Epigenetic Insights into the Impact of Disaster-Related Prenatal Stress: A Narrative Review.

Prenatal maternal stress can have a profound and enduring influence on child development. This represents an important public health issue and signals a need for intervention. However, despite an accumulating number of empirical studies, several key questions about the effects of prenatal maternal stress remain unanswered: 1) Few studies have focused on motor development, even though it is foundational for development across a range of other areas; 2) Research on mechanisms of transmission has focused on physiological processes, such as cascades of stress related hormones, and largely ignored the psychological cascades that can drive these underlying physiological responses; 3) Many prenatal stress studies only measure child development at one point in time, which provides information about the emergence of effects but cannot answer important questions about progression; and 4) Very few prenatal stress studies have looked at variables that can explain or reduce negative effects, which is essential information for effective intervention. This thesis investigates the relationship between different aspects of disaster-related prenatal maternal stress and child motor development, explores how stress reactions work together to predict motor development, and proposes a cascade of stress reactions as a psychological mechanism of transmission for the effects of prenatal maternal stress. It examines continuity and change in findings between 16 and 30 months and, finally, looks at whether maternal coping predicts child motor development. At recruitment, mothers (N = 224) exposed to a major flood during pregnancy completed questionnaires assessing flood exposure (QFOSS), peritraumatic distress (PDI) and dissociation (PDEQ), posttraumatic stress (IESR), a cognitive appraisal of the overall flood consequences, and coping (BriefCOPE). At 16 months (N = 145) and 30 months (N = 150) post-partum, children’s fine and gross motor development was assessed using the Bayley-III, and mothers completed questionnaires assessing postnatal stressors (i.e., life events, parenting stress and mental health). At 16 months, higher maternal posttraumatic stress predicted poorer child fine motor development and negative cognitive appraisal predicted poorer gross motor development. Both effects were only significant for children exposed to the flood from mid-gestation onwards. At 30 months, higher maternal posttraumatic stress again predicted poorer child fine motor development, but the relationship between cognitive appraisal and gross motor development was no longer evident. In addition, two new effects emerged: higher maternal dissociation predicted poorer child gross motor development, and flood exposure later in gestation predicted better gross motor development. Cascades of maternal stress reactions linked flood exposure to poorer child motor development, with different mechanisms for fine and gross motor development. Coping strategies predicted motor development indirectly via maternal stress. Both positive and negative effects were evident, depending on the type of coping strategy. Overall, this thesis makes several important contributions. It extends the current literature by establishing that different types of prenatal maternal stress can predict different areas of motor development in early childhood. It proposes potential psychological mechanisms of transmission for the effects of prenatal maternal stress on motor development, and provides further evidence that the effects of prenatal maternal stress can be enduring. It is also suggests that maternal coping indirectly predicts child development by influencing maternal stress. These findings have implications for the design of prenatal stress research, and for guiding interventions with pregnant mothers in the wake of natural disasters.

The role of microRNA miR223 in immune adaptation for pregnancy and fetal-placental development

Hats Off: Journal Awards 2018

Psychological stress during pregnancy is known to have a range of long-lasting negative consequences on the development and health of offspring. Here, we tested whether a measure of prenatal early-life stress was associated with a biomarker of physiological development at birth, namely epigenetic gestational age, using foetal cord-blood DNA-methylation data. Longitudinal cohorts from the Netherlands (Generation R Study [Generation R], n = 1,396), the UK (British Avon Longitudinal Study of Parents and Children [ALSPAC], n = 642), and Norway (Mother, Father and Child Cohort Study [MoBa], n1 = 1,212 and n2 = 678) provided data on prenatal maternal stress and genome-wide DNA methylation from cord blood and were meta-analysed (pooled n = 3,928). Measures of epigenetic age acceleration were calculated using three different gestational epigenetic clocks: "Bohlin", "EPIC overlap" and "Knight". Prenatal stress exposure, examined as an overall cumulative score, was not significantly associated with epigenetically-estimated gestational age acceleration or deceleration in any of the clocks, based on the results of the pooled meta-analysis or those of the individual cohorts. No significant associations were identified with specific domains of prenatal stress exposure, including negative life events, contextual (socio-economic) stressors, parental risks (e.g., maternal psychopathology) and interpersonal risks (e.g., family conflict). Further, no significant associations were identified when analyses were stratified by sex. Overall, we find little support that prenatal psychosocial stress is associated with variation in epigenetic age at birth within the general paediatric population.

