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Associations between maternal stroking at 9 weeks and child irritability at 7 years, in matched and mismatched prenatal and postnatal maternal anxiety groups. In the left hand panel the dotted regression lines show the association between maternal stroking age 9 weeks and irritability at age 9 years in each mismatched maternal anxiety group (low prenatal - high postnatal; high prenatal - low postnatal) and the solid lines in each matched group (low prenatal - low postnatal; high prenatal - high postnatal). The groups were generated using medians of the maternal anxiety distributions. The right hand panel shows the regression lines and 95% confidence intervals in the combined mismatched and matched groups.
Source publication
Sex-dependent effects of mismatched prenatal-postnatal maternal conditions are predicted by combining two evolutionary hypotheses: that foetal conditions provide a forecast of likely postnatal environments (Predictive Adaptive Response), and that the female foetus is better adapted than the male to maternal adversity (Trivers-Willard hypothesis). A...
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Citations
... The match/mismatch and PAR hypotheses both propose that moderate levels of early life stress can acquire resilience to renewed stress exposure later in life by preparing the offspring to better cope with a challenging adult environment [7,83]. However, if there is a mismatch between predicted and recent environment, this may also increase risk for adverse outcomes in later life [36]. This can be illustrated with the following example: If a fetus develops in a nutrition-low environment, its metabolism adapts to this lack of nutrition. ...
Fetal exposure to prenatal stress can have significant consequences on short- and long-term health. Epigenetic mechanisms, especially DNA methylation (DNAm), are a possible process how these adverse environmental events could be biologically embedded. We evaluated candidate gene as well as epigenome-wide association studies associating prenatal stress and DNAm changes in peripheral tissues; however, most of these findings lack robust replication. Prenatal stress-associated epigenetic changes have also been linked to child health including internalizing problems, neurobehavioral outcomes and stress reactivity. Future studies should focus on refined measurement and definition of prenatal stress and its timing, ideally also incorporating genomic as well as longitudinal information. This will provide further opportunities to enhance our understanding of the biological embedding of prenatal stress exposure.
... Results are therefore in the hypothesised direction for females, but in the opposite direction for males. Our examinations of sex differences were exploratory, not determined a-priori, and based on evidence from studies implicating sex differences in effects of early life stress on DNA methylation at the NR3C1 gene (33,69). Therefore, the sex difference in effect of treatment group on FKBP5 DNA methylation was not directly hypothesised and should be interpreted with caution. ...
Introduction
A major modifiable risk factor for behavioural difficulties is harsh and insensitive parenting, and it has been hypothesised that the biological mechanism by which parenting influences child behaviour is via changes in the child's DNA methylation. We attempted to, in part, address the hypothesis that parenting is associated with child DNA methylation and, in turn, behaviour.
Methods
Primary caregivers of young children with behavioural difficulties (children aged 12–36 months) were randomised to receive a video-feedback Intervention to promote Positive Parenting and Sensitive Discipline (VIPP-SD) ( n = 151), or usual care ( n = 149). Child buccal samples were collected at a 2-year post-randomisation follow up (children aged 3–5 years, VIPP-SD group n = 106, usual care group n = 117) and were assessed for DNA methylation at the NR3C1, FKBP5 and OXYR genes. Child behaviour was assessed at baseline, post-intervention and 2-years post-randomisation using the Preschool Parental Account of Children's Symptoms (PPACS). We examined group differences in DNA methylation, associations of DNA methylation with behaviour, and sex differences.
Results
For the NR3C1 and OXYR genes, there were no group differences, sex differences, or associations of DNA methylation with child behaviour, though all non-significant findings were in the hypothesised direction. For FKBP5 DNA methylation, there was a significant interaction between group and sex, such that males in the usual care group had higher DNA methylation than females, but in the intervention group females had higher DNA methylation than males. However, FKBP5 DNA methylation was not associated with behaviour in males or females.
Discussion
We provide the first evidence from a randomised controlled trial focused on improving parenting for sex-specific changes in child DNA methylation at a key gene involved in stress reactivity and psychopathology. This study adds to our understanding of causal mechanisms linking parenting with child behaviour, which is important for developing targeted interventions. A key limitation is that child DNA methylation was only assessed at one time point, so we were unable to assess change in DNA methylation over time. However, we demonstrate that is possible to collect and analyse DNA samples from families with young children receiving parenting interventions in the community, providing impetus for further research on this topic.
