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Perinatal outcomes in multiple sclerosis Lu, Ellen Meng-I 2013

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PERINATAL OUTCOMES IN MULTIPLE SCLEROSIS  by  ELLEN MENG-I LU  B.Sc., University of British Columbia, 2008  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  DOCTOR OF PHILOSOPHY  in  THE FACULTY OF GRADUATE STUDIES  (Experimental Medicine)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  April 2013  © Ellen Meng-I Lu, 2013  ABSTRACT Multiple sclerosis (MS) is a putative autoimmune disease of the central nervous system, affecting many adults of childbearing age. Although extensive research has examined the association between MS and traditional perinatal outcomes (i.e. cesarean section, birth weight and preterm birth), other important outcomes are understudied, partly due to existing methodological challenges. Using comprehensive populationbased databases including the British Columbia (BC) MS Database, BC Perinatal Database Registry, Vital Statistics Birth Registry, Population Data BC Consolidation File and Census GeoData, this dissertation investigated the association between MS (and related clinical factors) with: labour induction and augmentation; obstetrical epidural and spinal anesthesia; length of birth hospitalization in mothers and their newborns; as well as birth outcomes in fathers with MS. Overall, individuals with MS were not at increased risk for the investigated outcomes compared to the general population with the exception that multiparous women with MS had higher rates of epidural anesthesia compared to multiparous women in the general population. Within MS women, those with longer disease duration had less epidural anesthesia and those with greater disability had more labor induction. Men with greater MS disability tended to father offspring with lower mean birth weight, but their newborns were still within the normal range for the general population. Individuals with MS who wish to have children must also decide between initiating disease-modifying drug (DMD) early to minimize relapses (i.e. MS attacks) or delaying/stopping therapy prior to conception to avoid potential fetal harm from in utero DMD exposure. This dissertation explored perinatal outcomes in women and men with  ii  MS exposed to DMDs and includes a systematic review of DMD exposure on perinatal outcomes. Data from BC suggest that DMD exposure in men and women with MS does not increase the risk of unfavorable perinatal outcomes. However, best evidence from the systematic review indicates that interferon-beta exposure in women with MS is associated with preterm birth, lower mean birth weight and shorter mean birth length in newborns; nonetheless, growth parameters of exposed newborns remained within normal values for the general population and preterm births tended to be close to term.  iii  PREFACE I wrote the entire dissertation with direction and input from Drs. Helen Tremlett, Dessa Sadovnick, Anne Synnes and Leanne Dahlgren. Funding for the Operating Grant from the Canadian Institutes of Health Research (MOP-106607) was obtained by Dr. Helen Tremlett (Principal Investigator), Mia van der Kop, Drs. Anne Synnes, Leanne Dahlgren, Dessa Sadovnick, Ana-Luiza Sayao, Peter Rieckmann and Yinshan Zhao (co-investigators). These studies were approved by the British Columbia Ministry of Health and were conducted under ethical approval from the University of British Columbia Research Ethics Board (Certificate No.: H08-02127) and the Vancouver Coastal Health Authority (Certificate No.: V09-0006). Mia van der Kop initiated the first ethics application, data linkage proposal and data application to Perinatal Services BC and Population Data BC. I performed chart reviews for the data in the BCMS database and the subsequent annual ethics renewal with the UBC Research Ethics Board. I also liaised with Population Data BC and Perinatal Services BC for study amendments and the data linkage strategy for the fathers studies (Chapters 8 and 9). I completed all the data analysis (with guidance from Feng Zhu and Yinshan Zhao), interpretation and writing of all the published and to-be-published manuscripts in this dissertation. I also conceptualized the studies in Chapters 3 to 5 and 7. All coauthors involved in the different manuscripts assisted with data interpretation, manuscript revision and/or study conceptualization. Copyright permission has been obtained for all publications included in this dissertation. A version of Chapter 3 is published as an original peer-reviewed research article:  iv  Lu E, Zhu F, van der Kop M, Dahlgren L, Synnes A, Sadovnick AD, Traboulsee A, Tremlett H and the British Columbia Multiple Sclerosis Clinic Neurologists. Labor induction and augmentation in women with multiple sclerosis. Mult Scler 2013; Feb 5. [Epub ahead of print]. A version of Chapter 4 as an original research article has been submitted for peer-review publication: Lu E, Zhao Y, Dahlgren L, Preston R, van der Kop M, Synnes A, Sadovnick AD, Traboulsee A, Tremlett H and the British Columbia Multiple Sclerosis Clinic Neurologists. Obstetrical epidural and spinal anesthesia in multiple sclerosis. 2013; in submission. A version of Chapter 5 is published as an original peer-reviewed research article: Lu E, Zhao Y, Zhu F, van der Kop ML, Synnes A, Dahlgren L, Sadovnick AD, Sayao AL, Tremlett H and the British Columbia Multiple Sclerosis Clinic Neurologists. Birth hospitalization in mothers with multiple sclerosis and their newborns. Neurology  2013;80(5):447-452. This work has been presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis in Lyon, France, October 2012. A version of Chapter 6 is published as an original peer-reviewed research article: Lu E, Dahlgren L, Sadovnick AD, Sayao A, Synnes A, Tremlett H. Perinatal outcomes in women with multiple sclerosis exposed to disease-modifying drugs. Mult Scler 2012;18(4):460-470. This work has been presented at the 46th Annual Congress of the Canadian Neurological Sciences Federation in Vancouver, BC, Canada, June 2011 and the Multiple Sclerosis Research and Training Network Conference in Whistler, BC, Canada, December 2010.  v  A version of Chapter 7 has been published as separate peer-reviewed articles: 1) Systematic review: Lu E, Wang BW, Guimond C, Synnes A, Sadovnick D, Tremlett H. Disease-modifying drugs for multiple sclerosis in pregnancy: a systematic review. Neurology 2012;79(11):1130-1135. This work has been presented at the 64th Annual Meeting of the American Academy of Neurology, in New Orleans, LA, USA, April 2012. 2) Special report: Lu E, Wang BW, Guimond C, Synnes A, Sadovnick D, Dahlgren L, Traboulsee A, Tremlett H. Safety of multiple sclerosis drugs in pregnancy: current challenges and future directions for pharmacovilgilance. Expert Rev Neurother 2013;13(3):251-261. 3) Editor’s choice: Charles JA, Tremlett H, Lu E, Guimond C, Sadovnick AD. Diseasemodifying drugs for multiple sclerosis in pregnancy: a systematic review. Neurology 2013;80(11):1068-1069. A version of Chapter 8 as an original research article has been prepared for a peer-reviewed journal submission: Lu E, Zhu F, Zhao Y, van der Kop M, Synnes A, Sadovnick AD, Dahlgren L, Traboulsee A, Tremlett H and the British Columbia Multiple Sclerosis Clinic Neurologists. Birth outcomes of pregnancies fathered by men with multiple sclerosis. 2013. This work will be presented at the 23rd Meeting of the European Neurological Society in Barcelona, Spain, June 2013. A version of Chapter 9 as an original research article has been prepared for peer-reviewed journal submission: Lu E, Zhu F, Zhao Y, van der Kop M, Synnes A, Sadovnick AD, Dahlgren L, Traboulsee A, Tremlett H and the British Columbia Multiple Sclerosis Clinic Neurologists. Birth outcomes of pregnancies fathered by men with multiple sclerosis exposed to disease-modifying drugs. 2013.  vi  TABLE OF CONTENTS Abstract.…………………………………………………….………...………………..........ii Preface.………………………………………...……………………………………………. iv Table of Contents.………………………...…………………………………...…...……... vii List of Tables.…………………………………...………………………………………….. ix List of Figures.…………………………………………………………………..…...…….. xii List of Symbols and Abbreviations………..……………………….…………………... xiii Acknowledgements.……………………………………………...……….....…….……… xiv Dedication.……………………………………………………………………..………….…xvii Chapter 1: Introduction.…………………………………………………….…………….. 1 1.1 Multiple sclerosis……...……………………………………….……………… 1 1.2 Effect of pregnancy on multiple sclerosis.………………………..………… 2 1.3 Effect of multiple sclerosis on perinatal outcomes..…………………...….. 3 1.4 Effect of disease-modifying drugs for multiple sclerosis on perinatal outcomes..…………….………...…………...………………………...……… 4 1.5 Knowledge gaps, research questions and hypotheses……………..…….. 5 Chapter 2: Study Design………………………………………………………………….. 11 2.1 Data sources, database linkage and study participants.….………………. 11 2.2 Sample size calculations………….………………………….………………. 13 2.3 Approach to data analyses...………………………………………………….15 2.4 Statistical interpretation of data……………………………………………… 20 Chapter 3: Labour Induction and Augmentation in Multiple Sclerosis………...... 21 3.1 Methods…..…………………………………………………….……………… 21 3.2 Results………………………………………………………….……………….23 3.3 Discussion...…………………………………………………………………… 30 Chapter 4: Obstetrical Epidural and Spinal Anesthesia in Multiple Sclerosis..... 33 4.1 Methods…..…………………………………………………….……………… 33 4.2 Results………………………………………………………….……………….36 4.3 Discussion...…………………………………………………………………… 45 Chapter 5: Birth Hospitalization in Mothers with Multiple Sclerosis and Their Newborns………………………………………………………...………….... 49  vii  5.1 Methods…..…………………………………………………….……………… 49 5.2 Results………………………………………………………….…………….... 52 5.3 Discussion...…………………………………………………………………… 59 Chapter 6: Perinatal Outcomes in Women with Multiple Sclerosis Exposed to Disease-Modifying Drugs……………………………………………….….. 62 6.1 Methods…..…………………………………………………….……………… 62 6.2 Results………………………………………………………….……..……….. 64 6.3 Discussion...…………………………………………………………………… 73 Chapter 7: Disease-Modifying Drugs for Multiple Sclerosis in Pregnancy: A Systematic Review……….………..………………………………………… 77 7.1 Methods…..…………………………………………………….……………… 77 7.2 Results………………………………………………………….…………..….. 79 7.3 Discussion...………………………………………………………………..….. 86 Chapter 8: Birth Outcomes of Pregnancies Fathered by Men with Multiple Sclerosis...………….…………………………………………………………. 95 8.1 Methods…..…………………………………………………….……………… 95 8.2 Results………………………………………………………….……………….98 8.3 Discussion...……………………………………………………….…………... 108 Chapter 9: Birth Outcomes of Pregnancies Fathered by Men with Multiple Sclerosis Exposed to Disease-Modifying Drugs……….…………....... 112 9.1 Methods…..…………………………………………………….…………..….. 112 9.2 Results………………………………………………………….…………….... 114 9.3 Discussion...…………………………………………………………………… 121 Chapter 10: Conclusions.……………………………………………..………………….. 123 10.1 Analysis and integration of findings………………………….……….……... 123 10.2 Significance and contribution of findings...………………….……………… 124 10.3 Strengths and limitations of study design………………………………….. 125 10.4 Potential applications and future directions…………..……………………. 132 Bibliography…………………………………………………………………………...…… 135 Appendices…………………………………………………………………………….…… 156  viii  LIST OF TABLES Table 2.1.  A priori sample size calculation for primary outcomes…………………... 14  Table 3.1  Characteristics of women with attempted vaginal deliveries in BC.……. 24  Table 3.2  Clinical characteristics of MS women with attempted vaginal deliveries in BC……………..…………………………………………………………..….. 25  Table 3.3  Indications and methods of labor induction in women with induced labor in BC……………..…………………………...…………………………….…… 26  Table 4.1  Maternal characteristics and perinatal outcomes of deliveries in BC….. 37  Table 4.2  Clinical characteristics of MS women with deliveries in BC….……..…... 38  Table 4.3  Obstetrical pain management for women in BC…………………………..39  Table 4.4  Association between MS clinical factors and epidural (all deliveries) and spinal anesthesia (cesarean deliveries only)…………………..…............42  Table 4.5  Proportion of epidural and spinal anesthesia in women, grouped by parity, in the different modes of delivery…………………………………………...44  Table 5.1  Maternal and newborn characteristics in BC……………..………………. 52  Table 5.2  Clinical characteristics of MS women with births in BC………...……….. 54  Table 5.3  Association between maternal MS and the length of birth hospitalization……………..…………………………………………………. 56  Table 5.4  Association between MS clinical factors and the length of maternal hospitalization……….……………………………………………………….. 57  Table 5.5  Association between MS clinical factors and the length of newborn hospitalization……….……………………………………………………….. 58  Table 6.1  Characteristics of women with relapsing-onset MS who gave birth in BC…………............................................................................................. 67  Table 6.2  Perinatal outcomes of the DMD-exposed, previously treated and DMD naïve pregnancies in relapsing-onset MS women.................................. 70  Table 6.3  Perinatal outcomes according to the timing of DMD exposure in relapsingonset MS women.................................................................................... 72  ix  Table 7.1  Summary of studies examining DMD exposure during pregnancy and conception in MS……………….……………………………………………. 80  Table 7.2  Classification of studies based on level and quality of evidence……......82  Table 7.3  Perinatal outcomes from fair and good quality prospective cohort studies comparing DMD-exposed and unexposed mothers with MS……...…….85  Table 8.1  Characteristics of births fathered by men in BC……………….…….…… 101  Table 8.2  Clinical characteristics of MS fathers with newborns in BC…………….. 103  Table 8.3  Association between paternal MS and birth outcomes…………...……... 104  Table 8.4  Association between MS clinical factors and birth weight of the newborn...…………………………………………………………………….. 106  Table 8.5  Association between MS clinical factors and gestational age of the newborn………………………………..………………………………………107  Table 9.1  Characteristics of men with relapsing-onset MS with newborns in BC…118  Table 9.2  Birth outcomes of newborns with IFNβ-exposed, GA-exposed and unexposed relapsing-onset MS fathers…............................................... 120  Table A.1.1 Kurtzke Expanded Disability Status Scale…………………….………….. 156 Table A.1.2 FDA pregnancy risk categories……………………………..…………..…. 157 Table A.3.1 Baseline characteristics of MS mothers with EDSS scores available and unavailable closest to the time of delivery (±3 years) for attempted vaginal deliveries…………………………………………………...………………… 158 Table A.4.1 Baseline characteristics of MS mothers with EDSS scores available and unavailable closest to the time of delivery (±3 years) for all births……...159 Table A.4.2 Baseline characteristics of MS mothers with EDSS scores available and unavailable closest to the time of delivery (±3 years) for cesarean deliveries..……………………………………………………………………. 160 Table A.7.1 Level of evidence for studies………………………..……………………… 161 Table A.7.2 Quality of evidence for studies……………………………………..…….... 162 Table A.7.3 Class of recommendation…………….…………………………….…..….. 163  x  Table A.8.1 Baseline characteristics of MS fathers with EDSS scores available and unavailable closest to the time of conception (±3 years)…………..……. 164 Table A.9.1 Birth outcomes of newborns with IFNβ-exposed, GA-exposed and unexposed (excluding previously treated) relapsing-onset MS fathers...165 Table A.9.2 Birth outcomes of newborns with IFNβ-exposed, GA-exposed and unexposed relapsing-remitting MS fathers..............................................166  xi  LIST OF FIGURES Figure 3.1  Association between the presence of MS and the risk of labor induction or augmentation……………….…………..………..……………………..…….28  Figure 3.2  Association between MS clinical factors and the risk of labor induction or augmentation…………………..…………………………………………….. 29  Figure 4.1  Association between the presence of MS and epidural (all deliveries) and spinal anesthesia (cesarean deliveries only)…....................................... 40  Figure 6.1  Conceptual selection of MS women and linkage of the clinical and perinatal data……………………………..…………………………………….. 65  Figure 7.1  A conceptual timeline of pharmacokinetic and pharmacodynamic effects of drugs on pregnancy and potential methodological improvements to study design…………………………………………………………………………. 92  Figure 8.1  A conceptual overview of the database linkage allowing data on fathers and their newborns to be connected.….................................................. 99  Figure 9.1  Conceptual selection of births fathered by MS men and linkage of the clinical and perinatal data………………………………………..……........ 116  Figure A.2  Formulae used for sample size calculation in univariate analyses…..... 167  xii  LIST OF SYMBOLS AND ABBREVIATIONS α  level of statistical significance  β  regression coefficients  BC  British Columbia  BCMS  British Columbia Multiple Sclerosis  BCPDR  British Columbia Perinatal Database Registry  BMI  body mass index  CI  confidence interval  DMD  disease-modifying drug  EDSS  Expanded Disability Status Scale  FDA  Food and Drug Administration  FS  functional system  GA  glatiramer acetate  GEE  generalized estimating equations  ICD  International Classification of Disease  IFNβ  interferon-beta  LMP  last menstrual period  MS  multiple sclerosis  NICU  neonatal intensive care unit  OR  odds ratio  PHN  Personal Health Number  SD  standard deviation  US  United States  xiii  ACKNOWLEDGEMENTS I thank my supervisor, Dr. Helen Tremlett, for giving me the opportunity to choose and work on this ‘Pregnancy in MS’ project, which yielded many interesting research questions and helped me better understand epidemiology. I especially appreciate her mentorship, enthusiasm and prompt review of my work to advance my learning and progress in clinical research. I am also grateful for her understanding and encouragement during the rough patches of my training. She is, and always will be, a role model for me. In addition, I am happy to have worked together with Dr. Afsaneh Shirani, a MD Postdoctoral Fellow, who helped obtain the data expediently for this ‘Pregnancy in MS’ project. I also appreciate the extra support she has given me on my oral comprehensive exam and PhD defence. Without Mia van der Kop taking the initiative on the ethics and data applications before I started my training, I would not have had the opportunity to select this project as my PhD dissertation. Lastly, my appreciation goes out to Feng Zhu and Dr. Yinshan Zhao – the statistics wizards on these projects – for double-checking all my statistical models were beautifully done! Outside Dr. Tremlett’s Research Group, I would like to thank my supervisory committee members, Drs. Leanne Dahlgren, Dessa Sadovnick and Anne Synnes for their time at our meetings as well as their intellectual contribution and revisions of my work. In addition, I would like to thank Dr. Anthony Traboulsee, an MS specialist neurologist and the Director of the UBC MS Clinic, and Dr. Ralph Brands, a clinical epidemiologist, for their encouragement during my training and preparation for my oral comprehensive exam. Furthermore, Dr. Roanne Preston (an anesthelogist), Colleen Guimond (a genetic counselor) and Dr. Ana-Luisa Sayao (a MS neurologist) also lend  xiv  their valuable expertise to improve the manuscripts they have co-authored in. Special thanks to Bing Wei Wang, a fourth year UBC medical student, who sacrificed many of his weekends in 2011, to systematically review the literature on disease-modifying drug use for MS in pregnancy along with me, so that my first paper in Neurology was possible. I thank Dr. Claudia Jacova for her supporting reference letters for my graduate award applications as well as her role in chairing my comprehensive exam. Lastly, I thank Drs. Magnhild Sandberg-Wollheim (MS specialist neurologist), Lorne Kastrukoff (MS specialist neurologist) and Richard Mathias (epidemiologist) for evaluating my PhD dissertation and defence as well as Dr. Alexander MacKay for chairing my defence. I would like to acknowledge the Canadian Institutes of Health Research for granting me the Master’s Research Award and the Three-Year Doctoral Research Award; the Multiple Sclerosis Society of Canada for the Master of Science and Doctor of Philosophy Research Studentships as well as travel awards to attend workshops and conferences; and the University of British Columbia for the Graduate Entrance Scholarship, the Four-Year Doctoral Fellowship, three Faculty of Medicine Graduate Awards, the Faculty of Graduate Studies Travel Award, the Experimental Medicine Program Travel Award and the Third Place Winner of the 2011 Faculty of Medicine Thesis Competition. I am also grateful for the travel grants from the European Committee for Treatment and Research in Multiple Sclerosis and the European Neurological Society. Their support has allowed me to focus on learning the skills and knowledge to be a proficient researcher. Many thanks to the MS patients for their participation in research and the BCMS Neurologists who contributed to the study through patient examination and data  xv  collection (current members listed here by primary clinic): UBC MS Clinic: A. Traboulsee, MD, FRCPC (UBC Hospital MS Clinic Director and Acting Head of the UBC MS Programs); A-L. Sayao, MD, FRCPC (Clinical Director of the BCMS Database); V. Devonshire, MD, FRCPC; S. Hashimoto, MD, FRCPC (UBC and Victoria MS Clinics); J. Hooge, MD, FRCPC (UBC and Prince George MS Clinics); L. Kastrukoff, MD, FRCPC (UBC and Prince George MS Clinics); J. Oger, MD, FRCPC Kelowna MS Clinic: D. Adams, MD, FRCPC; D. Craig, MD, FRCPC; S. Meckling, MD, FRCPC; Prince George MS Clinic: L. Daly, MD, FRCPC; Victoria MS Clinic: O. Hrebicek, MD, FRCPC; D. Parton, MD, FRCPC; K. Atwell-Pope, MD, FRCPC. The views expressed in this dissertation do not necessarily reflect the views of each neurologist acknowledged. I thank Population Data BC and Perinatal Services BC, especially Tim Choi, the Research Liaison, and Terri Pacheco, the Data Analyst, who have been very helpful with the study amendments and the data release process for my projects. All inferences, opinions, and conclusions in this thesis may not reflect the opinions of Population Data BC or Perinatal Services BC. I thank Dr. Vincent Duronio, the Director of the Experimental Medicine Program, and Cornelia Reichelsdorfer, the program secretary, both who have been very caring and helpful in answering my questions and concerns during every stages of my training – for this, I am forever proud to have been a student in the UBC Experimental Medicine Program. Finally, my appreciation goes out to my friends and family for hearing me out during the stressful times of my training. The product of this dissertation would not have been possible without the support of each and every one of them!  xvi  Dedication  To my dreams and goals  xvii  CHAPTER 1 – INTRODUCTION An overview of the existing knowledge on multiple sclerosis and pregnancy. 1.1  Multiple sclerosis Multiple sclerosis (MS) is thought to be an autoimmune disease of the brain and  spinal cord.1 It is the most common cause of non-traumatic neurological disability in young adults.2 MS is characterized by inflammation and demyelination of white matter within the central nervous system leading to motor, sensory and autonomic dysfunction that often manifests as unilateral optic neuritis, numbness or weakness.3 The diagnosis of MS requires at least two separate episodes of demyelination separated by time (at least one month apart) and space (distinct lesions at different locations within the central nervous system) as well as the exclusion of other potential diagnoses.1 The disease course and prognosis of MS is highly variable; roughly 10-15% of patients have ‘primary progressive MS’ which is characterized by a progressive accumulation of disability from the onset of their symptoms.4 Another 75% have a ‘relapsing-remitting MS’ which is also known as a ‘relapsing-onset MS’ disease course characterized by intermittent attacks of MS with partial or full return to previous function between episodes; however, approximately 65% of individuals with relapsing-onset MS will eventually accumulate disability progressively in what is known as ‘secondary progressive MS’.5 The gold standard for monitoring disease progression in MS is the Kurtzke Expanded Disability Status Scale (EDSS) score with zero representing normal neurological examination and ten representing death by MS.6 Please see Table A.1.1 (Appendices) for a description of the EDSS score.  