Maternal Use of Psychiatric Medications During Pregnancy And
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MATERNAL USE OF PSYCHIATRIC MEDICATIONS DURING PREGNANCY AND ADVERSE BIRTH OUTCOMES AND NEURODEVELOPMENTAL PROBLEMS IN OFFSPRING Ayesha C. Sujan Submitted to the faculty of the University Graduate School in partial fulfillment of the requirements for the degree Doctor of Philosophy in the Department of Psychological and Brain Sciences, Indiana University July 2021 ii Accepted by the Graduate Faculty, Indiana University, in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Doctoral Committee _______________________________________________ Brian M. D’Onofrio, PhD _______________________________________________ Richard Viken, PhD _______________________________________________ Patrick D. Quinn, PhD _______________________________________________ Christina Ludema, PhD _______________________________________________ A. Sara Oberg, PhD, MD April 22nd, 2020 iii © 2021 Ayesha C. Sujan iv Ayesha Sujan MATERNAL USE OF PSYCHIATRIC MEDICATIONS DURING PREGNANCY AND ADVERSE BIRTH OUTCOMES AND NEURODEVELOPMENTAL PROBLEMS IN OFFSPRING Understanding consequences of prenatal exposure to psychiatric and analgesic medications is important because use of these medications among pregnant women is relatively common and increasing. Rodent experiments have shown effects of perinatal exposure to specific medications; however, these findings might not apply to humans. Human observational studies have been used to study prenatal exposure to psychiatric and analgesic medications rather than randomiZed control trials due to ethical concerns about exposing offspring to potentially harmful substances. However, it is unclear the extent to which the statistical associations documented in observational studies are due to causal mechanisms or background factors that differ among exposed and unexposed pregnancies (i.e., confounding factors). Therefore, the aim of my dissertation research was to evaluate consequences of prenatal exposure to psychiatric and analgesic medications on risk for adverse birth outcomes and neurodevelopmental problems by seeking converging evidence from multiple observational designs that target both measured and unmeasured confounding. The first study showed that after accounting for confounding, prenatal antidepressant exposure was associated with a small increased risk of preterm birth (PTB) but no increased risk of small for gestational age (SGA), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD). The second study suggested that observed associations between prenatal exposure to prescribed opioid analgesics (POAs) and risk for PTB and SGA were largely due to unmeasured confounding factors, although I could not rule out small independent associations. The third v study evaluated the consequences of combined exposure to POAs and selective-serotine reuptake inhibitor antidepressants on risk for PTB and SGA and suggested that the medications do not interact to increase the risk of either outcome. These findings may provide reassurance to women considering antidepressant and POA use during pregnancy. They also highlight the importance of screening pregnant women and women of childbearing age and providing evidence-based treatments to at-risk women. vi Table of Contents I. Introduction……………………………………………………………………… Page 1 Background………………………………………………………………… Page 2 Potential processes influencing associations with prenatal psychiatric medication exposure………………………………………………………... Page 4 Observation methods to study the consequences of maternal medication use during pregnancy……………………………………………………….. Page 6 Dissertation research………………………………………………………... Page 12 Table I.1. Swedish Registers……………………………………………….. Page 16 Figure I.1. HypothesiZed influences on neurodevelopmental outcomes…… Page 17 References…………………………………………………………………... Page 18 II. Paper 1: Associations of maternal antidepressant use during the first trimester of pregnancy with preterm birth, small for gestational age, autism spectrum disorder, and attention-deficit/hyperactivity disorder in offspring…………………. Page 32 Abstract……………………………………………………………………... Page 33 Introduction…………………………………………………………………. Page 35 Methods…………………………………………………………………….. Page 36 Results………………………………………………………………………. Page 41 Discussion…………………………………………………………………... Page 45 Conclusion………………………………………………………………….. Page 48 Figure II.1. Risk of Autism Spectrum Disorder and Attention- Deficit/Hyperactivity Disorder by Maternal Self-reported First-trimester Exposure. …………………………………………………………………... Page 49 Table II.1. Descriptive statistics in the whole sample and stratified by maternal self-reported first-trimester use of any antidepressant……………. Page 50 Table II.2. Baseline, adjusted, and sibling comparison associations