... An evolutionary perspective may help explain these results [13,36]. The concept of predictive adaptive response [13,37] explains that early experiences in utero are a source of information about the environment in which the child will live and that foetal development is an opportunity to adapt to that future environment and have a successful development. Therefore, children's emotional reactivity, anxiety/ depression, sleep, attention and aggression problems potentially reflect adaptative behaviours to predicted stressful environments [37]. ...
... The concept of predictive adaptive response [13,37] explains that early experiences in utero are a source of information about the environment in which the child will live and that foetal development is an opportunity to adapt to that future environment and have a successful development. Therefore, children's emotional reactivity, anxiety/ depression, sleep, attention and aggression problems potentially reflect adaptative behaviours to predicted stressful environments [37]. These predictive adaptative responses have an evolutionary value when the postnatal environment is perceived as dangerous, and behavioural and emotional outcomes help ensure survival in threatening environments [13]. ...
Purpose: Associations between prenatal earthquake exposure and children's mental health remain unclear. Moreover, there is a paucity of research using quasi-experimental statistical techniques to diminish potential selection bias. Thus, this study aimed to explore the impact of prenatal exposure to the Chilean earthquake of 2010 on children's behavioural and emotional problems between 1½ and 3 years old using propensity score matching.
Methods: Participants included 1549 families from the Encuesta Longitudinal de la Primera Infancia cohort in Chile. Maternal reports using the Child Behaviour Checklist (CBCL) were used to assess behavioural and emotional problems between 1½ and 3 years old. Information on prenatal earthquake exposure was collected via maternal report. The Kernel matching estimator was used to compare the average treatment effects of children who were exposed to the earthquake compared to those who were not.
Results: Five of the seven CBCL outcomes were statistically significant after matching and adjustment for multiple testing, suggesting greater difficulties for exposed children which included emotional reactivity, anxious/depressed, sleep problems, attention problems, and aggression (mean difference of 0.69, 0.87, 0.73, 0.85, 3.51, respectively). The magnitude of the effect was small to medium.
Conclusion: Findings contribute to the potential causal inferences between prenatal earthquake exposure and increased behavioural and emotional problems in early childhood. Results suggest that in utero experiences may have long-term consequences for infants' well-being, supporting the need for specific interventions in pregnancy after natural disasters.
... There is growing evidence that exposure to prenatal maternal stress increases risk of offspring affective problems and emotional instability. 2,3 By contrast, exposure to PNTD in either parent may reflect risk transmitted via altered parenting behaviour, and the overall effect may be similar with exposure to each parent owing to a shared parenting pathway. 4 In addition, given existing epidemiological evidence of gender differences 5 and animal evidence for a female fetal vulnerability to stress hormones in relation to maternal ANTD exposure (for an overview of the animal literature, see Kapoor et al 6 ), it is possible that female offspring may be more vulnerable to the effects of maternal ANTD. ...
Background
The relationships between offspring depression profiles across adolescence and different timings of parental depression during the perinatal period remain unknown.
Aims
To explore different timings of maternal and paternal perinatal depression in relation to patterns of change in offspring depressive mood over a 14 year period.
Method
Data were obtained from the Avon Longitudinal Study of Parents and Children (ALSPAC). Parental antenatal depression (ANTD) was assessed at 18 weeks gestation, and postnatal depression (PNTD) at 8 weeks postpartum. Population-averaged trajectories of offspring depressive symptoms were estimated using the Short Mood and Feelings Questionnaire (SMFQ) on nine occasions between 10 and 24 years of age.
Results
Full data were available for 5029 individuals. Offspring exposed to both timings of maternal depression had higher depressive symptoms across adolescence compared with offspring not exposed to ANTD or PNTD, characterised by higher depressive symptoms at age 16 (7.07 SMFQ points (95% CI = 6.19, 7.95; P < 0.001)) and a greater rate of linear change (0.698 SMFQ points (95% CI = 0.47, 0.93; P = 0.002)). Isolated maternal ANTD and to a lesser extent PNTD were also both associated with higher depressive symptoms at age 16, yet isolated maternal PNTD showed greater evidence for an increased rate of linear change across adolescence. A similar pattern was observed for paternal ANTD and PNTD, although effect sizes were attenuated.