1  There is considerable regional variability in the incidence of MS in Canada with studies indicating a range from 5.6~23.9/100,000;7,8 the overall prevalence of MS in Canada is estimated to be 240/100,0009 with British Columbia (BC) representing a high risk region for MS.5 MS predominately affects people of northern European ancestry with approximately a 3:1 female to male ratio.10 The etiology of MS is not wellunderstood, but is believed to involve an interplay between an individual’s genetic susceptibility11 and several potential environmental factors including (but not limited to) vitamin D levels,12 sunlight exposure,13 viral illnesses14 and smoking.15  1.2  Effect of pregnancy on multiple sclerosis Given that the symptoms of MS often first present in early adulthood,16 a life  stage where many individuals contemplate having a family, the issue of pregnancy and MS takes on great importance. Historically, women with MS were discouraged from having children due to concerns of an increased risk to mother and child associated with MS disease; it was believed that pregnancy could provoke relapses or accelerate disease progression in women with MS. However, to the contrary, there is compelling research indicating that some autoimmune diseases including MS improve during pregnancy and flare up again in the postpartum period.17-19 The decrease in relapse rate has been reported to be most pronounced in the third trimester of pregnancy20 while the increased risk of relapse has been found to be greatest within three months postpartum.21 Women with MS who breastfeed appeared to be at a lower risk of experiencing postpartum relapses.22 The use of assisted reproductive technology has been associated with an increased risk of relapse23-27 although fertility is generally not  2  considered an issue for women with MS.28,29 At two years postpartum, the relapse rate was similar to the rate one year pre-pregnancy and disease progression remained unchanged.21 There were conflicting findings regarding the association between parity and MS disease progression in women with MS; European studies found reduced disease progression with pregnancies30-32 whereas North American studies found no effect.33-36  1.3  Effect of multiple sclerosis on perinatal outcomes Increasingly, the prevailing research suggests that offspring of women with MS  are not at an increased risk of adverse birth outcomes.17,37 A recent meta-analysis reported that although there remained the possibility that mothers with MS were at increased risk of spontaneous abortion (i.e. miscarriage), the risk was not dramatically different from that of the general population.17 There were conflicting findings regarding whether women with MS are at an increased risk of assisted vaginal delivery (use of forceps or vacuum extraction)38-41 and cesarean section;38,40-43 however, data from the BC MS cohort suggests no increased risk.37 Newborns of women with MS do not appear to be at greater risk of low birth weight, prematurity or congenital anomalies (i.e. birth defects) compared to those from the general population.17 In contrast to the extensive research on mothers with MS, there are no studies reporting birth outcomes in fathers with MS.  3  1.4  Effect of disease-modifying drugs for multiple sclerosis on perinatal  outcomes Several DMDs are licensed worldwide for treating MS.44 In the United States (US), interferon-beta (IFNβ)-1b (Betaferon®, Betaseron®, Extavia®) was first approved in 1993 (1995 in Canada), followed by IFNβ-1a (Avonex® and Rebif®) and glatiramer acetate (GA; Copaxone®) in 1996, mitoxantrone (Novantrone®) in 2000 (not approved for treating MS in Canada) and natalizumab (Tysabri®) in 2004.45 FDA approved oral DMDs include fingolimod (Gilenya®, 2010) and teriflunomide (Aubagio®, 2012).45 Patients with relapsing-remitting disease course are often encouraged to start diseasemodifying drugs (DMD) early to reduce the frequency of relapse with the hopes of slowing disease progression.16 IFNβ and GA are currently considered as first line therapies whereas natalizumab, fingolimod, mitoxantrone and teriflunomide are typically reserved as second line options.46 MS women treated with a DMD who wish to become pregnant are commonly advised to discontinue therapy between one and three months prior to conceiving. 47 Although the risk of a relapse is decreased during pregnancy, particularly in the third trimester,48 some risk remains and relapse rates can increase immediately postpartum, such that some patients and physicians may be reluctant to stop DMD therapy. In other cases, women with MS may have an unplanned pregnancy while taking a DMD, resulting in unintentional in utero exposure. Women with MS who wish to conceive children are often faced with a dilemma: whether to start DMDs early to maximize the potential benefit of therapy or delay therapy until after pregnancy to avoid the possible adverse effects of fetal exposure.  4  Based on animal studies and limited human data (largely from observational studies and voluntary post-marketing surveillance), the Food and Drug Administration (FDA) has classified GA49 as pregnancy risk category B (no risk shown in animal studies; no adequate human studies)50 IFNβ,51,52 natalizumab53 and fingolimod54 are at present pregnancy risk category C (risk shown in animal studies; no adequate human studies).50 Mitoxantrone55 is pregnancy risk category D (positive evidence of human fetal risk).50 and teriflunomide is pregnancy risk category X (fetal malformation reported in animal studies).45 Please refer to Table A.1.2 (Appendices) for a complete list of Pregnancy Risk Categories used by the FDA.  1.5  Knowledge gaps, research questions and hypotheses Although it appears that the offspring of mothers with MS are not at an increased  risk for adverse perinatal outcomes, certain important aspects of the intrapartum and postpartum period remain understudied in women with MS. Fatigue and pelvic organ dysfunction are common in women with MS.56 These symptoms may predispose women to difficulty with initiating labor during pregnancy57 – potentially necessitating labor induction (the initiation of labor before the spontaneous onset of contractions) or augmentation (increased strength and frequency of existing uterine contractions) to avoid excessive maternal fatigue and stress during labor. To date, only one Norwegian group has examined the use of labor induction in women with MS;39,40,58 and there are no reports on labor augmentation in women with MS. The Norwegian authors compared women with MS to the general population and found that MS was associated with a greater likelihood of labor induction,39,40 but aside from maternal age and the year of  5  delivery, they were unable to account for additional important confounders. They also compared the risk of labor induction in women with pregnancy before and after the diagnosis of MS and found no increased risk.58 No data exist to date on whether MS clinical factors such as disease duration or disability at the time of delivery are associated with labor induction or augmentation; this investigation could allow clinicians to better advise women with MS when to start a pregnancy to avoid the potential risk of labor induction or augmentation. In Chapter 3, I investigate whether MS and related clinical factors are associated with an increased risk of labor induction or augmentation in attempted vaginal births. I hypothesize that maternal MS and MS clinical factors were associated with labor induction and augmentation. Effective pain management is important during labor and delivery with epidural and spinal techniques being commonly used.59 Despite initial concerns that these pain management techniques could worsen the short (or long) term course of MS, presumably by neurotoxicity from local anesthetic agents,57,60 data have shown no effect on overall MS disability20 or the precipitation of a MS relapse.20,21,57,60 However, both types of anesthesia can slow down labor progression and increase the risk of an assisted vaginal delivery.61 To date, few studies have compared patterns of obstetrical pain management techniques among women with MS versus the general population; these studies have found comparable patterns of use,39,41 but this requires verification as key confounders such as parity were not accounted for. In addition, no studies have investigated whether MS clinical factors, such as disease duration or degree of disability are associated with the use of epidural or spinal anesthesia. In Chapter 4, the association between obstetrical use of epidural (in all deliveries) and spinal anesthesia  6  (in cesarean deliveries only) with the presence of maternal MS and MS clinical factors were examined. I hypothesize that maternal MS and MS clinical factors are associated with less epidural and spinal anesthesia. The transition from the intrapartum to postpartum period may be challenging for mothers with MS. Although recent studies found no link between MS and adverse perinatal outcomes,17,37 two studies reported that women with MS had longer postpartum hospital stays compared to women from the general population. 38,42 One of the two studies also investigated duration of newborn birth hospitalization and reported longer stays for newborns of mothers with MS.38 Prolonged stays can have negative consequences, including an increased risk of hospital-acquired infection as well as creating a strain on scarce healthcare resources.62 Greater disease duration and level of disability may cause mothers with MS to have longer birth hospitalization stays due to increased fatigue and longer postpartum recovery periods. Newborns of mothers with more severe MS disease may require longer birth hospitalization due to worse birth outcomes. In Chapter 5, the duration of birth hospitalization in mothers with MS and their newborns compared to the general population as well as the impact of MS clinical factors on the length of birth hospitalization stay were investigated. I hypothesize that maternal MS and MS clinical factors are associated longer hospital stay for the mother and the newborns. Limited human studies exist for clinicians or women with MS regarding the incidence of DMD exposure during pregnancy and its potential harm to mother and newborn. The few cases of DMD exposure during pregnancy are likely due to the relatively short period of time that these drugs have been approved for clinical use,  7  challenges with the reporting and data collection of postmarketing exposures and the common clinical practice of advising MS women to discontinue DMD treatment prior to conceiving.47 Despite these precautions, cases of prenatal DMD exposure do occur, partly because up to 50% of all pregnancies are unplanned.63 Hence, the investigation of perinatal outcomes following DMD exposure during pregnancy is an important area of research for individuals with MS contemplating pregnancy. I investigate the incidence and effect of in utero DMD exposure on perinatal outcomes in Chapter 6 and hypothesize that maternal MS is associated with unfavorable perinatal outcomes. In Chapter 7, I systematically review the literature regarding safety of DMD use during pregnancy on perinatal and developmental outcomes in offspring of patients with MS from all existing studies to obtain the best evidence available to inform clinical practice. Although there has been extensive research investigating the association between maternal MS and birth outcomes, the association of paternal MS with birth outcomes, while recognized,64 remains unexplored, partly due to methodological challenges associated with investigating birth outcomes of fathers65 and partly because the role of fathers in this context has been historically overlooked. 66 There is evidence that the offspring of fathers with other chronic diseases may be predisposed to unfavorable birth outcomes; paternal celiac disease is associated with lower mean birth weight and gestational age of the offspring.67 Likewise, a study on fathers with inflammatory bowel disease (Crohn’s disease or ulcerative colitis) found an association with preterm birth.68 Men with MS have been reported to have a lower sperm count, decreased sperm motility and increased abnormal morphology compared to males from the general population.69 It is important to investigate the influence of paternal MS on  8  birth outcomes because having MS may influence would-be fathers to avoid having children. With research that clearly outlines the potential risk of adverse birth outcomes in offspring fathered by men with MS, patients and their clinicians would be able to make better informed, evidence-based decisions. Paternal MS could potentially cause adverse birth outcomes through several direct and indirect mechanisms. People with MS are at higher risk of certain comorbidities70,71 – including inflammatory bowel disease as well as epilepsy, anxiety, depression, chronic lung disease, and migraines – which may lead to a greater likelihood of adverse birth outcomes. In addition, the decreased sperm quality could be caused by unknown mechanisms related to MS disease or by increased rates of certain social behaviors.72 For example, paternal smoking is known to affect sperm quality and passive smoking exposure is associated with adverse birth outcomes.73,74 Men with MS could also indirectly influence birth outcomes if they decided against having children; fathering unplanned pregnancies or being less supportive of an unintended pregnancy are factors associated with adverse birth outcomes.75,76 In Chapter 8, the association between birth outcomes and paternal MS as well as MS clinical factors (i.e. disease duration and disability) was examined through linkage of several population-based databases comprising of clinical data from fathers with MS, corresponding maternal characteristics, perinatal data of their offspring, as well as demographic information of the father, mother and baby. I hypothesize that paternal MS and MS clinical factors are associated with adverse birth outcomes. Lastly, despite considerable research attention devoted to uncovering potential adverse effects associated with maternal DMD exposure during pregnancy, the effect of paternal DMD use on birth outcomes has been understudied. To date, only one study  9  has reported on birth outcomes of offspring to MS fathers exposed to DMD around the time of conception;77 the study found no increased risk of lower mean birth weight or gestational age associated with paternal DMD use at the time of conception. 77 While this German study is the first on this topic, there are some methodological limitations as recognized by the authors. Specifically, the study used voluntary survey responses and did not have information such as socioeconomic status and maternal obstetric history and comorbidities that could affect birth outcomes. A major barrier to investigating birth outcomes in fathers with MS following DMD exposure is that few research centres have comprehensive data on birth outcomes as well as clinical data of fathers with MS or the capability to link them. In Chapter 9, birth outcomes in MS fathers exposed and unexposed to a DMD within 64 days (duration of spermatogenesis)78 prior to conception were compared. I hypothesize that paternal DMD exposure is associated with unfavourable birth outcomes.  10  CHAPTER 2 – STUDY DESIGN The epidemiological approach and biostatistical analyses for studies in this dissertation. 2.1  Data sources, database linkage and study participants All research questions in this dissertation were investigated through a  retrospective cohort study design using data from population-based databases from health care settings or government sources. The British Columbia Multiple Sclerosis (BCMS) database, established in 1980, was used to identify men and women with MS. It contains MS-neurologist-generated clinical data, largely collected prospectively, on an estimated 80% MS patients in BC based on the prevalence of MS patients in 198279 and the number of MS patients registered in the database around that time.80 The BCMS database currently has data on ~9000 patients; based on the prevalence of MS individuals in BC in 2000/20019 and the general BC population at the time, an approximated figure of 80% coverage was obtained. Patients had to be registered at one of four MS specialty clinics in BC (Vancouver, Prince George, Victoria and Kelowna) with neurologist-confirmed laboratory supported or clinically definite MS (Poser81 or McDonald82 criteria). In 2005, another MS specialty clinic opened in Burnaby, BC; however, this site was not part of the BCMS database. Along with other database personnel, I performed extensive patient chart reviews on the data from the BCMS database and where necessary, consulted with the responsible physician to clarify unusual or missing data; for example, in some cases, the date of cessation of DMD therapy was not explicitly stated in the patient chart. For all studies in this dissertation, MS patient data collected up until December 31, 2008 were used.  11  The British Columbia Perinatal Database Registry (BCPDR) is a province-wide initiative of Perinatal Services BC that captures perinatal data of births ≥20 weeks gestational age or ≥500 grams birth weight in BC.83 Established in 1994, full provincial coverage was achieved in April 2000, providing data on birth outcomes as well as the associated maternal obstetrical and demographic information.83 For studies on maternal MS (Chapters 3 to 6), births up until March 31, 2009 (the study cut off date) were included; for studies on paternal MS (Chapters 8 and 9), births up until December 31, 2010 (the study cut off date) were included. Population Data BC is a multi-university data and education resource that oversees access to the British Columbia Vital Statistics Birth Registry, a database of all registered births in BC since 1985 as well as the Consolidation File, a central demographics file (established in 1986), which allows paternal age to be derived based on the fathers and children’s dates of birth.84 Population Data BC also contains the Census GeoData, which provides Statistics Canada generated neighborhood income quintiles based on postal codes of residence as an indicator of socioeconomic status.84 The smallest geographical unit for which census profile data is available for dissemination areas composed of one or more neighboring blocks with a population of 400-700 individuals.85,86 Data from Population Data BC up until December 31, 2010 were used for studies on paternal MS (Chapters 8 and 9). Linkage between databases occurred at the individual level via Personal Health Number (PHN), a government-issued personal identifier common to all databases and unique to each resident of BC. For the studies pertaining to maternal MS (Chapters 3 to 6), linkage occurred between only two databases – the BCMS database and the  12  BCPDR. Perinatal Services BC performed the linkage; maternal names and dates of birth were additionally used to verify the linkage; when PHNs were unavailable for mother or child, probabilistic data linkage by name and date of birth were used. For studies on paternal MS (Chapter 8 and 9), Population Data BC performed the linkage that occurred between all databases. The PHN of men was used to identify their newborns registered in the BC Vital Statistics Births Registry. The PHN of identified newborns was then used to link perinatal records in the BCPDR. For studies where births from the general population were needed to serve as controls (Chapters 3 to 5 and 8), mothers and fathers with International Classification of Disease (ICD) 9 or 10 codes for MS were excluded from the control group. Maternal age (±1 year), local health authority and delivery year were then used to frequency-match 4 births in from the general population cohort to every birth in the MS cohort. Before applying the exclusion criteria, a total of 762 births to 550 MS women and 259 newborns fathered by 172 MS men were found in the BCPDR. In all studies, non-singleton births (i.e. twins and triplets) were excluded due to an associated increased risk of perinatal morbidity and mortality.87 Within the MS cohort, all births to mothers and fathers with MS onset after delivery and conception, respectively, were excluded from the dataset.  2.2  Sample size calculations Prior to data analysis, the required sample size for each primary outcome of  interest was estimated with the assumption that I had equal sample sizes for subjects and controls. As shown in Table 2.1, I calculated the minimum sample size required to achieve 80% power with a 5% Type I error (one-tailed test) in univariate analyses – see  13  Figure A.2 (Appendices) for formulae.88 For binary outcomes, I compared two different proportions.88 For continuous outcomes, I compared two different means.88 The baseline proportion for binary outcomes and standard deviation (SD) for continuous outcomes were determined from either the 2008 British Columbia Perinatal Health Report83 or relevant existing literature. The desired effect sizes were based on estimates having some clinical value.89 These simple calculations were done a priori to actual data analysis as a guide for planning purposes; I recognize that larger sample sizes are likely needed to account for multiple variables and clustering effects due to multiple observations from the same subject.88,89 By having 4 controls births for every birth in the MS cohort, I increased the statistical power of the studies in this dissertation.90 Table 2.1. A priori sample size calculation for primary outcomes. Relevant Chapter 3 4  Relevant Chapter 5  Binary Outcome Labour induction Labour augmentation Epidural anesthesia in all deliveries (based on nullipara only) Spinal anesthesia in cesarean delivery only Non-Binary Outcome  Pbaseline (%) 21 40 48  Pexposure (%) 41 60 28  ƒ(α,β)one-tailed*  n  6.2 6.2 6.2  64 75 70  51  31  6.2  72  SD  Effect Size  ƒ(α,β)one-tailed*  n  Maternal hospitalization 34 hours +24 hours 6.2 25 Newborn hospitalization 70 hours +24 hours 6.2 106 6,8,9 Birth weight (based on 441 grams -500 grams 6.2 10 male babies with 39 weeks gestational age) Gestational age 1.7 weeks -2 weeks 6.2 9 P, proportion; SD, standard deviation; α, level of significance; β, type II error; n, sample size required in each cohort for univariate analysis *please refer to Figure A.2 (Appendices) for how ƒ(α,β)one-tailed is derived  14  2.3  Approach to data analyses All data analyses were completed with the Statistical Package for the Social  Sciences (SPSS, IBM, Armonk, NY). The specific exposure, potential confounders, outcomes of interest as well as statistical tests and models for the different research questions are stated in the methods section of each chapter. Unless otherwise stated, the approach to data analysis for all research questions is consistent with the process outlined in this chapter (Chapter 2). Since all studies in this dissertation were observational in nature, confounding is a potential issue.89,90 A confounder is a variable that is associated with the exposure (i.e. MS) and the outcomes of interest, but cannot be the effect of the exposure. 