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Early Life Exposure to Antibiotics and Mood and Anxiety Disorders in Children and Adolescents by Mahin Delara a Thesis Submi

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Early Life Exposure to Antibiotics and Mood and Anxiety Disorders in Children and Adolescents by Mahin Delara a Thesis Submi Early Life Exposure to Antibiotics and Mood and Anxiety Disorders in Children and Adolescents By Mahin Delara A thesis submitted to the Faculty of Graduate Studies of The University of Manitoba in partial fulfilment of the requirements of the degree DOCTOR OF PHILOSOPHY Department of Applied Health Science University of Manitoba Winnipeg Copyright © 2019 by Mahin Delara Dedication For my beloved children, Mina and Mohammad, always. Abstract Objective: Mood and anxiety disorders are among the most prevalent conditions in children and adolescents with unknown etiology. Exposure to antibiotics in early life has been proposed as a possible risk factor in animal studies. This study was aimed to assess maternal antibiotic use in pregnancy and child antibiotic use in the first three years of life as potential risk factors for subsequent development of these disorders during childhood and adolescence. Methods: A population-based retrospective cohort study was conducted using the Manitoba Population Research Data Repository. The cohort included children born in Manitoba between 1996 and 2012 (221,139 mother-child dyads). Children were followed until the earliest mood and anxiety disorders diagnoses, 19th birthday, migration, death or end of the study period. The antibiotic prescription was identified in the Drug Program Information Network. Physician- diagnosed mood and anxiety disorders were identified using hospital abstracts, medical claims and prescription records. Cox proportional hazard regression was used to compute crude and adjusted hazard ratios (aHRs) with 95% confidence intervals (CI). Results: Children born to mothers who received one antibiotic course or more in pregnancy had significantly higher rates of mood and anxiety disorders compared to children with no exposure (aHR 1.08, 95% CI 1.03 - 1.13) after adjusting for child antibiotic use and other potential confounders. Overall, child antibiotic use during the first three years of life did not increase the risk of developing mood and anxiety disorders (aHR 1.00, 95% CI 0.94 -1.07) after adjusting for maternal antibiotic use and other potential confounders. Children who received tetracyclines, aminoglycosides, quinolones (aHR 1.33, 95% CI 1.24 - 1.43) or sulfonamides and trimethoprim (aHR 1.28, 95% CI 1.22 - 1.34) were at increased risk of developing mood and anxiety disorders. i Conclusion: The modest associations observed for prenatal exposure to antibiotics overall and postnatal exposure to specific kinds of antibiotics may have been confounded by unmeasured factors. While the findings do not support a specific causal relationship between antibiotic use and mood and anxiety disorders due to study limitations, further exploration is merited, and nonetheless, it would be prudent to avoid unnecessary administration of antibiotics. ii Acknowledgement I would like to express my sincere gratitude to my advisor, Dr. Javier Mignone, for his continuous support and encouragement during my Ph.D. study, for his patience, motivation, and immense knowledge. His guidance helped me at all times during the research and writing of this dissertation. As a patient and positive mentor, his big picture always helped me, especially when I was stuck in the weeds. I could not have imagined having an advisor and mentor better than him. I am also grateful for the support of my dissertation committee, Dr. Diana McMillan and Dr. Nathan Nickel, for their insightful comments and encouragement, but also for the hard questions which pushed me to widen my research project from various perspectives. The range of expertise and advice they brought to my research was invaluable. My sincere thanks also go to Dr. Geert ‘t Jong, who provided me with an opportunity to join his research team as a research assistant and gave me access to the laboratory and research facilities. Without his precious support, it would not have been possible to conduct this research. I am also grateful for the support of Charles Burchill and Heather Prior, the programming staff at Manitoba Center for Health Policy (MCHP), for helping me to navigate the world of Statistical Analysis System (SAS) and all its intricacies. MCHP analyst Okechukwu Ekuma was incredibly helpful with statistical analysis. I also benefitted greatly from very helpful correspondence with Dr. Mohammad Jafari Jozani at the Department of Statistics, University of Manitoba and Dr. Mohammad Mamdani at the Leslie Dan Faculty of Pharmacy. I am also very grateful to Dr. Dallas Seitz at the department of psychiatry, Institute for Clinical Evaluative Sciences for his continued patience and guidance while I