David P. Laplante

Prenatal stress and brain development.

Prenatal stress (PS) has been linked to abnormal cognitive, behavioral and psychosocial outcomes in both animals and humans. Animal studies have clearly demonstrated PS effects on the offsprings brain, however, while it has been speculated that PS most likely affects the brains of exposed human fetuses as well, no study has to date examined this possibility prospectively using an independent stressor (i.e., a stressful event that the pregnant woman has no control over, such as a natural disaster). The aim of this review is to summarize the existing animal literature by focusing on specific brain regions that have been shown to be affected by PS both macroscopically and microscopically. These regions include the hippocampus, amygdala, corpus callosum, anterior commissure, cerebral cortex, cerebellum and hypothalamus. We first discuss the mechanisms by which the effects of PS might occur. In particular, we show that maternal and fetal hypothalamic-pituitary-adrenal (HPA) axes, and the placenta, are the most likely candidates for these mechanisms. We see that, although animal studies have obvious advantages over human studies, the integration of findings in animals and the transfer of these findings to human populations remains a complex issue. Finally, we show how it is possible to circumvent these challenges by studying the effects of PS on brain development directly in humans, by taking advantage of natural or man-made disasters and assessing the impact and consequences of such stressful events on pregnant women and their offspring prospectively.

Project Ice Storm: Prenatal Maternal Stress Affects Cognitive and Linguistic Functioning in 5½-Year-Old Children

OBJECTIVE This was a prospective study designed to determine the extent to which the degree of exposure to prenatal maternal stress due to a natural disaster explains variance in the intellectual and language performance of offspring at age 5(1/2) while controlling for several potential confounding variables. METHOD Subjects were eighty-nine 5(1/2)-year-old children whose mothers were pregnant during a natural disaster: the January 1998 ice storm crisis in the Canadian province of Québec that resulted in power losses for 3 million people for as long as 40 days. In June 1998, women completed several questionnaires including those about the extent of objective stress (Storm 32) and subjective distress (Impact of Events Scale-Revised) experienced due to the storm. Their children were assessed with the Wechsler Preschool and Primary Scale of Intelligence-Revised (IQ) and Peabody Picture Vocabulary Test-Revised (language) at 5(1/2) years of age, and mothers completed assessments of recent life events and psychological functioning. RESULTS Children exposed in utero to high levels of objective stress had lower Full Scale IQs, Verbal IQs, and language abilities compared to children exposed to low or moderate levels of objective prenatal maternal stress; there were no effects of subjective stress or objective stress on Performance IQs. Trend analyses show that for all outcome variables except Block Design, there was a significant curvilinear association between objective stress and functioning. CONCLUSIONS Prenatal exposure to a moderately severe natural disaster is associated with lower cognitive and language abilities at 5(1/2) years of age.

Physical Aggression and Expressive Vocabulary in 19-Month-Old Twins

In the prevention of physical aggression, possible etiological links with language development are rarely taken into account. Indeed, little is known about when language and aggressive behavior become linked during development and which mechanisms are responsible for this association. This study investigated the association between physical aggression and language in late infancy with a genetic design that involved 562 19-month-old twins. A modest but significant correlation (r = -.20) was found between physical aggression and expressive vocabulary. Substantial heritability was found for physical aggression. Quantitative genetic modeling suggests that the correlation between expressive vocabulary and physical aggression cannot be explained by shared etiologies. However, phenotype-to-phenotype models indicate that the covariation can be entirely accounted for by a significant phenotypic path from expressive vocabulary to physical aggression. The implications of these results for early prevention of chronic physical aggression are discussed.

The effects of prenatal maternal stress on children's cognitive development: Project Ice Storm

There exists considerable research on the effects of prenatal maternal stress on offspring. Animal studies, using random assignment to experimental and control groups, demonstrate the noxious effects of prenatal maternal stress on physical, behavioural and cognitive development. The generalizability of these results to humans is problematic given that cognitive attributions moderate reactions to stressors. In humans, researchers have relied upon maternal anxiety or exposure to life events as proxies for the stressors used with animals. Yet, the associations between maternal anxiety or potentially non-independent life events and problems in infants are confounded by genetic transmission of temperament from mother to child. We summarize the literature on prenatal maternal stress and infant cognitive development, leading to the conclusion that the human literature lacks the ability to separate the effects of the objective exposure to a stressor and the mothers subjective reaction. We then describe our prospective Project Ice Storm in which we are following 150 children who were exposed in utero to a natural disaster. We demonstrate significant effects of the objective severity of exposure on cognitive and language development at age two years with important moderating effects of the timing during pregnancy. The implications of our findings are discussed.