89,90 Hence, several steps (described later in this chapter) were undertaken to assess and control for potential confounding effects. Data analysis began with a summary description of all relevant variables (i.e. exposure, potential confounders and outcomes). Each variable was first plotted to reveal the data distribution – histograms for continuous variables and bar graphs for categorical (i.e. nominal or ordinal) variables.88 Proportion/percentage was calculated for categorical variables.88 For continuous variables, mean and SD were first calculated for normally distributed data; median and range for skewed data. 88 To avoid the potential influence of outliers, all demographic variables that were continuous were reported with the median and range. Outcomes of interest were reported with mean and SD as well as median and range. Relevant variables that were assessed in the univariate analysis as potential confounders varied slightly in some chapters, depending on the research question. In  15  general, univariate analysis between (i) exposure and potential confounders as well as (ii) potential confounders and outcome variables were assessed for evidence of association. The Chi-squared test (for all cells with expected count ≥5) or Fisher’s Exact test (for expected cell count <5) was used for pairs of categorical variables. 88 The Mann-Whitney U test (for 2 groups) or Kruskal-Wallis test (more than 2 groups) was used to compare continuous variables between groups.88 Spearman’s correlation test was used to assess for correlation between continuous variables. 88 In the analyses of association between exposure and outcome, multivariate regression models were built to adjust for relevant potential confounders.88,89 Logistic regression models were used for binary outcomes and linear regression models were used for continuous outcomes (with logarithmic transformation of the outcome variable if the data were skewed).88,89 These models assume that each observation is independent of each other.89 However, since studies in this dissertation contain multiple births to the same subject, these births may be correlated with one another (i.e. ‘clustered’). Failure to account for clustering effects may result in inaccurate standard errors, leading to inaccurate p values and confidence intervals (CI).89 Generalized estimating equations (GEE) are a flexible approach to adjust for correlated observations through modeling a variety of different relationships between risk factors and an outcome. 89,91 The GEE is a population-averaged models that focus on how the mean of the population changes; 89,91 it examines the impact of exposure and potential confounders on the population average of the outcome.91,92 The GEE can be used for outcomes of various data types (i.e. continuous, binary, categorical, ordinal) and covariates that do or do not change at each observation.89,91 It has the ability to incorporate different numbers of observations  16  for different subjects.89,91 The GEE approach is an extension of the standard regression models that allows for the possibility of taking into account the dependence between observations by incorporating a working correlation structure in the estimating equations.91 The ‘autoregressive’ working correlation structure is used for the GEE if the two observations close together in time within a subject tend to be more correlated than two other observations further apart in time from the same subject.89,91 On the other hand, the ‘exchangeable’ working correlation structure is used in the GEE if observations within a subject appear equally correlated with every other observation from that subject.89,91 To reflect the correlation of clustered observations, the GEE will have wider CI of point estimates compared to the standard regression models because a subject with at least 2 observations will have each observation being weighted less in the GEE than a sole observation from a subject.91 The GEE makes no assumptions on the distribution of the residuals.91 To assess how well the specified working correlation structure and potential confounders reflect the data, the ‘Quasi Likelihood under Independence Model Criterion’ under the full log quasi-likelihood function (part of SPSS output) was used to compare model fit.91,93 A lower value for the ‘Quasi Likelihood under Independence Model Criterion’ indicated a better model fit. 91,93 Different approaches exist for selecting variables for inclusion in the multivariate analysis.89 As the objective of the studies in this dissertation was not to determine the best predictors of the outcome, conventional stepwise regression via automated variable selection algorithm was not used. Conventional stepwise regression selects variables that fit the model best for the outcome, but can often lead to invalid estimates if the selected variables are actually extraneous variables that could not possibly lead to  17  the outcome.89,94 In addition, conventional stepwise regression does not take into account the association between the exposure and potential confounders for variable selection.94 Potential confounders were determined by a priori knowledge and preliminary univariate analysis. Some variables were included in the models as a priori potential confounders regardless of the statistical significance of their association with the exposure and outcome because they have been theorized or shown in previous research to be well-established confounders (i.e. maternal age, parity).89 Conversely, empirical confounders, not necessarily known to be associated with the outcome of interest in the existing literature, were considered for inclusion in the multivariate analysis if the association between the variable and exposure/outcome was below a cut-off of p<0.2 in univariate analysis.89 There is no single standard for the magnitude of an association required for a variable to be included as a potential confounder. 89 For potential confounders with data missing for >20% of subjects, the statistical significance of including and excluding the variable in the model was checked; these confounders were included in the model only if the change in association between the exposure and the outcomes of interest was statistically significant (i.e. p value changed from <0.05 to ≥0.05 or vice versa). If the change was not statistically significant, the confounders with data missing for >20% of subjects were dropped from the multivariate analysis in order to maintain internal validity for the study. In addition, variables that were viewed as potential steps in the causal pathway between exposure and outcome (regardless of their significance with the exposure) were not adjusted for because adjustments for these intervening variables may eliminate the true association between exposure and outcome.89 For pairs of potential confounders with continuous data showing strong  18  correlation on scatterplots (checked by excluding outliers), the variable that was less clinically important for the outcome or had less contribution to the model (as determined by a less significant p value) was dropped from the model to avoid multicolinearity.89 I also assessed for interactive effects where the combined influence of two variables on the outcome is more than additive.89,90 Interactions between exposure and potential confounders were checked by creating a product term between the two variables. 89 Each product term, along with the individual exposure and potential confounder, was incorporated into a GEE; if the interaction term had a p<0.15, it was considered for inclusion in the multivariate analysis along with all confounders. Ultimately, the interaction term was only included if it was statistical significant with the outcome (i.e. p<0.05). Since disease duration and EDSS scores could be included in the model as either continuous or categorical variables, the data type that revealed a significant association with the outcome took precedence. Disease duration was the time difference between date of MS symptom onset and the time of conception/birth; it was included as a continuous variable if no significant association with the outcome was found as either a continuous or categorical variable. EDSS scores represent MS disability in a scale from 0 (i.e. normal neurological examination) to 10 (i.e. death by MS) with 0.5 increments;6 a higher EDSS score means a more severe level of disability.6 If there was no significant association between the outcome and the EDSS score (as a continuous or a categorical variable), then the EDSS score was included as a categorical variable because the EDSS is an ordinal scale; each increment increase does not translate into an equal increase in disability. Likewise, for potential  19  confounders that could be included in the model as either a continuous or categorical variable, the data type that fit the model better took precedence. To assess for selection bias, when >20% of subjects cohorts had data missing for a single variable (such as EDSS score) sensitivity analyses were conducted to detect any differences in baseline characteristics and outcomes between subjects with and without data available for the specific variable.  2.4  Statistical interpretation of data The regression coefficient (β) in multivariate analysis is a measure of how the  outcome changes with the exposure/potential confounders while adjusting for other potential confounders in the model.88,89 For linear regression models, each unit increase/decrease in the exposure/potential confounder has an associated increase/decrease in the mean value of the outcome (β).88,89 For linear regression models, a positive value for β indicates a positive association between the exposure/potential confounder and the outcome;89 a negative value for β indicates an inverse association.89 For binary logistic regression models, the natural logarithm of the odds of the outcome is being modeled.89 The odds ratio (OR) is the likelihood of having the outcomes vs. not having the outcome in the exposed group compared the unexposed (i.e. control) group.89,90 In logistic regression, the OR equals eβ;89 one unit change in the exposure/potential confounder results in a multiplicative e β change in the outcome.89 The 95% CI for the OR is determined by eβ±1.96(standard error) where ‘1.96’ reflects the 95% of the central area under the standard normal distribution curve. 88,89  20  CHAPTER 3 – LABOR INDUCTION AND AUGMENTATION IN MULTIPLE SCLEROSIS Objectives: To investigate whether MS and related clinical factors are associated with an increased risk of labor induction or augmentation in attempted vaginal births. 3.1  Methods Please refer to Chapter 2 (page 11) for a general outline of the study design used  throughout the studies in this dissertation. Details regarding the methodology used in this particular study are described below. Study Participants Births to women with and without MS were included in this study. I excluded (i) non-singleton births (i.e. twin, triplet, etc.) because they are associated with worse birth outcomes compared to singleton births,87 (ii) stillbirths because the use of labor induction is different than that of live births95 (iii) late terminations because the new BCPDR data policy prohibits the use of these cases or (iv) births delivered by elective cesarean section because, by definition, a vaginal birth would not have been attempted. In the MS cohort, births to mothers with MS onset after delivery or those without clinically definite MS were excluded. Maternal and Clinical Characteristics Characteristics compared between women with and without MS included: maternal age, parity, lone parent status, use of alcohol, drugs or cigarettes, presence of hypertension or diabetes during pregnancy, as well as gestational age and birth weight of their newborn.  21  MS clinical factors included: disease course, age of MS onset, disease duration at the time of delivery, level of disability (as measured by the Expanded Disability Status Scale (EDSS) score6) closest to the time of delivery (±3 years). Indications for labor induction included those with strict definitions: post-dates pregnancy (defined as a gestational age ≥41 weeks) and premature rupture of membranes (defined as before onset of uterine contractions for a term pregnancy) as well as those determined by the attending healthcare professional: presence of fetal indication (e.g. intrauterine growth restriction); presence of an adverse maternal condition (being severe enough to potentially compromise the mother’s health during labor e.g. diabetes or hypertension); logistical issues (e.g. inability for the mother to access appropriate healthcare in a reasonable time) as well as ‘other’ (e.g. prior stillbirth). Methods of labor induction included: intra-vaginally administered prostaglandin, intravenous oxytocin, artificial rupture of membranes or ‘other’ (e.g. Foley catheter). Outcomes The primary outcomes of interest were labor induction and augmentation. The mode of delivery – spontaneous vaginal delivery, assisted vaginal delivery or emergency caesarean section – was also described. Statistical Analysis The Chi-Squared test or Fisher’s Exact test (for categorical variables) and the Mann-Whitney U test (for continuous variables) were used to compare maternal characteristics as well as indications and methods of labor induction for women with MS and those to mothers in the general population. Multivariate binary logistic regression models were used to determine whether  22  the presence of MS, disease duration or disability was associated with an increased likelihood of labor induction or augmentation. Clustering effects from multiple births to the same mother were accounted for using GEE with an exchangeable working correlation structure. Empiric confounders were included in the model along with a priori potential confounders. Factors that could alter the likelihood of labor induction included gestational age,96 maternal characteristics (age96 parity,97 cigarette use98) and comorbidities (hypertension96 and diabetes96). In the analysis of labor augmentation, maternal age,96 parity97 and birth weight96 were included as potential confounders. Interactions were checked and excluded from the model if no significant effect was found. Findings were reported as OR with 95% CI. Lastly, a sensitivity analysis was conducted to compare disease duration at delivery, maternal age, parity and the primary outcomes in attempted vaginal deliveries for MS women with and without EDSS scores available closest to the time of delivery (±3 years). A p value of <0.05 was considered statistically significant.  3.2  Results  Demographics and Clinical Characteristics The BCMS database contained 7,056 female MS patients; after linkage with obstetrical data from the BCPDR, 762 deliveries to 550 women with MS were identified. A frequency-matched sample of 3,048 births from the general population was selected for comparison. After applying the exclusion criteria, a final sample of 381 attempted vaginal births from the MS cohort and 2,615 attempted vaginal births from the general population cohort was included in this study. The relevant mothers’ characteristics are  23  shown in Table 3.1. MS clinical characteristics are given in Table 3.2. Women with MS were more likely to be nullipara and smoke cigarettes during pregnancy compared to women from the general population.  Table 3.1. Characteristics of women with attempted vaginal deliveries in BC. Characteristic MS General Population p value n=381 n=2,615 Maternal age – years 0.22a Median (range) 32 (19-44) 32 (16-44) Parity 0.02b Nullipara – n (%) 195 (51) 1,167 (45) Lone parent status 0.21b n (%) 12/352 (3) 120/2,437 (5) Exposure to alcohol during pregnancy 0.17c n (%) 1 (<1) 28 (1) Exposure to drug considered as harmful for pregnancy 0.65b n (%) 6 (2) 50 (2) Cigarette use during pregnancy 0.048b n (%) 51 (13) 263 (10) Hypertension during pregnancy 0.09b n (%) 29 (8) 142 (5) Abnormal glucose level or diabetes during pregnancy 0.07b n (%) 16 (4) 174 (7) Birth weight – grams 0.19a Median (range) 3,425 (1,985-5,770) 3,465 (900-5,660) Gestational age – weeks 0.60a n 381 2611 Median (range) 39 (32-42) 39 (23-43) BC, British Columbia; MS, multiple sclerosis a Mann-Whitney U test b Chi-Square test c Fisher’s Exact test  The majority of mothers in the MS cohort had a relapsing-onset disease course, had a median age at MS onset of 24 years and a relatively low level of disability (median EDSS score=1.5), see Table 3.2. Baseline characteristics between attempted vaginal deliveries in MS women with and without an EDSS score revealed that women  24  with EDSS scores available had a shorter duration of MS disease (<1 years on average) at the time of the childbirth compared to women without EDSS scores (Table A.3.1, Appendices).  Table 3.2. Clinical characteristics of MS women with attempted vaginal deliveries in BC. Characteristic Mothers Births to mothers with MS* with MS n=290 n=381 Disease course n 286 374 Relapsing-onset – n (%) 282 (99) 370 (99) Primary progressive – n (%) 4 (1) 4 (1) Age at MS onset n 279 364 Median (range) 24 (8-39) 24 (8-39) Disease duration at delivery – years n 279 364 Median (range) 6.4 (<1-28) 7.3 (<1-28) Disability at delivery (±3 years) – EDSS score n 206 262 Median (range) 1.5 (0-7.5) 1.5 (0-7.5) MS, multiple sclerosis; BC, British Columbia; EDSS, Expanded Disability Status Scale *based on the first birth in the study period  The indication and method of labor induction are summarized in Table 3.3. The most common indications for labor induction in women with MS were presence of an adverse maternal condition, followed by post-dates pregnancy and premature rupture of the membranes. The indications for labor induction were similar between women with and without MS (p>0.1, Table 3.3), but women with MS were significantly more likely to use more than one method of labor induction versus women in the general population (OR=1.94, 95% CI=1.23-3.06, p=0.004, Table 3.3).  25  Table 3.3. Indications and methods of labor induction in women with induced labor in BC MS General Population p value n=94 n=627 Indication – n (%) Post-dates pregnancy (≥41 weeks)a 23 (24) 204 (33) 0.12‡ b Premature rupture of membranes 21 (22) 148 (24) 0.79‡ Presence of fetal indicationc 8 (9) 45 (7) 0.64‡ d Adverse maternal condition 31 (33) 164 (26) 0.17‡ Logistical issuese 1 (1) 11 (2) 1.00¥ f Other 9 (10) 43 (7) 0.34‡ Unknown 1 (1) 12 (2) 1.00¥ Method – n (%) Prostaglandin only (administered 0.11‡ vaginally) 35 (37) 288 (46) Artificial rupture of membrane only 1.00¥ (instrument assistance) 4 (4) 31 (5) Oxytocin only (parenteral) 18 (19) 142 (23) 0.45‡ Otherg 1 (1) 14 (2) 0.71¥ More than one method 36 (38) 152 (24) 0.004‡ BC, British Columbia; MS, multiple sclerosis ‡ Chi-Square test ¥ Fisher’s Exact test a Post-dates pregnancy: a pregnancy that has extended beyond the due date (≥41 weeks) b Premature rupture of membranes: rupture of membrane occurred before onset of uterine contractions for a term pregnancy (>37 weeks) c Fetal indication: medical concern about the newborn’s condition, as determined by the attending healthcare professional d Adverse maternal condition: medical concern about mother’s condition, severe enough to compromise the mother’s health (e.g. diabetes, pregnancy-induced hypertension etc.) e Logistical issues: inability for the mother to access supportive healthcare within a reasonable time (e.g. past rapid labor, geographical barriers and difficulties etc.) f Other: prior stillbirth. g Other: Foley catheter etc.  26  Risk of Labor Induction and Augmentation Of 381 attempted vaginal births to MS women, 94 (25%) were exposed to a labor induction intervention and 147 (39%) to labor augmentation. Of these, 28 (7%) women with MS had both labor induction and augmentation. Similarly, of 2,615 attempted vaginal births to women in the general population, 627 (24%) were exposed to a labor induction intervention and 1,078 (41%) labor augmentation; of these, 155 (6%) women from the general population had both labor induction and augmentation. As shown in Figure 3.1, MS was not associated with a higher risk of labor induction before or after adjustment for clustering and confounding effects (unadjusted OR=1.04; 95% CI=0.811.33; p=0.77 and adjusted OR=0.91, 95% CI=0.68-1.22, p=0.54). Likewise, women with MS did not have a higher risk of labor augmentation (unadjusted OR=0.90; 95% CI=0.72-1.12, p=0.33; adjusted OR=0.91, 95% CI=0.72-1.15, p=0.43, Figure 3.1).  27  Figure 3.1. Association between the presence of MS and the risk of labor induction or augmentation. MS, multiple sclerosis Adjustments: maternal age, parity, smoking, diabetes, hypertension and gestational age for the analysis of labor induction; maternal age, parity, hypertension and birth weight for the analysis of labor augmentation  MS Clinical Factors Within the MS cohort, there was no association between disease duration and risk of labor induction or augmentation (adjusted p>0.2, Figure 3.2). However, higher EDSS scores were associated with labor induction (adjusted OR=1.24; 95% CI=1.021.52, p=0.04, Figure 3.2). Further adjustment for disease duration gave similar findings for the association between EDSS scores and labor induction (adjusted OR=1.25; 95% CI=1.01-1.53, p=0.04, Figure 3.2). The risk of labor augmentation was not significantly associated with EDSS scores, even after adjustment for disease duration (adjusted p>0.5, Figure 3.2). MS women with or without EDSS scores available did not have a significantly different proportion of labor induction or augmentation (Table A.3.1, Appendices). 28  Figure 3.2. Association between MS clinical factors and the risk of labor induction or augmentation. MS, multiple sclerosis; EDSS, Expanded Disability Status Scale Adjustments: maternal age, parity, smoking, diabetes, hypertension and gestational age for the analysis of labor induction; maternal age, parity and birth weight for the analysis of labor augmentation *in the analysis of disease duration, disability was additionally adjusted for; in the analysis of disability, disease duration was additionally adjusted for  29  Mode of Delivery in Women with Labor Induction and Augmentation Out of the 94 attempted vaginal deliveries in women with MS exposed to labor induction, 62 (66%) resulted in a spontaneous vaginal birth, 13 (14%) in an assisted vaginal delivery and 19 (20%) in an emergency cesarean section. Of 627 deliveries to women in the general population exposed to labor induction, the findings were 400 (64%), 70 (11%) and 157 (25%), respectively. Labor augmentation in 147 attempted vaginal deliveries to women with MS resulted in 103 (70%) spontaneous vaginal deliveries, 18 (12%) assisted vaginal deliveries and 26 (18%) emergency cesarean sections. Of 1078 deliveries to women with labor augmentation in the general population, the findings were: 736 (68%), 167 (15%) and 175 (16%), respectively.  