was struggling with the revision process. I also wish to thank MCHP and the government departments for providing access to the data used in this study. iii Last but not the least; I would like to thank my family, who were supporting me spiritually throughout writing this dissertation while being away from me. iv Table of Contents Abstract i Acknowledgement iii List of Tables viii List of Figures ix List of Abbreviations xi Chapter 1: Introduction 1 1.1 Introduction and rationale 1 1.2 Empirical objectives 3 Chapter 2: Background and Literature Review 6 2.1 Overview of mood and anxiety disorders 6 2.2 Canadian perspective 8 2.3 Contributing factors for the development of mood and anxiety disorders 12 2.3.1 Contextual factors 12 2.3.2 Individual factors 15 2.3.2.1 Non-modifiable risk factors 15 2.3.2.2 Modifiable risk factors 19 2.4 Antibiotics, microbiome and the brain 21 2.4.1 Overview of antibiotics 21 2.4.2 Overview of the microbiome 26 2.4.2.1 Microbiome and the brain 30 2.4.2.2 Gut-brain-axis 30 2.4.2.3 Microbiome metabolites 33 2.4.3 Antibiotics and microbiome dysbiosis 35 2.5 Literature review on antibiotic exposure and associated risk of developing mood and anxiety disorders 39 2.5.1 Review of animal studies 39 2.5.2 Review of human studies 41 2.6 Conclusion 44 Chapter 3: Methods 46 3.1 Overview of the study protocol 46 3.2 Research design elements 49 3.2.1 Developmental brain dysfunction theory 50 3.2.2 Microbiome-gut-brain, cognition theory 53 3.3 Study design 56 v 3.4 Datasets 57 3.5 Study sample 62 3.5.1 Inclusion criteria 62 3.5.2 Exclusion criteria 64 3.6 Variables 64 3.6.1 Exposure definition 64 3.6.1.1 Prenatal exposure 65 3.6.1.2 Postnatal exposure 65 3.6.2 Outcome measurement 65 3.6.2.1 Mood and anxiety disorders algorithm 65 3.6.2.2 Outcome codes for administrative data 66 3.6.2.3 Validation of mood and anxiety disorders algorithm 67 3.6.3 Potential confounders 68 3.6.3.1 Demographic variables 68 3.6.3.2 Health care utilization 72 3.6.3.3 Maternal history of mental health disorders 73 3.6.3.4 Child medical comorbidities 73 3.7 Statistical analyses 74 3.7.2 Comparing baseline characteristics between exposed and non-exposed groups 74 3.7.3 Checking for multicollinearity 75 3.7.4 Time-to-event analysis of outcome 76 3.7.4.1 Cox proportional hazards models 77 3.7.4.2 Additional analyses 80 3.8 Ethical considerations 83 Chapter 4: Results 84 4.1 Cohort creation 84 4.2 Descriptive statistics 86 4.2.1 Description of baseline characteristics 86 4.2.2 Description of prenatal exposure 88 4.2.3 Comparison of baseline characteristics between prenatally exposed and non-exposed groups 90 4.2.4 Description of postnatal exposure 93 4.2.5 Comparison of baseline characteristics between postnatally exposed and non-exposed groups 95 4.2.6 Mood and anxiety disorders 98 4.3 Inferential statistics 107 4.3.1 Prenatal exposure and mood disorders 107 vi 4.3.1.1 Results of bivariate analyses 107 4.3.1.2 Results of time-to-event analyses 112 4.3.2 Postnatal exposure and mood disorders 115 4.3.2.1 Results of bivariate analyses 115 4.3.2.2 Results of the time-to-event analysis 120 4.3.3 Sensitivity analyses 122 Chapter 5: Discussion 123 5.1 Purpose and overview 123 5.2 Current objectives 124 5.3 Summary of results 124 5.4 Interpretation of results 126 5.5 Comparison with previous studies 130 5.6 Limitations 133 5.7 Strengths 136 5.8 Future directions 137 5.8.1 Research implications 137 5.8.2 Policy implications 139 5.9 Conclusion 139 Appendices 141 Bibliography 165 vii List of Tables Table 1- Representative list of neurochemicals isolated from bacteria within the human gut 34 Table 2- Databases accessed through MCHP and relevant information extracted 61 Table 3- Descriptive univariate statistics for the whole study population 87 Table 4- Maternal antibiotic use during pregnancy in Manitoba, Canada, 1996-2012 89 Table 5- Distribution of covariates between exposed and non-exposed pregnancies 92 Table 6- Child antibiotic use in Manitoba, Canada, 1996-2012 94 Table 7- Distribution of covariates between exposed and non-exposed children during the first 97 three years of life Table 8- Distribution of characteristics amongst children with and without mood and anxiety 102 disorders Table 9- Outcome and censoring events for the survival analysis of the study population in 107 prenatal exposure Table 10- Distribution of covariates among children with mood disorders and maternal antibiotic 111 use in pregnancy Table 11- Hazard ratios for the diagnosis of mood and anxiety disorders in children after 114 exposure to antibiotics during pregnancy Table 12- Outcome and censoring events for the survival analysis of the study population for 115 postnatal exposure Table 13- Distribution of covariates among children with mood disorders and exposure to 119 antibiotics in the first three years of life Table 14- Hazard ratios for the diagnosis of mood and anxiety disorders in children who received
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