Fetal exposure to prenatal maternal stress can have lifelong consequences, with different types of maternal stress associated with different areas of child development. Fewer studies have focused on motor skills, even though they are strongly predictive of later development across a range of domains. Research on mechanisms of transmission has identified biological cascades of stress reactions, yet links between psychological stress reactions are rarely studied. This study investigates the relationship between different aspects of disaster-related prenatal maternal stress and child cognitive and motor development, and proposes a cascade of stress reactions as a potential mechanism of transmission. Mothers in the Queensland Flood Study (QF2011) exposed to a major flood during pregnancy completed questionnaires assessing flood exposure, symptoms of peritraumatic distress, dissociation, and posttraumatic stress (PTSD), and cognitive appraisal of the overall flood consequences. At 16 months post-partum, children's (N = 145) cognitive and motor development was assessed using the Bayley-III. Flood exposure predicted child cognitive development and maternal PTSD symptoms and negative cognitive appraisal were significantly negatively related to child motor development, with all relationships moderated by timing of exposure. Together, a cascade of stress reactions linked maternal flood exposure to poorer fine motor development. These findings suggest that the way stress reactions operate together is as important as the way they operate in isolation, and identifies a potential psychological mechanism of transmission for the effects of prenatal stress. Results have implications for conceptualizing prenatal stress research and optimizing child development in the wake of natural disasters. (PsycINFO Database Record

BackgroundExposure to prenatal stress is associated with later adverse health and adjustment outcomes. This is generally presumed to arise through early environmentally mediated programming effects on the foetus. However, associations could arise through factors that influence mothers' characteristics and behaviour during pregnancy which are inherited by offspring.MethodA ‘prenatal cross-fostering’ design where pregnant mothers are related or unrelated to their child as a result of in vitro fertilization (IVF) was used to disentangle maternally inherited and environmental influences. If links between prenatal stress and offspring outcome are environmental, association should be observed in unrelated as well as related mother–child pairs. Offspring birth weight and gestational age as well as mental health were the outcomes assessed.ResultsAssociations between prenatal stress and offspring birth weight, gestational age and antisocial behaviour were seen in both related and unrelated mother–offspring pairs, consistent with there being environmental links. The association between prenatal stress and offspring anxiety in related and unrelated groups appeared to be due to current maternal anxiety/depression rather than prenatal stress. In contrast, the link between prenatal stress and offspring attention deficit hyperactivity disorder was only present in related mother–offspring pairs and therefore was attributable to inherited factors.ConclusionsGenetically informative designs can be helpful in testing whether inherited factors contribute to the association between environmental risk factors and health outcomes. These results suggest that associations between prenatal stress and offspring outcomes could arise from inherited factors and post-natal environmental factors in addition to causal prenatal risk effects.