3.3  Discussion This study is one of the first to investigate the risk of labor induction in a North  American MS population. I found that the likelihood of women with MS having a labor induction or augmentation procedure was similar to women in the general population. In addition, the specific indication for labor induction did not differ between women with MS or those in the general population. To the best of my knowledge, no previous study has investigated the association between MS and labor augmentation or the association of MS clinical factors with labor induction and augmentation. In contrast to findings from this study, two Norwegian studies reported that women with MS were more likely to have been exposed to a labor induction procedure compared to women in the general population.39,40 Although these studies were sizable (n=649 and n=449), and  30  adjustments were made for delivery year and maternal age,39,40 they could not consider other potentially important factors such as maternal characteristics (e.g. parity) and comorbidities. These factors could confound the relationship between MS and either labor induction or augmentation. The increased risk of labor induction observed in the Norwegian studies, but not in this Canadian study, may also be due to differences in the clinical characteristics of the MS cohort, such as level of disability, which I observed may affect findings. Differences in findings might also reflect disparate healthcare practices or clinician/patient preferences between the two countries. Women with MS were more likely to receive more than one method of labor induction in this study. It is possible that once labor induction has been used, women with MS are more ‘resistant’ or less ‘responsive,’ necessitating greater efforts and interventions to reach the end goal of a safe and timely delivery. Perhaps even different labor induction modalities may have varied success in women with MS, although this possibility could not be explored in this study. Alternatively, health care professionals may have a different threshold for adding additional labor induction agents in women with MS versus women in the general population. This finding therefore requires further investigation. The association between MS disability and labor induction suggests that women with a greater disease burden (i.e. higher EDSS scores) have more difficulty initiating labor. These women are known to be at an increased risk of spasticity.99 The resultant decreased inhibition of lower motor neurons and related increased tone and decreased coordination of uterine, cervical and pelvic muscles may result in unsuccessful or difficult initiation of spontaneous labor.100  31  I recognize that this study highlights associations rather than proving causation; I cannot confirm that women with MS who underwent labor induction had a ‘true’ medical indication warranting an intervention, or were subjectively treated differently by healthcare providers because of having more obvious physical challenges (higher EDSS scores) and/or the women themselves requesting to be induced. However, previous work from our research group has not revealed any strong indication that women with MS were treated differently from women in the general population. For example, similar patterns of delivery methods37 were found between women with and without MS. Lastly, the BCMS database only captures an estimated 80% of MS patients in BC, it is possible that individuals with geographic barriers as well as very mild or severe disease may be underrepresented in the BCMS database; there were very few births to women with severe MS in this study. Nevertheless, all MS patients who attended MS clinics in BC were broadly captured and findings from this study are likely representative (given that the BCMS database has an estimated 80% coverage of MS patients in BC) and applicable to regions with a similar healthcare system as BC.  32  CHAPTER 4 – OBSTRETRICAL EPIDURAL AND SPINAL ANESTHESIA IN MULTIPLE SCLEROSIS Objectives: To examine the association between obstetrical use of epidural (in all deliveries) and spinal anesthesia (in cesarean deliveries only) with the presence of MS and related clinical factors. 4.1  Methods Please refer to Chapter 2 (page 11) for a general outline of the study design used  throughout the studies in this dissertation. Details regarding the methodology used in this particular study are described below. Study Participants Births to women with and without MS were included in this study. I excluded (i) non-singleton births (i.e. twin, triplet, etc.) because of the associated increased risk of cesarean delivery,101 requiring epidural or spinal anesthesia59 and (ii) late terminations because the new BCPDR data policy prohibits the use of these cases. In the MS cohort, I excluded births to mothers with MS onset after delivery or those without clinically definite MS. Births delivered vaginally and by cesarean section were included in the analysis of epidural anesthesia. I excluded vaginal births in the analysis of spinal anesthesia because spinal anesthesia is almost exclusively indicated for cesarean section.59 Demographics and Clinical Characteristics Maternal characteristics included: maternal age, parity, maternal hypertension, abnormal serum glucose levels or maternal diabetes and the mode of delivery which includes spontaneous vaginal delivery, assisted vaginal delivery (forceps and/or  33  vacuum extraction) or cesarean section (emergency and elective). Newborn characteristics included birth weight and gestational age. Clinical MS characteristics of specific interest for this study included: age at MS onset, disease duration, disability (recorded as the Expanded Disability Status Scale (EDSS)6 scored closest to, but no more than 3 years from, the delivery date) and disease course (relapsing-onset versus primary progressive). Outcomes The primary outcomes were the use of epidural analgesia/anesthesia (referred to as ‘anesthesia’ from hereon in) and spinal anesthetics. By definition, analgesics decrease the sensation of pain while anesthetics provides a more dense loss of sensation.59 Epidural anesthetics are administered into the epidural space, which is located immediately exterior to the dura mater and are commonly used in vaginal deliveries.59 Typical agents used in epidural anesthesia include local anesthetics (bupivacaine, lidocaine, ropivacaine and chloroprocaine), opioids (fentanyl, morphine and sufentanil) as well as epinephrine.59 Spinal anesthetics are administered into the cerebrospinal fluid, have a faster onset of action and are the most common type of anesthetic employed for cesarean deliveries.59 Agents used in spinal anesthesia included local anesthetics (bupivacaine, lidocaine, ropivacaine and rarely chloroprocaine) as well as opioids (fentanyl, morphine and sufentanil).59 The secondary outcomes, described descriptively, were the frequency of epidural and spinal anesthesia use grouped by parity (nulliipara vs. multipara) in the different modes of delivery (vaginal, emergency or elective cesarean deliveries).  34  Statistical Analyses Demographic characteristics and type of obstetrical pain management approach (grouped as epidural, spinal, pudendal nerve block, local anesthesia infiltration, opioids, nitrous oxide and oxygen gas, general anesthesia and ‘others’) were compared in women with MS and without MS using the Mann-Whitney U test for continuous variables and the Chi-Square test or Fisher’s Exact test for categorical variables. The association between MS and the use of epidural/spinal anesthesia was analyzed using multivariate binary logistic regression models, fitted using GEE. Confounders included in the model were: maternal age, parity,83 labor induction59 and birth weight.102 Additionally, in the analysis of epidural anesthesia use between mothers with and without MS, the mode of delivery59 (spontaneous vaginal delivery, assisted vaginal delivery and cesarean section) was adjusted for. Although some studies report no association between MS and the overall likelihood of cesarean delivery,17 no studies have examined the association between MS and emergency or elective cesarean sections. MS could potentially cause an increased risk of either elective or emergency cesarean sections, ultimately leading to an increased likelihood of epidural or spinal anesthetic use. Therefore, the overall frequency of cesarean section (rather than elective and emergency cesarean sections separately) was adjusted for in the mode of delivery in GEE. Two-way interactions between MS and potential confounders were also checked and included in the GEE only if a significant effect was found. The same approach was used for the association between MS clinical factors and epidural/spinal anesthetic use. MS disease duration was categorized as: <5 years, 5 to <10 years and  35  ≥10 years. Disease disability was grouped as EDSS of 0 (normal neurological exam), 1.0 to 1.5 (‘no disability with minimal neurological symptoms present’), 2.0 to 2.5 (‘minimal disability’) and ≥3.0 (‘mild to moderate’ disability or higher).6 Findings were reported as OR with 95% CI. Lastly, a sensitivity analysis was done to compare disease duration at delivery, maternal age, parity and the primary outcomes in all deliveries as well as cesarean deliveries in MS women with and without EDSS scores available closest to the time of delivery (±3 years). A p value of <0.05 was considered statistically significant.  4.2  Results  Cohort Characteristics As previously reported in Chapter 3, 762 deliveries to 550 women with MS were identified and frequency-matched to 3,048 deliveries to women in the general population. After applying the exclusion criteria, the final cohorts consisted of 432 deliveries to 321 women with MS and 2,975 deliveries to 2,958 women from the general population. Of these, women with MS had 128 cesarean sections and women from the general population had 848 cesarean sections. As shown in Table 4.1, women with MS were more likely to be nullipara compared to mothers from the general population. They were also more likely to have hypertension, but less likely to have diabetes. Other differences between the two groups were unremarkable (Table 4.1).  36  Table 4.1. Maternal characteristics and perinatal outcomes of deliveries in BC. Characteristic MS General Population p value n=432 n=2,975 Maternal age – years 0.18a Median (range) 32 (19-44) 32 (16-44) Parity 0.01b Nullipara – n (%) 209 (48) 1,239 (42) Hypertension during pregnancy 0.046b n (%) 33 (8) 157 (5) Abnormal glucose level or diabetes during pregnancy 0.01b n (%) 17 (4) 222 (8) Mode of delivery – n (%) Spontaneous vaginal delivery 265 (62) 1,811 (61) 0.63b Assisted vaginal delivery 39 (9) 316 (11) 0.34b Forceps only 17 (4) 98 (3) Vacuum extraction only 20 (5) 207 (7) Both 2 (<1) 11 (<1) Cesarean section 128 (30) 848 (29) 0.63b Elective 50 (12) 344 (12) Emergency 78 (18) 504 (17) Birth weightc – grams n 431 2959 0.05a Median (range) 3423 (1,985-5,770) 3,470 (900-5,660) c Gestational age – weeks n 431 2,954 0.53a Median (range) 39 (32-42) 39 (23-43) BC, British Columbia, MS, multiple sclerosis a Mann-Whitney U test b Chi-Square test c based on live births only  The clinical characteristics of the MS cohort are shown in Table 4.2, grouped by mode of delivery (all deliveries are shown as well as cesarean section deliveries only). Baseline characteristics between all deliveries (Table A.4.1, Appendices) as well as all caesarean deliveries (Table A.4.2, Appendices) in MS women with and without an EDSS score revealed that women with EDSS scores available had shorter MS disease duration (3 years on average) at the time of the childbirth than women without EDSS scores.  37  Table 4.2. Clinical characteristics of MS women with deliveries in BC. Characteristic All deliveries Cesarean deliveries only n=432 n=128 Disease course n 425 128 Relapsing-onset – n (%) 421 (99) 127 (99) Primary progressive – n (%) 4 (1) 1 (1) Age at MS onset – years n 414 125 Median (range) 24 (8-39) 26 (13-39) Disease duration at delivery – years n 414 125 <5 – n (%) 134 (32) 40 (32) 5 to <10 – n (%) 150 (36) 47 (38) ≥10 – n (%) 130 (31) 38 (30) Median (range) 7.3 (<1-28) 7.5 (0.1-21) Disability at delivery (±3 years) – EDSS score n 330 85 0 – n (%) 58 (18) 12 (14) 1.0 or 1.5 – n (%) 117 (35) 30 (35) 2.0 or 2.5 – n (%) 89 (27) 24 (28) ≥3.0 – n (%) 66 (20) 19 (22) Median (range) 1.5 (0-7.5) 2.0 (0-7.0) MS, multiple sclerosis; BC, British Columbia; EDSS, Expanded Disability Status Scale  Obstetrical Pain Management The different types of obstetrical pain management used during delivery by women with and without MS are shown in Table 4.3. Overall, for women with MS and those in the general population, nitrous oxide/oxygen gas was the most commonly used modality, followed by parenteral opioids, and then epidural, local and spinal anesthesia. No significant difference in frequency of use was observed between deliveries to women with and without MS for each type of pain management modality (p>0.1, Table 4.3). Of the 432 deliveries to women with MS mothers, 7 deliveries (1%) were exposed to four types of anesthesia, 47 (11%) to three types, 117 (27%) two types, 206 (48%) one type and 55 (13%) were not exposed to any.  38  Table 4.3. Obstetrical pain management for women in BC. Route of administration or type Deliveries to Deliveries to general p value of anesthesia – n (%) MS women population women n=432 n=2,975 Epidural 116 (27) 704 (24) 0.15a Spinal 85 (20) 622 (21) 0.56a Nerve block Pudendal Nerve 7 (2) 30 (1) 0.31b Infiltration Local 103 (24) 659 (22) 0.43a Parenteral Opioids 125 (29) 975 (33) 0.12a Inhalational Nitrous oxide and oxygen gas 157 (36) 1,179 (40) 0.11a Parenteral and inhalational General anesthesia 11 (3) 68 (2) 0.73b c Other 3 (1) 25 (1) 1.00b Unknown 2 (<1) 6 (<1) 0.27b Not used 55 (13) 389 (13) 0.84a BC, British Columbia; MS, multiple sclerosis a Chi-Square test b Fisher’s Exact test c any other pain management not mentioned in the other categories (e.g. transcutaneous electrical nerve stimulation, acetaminophen, sterile water injections)  Epidural and Spinal Anesthesia Out of 432 deliveries to women with MS, 116 deliveries were exposed to an epidural anesthetic and 85 deliveries to a spinal anesthetic (Table 4.3). Four deliveries (1%) to MS mothers were exposed to combined epidural and spinal anesthetic agents. Before adjustment for confounders, the proportion of MS and non-MS mothers exposed to an epidural anesthetic was comparable (27% vs. 24%, p=0.15, Table 4.3). After taking into account potential confounders, an interactive effect was found between MS and parity (p=0.002, data not shown) in the analysis of epidural anesthesia use. Among nullipara, epidural anesthesia use was similar between MS and the general population  39  (adjusted OR=0.85, 95% CI=0.62-1.17, p=0.32, Figure 4.1). However, epidural anesthesia was used more often in multipara with MS than multipara from the general population (adjusted OR=1.75, 95% CI=1.20-2.54, p=0.004, Figure 4.1). The frequency of spinal anesthesia use for caesarean sections was similar in mothers with MS compared to the general population regardless of parity (64% vs. 70%, p=0.16, data not shown; adjusted OR=0.84, 95% CI=0.55-1.31, p=0.45, Figure 4.1).  Figure 4.1. Association between the presence of MS and epidural (all deliveries) and spinal anesthesia (cesarean deliveries only). MS, multiple sclerosis The interactive effect between MS and parity is presented in the adjusted analysis of epidural anesthesia. Adjustments included maternal age, parity, labor induction and birth weight; the mode of delivery was additionally accounted for in epidural anesthesia.  40  MS Clinical Factors As shown in Table 4.4, deliveries in women with MS occurring 5 to <10 years after MS onset were significantly less likely to have an epidural anesthetic (adjusted OR=0.57, 95% CI= 0.34-0.95, p=0.03) compared to deliveries occurring <5 years after MS onset. This altered risk was also observed in deliveries to women with a disease duration ≥10 years (adjusted p=0.08), but did not reached significance, with the CI’s including unity. Conversely, cesarean deliveries within 5 to <10 years of MS onset were more likely to have a spinal anesthetic in the unadjusted analysis (OR=2.62, 95% CI=1.07-6.37, p=0.03, Table 4.4) versus those within <5 years of MS onset. However, after adjustments for confounders, only a trend for a higher rate of spinal anesthesia was observed in women with cesarean deliveries within 5 to <10 years of MS onset (adjusted OR=2.41, 95% CI=0.94-6.81, p=0.07, Table 4.4). The EDSS score was not significantly associated with having epidural or spinal anesthesia (adjusted p>0.1). MS women with or without EDSS scores available also did not have significantly different proportion of epidural or spinal anesthesia (Tables A.4.1 and A.4.2, Appendices).  41  Table 4.4. Association between MS clinical factors and epidural (all deliveries) and spinal anesthesia (cesarean deliveries only). Factor n (%) Unadjusted Adjusted for Clustering and Confounding Effectsa Epidural Anesthesia (all deliveries) OR 95% CI p value OR 95% CI p value MS disease duration at delivery – years <5 43/134 (32) Reference Reference 5 to <10 36/150 (24) 0.67 0.40-1.13 0.13 0.57 0.34 – 0.95 0.03 ≥10 32/130 (25) 0.69 0.40-1.19 0.18 0.56 0.29 – 1.08 0.08 Disability at delivery (±3 years) – EDSS score 0 17/58 (29) Reference Reference 1 or 1.5 35/117 (30) 1.03 0.51-2.05 0.93 0.97 0.42 – 2.24 0.95 2 or 2.5 25/89 (28) 0.94 0.45-1.96 0.87 0.91 0.40 – 2.11 0.83 ≥3 16/66 (24) 0.77 0.35-1.71 0.52 0.87 0.33 – 2.32 0.78 Spinal Anesthesia (cesarean deliveries only) MS disease duration at delivery – years <5 20/40 (50) Reference Reference 5 to <10 34/47 (72) 2.61 1.07-6.37 0.03 2.41 0.94 – 6.18 0.07 ≥10 25/38 (66) 1.92 0.77-4.79 0.16 1.87 0.63 – 5.57 0.26 Disability at delivery (±3 years) – EDSS score 0 6/12 (50) Reference Reference 1 or 1.5 20/30 (67) 2.00 0.51-7.81 0.32 4.11 0.68 – 24.95 0.13 2 or 2.5 13/24 (54) 1.18 0.30-4.74 0.81 2.33 0.40 – 13.72 0.35 ≥3 12/19 (63) 1.71 0.40-7.43 0.47 2.89 0.44 – 18.90 0.27 MS, multiple sclerosis; OR, odds ratio; CI, confidence interval; EDSS, Expanded Disability Status Scale a adjustments: maternal age, parity, labor induction, birth weight; the mode of delivery was also accounted for in the epidural anesthesia analyses  42  Epidural and Spinal Anesthesia, Grouped by Parity, in the Different Modes of Delivery In women with elective cesarean sections, >10% difference was found for the proportions of epidural anesthesia in multipara (16% vs. 1%, Table 4.5) and spinal anesthesia in nullipara (69% vs. 90%, Table 4.5) between the MS and the general population cohorts.  43  Table 4.5. Proportion of epidural and spinal anesthesia in women, grouped by parity, in the different modes of delivery. Subject Parity Mode of n (%) Epidural Spinal Combined epidural delivery anesthesia anesthesia and spinal anesthesia n (%) MS Nullipara Vaginal 139/209 (67) 40/139 (29) 2/139 (1) 1/139 (1) delivery Multipara 165/223 (74) 31/165 (19) 0/165 (0) 0/165 (0) General Nullipara 867/1239 (70) 303/867 (35) 17/867 (2) 3/867 (<1) population Multipara 1260/1736 (73) 156/1260 (12) 5/1260 (<1) 1/1260 (<1) MS Nullipara Emergency 57/209 (27) 29/57 (51) 25/57 (44) 1/57 (2) cesarean Multipara 21/223 (9) 5/21 (24) 14/21 (67) 1/21 (5) delivery General Nullipara 312/1239 (25) 158/312 (51) 115/312 (37) 22/312 (7) population Multipara 192/1736 (11) 42/192 (22) 127/192 (66) 8/192 (4) MS Nullipara Elective 13/209 (6) 1/13 (8) 9/13 (69) 1/13 (8) cesarean Multipara 37/223 (17) 6/37 (16) 31/37 (84) 0/37 (0) delivery General Nullipara 60/1239 (5) 2/60 (3) 54/60 (90) 3/60 (5) population Multipara 284/1736 (16) 3/284 (1) 264/284 (93) 3/284 (1) MS, multiple sclerosis  44  4.3  Discussion This study is believed to be one of the first in North America to compare  obstetrical anesthesia use in women with MS compared to women in the general population. Multiparous mothers with MS had a higher likelihood of using epidural anesthesia compared to multiparous mothers in the general population – a finding that is different from two existing European studies that reported no increased rate of epidural and spinal use in women with MS.39,41 This difference most likely stems from the fact that these previous studies did not account for parity and the interactive effect between MS and parity found in this study. However, it is possible that multiparous women with MS may experience more pain or be perceived to require more pain control by their clinicians versus multiparous women in the general population. A higher proportion of epidural use was found in multiparous women with MS undergoing elective cesarean sections (Table 4.5). This finding is remarkable because elective cesarean sections are typically done with spinal anesthesia, which has a higher success rate and a faster onset of anesthesia versus epidural anesthesia.59 Nonetheless, some anesthesiologists may prefer to perform an epidural because there is modest evidence that spinal anesthesia is associated with a greater risk of neurotoxicity and postpartum relapse in women with MS, especially with local agents at concentrations greater than 0.25% bupivacaine or 2% lidocaine.57 I was unable to find any previous studies examining the association between MS clinical factors and the type of anesthesia used. There was no association with degree of disability, although the majority of MS mothers in this study had relatively low EDSS scores. Longer MS disease duration was found to be associated with decreased  45  epidural use and a trend towards increased spinal anesthesia; this could be attributed to a higher rate of elective cesarean sections in women with longer disease duration (data not shown) because spinal rather than epidural anesthesia is commonly used for elective cesarean deliveries.59 Perhaps women with longer MS disease duration and their clinicians overseeing their care may be subjectively more inclined to opt for an elective cesarean delivery rather than attempt a vaginal delivery due to concerns about other medical conditions. This study has several methodological strengths compared to previous studies. In contrast to a study of 61 deliveries to MS mothers,41 this study was based upon substantially larger, representative cohorts. Although another study had a sample size (n=449)39 comparable with this study, the authors did not distinguish between different types of pain management approaches (i.e. spinal or epidural anesthesia). It is important to consider epidural and spinal anesthesia separately because these modalities have different indications, pharmacokinetics as well as risks of adverse events.59 Another strength of this study was that data were collected by trained health care professionals using standardized forms and common definitions; obstetrical data were collected at, or close to, the time of delivery, virtually eliminating potential recall bias. Subjects were also matched by health authority to control for geographic differences in epidural and spinal anesthesia rates between the MS and general population cohorts – an important consideration as the availability of anesthesia differs between the health regions serving the four MS clinics. In less urban regions of BC, the majority of obstetrical care is provided by family physicians and midwives who tend to have lower epidural rates. The use of multivariate models in this study also accounted  46  for consecutive deliveries from the same mother and controlled for several important confounders not considered previously; this allowed us to account for factors such as mode of delivery, parity, and the interactive effect between MS and parity that may lead to an over or underestimation of the association between epidural or spinal anesthesia use and MS. This study is not without its limitations. The effect of epidural or spinal anesthesia on relapse rates or disability progression in mothers with MS was not investigated; this study was not designed to address these outcomes, which have been explored in several earlier studies.20,21,57,60 In addition, the specific stage of labor at which anesthesia was administered was not ascertained; therefore, the use of epidural analgesia and anesthesia cannot be differentiated for the purpose of labor pain and/or that for operative delivery. It is possible that women who attempted vaginal delivery were given an epidural during labor, but continued onto an emergency cesarean section; as a result, additional anesthesia was provided via the existing epidural and it was therefore not a choice made between epidural or spinal for cesarean delivery. In addition, it is unknown what information the anesthesiologist received from women when deciding on epidural or spinal anesthesia for cesarean delivery, which could influence the choice between epidural and spinal anesthesia. Local anesthetic agents have the potential for neurotoxicity at higher concentrations,57 but data on the dose of agents used were unavailable. Data were also unavailable