Conclusions
This study adds to the literature demonstrating that exposure to two timings of maternal depression (ANTD and PNTD) is strongly associated with greater offspring trajectories of depressive symptoms.
... While there is growing support for the match-mismatch hypothesis, animal models suggest that not just prenatal effects, but also postnatal modifications play an important role for later neuropsychiatric outcomes. For instance, high maternal care, measured in tactile stimulation, may be related to improvements in HPA-axis functioning as well as related behaviors in the offspring across species (Hill et al. 2019;Lemaire et al. 2006;Weaver et al. 2004). In addition, increasing evidence suggests that the effects of stress on the fetus are sex-specific, and female offspring may be more vulnerable to the negative effects of glucocorticoids (Hill et al. 2019). ...
... For instance, high maternal care, measured in tactile stimulation, may be related to improvements in HPA-axis functioning as well as related behaviors in the offspring across species (Hill et al. 2019;Lemaire et al. 2006;Weaver et al. 2004). In addition, increasing evidence suggests that the effects of stress on the fetus are sex-specific, and female offspring may be more vulnerable to the negative effects of glucocorticoids (Hill et al. 2019). ...
Biological embedding of prenatal stress can increase the risk for maladaptive child neurodevelopmental outcomes. The search is on for more precise mechanisms implicated in this biological embedding. In recent years, researchers have focused on how epigenetic processes are implicated in the transmission of prenatal stress to the fetus. A number of specific epigenetic mechanisms have been studied to test the hypothesis that prenatal stress signals may alter epigenetic processes and, subsequently, fetal stress response systems. In this chapter, we briefly discuss the historical, theoretical, and empirical background linking epigenetic mechanisms with prenatal stress research. We describe common epigenetic mechanisms and the promises as well as difficulties inherent in examining epigenetic processes as mechanisms linking prenatal stress with child developmental outcomes in humans. As an example of our approach to examining these epigenetic processes, we review key genes that are implicated in the fetal programming of the stress response that could have downstream effects on immune system functioning and neurodevelopment. Finally, we discuss future directions for the study of epigenetic processes linking maternal prenatal stress with offspring neurodevelopmental outcomes.
... In the neurodevelopmental theory of depression [12], the authors emphasized the importance of early developmental stages for the onset of disease symptoms in adult life. This paper will focus on issues related to mother-child interactions, making an attempt to demonstrate the influence of their epigenetic mechanisms (mainly DNA methylation) leading in childhood and in adulthood to the occurrence of depressive symptoms [13]. ...
The genome (genes), epigenome, and environment work together from the earliest stages of human life to produce a phenotype of human health or disease. Epigenetic modifications, including among other things: DNA methylation, modifications of histones and chromatin structure, as well as functions of noncoding RNA, are coresponsible for specific patterns of gene expression. This refers also to mental disorders, including depressive disorders. Early childhood experiences accompanied by severe stressors (considered a risk factor for depression in adult life) are linked with changes in gene expression. They include genes involved in a response to stress (hypothalamic-pituitary-adrenal axis, HPA), associated with autonomic nervous system hyperactivity and with cortical, and subcortical processes of neuroplasticity and neurodegeneration. These are, among others: gene encoding glucocorticoid receptor, FK506 binding protein 5 gene (FKBP5), gene encoding arginine vasopressin and oestrogen receptor alpha, 5-hydroxy-tryptamine transporter gene (SLC6A4), and gene encoding brain-derived neurotrophic factor. How about personality? Can the experiences unique to every human being, the history of his or her development and gene-environment interactions, through epigenetic mechanisms, shape the features of our personality? Can we pass on these features to future generations? Hence, is the risk of depression inherent in our biological nature? Can we change our destiny?
... This mismatch effect was not seen in males, and the sex difference was supported by a three-way interaction between prenatal and postnatal depression and child sex. We have also shown moderation by prenatal anxiety of the association between postnatal maternal anxiety and child irritability at age 7 years, further moderated by levels of maternal stroking during infancy (Hill, Pickles, Wright, Braithwaite & Sharp, 2019). This effect also was seen only in girls. ...