Introduction: The amygdala is a brain structure involved in emotional regulation. Studies have shown that larger amygdala volumes are associated with behavioral disorders. Prenatal maternal depression is associated with structural changes in the amygdala, which in turn, is predictive of an increase in behavioral problems. Girls may be particularly vulnerable. However, it is not known whether disaster-related prenatal maternal stress (PNMS), or which aspect of the maternal stress experience (i.e., objective hardship, subjective distress, and cognitive appraisal), influences amygdala volumes. Nor is it known whether amygdala volumes mediate the effect of PNMS on behavioral problems in girls and boys.Aims: To assess whether aspects of PNMS are associated with amygdala volume, to determine whether timing of exposure moderates the effect, and to test whether amygdala volume mediates the association between PNMS and internalizing and externalizing problems in 11½ year old children exposed in utero, to varying levels of disaster-related PNMS.Methods: Bilateral amygdala volumes (AGV) and total brain volume (TBV) were acquired using magnetic resonance imaging, from 35 boys and 33 girls whose mothers were pregnant during the January 1998 Quebec Ice Storm. The mothers' disaster-related stress was assessed in June 1998. Child internalizing and externalizing problems were assessed at 11½ years using the Child Behavior Checklist (CBCL). Hierarchical regression analyses and mediation analyses were conducted on boys and girls separately, controlling for perinatal and postnatal factors.Results: In boys, subjective distress was associated with larger right AGV/TBV when mothers where exposed during late pregnancy, which in turn explained higher levels of externalizing behavior. However, when adjusting for postnatal factors, the effect was no longer significant. In girls, later gestational exposure to the ice storm was associated with larger AGV/TBV, but here, higher levels of objective PNMS were associated with more externalizing problems, which was, in part, mediated by larger AGV/TBV. No effects were detected on internalizing behaviors.Conclusion: These results suggest that the effects of PNMS on amygdala development and externalizing symptoms, as assessed in boys and girls in early adolescence, can be influenced by the timing of the stress in pregnancy, and the particular aspect of the mother's stress experience.

In Australia, anxiety disorders are the most common mental health problem experienced by children. Clinically significant anxiety in childhood comes with enduring social-functioning and academic personal costs, as well as societal economic burden. My thesis aims to add to our understanding of the populations at risk of developing anxiety disorders, with the aim of informing targeted intervention and prevention.The Developmental Origins of Health and Disease (DoHAD) framework posits that exposure to prenatal maternal distress (e.g., maternal anxiety or depression, emotional response to life events) has enduring effects on child development, including the development of anxiety symptoms and internalizing behaviors (herein referred to as “anxiety symptomatology”). Few studies have examined the relationship between prenatal maternal stress and child anxiety symptomatology in a way that disentangles prenatal effects from mother-child heritability effects (e.g., by using a natural experiment design). In a separate but potentially highly-related line of research, developmental psychopathology research suggests that early child temperament and parenting behaviors play a role in the development of anxiety symptomatology. Whether these factors, or their interplay, explain the development of childhood anxiety symptomatology following in utero exposure to maternal stress in pregnancy is unknown.My thesis examines models of anxiety symptomatology development in childhood, in a cohort of children exposed in utero to disaster-related maternal stress. I first look to investigate the relationship between different aspects of disaster-related prenatal maternal stress and child anxiety symptomatology. I then examine toddler temperamental characteristics as identifiable vulnerability markers of later anxiety symptomatology development, following exposure to prenatal maternal stress. Finally, I examine the role of parent-child interactions in the development of anxiety, following prenatal maternal stress exposure.In January 2011, the Australian state of Queensland experienced a severe flood that saw 78% of the state declared a disaster zone. The QF2011 Queensland Flood Study recruited pregnant women shortly after the flood (N = 230). At recruitment, mothers’ objective exposure to the floods, subjective stress (peritraumatic distress, peritraumatic dissociation, and post-traumatic stress symptoms), and cognitive appraisal of the flood’s impact were assessed. Maternal reports of toddler temperament (attentional control, negative reactivity, shy-inhibited behaviors) were collected at 16 months (N = 146) and 30 months (N = 133) via the Short Temperament Scale for Toddlers (STST). Child anxiety symptoms at age 4 were assessed using maternal (Child Behavior Checklist; CBCL/1.5-5; N = 118) and teacher reports (C-TRF/1.5-5; N = 92) of internalizing behaviors (withdrawal, anxiety, depression, and somatic complaints), as well as maternal reports of specific anxiety symptoms (Spence Preschool Anxiety Scale [SPAS]; 117). Observational videos of the maternal parenting styles (overcontrol, negativity) directed towards the child during a challenging puzzle-task were coded at 4 years (N = 109). At 6 years, 124 mothers reported on their child’s specific anxiety symptoms (SPAS). Information on maternal psychosocial factors during pregnancy and the postnatal period were obtained.At 4 years, greater maternal objective hardship due to the floods (e.g., financial burden, property damage) during pregnancy predicted greater maternal-reported anxiety symptomatology. Children whose mothers were exposed earlier in gestation to the flooding displayed more specific anxiety symptoms. Higher levels of negative reactivity in toddlers (16 months) accounted, in part, for the relationship between increased maternal objective hardship due to a flood disaster and higher levels of maternal- but not teacher-reported internalizing problems. At 30 months, greater exposure to maternal subjective stress in pregnancy was associated with less shy-inhibited behaviors. Unlike at 4 years, PNMS exposure did not predict anxiety symptoms at 6 years. The development of 6-year anxiety symptoms was not predicted by interactions between PNMS-exposure and parenting behaviors, nor early predispositions of shy-inhibited behaviors and parenting behaviors. At 6 years, only poor concurrent maternal mood predicted greater anxiety symptoms. Overall, pathways were dependent on the type of maternal stress experienced, toddler temperament profiles, and dimension of anxiety symptomatology (i.e. internalizing behaviors versus anxiety symptoms).My thesis uses a novel, innovative design to disentangle the unique effect of prenatal maternal stress on both child development and maternal parenting. The findings further our understanding of the many and varied developmental pathways of anxiety symptomatology, with a focus on conceptualizing the development of anxiety symptomatology as beginning prior to birth. Together, the studies highlight the salience of exposure to hardship due to an independent stressful event in pregnancy as a vulnerability factor in the development of early toddler temperament and anxiety symptomatology, independent of subjective stress from the event. Discontinuity of PNMS effects across development highlight the need to investigate the trajectories of anxiety symptoms across later childhood and adolescence, as well as potential moderators and mediators of PNMS effects across development. My findings illustrate the complexity of understanding the origins of childhood anxiety symptomatology. Finally, my research encourages discussion of how best to promote and deliver early prevention and intervention for at-risk children, especially in the wake of a natural disaster.