for other factors such as socioeconomic status and cultural beliefs regarding delivery, which could influence a mother’s choice of obstetrical pain management. Lastly, the geographic location of the four MS clinics in BC might prevent those with limited access and/or mild disease from  47  attending these MS specialty clinics. However, the sample in this study is likely representative for the majority of MS patients in BC (80% coverage) and generalizable to women with MS with access to similar publicly funded, ‘equal access’ healthcare system, as in BC.  48  CHAPTER 5 – BIRTH HOSPITALIZATION IN MOTHERS WITH MULTIPLE SCLEROSIS AND THEIR NEWBORNS Objectives: To compare the duration of birth hospitalization in mothers with MS and their newborns relative to the general population; to investigate the impact of MS clinical factors on the length of birth hospitalization stay. 5.1  Methods Please refer to Chapter 2 (page 11) for a general outline of the study design used  throughout the studies in this dissertation. Details regarding the methodology used in this particular study are described below. Study Participants Births to women with and without MS were included in this study. I excluded (i) non-singleton births (i.e. twin, triplet, etc.) because of an associated increased risk of perinatal complications,87 which could prolong the length of birth hospitalization and (ii) late terminations because the new BCPDR data policy prohibits the use of these cases. In the MS cohort, births to mothers with MS onset after delivery or those without clinically definite MS were excluded. In the analysis of newborn hospitalization, stillbirths were excluded because they tend to have markedly lower birth weight and gestational age than live births.103 Demographics and Clinical Characteristics Maternal characteristics included: age, body mass index (BMI), gravidity, parity, number of antenatal visits, lone parent status, alcohol- drug- and cigarette use (as identified by a physician or midwife as a risk during pregnancy), hypertension, abnormal serum glucose levels or diabetes, duration of the second stage of labor, assisted  49  vaginal delivery (forceps and/or vacuum extraction) and cesarean section. Newborn characteristics included: birth weight, gestational age, 5-minute Apgar score and congenital anomalies diagnosed at birth or on subsequent re-admission(s). MS clinical characteristics included: disease course (relapsing-onset, primary progressive or unknown), age at MS onset, disease duration and level of disability around the time of delivery (±3 years) as measured by the EDSS score.6 Outcomes Primary outcomes were the length of maternal and neonatal hospitalization related to delivery. Secondary outcomes included Neonatal Intensive Care Unit (NICU) admission rates and length of stay in the NICU. Statistical Analyses Maternal and newborn characteristics were compared between births to mothers with and without MS using the Chi-Square test or Fisher’s Exact test for categorical variables, and the Mann-Whitney U test for continuous variables. The GEE approach was employed to account for multiple singleton births to the same mother (clustering effects) and confounders. In building the GEE, a logarithmic transformation was applied to the length of birth hospitalization to account for the right-skewed data distribution. A priori potential confounders considered in the maternal hospitalization analysis included: cesarean section,104,105 maternal age,104 maternal comorbidity104 (hypertension or diabetes), number of antenatal visits,104 obesity as measured by BMI,106 parity104 and prolonged labor.104 For newborns, the following a priori confounders were considered: 5-minute Apgar score, birth weight, congenital anomaly, maternal age, comorbidity (hypertension or diabetes) and substance use exposure (i.e. alcohol, cigarettes or drugs  50  of abuse).104 When data on a priori potential confounders were unavailable for >20% of the MS cohort (i.e. BMI and duration of the second stage of labor), the effect of including, then excluding each variable was examined; where no significant effect on the outcome was found, then the confounder(s) were excluded from the final model. In addition, due to the closely intertwined relationship between the health of the mother and her newborn,107 any adverse event affecting the duration of newborn hospitalization was deemed a potential factor in the causal pathway affecting the duration of maternal hospitalization and vice versa; therefore, the newborn’s duration of hospitalization was not included as a potential confounder when examining the mothers duration of stay (and vice versa). In the analysis of MS mothers, MS disease duration was included as a continuous variable, and the level of disability (EDSS score) was categorized into 4 groups: EDSS of 0 (normal neurological exam), 1.0 to 1.5 (no disability but minimal neurological symptoms present), 2.0 to 2.5 (minimal disability) and ≥3.0 (mild to moderate disability or higher).6 Associations between MS (as well as disease duration and disability) and birth hospitalization on the logarithm scale were reported with β, 95% CI and p values. Admissions to NICU were reported descriptively only. Lastly, a sensitivity analysis was conducted to compare disease duration at delivery, maternal age, parity and the primary outcomes in all births of MS women with and without EDSS scores available closest to the time of delivery (±3 years). A p value of <0.05 was considered statistically significant.  51  5.2  Results  Demographics and Clinical Characteristics In 432 births to 321 women with MS and 2,975 births to 2,958 women from the general population, women with MS had one stillbirth whereas the sample of women in the general population had 16 stillbirths. The cohort characteristics are summarized in Table 5.1. Women in the MS group were more likely to be first time mothers, hypertensive, not diabetic, smoke cigarettes during pregnancy, have a higher BMI, attend more antenatal visits and have a longer duration of the second stage of labor. All other characteristics were comparable (Table 5.1).  Table 5.1. Maternal and newborn characteristics in BC. Characteristic MS General Population n=432 n=2,975 Maternal age – years Median (range) 32 (19-44) 32 (16-44) 2 Maternal BMI – kg/m n 321 2081 Underweight (<18.5) – n (%) 16 (5) 108 (5) Normal (18.5 to <25) – n (%) 174 (54) 1,314 (63) Overweight (25 to <30) – n (%) 89 (28) 421 (20) Obese (≥30) – n (%) 42 (13) 238 (12) Median BMI (range) 23.4 (16.1-46.9) 22.8 (14.4-56.8) Gravidity Median (range) 2 (1-11) 2 (1-15) Parity Nullipara – n (%) 209 (48) 1,239 (42) Antenatal visits – no. n 400 2,801 Median (range) 10 (1-22) 9 (0-25) Lone parent status n (%) 14/398 (4) 131/2,764 (5) Exposure to alcohol during pregnancy n (%) 1 (0) 30 (1) Exposure to drug considered as harmful for pregnancy n (%) 8 (2) 51 (2) Cigarette use during pregnancy n (%) 57 (13) 289 (10)  p value 0.18a 0.02a  0.15a 0.01b <0.001a 0.28b 0.17c 0.84b 0.03b  52  Characteristic  MS n=432  General Population n=2,975  Hypertension during pregnancy n (%) 33 (8) 157 (5) Abnormal glucose level or diabetes during pregnancy n (%) 17 (4) 222 (8) Duration of the second stage of labor – hours n 312 2,191 Median (range) 0.6 (0-6.6) 0.5 (0-26.6) Assisted vaginal delivery n (%) 39 (9) 316/2,123 (15) Cesarean section n (%) 128 (30) 848 (29) Birth weightd – grams n 431 2959 Median (range) 3,423 (1,985-5,770) 3,470 (900-5,660) Gestational aged – weeks n 431 2,954 Median (range) 39 (32-42) 39 (23-43) 5-minute Apgar scored – 10-point scale n 431 2,950 Median (range) 9 (5-10) 9 (3-10) Congenital anomalies n (%) 24 (6) 169 (6) BC, British Columbia; MS, multiple sclerosis; BMI, body mass index a Mann-Whitney U test b Chi-Square test c Fisher’s Exact test d based on live births only  p value 0.046b 0.01b 0.04a 0.34b 0.63b 0.05a 0.53a 0.28a 0.92b  In the MS cohort, four births were to women with a primary progressive MS course and the remainder were to women with relapsing-onset MS, of which 18 births were to women with secondary progressive MS. Mothers with MS had a median age at MS onset of 25 years and a median disease duration of 6.3 years at the time of delivery of their first birth in the study (Table 5.2). EDSS scores recorded around the time of delivery (±3 years) were available in 330 (76%) births to MS mothers; of these women, the median EDSS score was 1.0 (no disability but minimal neurological symptoms  53  present) for their first birth in the study period (Table 5.2). Baseline characteristics between births in MS women with and without an EDSS score revealed that women with EDSS scores available had shorter MS disease duration (three years on average) at the time of the childbirth than women without EDSS scores (Table A.4.1, Appendices).  Table 5.2. Clinical characteristics of MS women with births in BC. Characteristic Mothers with MS* Births to mothers with MS n=321 n=432 Disease course n 317 425 Relapsing-onset – n (%) 313 (99) 421 (99) Primary progressive – n (%) 4 (1) 4 (1) Age at MS onset – years n 309 414 Median (range) 25 (8-39) 24 (8-39) Disease duration at delivery – years n 309 414 Median (range) 6.3 (<1-28) 7.3 (<1-28) Disability at delivery (±3 years) – EDSS score n 252 330 0 – n (%) 46 (18) 58 (18) 1.0 or 1.5 – n (%) 87 (35) 117 (35) 2.0 or 2.5 – n (%) 69 (27) 89 (27) ≥3.0 – n (%) 50 (20) 66 (20) Median (range) 1.0 (0-7.5) 1.5 (0-7.5) MS, multiple sclerosis; BC, British Columbia; EDSS, Expanded Disability Status Scale *based on the first birth in the study period  Birth Hospitalization After accounting for clustering (multiple singleton births to the same mother) and confounding, the difference in length of maternal hospitalization on the logarithm scale was not statistically or clinically significant for mothers with MS (median difference of +1.5 hour, p=0.53) compared to the general population (Table 5.3). The duration of  54  newborn hospitalization was also not significantly different between births to MS mothers and the general population (median difference of +2.1 hours, p=0.48) (Table 5.3).  55  Table 5.3. Association between maternal MS and the length of birth hospitalization.a Factor n Mean ± SD Unadjusted Adjusted for Clustering and Median (range) Confounding Effectsb Maternal Hospitalization – hours β 95% CI p value β 95% CI p value Non-MS 2,974 56.4 ± 34.0 Reference level Reference level 50.0 (2-714) MS 429 57.4 ± 33.2 0.01 -0.02 – 0.03 0.74 -0.01 -0.03 – 0.02 0.53 51.5 (2-361) Newborn Hospitalization – hours Non-MS 2,959 64.1 ± 70.4 Reference level Reference level 50.4 (<1-1,080) MS 429 67.9 ± 80.1 0.01 -0.02 – 0.04 0.49 0.01 -0.02 – 0.05 0.48 52.5 (<1-973) MS, multiple sclerosis; SD, standard deviation; β, regression coefficient; CI, confidence interval a length of birth hospitalization was logarithmically transformed b adjustments for maternal hospitalization: maternal age, parity, cesarean section, diabetes, hypertension and number of antenatal visits; adjustments for newborn hospitalization: 5-minute Apgar score, birth weight, congenital anomaly, maternal age, hypertension, diabetes, alcohol-, cigarette- and drug use  No significant associations were found between length of maternal/newborn hospitalization and MS clinical factors (Tables 5.4 and 5.5). MS women with or without EDSS scores available also did not have significantly different lengths of maternal or newborn hospitalization (Table A.4.1, Appendices).  56  Table 5.4. Association between MS clinical factors and the length of maternal hospitalization.a Factor n Mean ± SD Unadjusted Adjusted for Clustering and Median (range) Confounding Effectsb Maternal Hospitalization – hours β 95% CI p value β 95% CI p value MS disease duration at delivery – years 0 -0.01 – 0.01 0.97 0 -0.01 – <0.01 0.73 <5 134 58.0 ± 28.4 53.7 (2-163) 5 to <10 150 56.4 ± 31.9 50.7 (2-184) ≥10 127 59.5 ± 39.7 51.5 (6-361) MS disability at delivery (±3 years) – EDSS score 0 58 54.1 ± 29.6 Reference level Reference level 47.4 (3-144) 1 or 1.5 117 58.3 ± 29.7 0.03 -0.05 – 0.12 0.46 0 -0.08 – 0.08 0.99 52.1 (2-163) 2 or 2.5 89 59.1 ± 41.9 0.04 -0.05 – 0.13 0.40 0 -0.07 – 0.08 0.93 54.3 (10-361) ≥3 66 58.6 ± 33.6 0.03 -0.07 – 0.12 0.57 0.01 -0.08 – 0.10 0.86 51.9 (3-182) MS, multiple sclerosis; SD, standard deviation; β, regression coefficient; CI, confidence interval; EDSS, Expanded Disability Status Scale a length of birth hospitalization was logarithmically transformed b adjustments: maternal age, parity, cesarean section, diabetes, hypertension and number of antenatal visits  57  Table 5.5. Association between MS clinical factors and the length of newborn hospitalization.a Factor n Mean ± SD Unadjusted Adjusted for Clustering and Median (range) Confounding Effectsb Newborn Hospitalization – hours β 95% CI p value β 95% CI p value Mothers MS disease duration at delivery – years 0 -0.01 – 0.01 0.82 0 -0.01 – 0.01 0.87 <5 134 63.4 ± 45.1 53.8 (<1-335) 5 to <10 150 70.8 ± 95.4 52.7 (2-973) ≥10 126 72.0 ± 93.3 51.9 (<1-748) Mothers MS disability at delivery (±3 years) – EDSS score 0 58 61.1 ± 47.3 Reference level Reference level 48.4 (3-303) 1 or 1.5 117 69.1 ± 78.9 0.01 -0.09 – 0.12 0.81 -0.02 -0.13 – 0.08 0.66 53.6 (<1-748) 2 or 2.5 89 63.0 ± 54.8 0.02 -0.09 – 0.13 0.70 0.02 -0.08 – 0.11 0.73 54.4 (10-389) ≥3 66 90.1 ± 142.6 0.08 -0.04 – 0.20 0.18 0.04 -0.07 – 0.14 0.53 56.7 (6-973) MS, multiple sclerosis; SD, standard deviation; β, regression coefficient; CI, confidence interval; EDSS, Expanded Disability Status Scale a length of birth hospitalization was logarithmically transformed b adjustments: 5-minute Apgar score, birth weight, congenital anomaly, maternal age, hypertension, diabetes, alcohol-, cigarette- and drug use  58  Admissions to Neonatal Intensive Care Units (NICU) Similar to the general population (n=53, 2%), a small proportion of newborns to MS mothers (n=12, 3%) were admitted to NICU after birth. The median length of stay for newborns in NICU was 4.5 days (range: 1-16 days) to mothers with MS, and 2 days (range: 1-40 days) to mothers from the general population.  5.3  Discussion Mothers with MS and their newborns had a similar duration of birth  hospitalization as the general population, in contrast with two other studies whose authors reported longer birth hospitalizations.38,42 The authors of one US study in Washington State concluded that mothers with MS (n=198) were more likely to have birth hospitalizations lasting 4-6 days (but not shorter [1-3 days] or longer [>6 days] stays) compared to the general population (RR=1.7, 95% CI: 1.2-2.6, adjusted for maternal age and delivery method).38 Another study, accessing a nationally representative database from all non-Federal short stay hospitals in the US, reported a slightly longer duration of birth hospitalization (3.0 days) in mothers with MS (n=7,697) compared to mothers from the general population (2.7 days, n=15,200,000) after adjustment for maternal age and ethnicity (p<0.001).42 Findings between studies may differ due to a number of reasons, including: variations in socioeconomic factors and comorbidities between study populations of mothers with MS, local healthcare policy, clinician practice, as well as the composition of public and private healthcare services. In addition, identification of subjects via un-validated methods, for instance requiring only a single ICD billing code, and requiring it to be present around the time of the birth  59  hospitalization may result in a bias towards patients with more active or severe MS in some studies. Consistent with this was the observation of an increased risk of cesarean sections – a known cause of longer birth hospitalizations104,105 in women with MS when MS was identified by ICD billing codes alone;42 something not found in other studies with a more comprehensive case ascertainment.37 One study examining hospital stays in the newborns of MS mothers reported longer stays (RR=1.5, 95% CI: 0.99-2.3) compared to newborns of non-MS mothers;38 however, the authors speculated this was due to the common practice of discharging mother and newborn home together, as no other adverse birth outcomes were observed. This study differed from previous studies38,42 examining birth hospitalizations in a number of ways: firstly, this study included a cohort of women with clinically definite MS confirmed by an MS specialist neurologist, rather than relying on a single ICD code for MS (a valid algorithm for MS requires multiple ICD billing codes recorded over a period of time)108 to identify MS. Secondly, the length of birth hospitalization in MS patients was not associated with disease duration or level of disability – something not previously reported. Thirdly, data clustering arising from consecutive births to the same mother and confounders not considered in previous studies were accounted for in this study. Failure to adjust for these important factors may over or underestimate the true effect of MS on birth hospitalization. Mothers with MS were also frequency-matched by delivery year and local health authority to a sample of mothers from the general population to minimize potential temporal and regional differences in birth discharge practices.  60  The BCMS database captures an estimated 80% of patients with MS in BC; a potential limitation is that MS patients with mild disease and/or limited access to an MS clinic in BC due to geographic distance may not have been captured in the BCMS database. Nonetheless, this study is likely broadly representative of MS patients in BC and generalizable to populations of MS mothers in western countries with similar access to healthcare. Few newborns were admitted to the NICU (with a similar proportion being admitted in the MS and general population cohorts), such that no firm conclusions could be drawn based on these data. Finally, factors such as parental ethnicity, parental perceptions of their childcare abilities, socioeconomic background, and the availability of support resources following discharge from hospital were not available, but could influence the length of birth hospitalization.104 Overall, findings from this study are reassuring for women with MS planning a pregnancy or already expecting a child; the presence of MS in the mother does not appear to alter the length of birth hospitalization for the mother or baby.  61  CHAPTER 6 – PERINATAL OUTCOMES IN WOMEN WITH MULTIPLE SCLEROSIS EXPOSED TO DISEASE-MODIFYING DRUGS Objectives: To investigate the incidence and effect of in utero DMD exposure on perinatal outcomes in mothers with MS. 6.1  Methods Please refer to Chapter 2 (page 11) for a general outline of the study design used  throughout the studies in this dissertation. Details regarding the methodology used in this particular study are described below. Study Participants Births to women with MS were included in this study. I excluded (i) non-singleton births (i.e. twin, triplet, etc.) because of an increased risk of unfavourable perinatal outcomes,87 (ii) births to mothers with MS onset after delivery, (iii) births to mothers without clinically definite MS or (iv) births to women with an unknown/undetermined disease course or primary-progressive MS because no DMD has been approved for use in primary-progressive MS. In the analysis of neonatal outcomes, stillbirths were excluded because they tend to have markedly lower birth weight and gestational age than live births.103 Births were classified and grouped according to DMD exposure. The two unexposed groups were (i) births to women with relapsing-onset MS who were DMD naïve (no exposure to a DMD before or during pregnancy) and (ii) births to women who were previously treated (used a DMD before pregnancy, but discontinued treatment at least one month prior to conception).47 The exposed group consisted of births to women  62  with relapsing-onset MS exposed to a DMD within one month prior to conception and/or during pregnancy. The date of conception was obtained by adding 2 weeks to the estimated first day of the last menstrual period (LMP),109 which was determined by subtracting the gestational age (as determined by Perinatal Services BC based on ultrasound, date of LMP, newborn exam, or a combination of the above, depending upon when the ultrasound was performed)83 from the baby’s date of birth. Demographics and Clinical Characteristics Maternal characteristics obtained from the BCPDR included maternal age at delivery, antenatal visits, lone parent status, alcohol, and tobacco use during pregnancy, local health area of delivery and pregnancy history (including parity, previous pregnancies, prior spontaneous abortions and infants with congenital anomalies). Clinical characteristics from the BCMS database included age of MS onset, disease duration at delivery, and disability as determined by the EDSS score6 closest to the time of delivery (±3 years). Outcomes Delivery outcomes included duration of the second stage of labor, assisted vaginal delivery (forceps and/or vacuum extraction), and Cesarean section (emergency or elective). Cesarean section was analyzed among births to nulliparous women only as a previous Cesarean section increases the likelihood of future Cesarean sections. 110 Neonatal outcomes included birth weight, gestational age, and the 5-minute Apgar score111 for live births only; congenital anomalies (major and minor)112 were reported for  63  both live and stillbirths. Statistical Analyses Clinical and maternal characteristics of exposed, previously treated, and DMD naïve women were compared using the Kruskal-Wallis test for continuous variables and Pearson’s Chi-Squared test for categorical variables. Comparisons of perinatal outcomes were made between DMD-exposed and previously treated women to provide a better assessment of the direct effect of in utero DMD exposure since women in both of these groups used a DMD before pregnancy. In addition, the DMD-exposed and naïve women were compared to assess the combined effect of long term DMD use before pregnancy and DMD exposure during pregnancy on perinatal outcomes. The Mann Whitney U test (for continuous variables) and Fisher’s exact test or Pearson’s Chi-Squared test (for categorical variables) were used to compare perinatal outcomes in births that were DMD-exposed vs. previously treated and DMD-exposed vs. naïve. Statistical significance was defined as a p <0.05. Perinatal outcomes were reported with p values and where appropriate, unadjusted OR with 95% CI. No adjustment was made for multiple comparisons in this exploratory study.  6.2  Results In all, 418 births to 311 women met inclusion criteria. A conceptual selection of  women with MS and linkage between the BCMS database and the BCPDR is shown in Figure 6.1. There was one stillbirth (to a DMD naïve woman) and this was excluded from the analysis of neonatal outcomes of live births. See Figure 6.1 for a summary of  64  the number of births exposed and unexposed to a DMD.  