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The Impact of Maternal Distress on Child Neurodevelopment in a Sex-Specific Manner: Examining the Mediating Role of the Infant Gut Microbiome

  • Author / Creator
    Tessier, Carmen A
  • Introduction
    Depression has taken over as the leading cause of disability worldwide. In Alberta, 7% of mothers reported prenatal depressive symptoms and more than 25% of women worldwide reported mental health-related concerns after childbirth. The DOHaD hypothesis aims to emphasize that both the prenatal and postnatal periods encompass sensitive windows of developmental plasticity in which exposures during the early life could impact the development of health and disease throughout the lifespan. Substantial evidence has demonstrated the negative consequences of maternal distress on offspring brain development with recent literature demonstrating potential sex differences. In a newly emerging field, maternal stress additionally appears to impact the developing gut microbiome and gut-brain axis; however, stress-microbiome pathways have not been fully explored in humans. The purpose of this research was to demonstrate the impact of maternal distress on child neurodevelopment in a sex-specific manner while exploring whether breastfeeding and the infant's gut microbiome sequentially mediated this association.
    Methods
    This study consisted of 646 healthy term infants from the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort. Maternal distress was measured using the Centre of Epidemiological Studies Depression Scale (CES-D) and Perceived Stress Scale (PSS) administered at several time points through pregnancy. Child neurodevelopment was assessed using the Bayley Scales of Infant Development (BSID-III) administered at one and two years of age. Exclusive breastfeeding duration was reported during infancy with infant fecal samples collected from a home assessment at four months of age. Microbiota from fecal samples were sequenced using 16S sequencing with C. difficile analyzed using qPCR with the appropriate
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    primers. Microbial metabolites were identified using NMR sequencing. Covariates were measured from study questionnaires or hospital birth records. A DAG approach was used to select the minimal adjustment set from potential covariates. Firstly, we tested multivariable linear regression models with child sex interactions to test whether the impact of maternal distress at different time points through pregnancy had sex-specific impacts on child neurodevelopment scores. Secondly, we built adjusted structural equation models to test sequential mediations of exclusive breastfeeding duration and infant gut microbial mediators on this association.
    Results
    In our study, approximately 16% of mothers experienced clinically significant depressive symptoms and 31% experienced higher than average perceived stress during the perinatal period. We found six significant interactions demonstrating that maternal distress had a time-and-sex-specific impact on child language and motor scores. Moreover, children’s cognitive and social-emotional scores did not demonstrate this sex-specific effect and were significantly reduced among both sexes following exposure to persistent distress. Exploring the gut-brain axis, we found several sex-specific mediation pathways. We found that 43% of healthy infants were colonized with C. difficile at four month of age and that the impact of prenatal depressive symptoms on child neurodevelopment scores was sequentially mediated by breastfeeding duration and C. difficile abundance. Specifically, depressive symptoms decreased exclusive breastfeeding duration which increased C. difficile abundance during infancy and lowered two-year cognitive and language scores among boys. We found a significant intervention in this pathway, in which increasing exclusive breastfeeding duration can reduce infant C. difficile abundance and increase boys’ cognitive, language, and motor scores. The positive impact of
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    exclusive breastfeeding duration on neurodevelopment scores was further mediated by increasing acetate abundance during infancy, specifically in girls.
    Conclusion
    Alongside the DOHaD hypothesis, the prenatal and postnatal periods represent sensitive windows in which stressors may impact a child’s developmental trajectory. We demonstrated that maternal distress had a time-and-sex specific impact on child neurodevelopment scores. Furthermore, colonization with C. difficile during infancy may not be as benign as the current literature supports as we revealed that C. difficile abundance during infancy had both direct and indirect effects of lowering neurodevelopment scores in childhood. Interestingly, we also found pathways demonstrating a significant intervention on this association in which supporting women to breastfeed for a longer duration could reduce the abundance of C. difficile and increase the abundance of microbial SCFA acetate during infancy which was associated with increased two-year neurodevelopmental scores. Future research should explore whether supplementation with acetate during infancy could mitigate the effects of shorter breastfeeding duration on neurodevelopment scores. This research emphasizes the significance of supporting women’s mental health through pregnancy and promoting exclusive breastfeeding duration as we revealed novel pathways indicating maternal distress symptoms may impact the development of the gut-brain axis among healthy children.

  • Subjects / Keywords
  • Graduation date
    Fall 2021
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/r3-e157-2a48
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.