on the developing baby with possible long-lasting consequences for behaviour and psychopathology. Respiratory Sinus Arrhythmia (RSA), "vagal tone", is thought to reflect autonomic regulatory capabilities that may underpin emotion regulation. However, little is known about possible fetal origins of vagal tone. Animal studies increasingly point to sex differences in the effects of prenatal stress, and this is supported by human studies of the prenatal origins of cardiovascular functioning and psychopathology. The current investigation examines whether prenatal depression and anxiety predict vagal tone in infancy, and whether the associations are modified by infant sex. Method: Two hundred mothers and infants from a high-risk consecutive community sample were examined prospectively from the first trimester of pregnancy until 29 weeks postnatal. Maternal self-reports of stress (EPDS and STAI) were collected in pregnancy (20 and 32 weeks) and postnatally (5 weeks and 29 weeks). Vagal tone was ascertained across five procedures, the "Helper-Hinderer" social evaluation task, toy exploration and the "Still Face" paradigm (2 minutes of social engagement, followed by 2 minutes of maternal unresponsiveness and concluded by 2 minutes of social reunion). Results: Principal Component Analysis of the RSA scores yielded a one-factor solution explaining over 70% of the variance, and so mean of RSA scores was used as the index of overall vagal tone, and the difference between overall and RSA during the Still Face as the estimate of vagal withdrawal. There were no main effects of prenatal maternal depression or anxiety on vagal tone or vagal withdrawal. However, there were significant prenatal stress by sex of infant interactions. Follow-up analyses revealed that increasing maternal depression and anxiety at 20 weeks gestation were associated with decreasing vagal tone in males and increasing vagal tone in females. Vagal withdrawal in response to the still face showed similar patterns i.e. decreased in males and increased in girls with elevated maternal anxiety at 32 weeks gestation. These associations were not explained by possible confounding variables assessed in pregnancy, nor by postnatal maternal depression and anxiety. Conclusions: The findings support the fetal origins hypothesis for vagal tone and vagal withdrawal, but only in interaction with sex of the infant. Longitudinal study is required to determine conditions under which increasing vagal tone and withdrawal in girls associated with prenatal depression and anxiety, and decreasing vagal tone and withdrawal in boys, are associated with later resilience or vulnerability to psychopathology.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Sex differences in the associations between vagal reactivity and oppositional defiant disorder symptoms

Background Vagal reactivity to stress in children has been associated with future psychiatric outcomes. However, results have been mixed possibly because these effects are in opposite direction in boys and girls. These sex differences are relevant in the context of development of psychopathology, whereby the rates of psychiatric disorders differ by sex. In this study, we aimed to examine the association between vagal reactivity, assessed as a reduction in respiratory sinus arrhythmia (RSA) in response to a challenge, and the development of future oppositional defiant disorder (ODD) symptoms in boys and girls. In addition, we examine the specific associations with ODD symptom dimensions, named irritability and headstrong. We hypothesized that increased vagal reactivity was associated with increased ODD symptoms in girls and a reduction in ODD symptoms in boys. Methods Participants were members of the Wirral Child Health and Development Study, a prospective epidemiological longitudinal study of 1,233 first-time mothers recruited at 20 weeks’ gestation. RSA during four nonstressful and one stressful (still-face) procedures was assessed when children were aged 29 weeks in a sample stratified by adversity (n = 270). Maternal reports of ODD symptoms were collected when children were 2.5 years old (n = 253), 3.5 years old (n = 826), and 5 years old (n = 770). Structural equation modeling (SEM) was employed to test our hypotheses. Results There was a significant sex difference in the prediction of ODD symptoms due to the opposite directionality in which increasing vagal reactivity was associated with an increase in ODD symptoms in girls and a reduction of ODD symptoms in boys. This Sex by Vagal reactivity interaction was common for both ODD dimensions, with no sex by dimension-specific associations. Conclusions Physiological reactivity to a stressful situation predicts differently ODD symptoms in boys and girls very early in life, with no difference across irritability and headstrong components. Findings are discussed in the context of the several mechanisms involved on the later development of distinct psychiatric disorders in boys and girls