Figure 6.1. Conceptual selection of MS women and linkage of the clinical and perinatal data. BC, British Columbia; MS, multiple sclerosis; BCPDR, British Columbia Perinatal Database Registry; DMD, disease-modifying drug; IFNβ, interferon-beta; GA, glatiramer acetate z excluded births: 105 occurred before onset of MS, 8 were non-singleton, 4 were to women with primary-progressive MS, 18 were to women with an unknown or undetermined disease course a births to women with relapsing-onset MS who had been exposed to a DMD within one month prior to conception and/or during pregnancy b births to women with relapsing-onset MS who were previously treated with a DMD before pregnancy, but discontinued treatment at least one month prior to conception c births to women with relapsing-onset MS who never used a DMD before or during pregnancy  65  Incidence of DMD Exposure The overall incidence of DMD exposure was 5% (21/418) of all births. Following discontinuation of a DMD during an exposed pregnancy, no mother re-initiated a DMD until after delivery. Among women who had ever initiated a DMD before pregnancy, 21% (21/101) of births were exposed to a DMD within one month prior to conception and/or during pregnancy; all were documented by the mother’s MS neurologist as being exposed unintentionally. All women discontinued DMD treatment when pregnancy was realized. Of the 21 births exposed to a DMD, 15 were to IFNβ and 6 were to GA; the mean duration of DMD exposure was 7.2 weeks. Five stopped the DMD (4 IFNβ and 1 GA) within the month prior to conception, 9 stopped within one month after conception (5 IFNβ and 4 GA) and 7 stopped within two months after conception (6 IFNβ and 1 GA). Thus, no woman was exposed to a DMD beyond the second month of gestation. Demographics and Clinical Characteristics Clinical and maternal characteristics were comparable between the three groups (DMD-exposed, previously treated, and naïve), apart from MS disease duration and disability (as measured by the EDSS score), which not unexpectedly, were lower in the DMD naïve group (p <0.05, Table 6.1). The local health area of delivery and previous pregnancy history (including parity, previous pregnancies, prior spontaneous abortions and infants with congenital anomalies) was also comparable between groups (data not shown).  66  Table 6.1. Characteristics of women with relapsing-onset MS who gave birth in BC.a Characteristic GAIFNβDMDDMD DMD naïved p valuee exposedb exposedb exposedb previously treatedc [1] n=6 [2] n=15 [1+2] n=21 [3] n=80 [4] n=317 [1+2] vs. [3] vs. [4] Age of MS onset – years 0.07 n 6 15 21 76 312 Median (range) 27 (20-29) 23 (13-33) 25 (13-33) 23 (13-33) 25 (8-39) Disease duration at delivery – years 0.01 n 6 15 21 76 312 Median (range) 8.1 (2-14) 10.0 (2-17) 8.9 (2-17) 8.3 (3-21) 6.8 (<1-28) Disability at delivery (±3 years) – EDSS score 0.001 n 5 13 18 58 214 Median (range) 2.0 (0-6.0) 2.0 (0-6.5) 2.0 (0-6.5) 2.0 (0-6.5) 1.5 (0-7.0) Maternal age at delivery – years 0.54 n 6 15 21 80 317 Median (range) 32 (27-42) 33 (26-40) 33 (26-42) 32 (21-43) 32 (19-44) Antenatal visits – no. 0.51 n 6 15 21 77 289 Median (range) 10 (5-15) 10 (6-18) 10 (5-18) 10 (1-19) 10 (1-22) Lone parent status 0.35 n (%) 0/6 (0) 0/14 (0) 0/20 (0) 1/67 (2) 13/298 (4) Alcohol use during pregnancy 0.61 n (%) 0/6 (0) 0/15 (0) 0/21 (0) 0/80 (0) 1/317 (0) Cigarette use during pregnancy 0.85 n (%) 1/6 (17) 3/15 (20) 4/21 (19) 11/80 (14) 38/317 (12) MS, multiple sclerosis; BC, British Columbia; GA, glatiramer acetate; IFNβ, interferon-beta; DMD, disease-modifying drug; EDSS, Expanded Disability Status Scale a 13 women had births belonging to different DMD groups during the study period: 5 women had 1 DMD naïve birth and 1 DMD previously treated birth; 2 women had 1 DMD naïve birth and 1 DMD-exposed birth; 4 women had 1 DMD previously treated birth and 1 DMD exposed birth; 2 women had 2 DMD naïve births and 1 DMD-exposed birth; birth order for all women: DMD naïve before DMD previously treated, and DMD previously treated before DMD-exposed  67  b  births to women with relapsing-onset MS who were exposed to a DMD within one month prior to conception and/or during pregnancy c births to women with relapsing-onset MS who were previously treated with a DMD before pregnancy, but discontinued treatment at least one month prior to conception d births to women with relapsing-onset MS who never used a DMD before or during pregnancy e comparisons between the DMD-exposeda, DMD previously treatedb, and DMD naïvec groups using Kruskal-Wallis test (continuous variables) and Pearson’s Chi-Squared test (categorical variables)  68  Perinatal Outcomes Compared to births in the DMD naïve group, births exposed to a DMD showed a trend towards a three-fold greater risk of assisted vaginal delivery (OR = 3.0; 95% CI: 1.0-9.2). All other comparisons of perinatal outcomes (duration of the second stage of labor, Cesarean section, birth weight, gestational age, 5-minute Apgar score and congenital anomalies) were unremarkable (p >0.05, Table 6.2). No cases of major or minor congenital anomalies were identified in the 21 DMD-exposed births (Table 6.2).  69  Table 6.2. Perinatal outcomes of the DMD-exposed, previously treated and DMD naïve pregnancies in relapsingonset MS women. a  a  GA-exposed [1] IFNβ-exposed [2] n=6 n=15 Duration of the second stage of labor – hours n 6 11 Mean ± SD 1.9 ± 1.4 1.0 ± 1.0 Median (range) 0.8 (0.6-4.3) 1.6 (0.1-2.7) Assisted vaginal delivery n (%) 2/6 (33) 3/12 (25) d,e Cesarean section n (%) 0/3 (0) 2/8 (25) Emergency – n (%) – 2/2 (100) Elective – n (%) – 0/2 (0) e Birth weight – grams n 6 15 Mean ± SD 3,449 ± 403 3,412 ± 404 Median (range) 3,305 (2,938-3,967) 3,483 (2,595-4,025) e Gestational age – weeks n 6 15 Mean ± SD 39.3 ± 1.4 38.9 ± 1.2 Median (range) 39 (38-41) 39 (36-41) e 5-minute Apgar score – 10-point scale n 6 15 Median (range) 9 (9-10) 9 (7-10) Congenital anomalies n (%) 0/6 (0) 0/15 (0) Outcome  a  c  DMD-exposed [1+2] n=21  DMD previously b treated [3] n=80  DMD naïve [4] n=317  17 1.3 ± 1.2 0.9 (0.1-4.3)  57 1.2 ± 1.3 0.7 (0.0-5.6)  227 1.0 ± 1.0 0.6 (0.0-6.6)  5/18 (28)  8/55 (15)  25/221 (11)  2/11 (18) 2/2 (100) 0/2 (0)  16/48 (33) 13/16 (81) 3/16 (19)  50/146 (34) 41/50 (82) 9/50 (18)  21 3,423 ± 394 3,310 (2,595-4,025)  80 3,307 ± 450 3,368 (1,985-4,160)  316 3,461 ± 496 3,444 (2,085-5,770)  21 39.0 ± 1.3 39 (36-41)  80 38.5 ± 1.7 39 (33-41)  316 39.0 ± 1.4 39 (33-42)  21 9 (7-10)  79 9 (7-10)  316 9 (5-10)  0/21 (0)  7/80 (9)  17/317 (5)  DMD, disease-modifying drug; MS, multiple sclerosis; GA, glatiramer acetate; IFNβ, interferon-beta a births to women with relapsing-onset MS who were exposed to a DMD within one month prior to conception and/or during pregnancy b births to women with relapsing-onset MS who were previously treated with a DMD before pregnancy, but discontinued treatment at least one month prior to conception c births to women with relapsing-onset MS who never used a DMD before or during pregnancy d based on first birth only e based on live births only  70  Timing of DMD Exposure Perinatal outcomes of the DMD-exposed group were comparable regardless of the timing of exposure (Table 6.3). However, the range of exposure was relatively narrow, with no pregnancy being exposed to a DMD beyond the first trimester.  71  Table 6.3. Perinatal outcomes according to the timing of DMD exposure in relapsing-onset MS women. Outcome <1-month prior <1-month during 1-to-2-month during All DMD exposuresa conception n=5 pregnancy n=9 pregnancy n=7 n=21 Assisted vaginal delivery n (%) 2/4 (50) 2/8 (25) 1/6 (17) 5/18 (28) b,c Cesarean section n (%) 1/3 (3) 0/3 (0) 1/5 (20) 2/11 (18) Emergency – n (%) 1/1 (100) 0 (0) 1/1 (100) 2/2 (100) Duration of the second stage of labor – hours Mean ± SD 1.6 ± 1.3 0.9 ± 0.6 1.7 ± 1.5 1.3 ± 1.2 Median (range) 1.7 (0.1-2.7) 0.7 (0.1-2.2) 1.4 (0.2-4.3) 0.9 (0.1-4.3) Birth weightc – grams Mean ± SD 3,489 ± 381 3,485 ± 393 3,295 ± 431 3,423 ± 394 Median (range) 3,305 (3,108-4,025) 3,655 (2,938-3,967) 3,310 (2,595-3,870) 3,310 (2,595-4,025) Gestational agec – weeks Mean ± SD 39.0 ± 0 38.6 ± 1.4 39.6 ± 1.4 39.0 ± 1.3 Median (range) 39 (39-39) 38 (36-41) 40 (37-41) 39 (36-41) 5-minute Apgar scorec – 10-point scale Median (range) 9 (8-10) 9 (7-10) 9 (9-10) 9 (7-10) Congenital anomalies n (%) 0/5 (0) 0/9 (0) 0/7 (0) 0/21 (0) DMD, disease-modifying drug; MS, multiple sclerosis a births to women with relapsing-onset MS who were exposed to a DMD within one month prior to conception and/or during pregnancy b based on first birth only c based on live births only  72  6.3  Discussion This study is one of the first to assess the incidence of DMD exposure during  pregnancy in women with MS. By using clinical data obtained from the BCMS database and perinatal outcomes from the BCPDR, this study minimizes under-reporting that may affect postmarketing surveillance studies. The data were generated by MS specialist neurologists at four MS clinics in BC, thus eliminating participant and reporting biases. This study had a relatively low incidence of exposure to a DMD during pregnancy (5% of all births) in clinical practice; this is markedly lower than a 2010 Italian multicenter study which reported a 20% (76 IFNβ-exposed births/372 births to MS women) exposure rate.113 The proportion of exposed births in BC, however, increases to 21% (21/101) if one only considers women ever exposed to a DMD. In comparison, this incidence was much lower than a 2008 single-centered Italian study that reported 65% (13/20)114 or a 2010 Finnish study that reported a 36% (12/33) incidence.41 The incidence of DMD exposure in MS women could vary by region and individual prescribing practices. The low overall incidence of DMD exposure observed in this study may be due to the comprehensive patient education and reproductive counseling offered at the MS clinics in BC as well as the strict prescribing criteria in BC;115 patients are not eligible for DMD coverage by the BC Ministry of Health if the patient is “pregnant, plans to become pregnant or is nursing.” To my knowledge, this study is the first to assess the impact of DMD exposure during pregnancy on the length of the second stage of labor and the risk of assisted vaginal delivery; only one previous study has examined the effect of in utero DMD exposure on the risk of Cesarean section.113 Similar to this Italian study,113 I found no  73  increased risk of Cesarean section for DMD-exposed women relative to DMDunexposed women with MS. The second stage of labor was found to be similar, regardless of DMD exposure. However, there was a trend for an increased risk of assisted vaginal delivery in DMD-exposed versus DMD naïve women with MS. IFNβ is a cytokine that has immune, antiproliferative, and antiviral effects, however the full biological effects are unknown;116 the drug may interact with other surface receptors,117 altering maternal physiology. Findings from this study may also be due to the disease itself because the DMD-exposed women were more disabled (as measured by the EDSS) with a longer disease duration and hence perhaps had greater neuromuscular weakness (compared to the DMD naïve women), leading to exhaustion during labor. 40 However, van der Kop et al. reported no strong association between assisted vaginal delivery and disease duration or disability in women with MS37 – supporting the possibility that DMD exposure was responsible for the increased risk of assisted vaginal delivery. The associated risk of assisted vaginal delivery may increase the likelihood of mothers with MS experiencing hemorrhage, infection or birth trauma, and their newborns experiencing bruising, hematomas as well as eye or facial nerve injuries.118 I was unable to find another published study examining the 5-minute Apgar scores in DMD-exposed births. The 5-minute Apgar score assesses the immediate need for resuscitation of the newborn based on appearance, pulse, grimace, activity and respiration.119 The 5-minute Apgar score, birth weight, and gestational age of exposed babies were comparable to those from babies of DMD naïve and previously treated women in this study. With respect to birth weight and gestational age, findings from this study were similar to an earlier Canadian study;120 the birth weight of DMD-  74  exposed newborns were well within the normal range for the general population. 83 However, an association between in utero IFNβ exposure and lower mean birth weight was found in two larger studies from Germany121 and Italy;113 the smaller sample size of this study might have contributed to these differences. There was no increased risk of congenital anomaly found in this study – similar to all,113,114,120-125 but one study.126 The interpretation of findings from this study was limited because of the small sample size. This also prevented us from adjusting for potential confounders, which larger prospective studies were able to do (e.g. Amato et al. (88 exposed pregnancies)113 and Weber-Schoendorfer et al. (100 exposed pregnancies)121). In addition, since data on abortions are not available in the BCPDR, cases of congenital anomalies that ended in spontaneous or elective abortion could not be captured. No subject was exposed to a DMD beyond the second month of pregnancy and consequently, the safety of DMD use beyond the first trimester of pregnancy remains unknown. Theoretically, randomised controlled trials are the most scientifically valid approach to studying the effect of DMDs on perinatal outcomes, but this would be unethical, impractical, and prohibitively costly. Thus, adequately controlled, retrospective or prospective observational studies with large study populations remain the best way to investigate the effect of DMD exposure during pregnancy on perinatal outcomes. The data in this study are valuable and could contribute to future metaanalyses. In summary, no strong evidence of an increased risk of adverse perinatal outcomes associated with DMD exposure during conception and the first trimester of pregnancy was found in this study. This study suggests that if DMD use is promptly  75  discontinued, early in pregnancy, women with MS may not be at a greater risk of adverse perinatal outcomes. However, the possible trend towards an increased risk of assisted vaginal delivery after pregnancy-related DMD exposure warrants further investigation. Larger studies are needed to ascertain the safety of DMD use throughout pregnancy in MS. In future studies, it would also be worthwhile to investigate the longterm effects of DMD exposure on maternal and neonatal health. For patients with MS, reproductive counseling and close involvement of clinicians are important factors to promote a healthy pregnancy.64,127 Women with MS are still advised to discontinue DMD therapy prior to conception.  76  CHAPTER 7 – DISEASE-MODIFYING DRUGS FOR MULTIPLE SCLEROSIS IN PREGNANCY: A SYSTEMATIC REVIEW Objectives: To systematically review the literature regarding safety of DMD use during pregnancy on perinatal and developmental outcomes in offspring of patients with MS. 7.1  Methods  Evidence Evaluation Template The International Liaison Committee on Resuscitation (ILCOR) 2010 Evidence Evaluation Template128 was used. This is a validated tool for assessing systematic reviews endorsed by 11 international bodies on cardiovascular health and meets all criteria from “a measurement tool for the 'assessment of multiple systematic reviews’ (AMSTAR).”129 Research Question In men or women with MS, does periconceptional or in utero exposure to IFNβ, GA, natalizumab, mitoxantrone or fingolimod have an effect on perinatal and developmental outcomes in offspring compared to no periconceptional or in utero exposure? Search Strategy PubMed (1947 to February 2012) and EMBASE (1980 to February 2012) were searched using the keywords: multiple sclerosis AND [interferon beta; glatiramer acetate; natalizumab; mitoxantrone; fingolimod] AND [pregnancy; conception; child development; spermatozoa; ovum; reproduction; birth; delivery; fetal; neonatal; obstetric]. Alternative terms identified via either database were also included. Keywords were “exploded” and selected from MeSH terms for PubMed or advanced keyword  77  searches for EMBASE. References from relevant articles were also searched manually. To avoid overlooking important emerging research, I also searched 2010 and 2011 proceedings from the largest conferences covering MS research – the Annual Meetings of the American Academy of Neurology (AAN), and the European and Americas Committees of Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS) – as a discussion point only, not in the data analysis. Inclusion and Exclusion Criteria Studies with the a priori aim of assessing perinatal and/or developmental outcomes in offspring of men or women with MS exposed to one of the following DMD – IFNβ (1a and 1b), GA, natalizumab, mitoxantrone or fingolimod – during pregnancy and/or conception were included. Congenital anomalies included any structural or functional abnormalities present at birth, resulting from malformation, deformation, disruption or dysplasia. Only English language, peer-reviewed original manuscripts with human subjects were considered for data analysis. No relevant systematic reviews or meta-analyses were identified. Data Analysis The level and quality of evidence was determined by the study design, sample size, potential bias, statistical analysis, use of controls and data collection strategy128 (Tables A.7.1 and A.7.2, Appendices). Potential conflicts of interest were noted, but not included in the quality assessment. Each DMD was assigned an ILCOR Class of Recommendation regarding its use during pregnancy (Table A.7.3, Appendices). Articles were independently selected and reviewed by E.L. and B.W. and consensus on disagreements was reached between H.T., E.L. and B.W.  78  7.2  Results  Search Results Pubmed yielded 237 hits and EMBASE 278, with 461 unique citations identified. A total of 15 studies were selected (4 prospective cohort,113,120,121,130 5 retrospective cohort77,114,126,131,132 and 6 case-series122-125,133,134 studies) for a total of 761 IFNβ-, 97 GA- and 35 natalizumab-exposed pregnancies. See Table 7.1 for a summary of the study characteristics. From the 15 studies analyzed, there were more negative than positive findings reported and most studies did not appear to have potential conflicts of interest. However, studies with negative findings appeared more likely to have industry funding support. Overall, the level of evidence ranged from level 3 to 5 (prospective cohort to case-series) while the quality ranged from Poor to Good (Table 7.2).  79  Table 7.1. Summary of studies examining DMD exposure during pregnancy and conception in MS. Country Study Design; DMD Type and Definition of DMD Average Duration of (Publication Year) target MS Patients Number of Exposure DMD Exposure Exposed Pregnancies 126 Argentina (2009) Retrospective cohort; 23 DMD (IFNβ, GA) Within 15 days prior to 4 weeks (mean) women conception and/or during pregnancy Brazil (2009)123 Case-series;a women 17 IFNβ, 15 GA During pregnancy 12 cases exposed to GA throughout pregnancy; no information on IFNβ exposure 122 Brazil (2010) Case-series; women 11 GA During pregnancy 8.4 months (mean) Brazil (2011)134 Case-series; women 99 DMD (69 IFNβ, During pregnancy 8 weeks (mean) 20 GA, 10 Other) Canada (2005)120 Prospective cohort; 23 IFNβ During pregnancy 9 weeks (mean) women Canada (2012)132 Retrospective cohort; 21 DMD (15 IFNβ, Within 1 month prior to 7.2 weeks (mean) women 6 GA) conception and/or during pregnancy 121 Germany (2009) Prospective cohort; 69 IFNβ, 31 GA During pregnancy IFNβ: 8.8 weeks (median) women GA: 6.9 weeks (median) b Germany (2010)77 Retrospective cohort; 46 DMD (IFNβ, GA, Conception Not applicable men natalizumab, methotrexate, azathioprine) to fathers only b Germany Prospective cohort; 35 natalizumab Within 8 weeks prior to 6 cases had last infusion (2011)130 women last menses (i.e. ~10 21.3 days (mean) prior to weeks prior to the last menstrual period conception) and/or (LMP); 29 cases had last during pregnancy infusion 22.6 days (mean) after LMP  80  Country (Publication Year)  Study Design; target MS Patients  d  Retrospective cohort; women Prospective cohort; women  Italy (2008)114  b,c  Italy (2010)113  b  Spain (2007)131  d  United Kingdom (2010)133 c Europe and North America (2005)125 b,c  DMD Type and Number of Exposed Pregnancies 14 IFNβ  Definition of DMD Exposure  Average Duration of DMD Exposure  During pregnancy  9.1 weeks (mean)  88 IFNβ  Within 4 weeks prior to conception and/or during pregnancy During pregnancy  4.6 weeks (mean)  During pregnancy  31.9 weeks (mean)  Within 2 weeks prior to conception and/or during pregnancy During pregnancy  16 cases within 1-4 weeks; 3 within 5-8 weeks; 1 with 16 weeks 4 weeks (mean)  Retrospective cohort; women Case-series; women  34 DMD (unspecified) 14 GA  Case-series;a women  41 IFNβ-1a  5.4 weeks (mean)  Worldwide Case-series;a women 425 IFNβ-1a (mainly Europe and North America) (2011)124 DMD, disease-modifying drug; MS, multiple sclerosis; IFNβ, interferon-beta; GA, glatiramer acetate a cases were compared to population estimates instead of individual subjects recruited as controls b studies with potential conflicts of interest due to direct funding support from the pharmaceutical manufacturer c studies with potential conflicts of interest due to employment of author by the pharmaceutical manufacturer d studies with unknown/unclear conflicts of interest  81  Table 7.2. Classification of studies based on level and quality of evidence.* Quality of Evidence Level of Evidence 3 4 5 Prospective cohort Retrospective cohort Case-series Good Italy (2010)113 ----120 132 123 Fair Canada (2005) Canada (2011) Brazil (2009) Germany (2009)121 Italy (2008)114 Brazil (2010)122 130 131 Germany (2011) Spain (2007) Brazil (2011)134 Europe and North America (2005)125 Worldwide (mainly Europe and North America, 2011)124 126 Poor --Argentina (2009) United Kingdom (2010)133 Germany (2010)77 *See Tables A.7.1 and A.7.2 (Appendices) for detailed level and quality of evidence criteria adapted from the International Liaison Committee on Resuscitation (ILCOR) evidence evaluation template  82  Perinatal Outcomes based on Best Evidence Interferon-beta Maternal exposure studies reported mixed findings regarding the risk of lower mean birth weight,113,114,120,121 lower mean gestational age,114,120 preterm birth113,121 and spontaneous abortion.113,121 However, best evidence (good quality, level 3) suggested that IFNβ exposure was associated with lower mean birth weight, shorter mean birth length and preterm birth (<37 weeks), but not spontaneous abortion, Cesarean delivery or low birth weight (defined as <2500 grams) (Table 7.3).113 Fair quality level 3 evidence studies showed no increased risk of lower mean gestational age120 or congenital anomalies121 in IFNβ-exposed births (Table 7.3). However, the existing data on congenital anomalies remains inconclusive; a large prospective case series reported no increased risk124 but preliminary data from a more recent study suggests an increased risk of congenital anomalies.135 Descriptively, the incidence of therapeutic abortion was higher in IFNβ-exposed vs. unexposed pregnancies, but lower than the general population.113,114,125 Glatiramer acetate Based on fair quality level 3 evidence, GA exposure was not associated with lower mean birth weight, lower mean gestational age, preterm birth (<37 weeks), congenital anomaly or spontaneous abortion (Table 7.3).121 Natalizumab From only one fair quality level 3 evidence study of natalizumab, exposure was not associated with shorter mean birth length, lower mean birth weight or lower mean gestational age (Table 7.3).130  83  Mitoxantrone and fingolimod No identified studies assessed the safety of mitoxantrone or fingolimod exposure. Paternal DMD use Forty-six pregnancies were fathered by 32 men with MS who conceived offspring while being treated with a DMD, resulting in birth weights and lengths comparable to the general population (Table 7.1).77 Descriptively, the risk of congenital anomaly and spontaneous abortion was similar to pregnancies of mothers from the general population.77 Developmental Outcomes Two studies reported no increased risk of developmental abnormalities associated with IFNβ exposure,113,114 although follow-up was limited to 1 year in one study114 and a median follow-up of 2.1 years in the other.113 One developmental abnormality (inadequate language performance) was described in a case-series (level 5 evidence) of 11 newborns exposed to GA for at least 7 months gestation. 122 No other studies examining longer-term developmental outcomes were found.  