SAFETY ASPECTS AND PATTERNS OF MEDICATION USE IN PREGNANCY WITH SPECIAL FOCUS ON PSYCHOTROPIC MEDICATION AND MENTAL HEALTH Angela Lupattelli PharmacoEpidemiology and Drug Safety Research Group, School of Pharmacy, PharmaTox Strategic Research Initiative, Faculty of Mathematics and Natural Sciences, University of Oslo, Norway Submitted for the degree of PhD at the School of Pharmacy, Faculty of Mathematics and Natural Science, University of Oslo, Norway © Angela Lupattelli, 2015 Series of dissertations submitted to the Faculty of Mathematics and Natural Sciences, University of Oslo No. 1660 ISSN 1501-7710 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission. Cover: Hanne Baadsgaard Utigard. Printed in Norway: AIT Oslo AS. Produced in co-operation with Akademika Publishing. The thesis is produced by Akademika Publishing merely in connection with the thesis defence. Kindly direct all inquiries regarding the thesis to the copyright holder or the unit which grants the doctorate. Acknowledgements The work described in this thesis was carried out at the Department of Pharmacy, School of Pharmacy, University of Oslo, in the period 2011-2015. Part of this work was also carried out at The Motherisk Program, Toronto Hospital for Sick Children, Canada. First and foremost I want to thank all those women who participated in the Norwegian Mother and Child Cohort Study and in the Multinational Medication Use in Pregnancy Study. Without them, it would not have been possible to carry out the studies for this thesis. An additional heartfelt thanks to the women who participated in Multinational Medication Use in Pregnancy Study for agreeing to share with me their thoughts and fears about use of medication during SUHJQDQF\VRPHRIWKHZRPHQ¶VQDUUDWLYHVDUHSUHVHnted in this doctoral work. I am deeply grateful to my supervisors Professor Hedvig Nordeng and Professor Olav Spigset. Thanks for all the guidance throughout this journey and for bringing up such an interesting and relevant problem to study. I cannot think of better supervisors to have! Hedvig, thank you for being so supportive, inspiring and for making my Ph.D. experience productive and stimulating. The joy and enthusiasm you have for your research was contagious and motivational for me, even during difficult times in the Ph.D. pursuit. Olav, thank you for the great mentorship. You have always been available to advise and support me. I am very grateful for your patience, motivation, kindness, enthusiasm and outstanding expertise in clinical pharmacology. I wish to thank the Faculty of Mathematics and Natural Sciences within the University of Oslo for giving me the opportunity to carry out my doctoral work. A heartfelt thanks to the current Director of the School of Pharmacy, Henrik Schultz, and to his predecessor, Karen Marie Ulshagen, for promoting the research activities within the School of Pharmacy and for being so positive towards international collaboration. Thanks to all the people at the School of Pharmacy for creating such a pleasant work environment. Halvor, thanks for being such a helpful and kind colleague. I express my heartfelt gratitude to all my colleagues at the Galenic and Social Pharmacy groups within the Department of Pharmacy, in particular Ingunn Björnsdottir, Åse Ertesvåg, Janne Smedberg, Katerina Nezvalova-Henriksen, Raghnild Eek Brandilistuen, Karin Svenberg, Gro C. Havnen, Else-Lydia Toverud, Walaa Abuelmagd, Girma B. Gutema, Helle Håkonsen, and Karine Wabø Ruud. I also wish to thank Leila Torgeresen for all the good discussions about eating disorders and Hein Stigum for being such a good lecturer. I am grateful to the national coordinators involved in the Multinational Medication Use in Pregnancy Study for the positive and productive collaboration: Ann-Charlotte Mårdby, Herbert Juch, Michael Twigg, Ksenia Zagorodnikova, Myla Moretti, Mariola Drozd, Alice Panchaud, Katri Hameen-Anttila, Andre Rieutord, Romana Gjergja Juraski, Marina Odalovic, Debra Kennedy, Gorazd Rudolf, Anneke Passier, and Ingunn Björnsdóttir. I also wish to thank my coauthors Stephanie Zerwas, Marianne Hatle, Ted Reichborn-Kjennerud and Cynthia M Bulik. A special thanks to Dr. Gideon Koren and to Professor Pierpaolo Mastroiacovo. The research stay at the Motherisk Program and attendance to the WHO Training Program on Surveillance and Prevention of Birth Defects and Preterm Births have both been wonderful experiences. Listening to your talks and lectures has been an honor for me. Your expertise, experience and deep motivation in the work you do has inspired me in the pursuit of my Ph.D. My heartfelt thanks to the Norwegian Research Council of Norway, Unifor, the Foundation for Promotion of Norwegian Pharmacies, the Norwegian Pharmaceutical