... It can be seen that girls exposed to the mismatch between prenatal and postnatal conditions (low prenatal depression-high postnatal depression) have higher emotional symptoms than the boys. In the panel showing the sex difference following high prenatal depression, the boys exposed to matched (high prenatal-high postnatal) conditions have higher emotional symptoms than the girls [Colour figure can be viewed at wileyonlinelibrary.com] publications from WCHADS, that prenatal affective symptoms moderate associations between postnatal exposures and child outcomes, assessed as NR3C1 methylation at age 14 months (Murgatroyd, Quinn, Sharp, Pickles & Hill, 2015), child emotional symptoms up to age 5 years Hill, Pickles, Wright, Quinn, et al., 2019) and irritability at age 7 years (Hill, Pickles, Wright, Braithwaite, et al., 2019). In each case, these effects were modified by sex of child. ...
... At 6 months, this PAR effect was confined to female infants, consistent with the T-W hypothesis, although the sex difference was no longer evident by 12 months (Sandman et al, 2013). As outlined earlier, we have previously shown higher NR3C1 methylation levels in the children of mothers with the incongruent low prenatal and high postnatal depression than congruent high prenatal-high postnatal levels, and mediation by NR3C1 methylation of the association with later anxious-depressed symptoms, in girls only (Hill, Pickles, Wright, Quinn, et al., 2019;Hill, Pickles, Wright, Braithwaite, et al., 2019;Murgatroyd et al, 2015). Further studies with outcomes that are not confounded by reporter effects for example of observed behaviour or biological measures are needed. ...
Background
Based on previous findings from the Wirral Child Health and Development Study (WCHADS), and on evolutionary hypotheses, we preregistered analyses of data from a large epidemiological sample (https://osf.io/fn5g9/register/564d31db8c5e4a7c9694b2be), to test for sex‐dependent moderation by prenatal maternal depressive symptoms of the association between postnatal maternal depressive symptoms and child emotional problems.
Methods
A total of 8,354 mothers and children were followed from pregnancy to 3.5 years in the Avon Longitudinal Study of Parents and Children (ALSPAC). Self‐report measures of prenatal and postnatal maternal depressive symptoms, and maternal report of child emotional symptoms were administered.
Results
There was a three‐way interaction between maternal prenatal and postnatal depression, and child sex (Coeff .042 95% CI 0.015 to 0.068, p = .002). This arose from moderation by prenatal depression, in opposite directions in boys and in girls. In boys, the association between postnatal depression and child emotional symptoms was weaker following lower prenatal depressive symptoms (interaction term coeff = .030, p = .001), and in girls, to a lesser extent, the association was stronger following lower prenatal depressive symptoms (interaction term coeff = −.012, p = .221).
Conclusions
We replicated the finding from the WCHADS that prenatal depression modifies the association between postnatal depression and children's emotional problems in a sex‐dependent fashion. In ALSPAC, the sex difference was explained mainly by a protective effect of low prenatal depression in boys, while in WCHADS, it arose from greater vulnerability of girls to postnatal depression following low prenatal depression. In the light of these findings, in evaluating and implementing early interventions, there is need to consider that risks associated with postnatal depression may vary depending on maternal mood during pregnancy and may differ between boys and girls.
... In the neurodevelopmental theory of depression [15], the authors emphasized the importance of early developmental stages for the onset of disease symptoms in adult life. This paper will focus on issues related to the mother-child interactions, making an attempt to demonstrate the influence of their nature on epigenetic mechanisms (mainly DNA methylation) leading in childhood and in adulthood to the occurrence of depressive symptoms [21]. ...
The genome (genes), epigenome and environment work together from the earliest stages of human life to produce a phenotype of human health or disease. Epigenetic modifications, including among other things: DNA methylation, modifications of histones and chromatin structure, as well as functions of non-coding RNA, are co-responsible for specific patterns of gene expression. This refers also to mental disorders, including depressive disorders.