84  Table 7.3. Perinatal outcomes from fair and good quality prospective cohort studies comparing DMD-exposed and unexposed mothers with MS.a Outcome   Risk  Shorter birth length (mean)  Yes  Lower birth weight (mean)  Yes  Low birth weight (<2500 grams)  No  Cesarean delivery  No  Congenital anomaly Lower gestational age (mean) Preterm Birth (<37 weeks)  No  Spontaneous abortion  No  b  No Yes  Interferon-beta Quality OR (95% CI) or p value Good p<0.0001, propensity-score 113 adjusted Good p<0.0001, propensity-score 113 adjusted Good 1.14 (0.41-3.15), propensity-score 113 adjusted Good 0.84 (0.49-1.44), propensity-score 113 adjusted Fair 0.9 (0.17-2.88), 121 unadjusted Fair p>0.05, 120 unadjusted Good 2.11 (1.18-3.78), propensity-score 113 adjusted Good 1.08 (0.40-2.89), propensity-score 113 adjusted  Glatiramer Acetate Quality OR (95% CI) or p value Unknown  Risk  No  Fair  p>0.05, 121 adjusted   Risk No  No  Unknown  Unknown  Unknown  Unknown  b  No  Fair  p>0.05, 121 unadjusted  Unknown  Natalizumab Quality OR (95% CI) or p value Fair p>0.05, 130 unadjusted Fair  p=0.07, 130 unadjusted  Fair  p>0.05, 130 unadjusted  Unknown No  No  Fair  p>0.05, 121 unadjusted  Unknown  No  Fair  p>0.05, 121 unadjusted  Unknown  DMD, disease-modifying drug; MS, multiple sclerosis; OR, odds ratio; CI, confidence interval a No study was rated as ‘excellent.’ See A.7.1 and A.7.2 (Appendices) for detailed level and quality of evidence criteria adapted from the International Liaison Committee on Resuscitation (ILCOR) evidence evaluation template; case-series studies were not used to complete this table because of the absence of a suitable control group for comparison; I assumed that p>0.05 when studies commented in their result or discussion sections that there was no difference between the groups, but did not specifically provide an OR or p-value b study was likely underpowered (IFN n=69 and GA n=31)121 to adequately assess the risk of congenital anomaly as the incidence is approximately 3% in newborns from the general population.136  85  7.3  Discussion Based on an overall assessment of the literature, the following ‘class of  recommendation’128 was assigned to each DMD for the following reasons:  IFNβ: III – evidence from some studies suggests potential harm, specifically lower mean birth weight, shorter mean birth length and preterm birth  GA: indeterminate – further research is needed as results are not compelling; 3 of the 4 existing human studies of GA were small case-series  Natalizumab: indeterminate – further research is needed as results are not compelling  Mitoxantrone: III – animal studies and human case reports suggest potential harm with no controlled human studies to date  Fingolimod: indeterminate – further research is needed as the drug only recently entered the market Evidence on other DMDs, paternal exposure to DMDs around the time of conception (poor, level 4 evidence)77 or longer-term developmental outcomes113,123,132 remains extremely limited. Emerging research (published in abstract form only) from 2010 and 2011 conference proceedings regarding IFN and GA exposure during pregnancy,137-140 has been largely consistent with the analyzed results of this systematic review. For natalizumab, a case series of 277 exposed pregnancies to mothers with MS found 31 spontaneous abortions and 23 congenital anomalies.141 For fingolimod, 34 exposed pregnancies resulted in 1 case of tibial malformation, 1 case of tetralogy of Fallot (a congenital heart defect) and 5 spontaneous abortions;142 authors from both studies concluded that small numbers limited conclusions at present.141,142  86  Strength and Limitations of Existing Studies At the time of this systematic review, few studies were considered of high quality, when evaluated using internationally accepted criteria.128 However, these criteria must be balanced against the real-world limitations inherent in research involving pregnant women.143 Nonetheless, most studies were susceptible to recall, voluntary participation, surveillance or reporting bias. Further, studies with small sample size are often unable to adjust for potential confounders including family history, maternal age, previous obstetric history, comorbid illnesses, as well as exposures to other medications or recreational drugs. There was also considerable heterogeneity in methodology. For example, when classifying DMD exposure, some defined in utero DMD exposure as within one month prior to conception whereas others used the estimated time of conception. All these issues outlined here could contribute to the differences in reported findings between studies – with some studies reporting harm113,114,120,121,126 and others not.77,122-125,130-134 Some of the best available studies have been prospective, which by their nature, minimize reporting and recall bias (a common challenge in pregnancy-related pharmacovigilance studies). Three such cohort studies have been published to date and all examined IFNβ exposure.113,120,121 Of these, two had relatively large sample sizes113,121 (n=69 and 88), which also allowed for adjustment of important confounders (including gestational age, parity, socioeconomic status and cigarette or alcohol use) to better estimate the true effect of IFNβ exposure. In addition, some studies were able to report on DMD exposure late in pregnancy; three small studies122,123,133 (n=9, 11 and 12 pregnancies) reported on GA exposure up to the third trimester of pregnancy while  87  others followed longer-term developmental outcomes beyond the immediate perinatal period in GA122 or IFNβ113,114 in utero exposed offspring. Individual studies have also investigated maternal natalizumab exposure during pregnancy130 and paternal DMD use around conception77 – both represent the first cohort studies published on these topics. These studies did not find evidence of harm; however, given their relatively small sample sizes, further studies should seek to confirm these findings. Challenges with Ascertainment of Specific Outcomes Perhaps one of the biggest challenges to date when examining pregnancy outcomes in MS relates to study power because small sample sizes limit the ability to examine many important outcomes. Most studies of DMD exposure in pregnancy have involved relatively few women. From our own experience in BC, Canada, this is related largely to good clinical practice, with women following advice to discontinue DMD prior to conception.132 In addition, given the relatively short period of time that DMDs have been licensed for MS, there is limited long-term post-marketing data available to assess safety. Consequently, many studies have been unable to adequately assess rarer outcomes such as specific birth defects or syndromes. Other outcomes, such as spontaneous abortion, are difficult to ascertain. These are discussed in more detail below. Spontaneous abortion IFNβ has been found to cause spontaneous abortion in animals; 51 however, there was mixed evidence from human observational studies.113,120,124 Spontaneous abortions are difficult to detect in practice, especially those that occur early enough in gestation to avoid routine detection by patient or clinician. The symptoms of early pregnancy can be  88  vague and easily confused with transitory illnesses (e.g. viral illnesses) or normal menstrual cycle variability.144 If pregnancy is not recognized, a spontaneous abortion may be mistaken for heavier than normal menses or a passed clot – underestimating the true risk of spontaneous abortion. Prospective enrollment through pregnancy registries as well as regular use of objective pregnancy detection methods such as home pregnancy kits and/or serum beta human chorionic gonadrotropin levels may improve ascertainment of spontaneous abortions. Congenital anomalies and related rare outcomes Roughly 260 DMD-exposed pregnancies are needed for a study to achieve 80% power with a Type I error of 5% to identify a 5% absolute increased risk of congenital anomaly from a baseline risk of 3% in the general population. 88,145 Consequently, most studies to date have lacked a sufficient sample size to investigate these rarer outcomes. In addition, since the majority of identified cases of in utero DMD exposure occur within the first trimester, the risk of congenital anomalies (or other adverse outcomes) associated with exposure beyond the first trimester remain largely unknown. 132 One potential solution to improve ascertainment of rare outcomes is the creation of universal standardized research templates to investigate drug safety in pregnancy. Multicenter pregnancy registries with prospective recruitment of women initiated on DMD therapy may be the ideal platform to investigate newly licensed drugs using these standardized forms; presently, there are some drug-specific worldwide registries, for example for natalizumab141 and fingolimod142 that are actively recruiting patients. Such an approach would permit future meta-analyses because these templates would include key demographic, obstetrical and medical data using common definitions. These  89  standardized forms should also capture key developmental outcomes such as gross and fine motor milestones, intellectual development and behavioral measures – all largely understudied outcomes. Another approach is through data linkage where clinical data from many mothers are connected to their birth outcomes from another database via unique personal identifiers.146 Data on confounders is also crucial because drugs are estimated to be responsible for only 1% of birth defects147 – albeit an important preventable cause. Potential Biological Mechanism(s) Of interest, although most pregnant women with MS exposed to IFNβ discontinued therapy early in pregnancy, IFNβ was associated with prematurity and decreased fetal growth – outcomes often associated with adverse events occurring later in pregnancy. Since the first trimester of pregnancy is characterized by rapid cell division and precisely choreographed gene expression that lay the foundation for later fetal growth and development,148 it is entirely possible that early IFNβ exposure may have affected these early processes to cause later prematurity and decreased growth. Among the DMDs for MS, only mitoxantrone has an established biological mechanism for fetal harm.149 Mitoxantrone is toxic to DNA, causing inhibition of topoisomerase II and DNA strand breakage, with a cytocidal effect on cells. 147 It is known to cause growth retardation and preterm birth in animals.55 Spontaneous abortion and decreased fetal growth were observed in women with in utero mitoxantrone exposure for cancer treatment.150 In men undergoing cancer chemotherapy, mitoxantrone may cause azoospermia with a return to normospermic levels 3 to 4 months postchemotherapy for most patients.151  90  For the other DMDs, although only in utero IFNβ exposure has been associated with unfavorable perinatal outcomes, this might just reflect the low number of studies involving the other DMDs. Although it is unlikely that a large macromolecule such as IFNβ can cross the placenta to directly affect the developing fetus,152 IFNβ is a cytokine that has immune, antiproliferative, and antiviral effects.153 It is known to increase transcription of over 100 different genes;154 hence, IFNβ and its metabolites could trigger downstream production of maternal cytokines that affect the developing placenta or cross the placental barrier to affect the fetus. This could disrupt the complex, sequential pattern of chemical signals required for normal fetal growth and development.155 Potential mechanisms of action are equally speculative for the other DMDs. The relationship between DMD exposure and adverse birth outcomes is further obscured by our limited understanding of the pharmacokinetic properties of these agents. Based on studies of healthy human subjects, IFNβ has a half-life of hours to days (depending on the specific formulation),51,52 while the half-life of GA is unknown although most of the drug appears to be hydrolyzed locally at the injection site. 49 Natalizumab has a half-life of 11 ± 4 days,53 and fingolimod has a half-life of 6-9 days.54 One commonly studied biomarker of IFNβ bioactivity, the protein MxA, remains in circulation for days to weeks post-administration.156 Even with total clearance of a drug from the body, the potential pharmacodynamic effects that persist after cessation of drug therapy should not be overlooked when investigating the risk of fetal harm, especially since in utero exposure at different stages of pregnancy can result in dramatically different outcomes for fetal development and morphology.157  91  Proposed methodological improvements as well as pharmacokinetic and pharmacodynamic considerations for future observational studies of drug exposure in pregnancy have been summarized in Figure 7.1. In addition, substantial physiological changes occur during pregnancy158 which can affect the pharmacokinetic/dynamic properties of drugs. However, these changes may not be as relevant in women with DMD exposure since most cases of DMD exposure (based on existing studies to date) occur early in gestation when these physiological effects may be not as prominent.  Figure 7.1. A conceptual timeline of pharmacokinetic and pharmacodynamic effects of drugs on pregnancy and potential methodological improvements to study design. ‘All or none’ refers to the time from conception until implantation when insults to the embryo are likely to result in either death or intact survival of the embryo. The ‘critical period’ refers to early organogenesis during which all the major organ systems of the body are being formed; drug exposure during this period can result in significant congenital anomalies (although exposure at anytime during pregnancy has the potential for adverse effects).  92  Potential Role of Clinical Trials The active recruitment of pregnant women (or those actively planning pregnancy) into a randomized controlled trial of a drug for MS is typically considered unethical. Nonetheless, women enrolled in clinical trials124,125 do occasionally become pregnant accidentally. Collectively, these data can still be invaluable as they often represent the first human exposures to drug during pregnancy. However, these women represent a specific MS subpopulation that might not be generalizable to the wider MS population. Nonetheless, increasingly there has been debate about the merits of including a limited number of pregnant women in clinical trials.159 There are some situations where the use of drug therapy during pregnancy may be justifiable. For example, a woman with severe MS may remain on DMDs during pregnancy to minimize the risk of a relapse. Likewise, a woman with epilepsy may be safer continuing anticonvulsants throughout pregnancy rather than risk having significant hypoxic events due to seizures that could be lifethreatening to mother and child.160 When clinically justified, a smaller scale clinical trial with regular, close follow-up of mothers has been suggested – especially if drug therapy during pregnancy is unavoidable due to the mother’s medical condition. 159 Future Directions Future research on drug safety in pregnancy should strive to minimize methodological limitations and fully consider pharmacokinetic and pharmacodynamic factors. In addition, standardized, comprehensive approaches to data collection may improve comparability between studies and allow adequate investigation of more rare outcomes. It is encouraging to find recent studies also investigating longer-term developmental outcomes in offspring associated with in utero drug exposure113,114 as  93  well as the potential effects of paternal drug use on pregnancy;77 future studies should continue to expand on these areas of research. The potential benefits of clinical trials involving a limited number of pregnant women warrant further consideration as a viable approach to investigating drug safety in pregnancy. Women with MS should still be advised to discontinue DMDs if they are planning to conceive. Following unintentional DMD exposure during pregnancy, women should consider discontinuation of their MS drugs. However, mitoxantrone aside, there is currently a lack of evidence to strongly support consideration of pregnancy termination following paternal or maternal exposure to the MS DMDs. Future research should further explore long-term development in offspring exposed to DMDs.  94  CHAPTER 8 – BIRTH OUTCOMES OF PREGNANCIES FATHERED BY MEN WITH MULTIPLE SCLEROSIS Objectives: To investigate if paternal MS is associated with unfavorable birth outcomes compared to the fathers without MS; to examine the association between MS clinical factors and birth outcomes. 8.1  Methods Please refer to Chapter 2 (page 11) for a general outline of the study design used  throughout the studies in this dissertation. Details regarding the methodology used in this particular study are described below. As a requirement of data access/privacy policies involving Population Data BC, cells with <5 individuals could not be shown (these restrictions are only applicable to Chapters 8 and 9). Study Participants Births fathered by men with MS and men in the general population were included in this study. Non-singleton births (i.e. twins and triplets, etc.) were excluded because of an increased risk of adverse birth outcomes.87 In the MS cohort, births fathered by men with MS symptom onset after conception or those who first attended the MS clinic after conception with an unknown date of MS onset were also excluded. The date of conception was estimated by adding 2 weeks to the first day of the LMP.109 The first day of the LMP was determined by subtracting the final gestational age (determined by Perinatal Services BC based on ultrasound, date of LMP, newborn exam, or a combination of the above) from the baby’s date of birth.83  95  Demographics and Clinical Characteristics Demographics characteristics included: paternal and maternal age, maternal parity, maternal alcohol-, drug-, cigarette use during pregnancy, pre-pregnancy body mass index (BMI), sex of the newborn and neighborhood income quintile (in the year of conception) with the first quintile indicating the lowest and the fifth quintile the highest income. Paternal clinical characteristics (as recorded in the BCMS database) included: MS disease course (relapsing-onset or primary progressive), age at MS onset, disease duration at the time of conception and the degree of disability as measured by the Expanded Disability Status Scale (EDSS)6 score closest to and within 3 years of conception. Maternal clinical characteristics (as recorded in the BCPDR) included the presence of hypertension, diabetes and past obstetrical history (including previous spontaneous abortion, stillbirth, a previous low birth weight or preterm baby, or a baby with a congenital anomaly). Outcomes Primary outcomes of interest were birth weight and gestational age. Secondary descriptive outcomes included the 5-minute Apgar score and the presence of one or more congenital anomalies. The Apgar score assesses the immediate need for resuscitation of the newborn based on appearance, pulse, grimace, activity and respiration.119 Statistical Analysis The Mann Whitney U test (for continuous data), and Chi-Squared test (for  96  categorical data) were used to compare characteristics between the MS family cohort (father with MS, mother and baby) and the general population family cohort. To account for multiple births identified to the same father (i.e. clustering effects) and confounders, GEE with an exchangeable working correlation structure were developed. A priori confounders considered for the GEE included: paternal and maternal age, socioeconomic status, maternal parity and pre-pregnancy BMI, presence of maternal hypertension (blood pressure ≥140/90 on two consecutive readings during pregnancy, prior to labor), diabetes, and use of alcohol, cigarette or drugs (prescription/nonprescription/illicit) listed as a risk factor in the current pregnancy by the physician. Advanced paternal age,161 maternal age,162 low socioeconomic status,163 nulliparity,83 maternal comorbidities,106,164,165 maternal cigarette-,166 drug-,167 and alcohol use168 are known to be associated with adverse birth outcomes. The sex of the newborn was additionally considered in the analysis of birth weight because male newborns tend to be heavier than female newborns.83 When the presence of a variable occurred in <5 individuals in the MS cohort (i.e. maternal hypertension, alcohol- and drug use) or data on a priori potential confounders were unavailable for >20% of the MS cohort (i.e. maternal BMI), the effect of including, then excluding each variable was examined; if no significant association between MS and the outcome was found, then the variables were excluded from the final model. Two-way interactions between MS and confounders were also assessed and excluded from the model if no significant effect on the outcome was found. The same approach outlined above was used to analyze the association of birth outcomes with paternal MS clinical factors. Disease duration was included as a  97  continuous variable and disability (EDSS score)6 as a categorical variable (0-1.0; 1.52.0; 2.5-3.0; and ≥3.5). Findings were reported with β and corresponding 95% CI. Lastly, a sensitivity analysis was done to compare disease duration at conception, paternal age, neighborhood income quintile in the year of conception and the primary outcomes in births fathered by men with and without EDSS scores available closest to the time of conception (±3 years). A p value <0.05 was considered significant.  8.2  Results  Demographics and Clinical Characteristics A conceptual overview of the linkage strategy is outlined in Figure 8.1. From 1,846 males with MS identified via the BCMS database, linkage with BC Vital Statistics Birth Registry and the BCPDR retrieved 259 births with perinatal records to 172 men with MS. A sample of 1,004 control births from the general population was selected. After excluding non-singleton births (n=32), births fathered by MS men who first attended the MS clinic after conception with an unknown symptom onset date (n=23), and births fathered by men with MS onset after conception (n=25), a final cohort of 202 births fathered by 141 men with MS and 981 births in the general population cohort was included in this study.  98  Figure 8.1. A conceptual overview of the database linkage allowing data on fathers and their newborns to be connected. BC, British Columbia; MS, Multiple Sclerosis  99  Demographic characteristics of the MS and the control groups are summarized in Table 8.1. On average, fathers with MS were one year older than the fathers from the general population (p=0.02) due to a relatively lower proportion of fathers under 30 years of age in the MS cohort. In addition to characteristics presented in Table 8.1, other maternal characteristics such as a previous history of: stillbirth, a preterm or low birth weight baby or a baby with a congenital anomaly, as well as maternal alcohol and/or drug use, or presence of hypertension during the current pregnancy were similar between the two groups – data not shown.  100  Table 8.1. Characteristics of births fathered by men in BC. Characteristic MS Controls n=202 n=981 Paternal age – years n 202 933 <30 – n (%) 25 (11) 213 (23) 30 to <40 – n (%) 143 (72) 562 (60) ≥40 – n (%) 34 (17) 158 (17) Median (range) 34 (24-58) 33 (20-60) Maternal age – years Median (range) 32 (20-43) 31 (20-43) Neighborhood income quintile (year of conception) n 198 836 First (lowest income) – n (%) 37 (18) 152 (18) Second – n (%) 39 (20) 147 (18) Third – n (%) 45 (23) 169 (20) Fourth – n (%) 45 (23) 195 (23) Fifth (highest income) – n (%) 32 (16) 173 (21) Maternal parity Nullipara – n (%) 90 (45) 400 (41) Maternal cigarette use during pregnancy n (%) 15 (7) 97 (10) Maternal BMI – kg/m2 n 150 715 <18.5 (underweight) – n (%) 8 (5) 30 (4) 18.5 to <25 (normal) – n (%) 74 (50) 425 (60) 25 to <30 (overweight) – n (%) 44 (29) 174 (24) ≥30 (obese) – n (%) 24 (16) 86 (12) Median (range) 23.8 (13.5-48.6) 23.3 (15.7-46.3) Maternal diabetes during pregnancy n (%) 21 (10) 101 (10) Previous spontaneous abortion n (%) 52/201 (26) 210/969 (22) Sex of the newborn n 202 944 Male – n (%) 109 (54) 460 (49) Female – n (%) 93 (46) 484 (51) BC, British Columbia; MS, multiple sclerosis; BMI, body mass index a Chi-Square test b Mann-Whitney U test  p value 0.003a  0.02b 0.12b 0.63a  0.32a 0.28a 0.24a  0.38b 0.97a 0.19a 0.18a  101  As shown in Table 8.2, almost all fathers in the MS cohort had a relapsing-onset disease course; seven births were fathered by men in the secondary progressive MS phase. Based on the first birth in the study, the median age at MS onset was 27 years old, the median disease duration was 6.1 years at conception, and the median EDSS score was 2.0 (Table 8.2). Few births (n=5; 2%) were fathered by men with ‘severe’ disability (i.e. an EDSS score of 6.0 (requiring a cane to walk) or higher). Baseline characteristics between MS fathers with and without an EDSS score revealed that fathers with EDSS scores available had shorter MS disease duration (three years on average) at the time of conception than fathers without EDSS scores (Table A.8.1, Appendices).  