Frequency of infant stroking reported by mothers moderates the effect of prenatal depression on infant behavioural and physiological outcomes

Animal studies find that prenatal stress is associated with increased physiological and emotional reactivity later in life, mediated via fetal programming of the HPA axis through decreased glucocorticoid receptor (GR) gene expression. Post-natal behaviours, notably licking and grooming in rats, cause decreased behavioural indices of fear and reduced HPA axis reactivity mediated via increased GR gene expression. Post-natal maternal behaviours may therefore be expected to modify prenatal effects, but this has not previously been examined in humans. We examined whether, according to self-report, maternal stroking over the first weeks of life modified associations between prenatal depression and physiological and behavioral outcomes in infancy, hence mimicking effects of rodent licking and grooming. From a general population sample of 1233 first time mothers recruited at 20 weeks gestation we drew a stratified random sample of 316 for assessment at 32 weeks based on reported inter-partner psychological abuse, a risk to child development. Of these 271 provided data at 5, 9 and 29 weeks post delivery. Mothers reported how often they stroked their babies at 5 and 9 weeks. At 29 weeks vagal withdrawal to a stressor, a measure of physiological adaptability, and maternal reported negative emotionality were assessed. There was a significant interaction between prenatal depression and maternal stroking in the prediction of vagal reactivity to a stressor (p = .01), and maternal reports of infant anger proneness (p = .007) and fear (p = .043). Increasing maternal depression was associated with decreasing physiological adaptability, and with increasing negative emotionality, only in the presence of low maternal stroking. These initial findings in humans indicate that maternal stroking in infancy, as reported by mothers, has effects strongly resembling the effects of observed maternal behaviours in animals, pointing to future studies of the epigenetic, physiological and behavioral effects of maternal stroking

Reduced Working Memory Mediates the Link between Early Institutional Rearing and Symptoms of ADHD at 12 Years

Children who are raised in institutions show severe delays across multiple domains of development and high levels of psychopathology, including attention deficit/hyperactivity disorder (ADHD). Low performance in executive functions (EFs) are also common in institutionally reared children and often do not remediate following improvements in the caregiving environment. ADHD symptomatology also remains elevated even after children are removed from institutional care and placed in families. We investigate whether poor EF is a mechanism explaining elevated rates of ADHD in children reared in institutional settings in the Bucharest Early Intervention Project (BEIP). In the current study, we examine the potentially mediating role of poor EF in the association between institutionalization and symptoms of ADHD at age 12 years. A total of 107 children were assessed with the Cambridge Neuropsychological Test Automated Battery (CANTAB) on working memory, set-shifting and planning. We also obtained concurrent teacher reports on their levels of ADHD symptoms (inattention and impulsivity separately). Institutionalization strongly predicted elevations in symptoms of inattention and impulsivity at age 12 years (ps < 0.01). Indices of working memory and planning were also associated with ADHD after controlling for potential confounders (ps < 0.03). Mediation analyses revealed that poor working memory performance mediated the link between exposure to early institutionalization and higher scores of both inattention and impulsivity. These results replicate and extend the findings that we reported in the BEIP sample at age 8 years. Together, they suggest that compromised working memory is a key mechanism that continues to explain the strikingly high levels of ADHD in late childhood among children institutionalized in early life. Interventions targeting working memory may help to prevent ADHD among children exposed to institutional care

Maternal prenatal cortisol predicts infant negative emotionality in a sex-dependent manner