Society, the National PhD School of Pharmacy, and the School of Pharmacy for granting me the necessary funding to carry out the Multinational Medication Use in Pregnancy Study, to attend relevant courses abroad, to travel and disseminate my research at international conferences. My time at the School of Pharmacy was made enjoyable in large part due to the many friends that became a part of my life. Milica, Lilia, Katerina, Teresa, Jan, Wei and Afonso, thanks for the support and good discussions, and most importantly for the good time we had together during these years. Karin, thanks for the sharing of ideas, and for being such a great colleague and friend. Mollie, Janne and Ragnhild, thanks for being so cheerful and for creating such a lively work environment. Ornella, Sara and Cecilia, thanks for the ³,WDOLDQ´WDONVDQGIRUWKH ODXJKVZHKDGWRJHWKHU,WZDVQLFHWRKDYHD³/LWWOH,WDO\´DWWKHUniversity of Oslo. Lastly, I would like to thank my family for all their love and encouragement. Words cannot express how grateful I am to my parents for supporting me in all my pursuits and not least for believing in me. Espen, thanks for convincing me to get into the Ph.D. program and for all the patience you demonstrated during these four years. Thanks for supporting my research career by following me in Toronto and soon in Boston. Becoming a mother during this journey has indeed been of value and has changed my personal perspective into pregnancy and motherhood, which are my field of research. Thanks to my wonderful twin girls Eva and Mia, for bringing such happiness into my life and for reminding me every day how special the mother-child bond is. Content Abbreviations 3 Abstract 5 List of publications 7 1. Introduction 8 1.1 Lesson learned from the past and ethical considerations 8 1.2 Introduction to maternal disorders and medication use in pregnancy 10 1.3 Psychiatric disorders and related pharmacotherapy during pregnancy 12 1.3.1 The burden of psychiatric disorders in pregnancy 12 1.3.2 Psychotropic medication use in pregnancy 13 1.3.3 The impact of maternal psychiatric disorders on maternal-fetal health 23 1.4 Adherence to pharmacotherapy with psychotropics during pregnancy 25 1.4.1 Factors associated with medication adherence 26 1.5 Safety of antidepressants in pregnancy 28 1.5.1 Neonatal safety 28 1.5.2 Maternal safety 33 1.6 Pharmacoepidemiology 34 1.6.1 Drug utilization research 35 1.6.2 Observational, analytic pharmacoepidemiology 35 1.6.3 Critical appraisal of observed associations in pregnancy studies 41 1.6.4 Proof of exposure in pregnancy 44 1.6.5 Extrapolation of relative measures into absolute terms 44 2. Objectives 46 3. Materials and Methods 48 3.1 Study design and data collection 49 3.1.1 The Multinational Medication Use in Pregnancy Study 49 3.1.2 The Norwegian Mother and Child Cohort Study 50 3.1.3 The Medical Birth Registry of Norway 51 3.2 Study population 52 3.3 Ethics 53 3.4 Measures 53 3.4.1 Outcome variables 54 3.4.2 Explanatory variables 57 3.4.3 Other variables 59 3.5 Use and translation of psychometric instruments 61 3.6 Statistical analysis 61 3.6.1 Associations between explanatory and outcome variables 61 ϭ 3.6.2 Sensitivity analysis 63 3.6.3 Power calculation 64 3.6.4 Imputation 65 4. Main findings 66 4.1 Study I: Medication use in pregnancy: a cross-sectional, multinational web-based study 66 4.2 Study II: Medication use before, during, and after pregnancy among women with eating disorders: a study from the Norwegian Mother and Child Cohort Study 68 4.3 Study III: Patterns and factors associated with low adherence to psychotropic medications during pregnancy - a cross-sectional, multinational web-based study 69 4.4 Study IV: Risk of vaginal bleeding and postpartum hemorrhage after use of antidepressants in pregnancy: a study from the Norwegian Mother and Child Cohort Study 71 4.5 Sensitivity analyses 72 5. Discussion 75 5.1 Summary of the most relevant findings 75 5.2 Interpretation and comparison with other studies 76 5.2.1 Overall medication use in pregnancy 76 5.2.2 Psychotropic medication use in pregnancy 79 5.2.3 Adherence to psychotropics in pregnancy 85 5.2.4 Maternal safety after use of antidepressants in pregnancy 88 5.3 Methodological considerations 93 5.3.1 The Multinational Medication Use in Pregnancy Study (studies I, III) 93 5.3.2 The Norwegian Mother and Child Cohort Study and Medical Birth Registry of Norway (studies II and IV) 99 6. Clinical implications and future research 105 7. References 111 Papers I-IV Appendices Ϯ Abbreviations AN Anorexia nervosa ATC Anatomical Therapeutic Chemical classification system BDS 6ORQH(SLGHPLRORJ\FHQWHU¶V%LUWK'HIHFW6WXG\ BED Binge eating disorder BMI Body mass index BMQ-specific Beliefs About Prescribed Medicines