Early childhood experiences accompanied by severe stressors (considered a risk factor for depression in adult life) are linked with changes in gene expression. They include: genes involved in a response to stress (hypothalamic-pituitary-adrenal axis, HPA), associated with autonomic nervous system hyperactivity and with cortical and subcortical processes of neuroplasticity and neurodegeneration. These are, among others: gene encoding glucocorticoid receptor, FK506 binding protein 5 gene (FKBP5), gene encoding arginine vasopressin and oestrogen receptor alpha, 5-hydroxy-tryptamine transporter gene (SLC6A4), and gene encoding brain-derived neurotrophic factor.
How about personality? Can the experiences unique to every human being, the history of his or her development and gene-environment interactions, through epigenetic mechanisms, shape the features of our personality? Can we pass on these features to future generations? Hence, is the risk of depression inherent in our biological nature? Can we change our destiny?
... Fetal programming can be part of a "predictive adaptive response" (Gluckman, Hanson, & Spencer, 2005;Hill, Pickles, Wright, Braithwaite, & Sharp, 2019). These predictive responses may be "plastic decisions made by the embryo/fetus/neonate in response to how it interprets the current environment as a predictor of the future one" (Gluckman, Beedle, Buklijas, Low, & Hanson, 2016). ...
The impact of stress on brain health begins in the womb. Both animal and human studies have found that prenatal maternal stress affects the brain and behavior of the offspring. Stressful life events, exposure to a natural disaster, and symptoms of maternal anxiety and depression increase the risk for the child having a range of emotional, behavioral and/or cognitive problems in later life. These include depression, anxiety, Attention Deficit Hyperactivity Disorder (ADHD), and/or conduct disorders. There is an increased risk for other outcomes also, including preterm delivery and reduced telomere length, possibly indicative of an accelerated life history. The causal role of prenatal maternal stress on the etiology of the neurodevelopmental disorders is supported by large population cohorts, which have controlled for a wide range of potential confounders, including postnatal maternal mood. More recently, research has begun to explore the biological correlates and mediators of these findings. These studies suggest that the hypothalamic pituitary adrenal (HPA) axis plays a role in mediating the effects of maternal stress on the fetal brain. Further, in vivo brain imaging research reports that maternal stress is associated with changes in limbic and frontotemporal networks, and the functional and microstructural connections linking them. The structural changes include cortical thinning and an enlarged amygdala. While these studies have been conducted on smaller sample sizes and could not control for many confounders, the observed brain changes do plausibly underlie many of the emotional, behavioral and cognitive changes found to be associated with prenatal stress.
... We previously reported that the association between prenatal anxiety and child emotional and behavioural outcomes is only seen in the presence of low maternal stroking, consistent with animal studies of the protective effects of postnatal tactile stimulation [8]. In addition, we showed that mismatched prenatal-postnatal maternal anxiety was associated with elevated child irritability at age 7 years, only in the presence of low maternal stroking [10], consistent with a mismatch effect creating vulnerability that is modified by early tactile stimulation. ...
Evolutionary hypotheses predict that male fetuses are more vulnerable to poor maternal conditions (Sex-biased Maternal Investment), but female fetuses are at greater risk of glucocorticoid-mediated disorders where there is a mismatch between fetal and postnatal environments (Predictive Adaptive Response). Self-reported prenatal and postnatal depression and maternal report of child anxious-depressed symptoms at 2.5, 3.5 and 5.0 years were obtained from an ‘extensive’ sample of first-time mothers (N = 794). Salivary NR3C1 1-F promoter methylation was assayed at 14 months in an ‘intensive’ subsample (n = 176) and stratified by psychosocial risk. Generalised structural equation models were fitted and estimated by maximum likelihood to allow the inclusion of participants from both intensive and extensive samples. Postnatal depression was associated with NR3C1 methylation and anxious-depressed symptoms in daughters of mothers with low prenatal depression (prenatal-postnatal depression interaction for methylation, p < 0.001; for child symptoms, p = 0.011). In girls, NR3C1 methylation mediated the association between maternal depression and child anxious-depressed symptoms. The effects were greater in girls than boys: the test of sex differences in the effect of the prenatal-postnatal depression interaction on both outcomes gave X2 (2) = 5.95 (p = 0.051). This was the first human study to show that epigenetic and early behavioural outcomes may arise through different mechanisms in males and females.