between maternal self-reported first-trimester use and birth and neurodevelopmental outcomes……………………………………………... Page 52 Table II.3. Adjusted associations between maternal antidepressant dispensations before pregnancy and during the first trimester of pregnancy and birth and neurodevelopmental outcomes………………………………. Page 53 Table II.4. Baseline associations between paternal first-trimester antidepressant dispensations and birth and neurodevelopmental outcomes... Page 54 References…………………………………………………………………... Page 55 SII.1 Appendix: Descriptive Statistics Based on Maternal Self-reported Antidepressant Use…………………………………………………………. Page 60 SII.2 Appendix: Descriptive Statistics and Analyses Based on Antidepressant Dispensation Records……………………………………… Page 68 SII.3 Appendix: Test of Exposure Misclassification……………………….. Page 80 SII.4 Appendix: Test of GeneraliZability of Sibling Comparisons…………. Page 83 SII.5 Appendix: Test of Confounding from Exposure to Other Psychotropic Medications…………………………………………………... Page 85 SII.6 Appendix: Test of Bias from Left Censoring and Cohort Effects……. Page 91 SII.7 Appendix: Test of Validity of Early Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder Diagnoses……………………… Page 93 vii SII.8 Appendix: Associations Between Dispensations During Later Pregnancy and Offspring Outcomes Among Those with a First-trimester Dispensation………………………………………………………………... Page 96 III. Paper 2: Maternal prescribed opioid analgesic use during pregnancy and associations with adverse birth outcomes: A population-based study……………… Page 99 Abstract……………………………………………………………………... Page 100 Introduction…………………………………………………………………. Page 102 Methods…………………………………………………………………….. Page 103 Results……………………………………………………………………..... Page 111 Discussion…………………………………………………………………... Page 115 Table III.1. Demographics in the target sample……………………………. Page 119 Table III.2. Proportion of infants with prescribed opioid analgesic and acetaminophen exposure in the analytic sample…………………………… Page 122 Table III.3. Associations between prescribed opioid analgesic exposure and adverse birth outcomes………………………………………………… Page 123 References…………………………………………………………………... Page 124 SIII.1 Appendix: STROBE Checklist………………………………………. Page 131 SIII.2 Appendix: Planned analyses…………………………………………. Page 133 SIII.3 Appendix: Additional information on medication exposures……….. Page 137 SIII.4 Appendix: Preliminary analyses exploring for sensitive periods of exposure…………………………………………………………………….. Page 142 SIII.5 Appendix: Review of models used to evaluate associations between prescribed opioid analgesic use and birth outcomes………………………... Page 144 SIII.6 Appendix: All parameter estimates from adjusted models estimating associations with maternal prescribed opioid filled prescriptions anytime during pregnancy…………………………………………………………… Page 147 SIII.7 Appendix: Sensitivity analyses evaluating for potential bias from exposure misclassification…………………………………………………. Page 152 SIII.8 Appendix: Sensitivity analyses evaluating the influence of type of opioid……………………………………………………………………….. Page 155 SIII.9 Appendix: Sensitivity analyses evaluating influence of inclusion of combination prescribed opioid analgesic medications…………………… Page 157 SIII.10 Appendix: Sensitivity analyses evaluating the role of polypharmacy Page 159 SIII.11 Appendix: Sensitivity analyses evaluating assumptions of sibling comparisons results…………………………………………………………. Page 161 SIII.12 Appendix: Sensitivity analyses evaluating associations with continuous outcomes……………………………………………………….. Page 164 SIII.13 Appendix: Sensitivity analyses evaluating the influence of missing data………………………………………………………………………….. Page 166 SIII.14 Appendix: Prevalence of the covariates stratified by exposure status in the target sample…………………………………………………... Page 168 SIII.15 Appendix: Prevalence of preterm birth and small for gestational age among all exposure and comparison groups…………………………… Page 172 IV. Paper 3: A Population-based study of concurrent prescriptions of opioid analgesic and selective-serotonin reuptake inhibitor medications during pregnancy and risk for adverse birth outcomes Page 174 viii Abstract……………………………………………………………………... Page 175 Introduction………………………………………………………………… Page 177 Methods…………………………………………………………………….. Page 178 Results……………………………………………………………………..... Page 182 Discussion…………………………………………………………………... Page 183 Table IV.1. Prevalence of exposure groups, background characteristics, and outcomes in the target sample (n=688,914) …………………………… Page 188 Table IV.2. Preterm birth…………………………………………………… Page 191 Table IV.3. Small for gestational age………………………………………. Page 192 References…………………………………………………………………... Page 193 sTable IV.1. Other psychiatric medication anatomical therapeutic class codes………………………………………………………………………... Page 200 sTable IV.2.