Objective Prenatal stress influences fetal developmental trajectories, which may implicate glucocorticoid mechanisms. There is also emerging evidence that effects of prenatal stress on offspring development are sex-dependent. However, little is known about the prospective relationship between maternal prenatal cortisol levels and infant behaviour, and whether it may be different in male and female infants. We sought to address this question using data from a prospective longitudinal cohort, stratified by risk. Method The Wirral Child Health and Development Study (WCHADS) cohort (n = 1233) included a stratified random sub-sample (n = 216) who provided maternal saliva samples, assayed for cortisol, at home over two days at 32 weeks of pregnancy (on waking, 30-min post-waking and during the evening) and a measure of infant negative emotionality from the Neonatal Behavioural Assessment Scale (NBAS) at five weeks-of-age. General population estimates of associations among measures were obtained using inverse probability weights. Results Maternal prenatal cortisol sampled on waking predicted infant negative emotionality in a sex-dependent manner (interaction term, p = 0.005); female infants exposed to high levels of prenatal cortisol were more negative (Beta = 0.440, p = 0.042), whereas male infants were less negative (Beta = − 0.407, p = 0.045). There was no effect of the 30-min post-waking measure or evening cortisol. Discussion Our findings add to an emerging body of work that has highlighted sex differences in fetal programming, whereby females become more reactive following prenatal stress, and males less reactive. A more complete understanding of sex-specific developmental trajectories in the context of prenatal stress is essential for the development of targeted prevention strategies

Causal effects of the early caregiving environment on development of stress response systems in children

Disruptions in stress response system functioning are thought to be a central mechanism by which exposure to adverse early-life environments influences human development. Although early-life adversity results in hyperreactivity of the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis in rodents, evidence from human studies is inconsistent. We present results from the Bucharest Early Intervention Project examining whether randomized placement into a family caregiving environment alters development of the autonomic nervous system and HPA axis in children exposed to early-life deprivation associated with institutional rearing. Electrocardiogram, impedance cardiograph, and neuroendocrine data were collected during laboratory-based challenge tasks from children (mean age = 12.9 y) raised in deprived institutional settings in Romania randomized to a high-quality foster care intervention (n = 48) or to remain in care as usual (n = 43) and a sample of typically developing Romanian children (n = 47). Children who remained in institutional care exhibited significantly blunted SNS and HPA axis responses to psychosocial stress compared with children randomized to foster care, whose stress responses approximated those of typically developing children. Intervention effects were evident for cortisol and parasympathetic nervous system reactivity only among children placed in foster care before age 24 and 18 months, respectively, providing experimental evidence of a sensitive period in humans during which the environment is particularly likely to alter stress response system development. We provide evidence for a causal link between the early caregiving environment and stress response system reactivity in humans with effects that differ markedly from those observed in rodent models

Evidence for sex differences in fetal programming of physiological stress reactivity in infancy

Associations between low birth weight and prenatal anxiety and later psychopathology may arise from programming effects likely to be adaptive under some, but not other, environmental exposures and modified by sex differences. If physiological reactivity, which also confers vulnerability or resilience in an environment-dependent manner, is associated with birth weight and prenatal anxiety, it will be a candidate to mediate the links with psychopathology. From a general population sample of 1,233 first-time mothers recruited at 20 weeks gestation, a sample of 316 stratified by adversity was assessed at 32 weeks and when their infants were aged 29 weeks (N = 271). Prenatal anxiety was assessed by self-report, birth weight from medical records, and vagal reactivity from respiratory sinus arrhythmia during four nonstressful and one stressful (still-face) procedure. Lower birth weight for gestational age predicted higher vagal reactivity only in girls (interaction term, p = .016), and prenatal maternal anxiety predicted lower vagal reactivity only in boys (interaction term, p = .014). These findings are consistent with sex differences in fetal programming, whereby prenatal risks are associated with increased stress reactivity in females but decreased reactivity in males, with distinctive advantages and penalties for each sex

Interaction between maternal stroking and prenatal depression on infant vagal withdrawal.

<p>Simple regression lines and 95% confidence envelopes showing the interaction between maternal reports of stroking (median split) and prenatal depression, with infant vagal withdrawal at 29 weeks (p = 0.01 from multivariate regression).</p

Latent variable model for stroking items and respiratory sinus arrhythmia (RSA) estimate of vagal tone.

<p>The figure shows the factor loadings for mothers' reports of stroking at 5 and 9 weeks, and RSA at 29 weeks. The values of λ (direct effect of stroking on vagal withdrawal), δ₁, δ₂, and β (associations of risks and confounders with stroking, vagal tone and vagal withdrawal respectively), and γ (interaction between maternal stroking and prenatal maternal depression), are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0045446#pone.0045446-t003" target="_blank">Table 3</a>.</p