DNA methylation signatures triggered by prenatal maternal stress exposure to a natural disaster: Project Ice Storm.

Background Prenatal maternal stress (PNMS) predicts a wide variety of behavioral and physical outcomes in the offspring. Although epigenetic processes may be responsible for PNMS effects, human research is hampered by the lack of experimental methods that parallel controlled animal studies. Disasters, however, provide natural experiments that can provide models of prenatal stress. Methods Five months after the 1998 Quebec ice storm we recruited women who had been pregnant during the disaster and assessed their degrees of objective hardship and subjective distress. Thirteen years later, we investigated DNA methylation profiling in T cells obtained from 36 of the children, and compared selected results with those from saliva samples obtained from the same children at age 8. Results Prenatal maternal objective hardship was correlated with DNA methylation levels in 1675 CGs affiliated with 957 genes predominantly related to immune function; maternal subjective distress was uncorrelated. DNA methylation changes in SCG5 and LTA, both highly correlated with maternal objective stress, were comparable in T cells, peripheral blood mononuclear cells (PBMCs) and saliva cells. Conclusions These data provide first evidence in humans supporting the conclusion that PNMS results in a lasting, broad, and functionally organized DNA methylation signature in several tissues in offspring. By using a natural disaster model, we can infer that the epigenetic effects found in Project Ice Storm are due to objective levels of hardship experienced by the pregnant woman rather than to her level of sustained distress.

Prenatal maternal stress from a natural disaster predicts dermatoglyphic asymmetry in humans.

Dermatoglyphic asymmetry of fingertip ridge counts is more frequent in schizophrenia patients than normal controls, and may reflect disruptions in fetal development during Weeks 14-22 when fingerprints develop. However, there are no data in humans linking specific adverse events at specific times to dermatoglyphic asymmetries. Our objective was to determine whether prenatal exposure to a natural disaster (1998 Quebec ice storm) during Weeks 14-22 would result in increased dermatoglyphic asymmetry in children, and to determine the roles of maternal objective stress exposure, subjective stress reaction, and postdisaster cortisol. Ridge counts for homologous fingers were scored for 77 children (20 target exposed [Weeks 14-22] and 57 nontarget exposed [exposed during other gestation weeks]). Children in the target group had more than 0.50 SD greater asymmetry than the nontarget group. Within the target group, children whose mothers had high subjective ice storm stress had significantly greater asymmetry than those with lower stress mothers, and maternal postdisaster cortisol had a significant negative correlation with the childrens dermatoglyphic asymmetry (r = -.56). Prenatal maternal stress during the period of fingerprint development results in greater dermatoglyphic asymmetry in their children, especially in the face of greater maternal distress.

Cortisol response to a psychosocial stressor in schizophrenia: blunted, delayed, or normal?

BACKGROUND Patients with schizophrenia may differ from healthy controls by having dysregulated physiological responses to stress. Our objective was to determine the extent to which cortisol reaction can discriminate between controls and schizophrenia patients while controlling for symptom severity, personality, body mass index (BMI) and smoking. METHOD 30 chronic schizophrenia patients and 30 matched controls underwent a modified version of the Trier Social Stress Test (TSST), consisting of public speaking and mental arithmetic. Heart rate, blood pressure, and salivary cortisol were measured repeatedly throughout the TSST. In addition, participants completed the NEO Personality Inventory (NEO-FFI), and were interviewed with the Brief Psychiatric Rating Scale (BPRS). RESULTS Both groups had a significant increase in heart rate and mean arterial pressure following the TSST. Results of a logistic regression suggests that patients can be discriminated from controls with a smaller change in cortisol between baseline and 15 min post-TSST, controlling for BMI and severity of positive symptoms. There was a trend for lower overall cortisol secretion in patients. CONCLUSIONS Despite demonstrable effects of the stressor on cardiac measures, schizophrenia patients tend to have smaller acute cortisol reaction to psychosocial stress. The significance of this conclusion for vulnerability-stress models of schizophrenia is discussed.