DNA methylation as a mediator in the association between prenatal maternal stress and child mental health outcomes: Current state of knowledge

The 5-HTTLPR polymorphism of the serotonin transporter has been shown to play a role in autism spectrum disorders (ASD). Moreover, disaster-related prenatal maternal stress (PNMS) has also been shown to be associated with ASD. However, no study to date has examined whether these two factors, either individually or in combination, are predictive of ASD traits in the same sample. We hypothesized that children, particularly boys, with the LL genotype exposed to high levels of disaster-related PNMS would exhibit higher levels of ASD traits compared to boys with the LS or SS genotypes and girls regardless of genotype. Genotype and ASD levels obtained using the Australian normed Autism Spectrum Rating Scales - Short Form were available for 105 30-month-old children exposed to varying levels of PNMS following the 2011 Queensland Flood. For boys, higher ASD traits were associated with the 5-HTTLPR LL genotype in combination with either a negative maternal appraisal of the flood, or high levels of maternal composite subjective stress, PSTD-like or peritraumatic dissociation symptoms. For girls, maternal peritraumatic dissociation levels in combination with the 5-HTTLPR LS or SS genotype were associated with higher ASD traits. The present findings are the first to demonstrate that children's genotype moderates effects of disaster-related PNMS on ASD traits, with different pattern according to child sex.

