Maternal prenatal stress and fetal programming: long term biobehavioural outcomes in the child and potential placental mechanisms

Mounting evidence suggests prenatal stress can affect child development. Clinical studies of this concept, termed fetal programming, focus predominantly on early childhood. Also, little is known about the mechanisms underlying how maternal stress is transmitted to the fetus. This thesis will test if maternal anxiety during pregnancy is associated with (1) behavioural outcomes from childhood to early adolescence, (2) cortisol output in adolescence and (3) an altered placental phenotype. For Studies 1 and 2 participants were drawn from the Avon Longitudinal Study of Parents and Children (ALSPAC). Psychometric data from 9,871 mother child pairs (5,098 males, 4,773 females) were analysed using latent growth curve analysis. A subsample of the ALSPAC children aged 15 years (n = 899) provided saliva samples on three days at waking, +35mins, after school and before bed, for later cortisol analysis. For Study 3 a new cohort of women (n= 73) was recruited. Maternal psychometric data was collected one day prior to elective caesarean section, and the placenta collected after delivery. Study 1 showed that maternal prenatal anxiety was associated with conduct and emotional problems, and symptoms of ADHD at age 13 years, after allowing for a range of confounders, including postnatal anxiety. There were marked sex differences in the developing patterns. Saliva cortisol demonstrated a marked diurnal profile with a clear sex difference at age 15. Higher maternal prenatal anxiety was associated with a reduced cortisol awakening response. High levels of maternal prenatal anxiety were associated with reduced placental expression and activity of the cortisol metabolising enzyme 11β-Hydroxy steroid dehydrogenase 2 (11β-HSD2) and also with reduced placental weight. This thesis provides evidence that maternal prenatal anxiety can affect behavioural and neuroendocrine outcomes in adolescence. It also provides preliminary evidence that maternal anxiety is associated with alterations in the function of the placenta, which may underlie some aspects of fetal programming. These findings have public health implications. Increasing awareness about the lasting effects of prenatal anxiety may ultimately benefit mothers, the care they receive and their families

Prenatal versus postnatal sex steroid hormone effects on autistic traits in children at 18 to 24 months of age.

BACKGROUND: Studies of prenatal exposure to sex steroid hormones predict autistic traits in children at 18 to 24 and at 96 months of age. However, it is not known whether postnatal exposure to these hormones has a similar effect. This study compares prenatal and postnatal sex steroid hormone levels in relation to autistic traits in 18 to 24-month-old children.Fetal testosterone (fT) and fetal estradiol (fE) levels were measured in amniotic fluid from pregnant women (n = 35) following routine second-trimester amniocentesis. Saliva samples were collected from these children when they reached three to four months of age and were analyzed for postnatal testosterone (pT) levels. Mothers were asked to complete the Quantitative Checklist for Autism in Toddlers (Q-CHAT), a measure of autistic traits in children 18 to 24 months old. FINDING: fT (but not pT) levels were positively associated with scores on the Q-CHAT. fE and pT levels showed no sex differences and no relationships with fT levels. fT levels were the only variable that predicted Q-CHAT scores. CONCLUSIONS: These preliminary findings are consistent with the hypothesis that prenatal (but not postnatal) androgen exposure, coinciding with the critical period for sexual differentiation of the brain, is associated with the development of autistic traits in 18 to 24 month old toddlers. However, it is recognized that further work with a larger sample population is needed before the effects of postnatal androgen exposure on autistic traits can be ruled out. These results are also in line with the fetal androgen theory of autism, which suggests that prenatal, organizational effects of androgen hormones influence the development of autistic traits in later life.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Maternal prenatal anxiety and child COMT genotype predict working memory and symptoms of ADHD

Maternal prenatal anxiety is an important risk factor for altered child neurodevelopment but there is uncertainty concerning the biological mechanisms involved and sources of individual differences in children's responses. We sought to determine the role of functional genetic variation in COMT, which encodes catechol-O-methyltransferase, in the association between maternal prenatal anxiety and child symptoms of ADHD and working memory. We used the prospectively-designed ALSPAC cohort (n = 6,969) for our primary data analyses followed by replication analyses in the PREDO cohort (n = 425). Maternal prenatal anxiety was based on self-report measures; child symptoms of ADHD were collected from 4-15 years of age; working memory was assessed from in-person testing at age 8 years; and genetic variation in COMT at rs4680 was determined in both mothers and children. The association between maternal prenatal anxiety and child attention/hyperactivity symptoms and working memory was moderated by the child's rs4680 genotype, with stronger effects obtained for the val/val (G: G) genotype relative to val/met (A:G) (all p <0.01) and met/met (A: A) groups (all p <0.05). Similar findings were observed in the PREDO cohort where maternal prenatal anxiety interacted with child rs4680 to predict symptoms of ADHD at 3.5 years of age. The findings, from two cohorts, show a robust gene-environment interaction, which may contribute to inter-individual differences in the effects of maternal prenatal anxiety on developmental outcomes from childhood to mid-adolescence.Peer reviewe