Prenatal maternal stress exposure and immune function in the offspring

Abstract The intra-uterine environment provides the first regulatory connection for the developing fetus and shapes its physiological responses in preparation for postnatal life. Psychological stress acts as a programming determinant by setting functional parameters to abnormal levels, thus inducing postnatal maladaptation. The effects of prenatal maternal stress (PNMS) on the developing immune system have been documented mostly through animal studies, but inconsistent results and methodological differences have hampered the complete understanding of these findings. As the immune system follows a similar ontogenic pattern in all mammals, a translational framework based on the developmental windows of vulnerability proposed by immunotoxicology studies was created to integrate these findings. The objective of this review is to examine the available literature on PNMS and immune function in the offspring through the above framework and gain a better understanding of these results by elucidating the moderating influence of the stressor type, timing and duration, and the offspring species, sex and age at assessment. The evaluation of the literature through this framework showed that the effects of PNMS are parameter specific: the moderating effects of timing in gestation were relevant for lymphocyte population numbers, Natural Killer cell function and mitogen-induced proliferation. The presence of an important and directional sexual dimorphism was evident and the influence of the type or duration of PNMS paralleled that of stress in non-pregnant animals. In conclusion, PNMS is a relevant factor in the programming of immune function. Its consequences may be related to disorders with an important immune component such as allergies.

Prenatal exposure to a natural disaster increases risk for obesity in 5-year-old children

Introduction:An adverse environment in utero, including exposure to prenatal maternal stress (PNMS), can result in poor birth outcomes such as low birth weight, which increases risk of later cardiometabolic diseases such as hypertension and obesity. It is unclear to what extent PNMS influences obesity risk independent of its impact on birth characteristics, especially among humans. Our objective was to determine whether PNMS resulting from a natural disaster influenced risk of childhood obesity.Results:Eight children with high objective PNMS exposure (14.5%) were obese compared to one child (1.8%) with low exposure (P = 0.02). Objective PNMS increased obesity risk (model 1, P = 0.02, odds ratio = 1.37) after controlling for other potential risk factors.Discussion:Results suggest that PNMS might be an independent risk factor in the development of childhood obesity.Methods:Participants included 111 women who were pregnant during the January 1998 Québec Ice Storm or who conceived within the following 3 months and their children. We tested associations between objective and subjective PNMS from the storm and childhood obesity status at age 5½, controlling for children’s birth characteristics and breastfeeding status; household socioeconomic status; maternal obstetric complications, life events and smoking during pregnancy, psychological functioning, and height (model 1, n = 111) or BMI (for a subset of 69 participants, model 2).

Prenatal maternal stress predicts autism traits in 6½ year-old children: Project Ice Storm

Research implicates prenatal maternal stress (PNMS) as a risk factor for neurodevelopmental disorders; however few studies report PNMS effects on autism risk in offspring. We examined, prospectively, the degree to which objective and subjective elements of PNMS explained variance in autism-like traits among offspring, and tested moderating effects of sex and PNMS timing in utero. Subjects were 89 (46F/43M) children who were in utero during the 1998 Quebec Ice Storm. Soon after the storm, mothers completed questionnaires on objective exposure and subjective distress, and completed the Autism Spectrum Screening Questionnaire (ASSQ) for their children at age 6½. ASSQ scores were higher among boys than girls. Greater objective and subjective PNMS predicted higher ASSQ independent of potential confounds. An objective-by-subjective interaction suggested that when subjective PNMS was high, objective PNMS had little effect; whereas when subjective PNMS was low, objective PNMS strongly affected ASSQ scores. A timing-by-objective stress interaction suggested objective stress significantly affected ASSQ in first-trimester exposed children, though less so with later exposure. The final regression explained 43% of variance in ASSQ scores; the main effect of sex and the sex-by-PNMS interactions were not significant. Findings may help elucidate neurodevelopmental origins of non-clinical autism-like traits from a dimensional perspective.