Intrauterine stress exposure is associated with offspring health. DNA methylation (DNAm) is a putative underlying mechanism, but large population-based studies reported limited associations between prenatal stress and DNAm. Recent research has shown that environmental factors in interaction with genetic variants are better predictors of DNAm than environment or genotype alone. We investigated whether interactions of maternal prenatal stress with genetic variants are associated with DNAm at birth. We examined 2963 mother-child pairs from the population-based Generation R Study and Avon Longitudinal Study of Parents and Children, using a harmonized, comprehensive cumulative prenatal stress measure. We tested genome-wide genotype-by-prenatal stress interactions on epigenome-wide DNAm (GxEmodel), and models including only genetic variants (Gmodel) or prenatal stress (Emodel) as predictors. Follow-up analyses included Gene Ontology analyses and mediation analyses of prenatal alcohol intake, smoking, gestational age, and birth weight. We report two independent gene-by-prenatal-stress interactions on DNAm after multiple testing correction, including five genetic variants in CHD2 and ORC5, and two DNAm sites in EPPK1. By comparison, the Gmodel showed 691,202 associations and the Emodel showed three associations in genes AHRR, GFI1, and MYO1G, which could largely be explained by prenatal smoking. Genes linked to suggestive GxEmodel results were often involved in neuronal development. Our results provide some support of interaction of prenatal stress with the child’s genome on DNAm of genes related to neuronal development. Based on these models, genetic main effects on DNA methylation at birth were much more abundant than gene-by-prenatal stress interactions were.

Prenatal maternal stress is associated with toddler cognitive functioning: The Iowa Flood Study

Disaster-related prenatal maternal stress, and childhood HPA-axis regulation and anxiety: The QF2011 Queensland Flood Study

Evidence from both animals and humans suggests that maternal prenatal anxiety and stress can have adverse consequences on the offspring's development. Animal models also show that prenatal stress has programming effects on the physical health of the offspring, such as immune functioning. In human studies, however, physical health outcomes are often restricted to birth complications; studies on the effects of acquiring illnesses are scarce. This study aimed to examine whether maternal prenatal anxiety and stress, measured both by self-report and by cortisol physiology, are related to more infant illnesses and antibiotic use during the first year of life. Participants in the study were 174 mothers with normal pregnancies and term deliveries (71 firstborns; 91 boys). The mothers filled out third-trimester questionnaires on general and pregnancy-specific anxiety and stress and provided saliva samples for circadian cortisol. Information on infant illnesses and antibiotic use was obtained through monthly maternal interviews across the infant's first year of life. Hierarchical multiple regressions showed that, even after controlling for many relevant confounders, prenatal anxiety and stress predicted a considerable amount of variance in infant illnesses and antibiotic use: 9.3% for respiratory, 10.7% for general, 8.9% for skin, and 7.6% for antibiotic use. Digestive illnesses were not related to prenatal anxiety and stress. Although replication is warranted, to our knowledge, this is the first evidence linking maternal prenatal anxiety and stress to infant illnesses and antibiotic use early in life.

Developmental exposure to lead (Pb) and prenatal stress (PS) both impair cognition, which could derive from their joint targeting of the hypothalamic-pituitary-adrenal axis and the brain mesocorticolimbic (MESO) system, including frontal cortex (FC) and hippocampus (HIPP). Glucocorticoids modulate both FC and HIPP function and associated mediation of cognitive and other behavioral functions. This study sought to determine whether developmental Pb ± PS exposures altered glucocorticoid-related epigenetic profiles in brain MESO regions in offspring of female mice exposed to 0 or 100 ppm Pb acetate drinking water from 2 mos prior to breeding until weaning, with half further exposed to prenatal restraint stress from gestational day 11-18. Overall, changes in females occured in response to Pb exposure. In males, however, Pb-induced neurotoxicity was modulated by PS. Changes in serum corticosterone levels were seen in males, while glucocorticoid receptor changes were seen in both sexes. In contrast, both Pb and PS broadly impacted brain DNA methyltransferases and binding proteins, particularly DNMT1, DNMT3a and methyl-CpG-binding protein 2, with patterns that differed by sex and brain regions. Specifically, in males, effects on FC epigenetic modifiers were primarily influenced by Pb, whereas extensive changes in HIPP were produced by PS. In females, Pb exposure and not PS primarily altered epigenetic modifiers in both FC and HIPP. Collectively, these findings indicate that epigenetic mechanisms may underlie associated neurotoxicity of Pb and of PS, particularly associated cognitive deficits. However, mechanisms by which this may occur will be different in males versus females.