Effects of Antenatal Maternal Depressive Symptoms and Socio-Economic Status on Neonatal Brain Development are Modulated by Genetic Risk

This study included 168 and 85 mother-infant dyads from Asian and United States of America cohorts to examine whether a genomic profile risk score for major depressive disorder (GPRSMDD) moderates the association between antenatal maternal depressive symptoms (or socio-economic status, SES) and fetal neurodevelopment, and to identify candidate biological processes underlying such association. Both cohorts showed a significant interaction between antenatal maternal depressive symptoms and infant GPRSMDD on the right amygdala volume. The Asian cohort also showed such interaction on the right hippocampal volume and shape, thickness of the orbitofrontal and ventromedial prefrontal cortex. Likewise, a significant interaction between SES and infant GPRSMDD was on the right amygdala and hippocampal volumes and shapes. After controlling for each other, the interaction effect of antenatal maternal depressive symptoms and GPRSMDD was mainly shown on the right amygdala, while the interaction effect of SES and GPRSMDD was mainly shown on the right hippocampus. Bioinformatic analyses suggested neurotransmitter/neurotrophic signaling, SNAp REceptor complex, and glutamate receptor activity as common biological processes underlying the influence of antenatal maternal depressive symptoms on fetal cortico-limbic development. These findings suggest gene-environment interdependence in the fetal development of brain regions implicated in cognitive-emotional function. Candidate biological mechanisms involve a range of brain region-specific signaling pathways that converge on common processes of synaptic development

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

Maternal prenatal stress and fetal programming : long term biobehavioural outcomes in the child and potential placental mechanisms

Mounting evidence suggests prenatal stress can affect child development. Clinical studies of this concept, termed fetal programming, focus predominantly on early childhood. Also, little is known about the mechanisms underlying how maternal stress is transmitted to the fetus. This thesis will test if maternal anxiety during pregnancy is associated with (1) behavioural outcomes from childhood to early adolescence, (2) cortisol output in adolescence and (3) an altered placental phenotype. For Studies 1 and 2 participants were drawn from the Avon Longitudinal Study of Parents and Children (ALSPAC). Psychometric data from 9,871 mother child pairs (5,098 males, 4,773 females) were analysed using latent growth curve analysis. A subsample of the ALSPAC children aged 15 years (n = 899) provided saliva samples on three days at waking, +35mins, after school and before bed, for later cortisol analysis. For Study 3 a new cohort of women (n= 73) was recruited. Maternal psychometric data was collected one day prior to elective caesarean section, and the placenta collected after delivery. Study 1 showed that maternal prenatal anxiety was associated with conduct and emotional problems, and symptoms of ADHD at age 13 years, after allowing for a range of confounders, including postnatal anxiety. There were marked sex differences in the developing patterns. Saliva cortisol demonstrated a marked diurnal profile with a clear sex difference at age 15. Higher maternal prenatal anxiety was associated with a reduced cortisol awakening response. High levels of maternal prenatal anxiety were associated with reduced placental expression and activity of the cortisol metabolising enzyme 11β-Hydroxy steroid dehydrogenase 2 (11β-HSD2) and also with reduced placental weight. This thesis provides evidence that maternal prenatal anxiety can affect behavioural and neuroendocrine outcomes in adolescence. It also provides preliminary evidence that maternal anxiety is associated with alterations in the function of the placenta, which may underlie some aspects of fetal programming. These findings have public health implications. Increasing awareness about the lasting effects of prenatal anxiety may ultimately benefit mothers, the care they receive and their families.EThOS - Electronic Theses Online ServiceNational Institute of Health, the Medical Research Council and The Genesis Research TrustGBUnited Kingdo

Maternal prenatal stress and fetal programming : long term biobehavioural outcomes in the child and potential placental mechanisms

Mounting evidence suggests prenatal stress can affect child development. Clinical studies of this concept, termed fetal programming, focus predominantly on early childhood. Also, little is known about the mechanisms underlying how maternal stress is transmitted to the fetus. This thesis will test if maternal anxiety during pregnancy is associated with (1) behavioural outcomes from childhood to early adolescence, (2) cortisol output in adolescence and (3) an altered placental phenotype. For Studies 1 and 2 participants were drawn from the Avon Longitudinal Study of Parents and Children (ALSPAC). Psychometric data from 9,871 mother child pairs (5,098 males, 4,773 females) were analysed using latent growth curve analysis. A subsample of the ALSPAC children aged 15 years (n = 899) provided saliva samples on three days at waking, +35mins, after school and before bed, for later cortisol analysis. For Study 3 a new cohort of women (n= 73) was recruited. Maternal psychometric data was collected one day prior to elective caesarean section, and the placenta collected after delivery. Study 1 showed that maternal prenatal anxiety was associated with conduct and emotional problems, and symptoms of ADHD at age 13 years, after allowing for a range of confounders, including postnatal anxiety. There were marked sex differences in the developing patterns. Saliva cortisol demonstrated a marked diurnal profile with a clear sex difference at age 15. Higher maternal prenatal anxiety was associated with a reduced cortisol awakening response. High levels of maternal prenatal anxiety were associated with reduced placental expression and activity of the cortisol metabolising enzyme 11β-Hydroxy steroid dehydrogenase 2 (11β-HSD2) and also with reduced placental weight. This thesis provides evidence that maternal prenatal anxiety can affect behavioural and neuroendocrine outcomes in adolescence. It also provides preliminary evidence that maternal anxiety is associated with alterations in the function of the placenta, which may underlie some aspects of fetal programming. These findings have public health implications. Increasing awareness about the lasting effects of prenatal anxiety may ultimately benefit mothers, the care they receive and their families.EThOS - Electronic Theses Online ServiceNational Institute of Health, the Medical Research Council and The Genesis Research TrustGBUnited Kingdo

Impact of parental socioeconomic status on offspring’s mental health: protocol for a longitudinal community-based study

Introduction Socioeconomic status (SES) affects physical and mental health and cognitive functioning. The association between SES changes (SES mobility) and health has ethical and political implications in that the pernicious effects of inequality and the differential impact on social classes of economic and social policies. There is a lack of research conducted to explore the intergenerational transmission of parental SES changes on the offspring’s mental health and cognitive functioning. We aim to fill this gap and identify roles of parental SES changes in offspring’s mental health and cognitive outcomes.Methods and analysis This study will be based on a longitudinal cohort from the most populous municipality in the Canadian province of Quebec. Participants and their biological offspring will be invited to this study. For those with informed consent, we will collect their information on mental health, psychiatric disorders, cognitive functioning and early life experiences for offspring. Latent class growth analysis will be used to identify parental SES mobility groups. Multivariate regression analyses will be used to explore the roles of early life stress, parental SES mobility and their interactions in psychiatric disorders and cognitive functioning. Subgroup analyses (males and females) are also planned.Ethics and dissemination This study has been given ethical approval by the Research Ethics Board of the Douglas Mental Health University Institute (IUSMD-18/17). Each participant will provide informed consent on participation. We will disseminate research findings through publication in peer-reviewed academic journals and presentations at conferences. Lay summaries of major research findings will also be shared annually with our partners in the health system and community agencies located in the catchment area

Temperature variability and birthweight: Epidemiological evidence from Africa

Background: Mounting evidence supports an association between nonoptimal ambient temperatures (i.e., heat or cold) and risk of low birthweight (LBW) (<2500 g), while the effect of temperature variability (TV) is largely unknown. We aimed to quantify the association between TV and risk of LBW in Africa. Methods: Data on birthweight in 37 countries during 1990–2020 were collected from the Demographic and Health Surveys program. We calculated overall, intraday, and interday TV during the entire pregnancy and each trimester using hourly temperatures at ∼ 9 km resolution from ERA5-Land. We employed generalized linear mixed logistic regression, with random effects for country and survey cluster, to quantify the association between LBW and three separate TV metrics. Results: In total there were 33,863 (10.2%) LBW births out of 333,618 records. We found a J-shaped association between TV and LBW. Compared to the reference TV where the lowest risk was observed, extremely high (97.5th percentile) overall, intraday, and interday TV during the entire pregnancy increased the odds of LBW birth by 37.3% (26.7–48.8%), 24.1% (16.4–32.3%), and 15.1% (6.9–24.0%), respectively. In total, 7.3% of all LBW births in Africa were attributable to elevated overall TV. These associations were observed in dry climate zones, but not in tropical or temperate zones. Conclusions: Our study suggests an adverse impact of TV on the risk of LBW in Africa, according to three different TV definitions, underlining the significance of climate-health risk assessment in those most vulnerable to climate change