102  Table 8.2. Clinical characteristics of MS fathers with newborns in BC. Characteristic Fathers with MS* Births fathered by men with MS n=141 n=202 Disease course – n (%) Relapsing-onset 137 (97) 195 (97) Primary progressive 4 (3) 7 (3) Age at MS onset – years n 136 196 <20 – n (%) 17 (12) 27 (14) 20 to <25 – n (%) 37 (27) 53 (27) 25 to <30 – n (%) 49 (36) 68 (35) 30 to <35 – n (%) 24 (18) 36 (18) ≥35 – n (%) 9 (7) 12 (6) Median (range) 27 (10-48) 26 (10-48) Disease duration at conception – years n 136 196 <5 – n (%) 54 (40) 64 (33) 5 to <10 – n (%) 48 (35) 75 (38) ≥10 – n (%) 34 (25) 57 (29) Median (range) 6.1 (<1-24) 6.9 (<1-26) Disability at conception (±3 years) – EDSS score n 105 148 0 or 1.0 – n (%) 37 (35) 49 (33) 1.5 or 2.0 – n (%) 23 (22) 38 (26) 2.5 or 3.0 – n (%) 24 (23) 35 (24) ≥3.5 – n (%) 21 (20) 26 (17) Median (range) 2.0 (0-8.0) 2.0 (0-8.0) MS, multiple sclerosis; BC, British Columbia; EDSS, Expanded Disability Status Scale *based on the first birth in the study period  Birth Weight and Gestational Age In the MS cohort, six (3%) babies had low birth weight (<2500 grams) and 13 (6%) were premature (<37 weeks gestational age) compared to 24 (2%) and 60 (6%), respectively, in the comparison group. The mean birth weight and gestational age were not statistically or clinically different for babies with or without an MS father, before or after adjustments for clustering and confounding effects (p>0.60, Table 8.3). There were no stillbirths in either group. 103  Table 8.3. Association between paternal MS and birth outcomes. Factor  n  Mean ± SD Median (range)  Unadjusted β  Birth weight – grams Controls MS  836 198  3,483 ± 519 3,475 (1,330-5,340) 3,501 ± 552 3,503 (1,492-4,996)  95% CI  p value  Reference 17.4  -62.0 – 96.8  Adjusted for Clustering and Confounding Effects* β 95% CI p value Reference  0.67  -19.9  -108.7 – 68.9  0.66  Gestational age – weeks Controls 836  39.0 ± 1.6 Reference Reference 39 (28-44) MS 198 39.0 ± 1.8 -0.02 -0.28 – 0.23 0.86 -0.08 -0.37 – 0.22 0.61 39 (29-43) MS, multiple sclerosis; SD, standard deviation; β, regression coefficient; CI, confidence interval *adjustments: paternal age, maternal age, neighborhood income, parity, maternal diabetes and cigarette use. Sex of the newborn was additionally adjusted for in the analysis of birth weight.  104  MS Clinical Factors In the unadjusted analysis, longer paternal MS disease duration at conception appeared to be associated with higher birth weight of the newborn (unadjusted p=0.02, Table 8.4). Paternal age was significantly associated with paternal MS disease duration (p<0.001, data not shown). After accounting for relevant factors, paternal MS disease duration was no longer associated with birth weight (adjusted p=0.48, Table 8.4). Compared to men with EDSS scores of 0 or 1.0, men with an EDSS score of 1.5 and 2.0 around the time of conception were at greater risk of fathering newborns with lower mean birth weight (adjusted p=0.02, Table 8.4). Risks were also observed in births fathered by men with an EDSS score greater than 2.0 although these findings did not reach statistical significance (Table 8.4). No clear association was found between gestational age and paternal MS disease duration or disability (p>0.10, Table 8.5). MS men with or without EDSS scores available did not have significantly different mean birth weight or gestational age (Table A.8.1, Appendices).  105  Table 8.4. Association between MS clinical factors and birth weight of the newborn. Factor n Mean ± SD Unadjusted Adjusted for Clustering and Median (range) Confounding Effects* Birth weight – grams β 95% CI p value β 95% CI p value Paternal disease duration at conception – years 17.4 2.9 – 31.9 0.02 6.4 -11.2 – 24.1 0.48 <5 62 3,446 ± 575 3,484 (1,492-4,704) 5 to <10 75 3,469 ± 539 3,448 (1,500-4,680) ≥10 55 3,612 ± 559 3,623 (2,075-4,996) Paternal disability at conception (±3 years) – EDSS score 0 or 1.0 49 3,598 ± 486 Reference Reference 3,600 (1,726-4,548) 1.5 or 2.0 36 3,447 ± 467 -151.1 -374.4 – 72.2 0.19 -215.9 -396.3 – -35.4 0.02 3,455 (2,525-4,996) 2.5 or 3.0 34 3,499 ± 560 -98.2 -326.8 – 130.4 0.40 -115.0 -355.9 – 105.9 0.31 3,444 (2,075-4,704) ≥3.5 26 3,499 ± 664 -98.5 -349.2 – 152.1 0.44 -150.1 -426.1 – 125.9 0.29 3,555 (1,492-4,680) MS, multiple sclerosis; SD, standard deviation; β, regression coefficient; CI, confidence interval; EDSS, Expanded Disability Status Scale *adjustments: paternal age, maternal age, neighborhood income, maternal parity, maternal diabetes, cigarette use and sex of the newborn  106  Table 8.5. Association between MS clinical factors and gestational age of the newborn. Factor n Mean ± SD Unadjusted Adjusted for Clustering and Median (range) Confounding Effects* Gestational age – weeks β 95% CI p value β 95% CI p value Paternal disease duration at conception – years 0.02 -0.03 – 0.07 0.38 0.01 -0.05 – 0.06 0.86 <5 62 38.9 ± 2.2 39 (29-42) 5 to <10 75 38.9 ± 1.7 39 (30-43) ≥10 55 39.3 ± 1.6 40 (34-42) Paternal disability at conception (±3 years) – EDSS score 0 or 1.0 49 39.1 ± 1.7 Reference Reference 39 (30-41) 1.5 or 2.0 36 39.0 ± 1.3 -0.06 -0.82 – 0.71 0.89 -0.19 -0.84 – 0.46 0.56 39 (36-41) 2.5 or 3.0 34 39.1 ± 1.8 0.03 -0.75 – 0.82 0.94 0.10 -0.65 – 0.85 0.80 39 (34-42) ≥3.5 26 39.0 ± 1.8 -0.62 -1.48 – 0.24 0.16 -0.63 -1.78 – 0.51 0.28 39 (29-43) MS, multiple sclerosis; SD, standard deviation; β, regression coefficient; CI, confidence interval; EDSS, Expanded Disability Status Scale *adjustments: paternal age, maternal age, neighborhood income, maternal parity, maternal diabetes and cigarette use  107  5-minute Apgar Score and Congenital Anomalies The median 5-minute Apgar score was 9 for both the MS cohort (range 1 to 10) and the general population (range 4 to 10). Seven out of 200 (4%) babies in the MS cohort and 15 out of 979 (2%) newborns from the general population had a 5-minute Apgar score below 7 (i.e. indicating that special medical attention was needed). There were 12 (6%) babies in the MS cohort and 56 (6%) newborns from the general population with at least one congenital anomaly.  8.3  Discussion This study is a comprehensive investigation of birth outcomes in newborns  fathered by men with MS using linkage of population clinical and administrative databases. Paternal MS was not found to be associated with unfavorable birth outcomes compared to the general population. Although I am unaware of any existing studies of birth outcomes in men with MS, an Iranian study of sperm morphology found that men with MS had decreased sperm count, motility and percentage of normal sperm compared to men from the general population.69 However, I recognize that poor overall sperm quality does not necessarily translate into worse birth outcomes given that typically only the fittest sperm typically fertilize the embryo. While comparisons between studies cannot be made, it is worth noting that the Iranian study included a higher proportion of men with MS with progressive disease (either primary or secondary progressive) compared to this study, and that this study may exclude some men with worse sperm quality because fathering a child was a re-requisite to study inclusion. While comparable studies with MS fathers do not exist, others have found associations  108  between the presence of chronic autoimmune diseases in fathers – specifically, inflammatory bowel disease and celiac disease – and poorer birth outcomes.67,68 Interestingly, the association between inflammatory bowel disease and lower mean birth weight strengthened if the father’s first degree relatives also had inflammatory bowel disease.68 The possibility that inflammatory bowel disease and celiac disease may confer a genetic predisposition for prematurity and decreased growth in offspring has been raised.67,68 Within the MS cohort, babies fathered by men with greater levels of disability appeared to have lower mean birth weight – albeit the difference was not clinically significant as the mean birth weight was within the normal range for the general population. Relative to men with relapsing-remitting MS, the Iranian study found worse sperm quality in men with progressive MS69 who presumably have higher EDSS scores.169 Hence, it is possible that men with higher EDSS scores have poorer quality sperm, leading to a greater risk of offspring with lower mean birth weight. Nevertheless, this finding requires further investigation. In addition, there appeared to be a difference in the proportion of babies with a low 5-minute Apgar score (<7) between MS fathers and the general population; however, so few babies were affected in either group that no firm conclusions could be drawn. This study has several notable strengths. By harnessing multiple comprehensive, population-based databases, a highly representative cohort of MS fathers and their offspring was generated. The clinical data on MS fathers, as well as data on the maternal and newborn characteristics are considered reliable and with minimal bias, being generated by healthcare professionals in a prospective manner using common  109  definitions without a priori knowledge of the research question. In addition, important factors which could influence birth outcomes were accounted for, including paternal age and socioeconomic status as well as maternal obstetrical and medical characteristics. Although other paternal medical conditions or use of medications were not accounted for in this study, evidence suggests that most paternal medication exposures are not associated with adverse birth outcomes.170 Data were unavailable on paternal smoking and alcohol use, but the effects of maternal smoking and alcohol use, which are well documented causes of adverse neonatal outcomes,166,168 were taken into consideration for this study. Findings from this study may not be generalizable to men with primary progressive MS171 (or higher levels of disability)169 who, presumably because of more advanced age, are less likely to have children (in part due to the greater likelihood of their partner being older as well). It would certainly be challenging for any study to gather a large cohort of these types of patients, especially when primary-progressive MS patients represent a relatively low proportion (10%) of all MS patients, with a later onset age, averaging 40 years.171 The biological relationship between fathers and offspring identified through the BC Vital Statistics Birth Registry could not be verified; however, a recent meta-analysis indicates that non-paternity is only present in approximately 3% of births in developed countries.172 The BCPDR did not establish full provincial coverage until April 2000; some births identified in the BC Vital Statistics Birth Registry were not captured by the BCPDR. The risk of spontaneous abortion associated with paternal MS could not be investigated because data were unavailable for births <20 weeks gestational age if the newborn did not exceed 500 grams in birth weight. Lastly, while there is some interest regarding the relative fertility of men with MS compared to  110  the general population, this study was not designed to estimate the number of biological children that fathers with MS had (a general measure of fertility) and data from this study should not be used to infer fertility (or lack thereof) or the processes surrounding decision making with regards to family planning. In general, birth outcomes in men with chronic diseases are understudied. Overall, this novel study found no increased risk of adverse birth outcomes in newborns of men with MS compared to the general population; these findings should provide greater reassurance to clinicians and expecting fathers with MS.  111  CHAPTER 9 – BIRTH OUTCOMES OF PREGNANCIES FATHERED BY MEN WITH MULTIPLE SCLEROSIS EXPOSED TO DISEASE-MODIFYING DRUGS Objective: To compare birth outcomes in offspring of MS fathers exposed and unexposed to a disease-modifying drug within 64 days (duration of spermatogenesis) prior to conception. 9.1  Methods Please refer to Chapter 2 (page 11) for a general outline of the study design used  throughout the studies in this dissertation. Details regarding the methodology used in this particular study are described below. As a requirement for data access/privacy policies involving Population Data BC, cells with <5 individuals could not be shown (these restrictions are only applicable to Chapters 8 and 9). Study Participants Births fathered by men with MS were included in this study. I excluded (i) nonsingleton births (i.e. twin, triplet, etc.) because of an increased risk of unfavourable perinatal outcomes,87 (ii) births fathered by men with MS symptom onset after conception, (iii) births fathered by men who first attended the MS clinic after conception with an unknown date of MS onset or (iv) births fathered by men with primaryprogressive MS because no DMD has been approved for use in primary-progressive MS. Births were classified and grouped according to DMD exposure. The two exposed group consisted of births fathered by men with relapsing-onset MS (relapsingremitting MS and secondary progressive MS) exposed to (i) IFNβ or (ii) GA within 64 days (i.e. the duration of spermatogenesis)78 prior to conception. The unexposed group  112  consisted of births fathered by men with relapsing-onset MS who had no history of DMD use or stopped DMD therapy more than 64 days prior to conception. The date of conception was estimated by adding 2 weeks to the first day of the LMP.109 The first day of the LMP was determined by subtracting the final gestational age (determined by Perinatal Services BC based on ultrasound, date of LMP, newborn exam, or a combination of the above) from the baby’s date of birth. 83 Demographics and Clinical Characteristics Paternal characteristics included: age at MS onset, disease duration at conception, disability (as measured by the EDSS score) closest to the time of conception (±3 years), paternal age, duration of DMD use prior to conception, and neighborhood income in the year of conception. Maternal characteristics included: maternal age, parity, pre-pregnancy body mass index (BMI), hypertension, diabetes, alcohol-, cigarette-, drug use identified as a risk factor for this pregnancy, sex of the newborn and a previous history of spontaneous abortion, low birth weight baby, preterm births or congenital anomalies. Outcomes Primary birth outcomes were birth weight and gestational age. Secondary outcomes included the 5-minute Apgar score and presence of one of more congenital anomalies. Statistical Analyses Demographics and clinical characteristics of IFNβ-exposed, GA-exposed and unexposed births fathered by men with MS were compared using the Kruskal-Wallis test for continuous variables and Pearson’s Chi-Squared test for categorical variables.  113  The GEE approach was used to compare the association between birth outcomes in IFNβ-exposed, GA-exposed and unexposed births fathered by men with MS. In addition to taking into account clustering effects from multiple births fathered by individual men, confounders adjusted in the analysis included the duration of DMD use prior to conception and the sex of the newborn. Findings were reported with β and corresponding 95% CI. Statistical significance was defined as a p<0.05. As the long-term impact of DMD use on spermatogenesis is unknown, I ran a sensitivity analysis where the ‘unexposed’ group consisted only of births fathered by men with relapsing-onset MS with no history of DMD use. I also ran a sensitivity analysis that excluded births fathered by men with secondary progressive MS because it is unknown if the secondary progressive disease course in fathers with MS impacts birth outcomes differently than the relapsing-remitting disease course.  9.2  Results During the study period, a total of 64 births were excluded for the following  reasons: first clinic visit after conception with an unknown date of MS onset (n=23), paternal MS onset after conception (n=25), father with primary progressive MS (n=7) and non-singleton births (n=9). A final sample of 195 births fathered by men with MS was included in the study. There were 7 births fathered by men with secondary progressive MS for a median of 3.1 years at the time of conception (range: <1-5 years). Of the 195 newborns fathered by men with MS, 116 (59%) had fathers who used a DMD (78 before and 38 after conception). Of the 78 births fathered by men using DMD before conception, 18 births (23%) were exposed to GA and 41 (53%) to INFβ within 64  114  days prior to conception; 19 births (24%) were fathered by men previously treated with a DMD but were not exposed within 64 days prior to conception. For births fathered by men previously treated with a DMD, the median duration of DMD cessation at the time of conception was 2 years (range: <1-8 years). Out of the 59 exposed births, only one birth was fathered by a man who stopped IFNβ one month before conception (reason unknown); the rest were exposed throughout the 64 days before conception. Including 79 births who never use a DMD before or after conception to 38 births with DMD use after conception, a total of 117 births were fathered by men who never used a DMD before conception. There were no births fathered by men with MS who used natalizumab or mitoxantrone 64 days prior to conception. Fingolimod and teriflunomide were not licensed for treating MS at the study cut-off date. The conceptual selection of births fathered by men with MS is shown in Figure 9.1.  115  Figure 9.1. Conceptual selection of births fathered by MS men and linkage of the clinical and perinatal data. BCMS, British Columbia Multiple Sclerosis; BCPDR, British Columbia Perinatal Database Registry; IFNβ, interferon-beta; GA, glatiramer acetate  116  Cohort Characteristics Births fathered by men who were exposed to INFβ or GA within 64 days prior to conception had a significantly longer duration of DMD treatment prior to conception compared to fathers unexposed to a DMD within 64 days prior to conception (p<0.001, Table 9.1). Maternal hypertension during pregnancy (p=0.01, data not shown due to <5 cell counts) and female gender for newborns (p=0.01, Table 9.1) were more common in births fathered by men exposed to either IFNβ or GA within the 64 days prior to conception. No births in this study had a mother where maternal drug use was identified as a risk by the physician for the pregnancy. Also, no mothers had a previous history of stillbirths or congenital anomalies. In addition to the characteristics presented in Table 9.1, all other characteristics mentioned in the Methods section were comparable across the INFβ-, GA-exposed and unexposed groups (p>0.05, data not shown).  117  Table 9.1. Characteristics of men with relapsing-onset MS with newborns in BC.a Characteristic GA-exposedb IFNβ-exposedb n=18 n=41 Age of MS onset – years n 17 41 Median (range) 27 (19-33) 27 (17-37) Disease duration at conception – years n 17 41 Median (range) 7.3 (2-16) 6.6 (1-24) Disability at conception (±3 years) – EDSS score n 17 36 Median (range) 1.5 (0-6.0) 1.5 (0-6.5) Duration of DMD use prior to conception – years Median (range) 2.8 (<1-5) 3.2 (<1-10) Paternal age – years Median (range) 33 (27-41) 34 (26-44) Maternal age – years Median (range) 32 (24-38) 32 (24-40) Neighborhood income quintile (year of conception) n 18 40 First (lowest income) – n (%) 3 (17) 9 (23) Second – n (%) 4 (22) 6 (14) Third – n (%) 7 (39) 9 (23) Fourth – n (%) 3 (16) 8 (20) Fifth (highest income) – n (%) 1 (6) 8 (20) Maternal parity – n (%) Nullipara 8 (44) 16 (39) 2 Maternal BMI – kg/m n 11 30 Median (range) 25.1 (20.3-36.6) 24.3 (18.3-48.6) Sex of the newborn – n (%) Female 13 (72) 22 (54)  Unexposedc n=136  p valued 0.79  131 26 (10-48) 0.86 131 6.9 (<1-26) 0.97 93 2.0 (0-8.0) <0.001 0 (0-6) 0.85 34 (24-58) 0.81 32 (20-43) 0.61 133 25 (19) 28 (21) 25 (19) 34 (25) 21 (16) 0.76 62 (46) 0.46 105 23.7 (13.5-35.9) 0.01 53 (39)  118  MS, multiple sclerosis; BC, British Columbia; GA, glatiramer acetate; IFNβ, interferon-beta; EDSS, Expanded Disability Status Scale; BMI, body mass index a 11 men had children belonging to different DMD groups during the study period: 9 men had 1 DMD unexposed and 1 IFNβ-exposed births; 1 man had 1 DMD unexposed and 1 GA-exposed births; 1 man had 1 DMD unexposed and 2 GAexposed births. b births fathered by men with relapsing-onset MS (including secondary progressive MS) who were exposed within 64 days prior to conception c births fathered by men with relapsing-onset MS (including secondary progressive MS) who never used a DMD before conception or previously treated with a DMD but stopped 64 days prior to conception d comparisons between the IFNβ-exposed, GA-exposed and unexposed groups using Kruskal-Wallis test (continuous variables) and Pearson’s Chi-Squared test (categorical variables)  Birth Outcomes Mean birth weight and gestational age were not significantly different across all groups before or after adjustment for clustering and confounding effects (p>0.05, Table 9.2). The median 5-minute Apgar score was 9 across all groups (p=0.73). The proportion of births with congenital anomalies was not higher in the IFNβ- or GA-exposed group compared to the unexposed group (p>0.05, data not shown due to <5 cell counts). There were no cases of stillbirth in any group. Birth outcomes remained comparable between exposed and unexposed groups (adjusted p>0.05) after births fathered by previously treated men with MS (adjusted p>0.05, Table A.9.1 in Appendices) or those with secondary progressive MS (adjusted p>0.05, Table A.9.2 in Appendices) were excluded.  119  Table 9.2. Birth outcomes of newborns with IFNβ-exposed, GA-exposed and unexposed relapsing-onset MS fathers.a Factor  n  Mean ± SD Median (range)  Unadjusted β  Birth weight – grams Unexposedc 136 IFNβ-exposedd  41  GA-exposedd  18  3,536 ± 548 3,494 (1,726-4,996) 3442 ± 592 3,574 (1,492-4,680) 3483 ± 347 3,503 (2,882-4,230)  95% CI  p value  Reference  Adjusted for Clustering and Confounding Effectsb β 95% CI p value Reference  -93.7  -282.0 – 94.5  0.33  -135.3  -389.4 – 118.7  0.30  -53.2  -318.1 – 211.8  0.69  -0.5  -242.5 – 241.5  1.00  Gestational age – weeks Unexposedc 136  39.1 ± 1.6 Reference Reference 39 (30-42) IFNβ-exposedd 41 38.6 ± 2.1 -0.56 -1.15 – 0.03 0.07 -0.45 -1.36 – 0.45 0.33 39 (29-42) GA-exposedd 18 39.1 ± 1.4 -0.01 -0.84 – 0.83 0.99 0.13 -0.68 – 0.93 0.76 39 (37-43) IFNβ, interferon-beta; GA, glatiramer acetate; MS, multiple sclerosis, SD, standard deviation; β, regression coefficient; CI, confidence interval a 11 men had children belonging to different DMD groups during the study period: 9 men had 1 DMD unexposed and 1 IFNβ-exposed births; 1 man had 1 DMD unexposed and 1 GA-exposed births; 1 man had 1 DMD unexposed and 2 GAexposed births. b adjustments: sex of newborn and duration of drug use before conception c births fathered by men with relapsing-onset MS (including secondary progressive MS) who never used a DMD before conception or previously treated with a DMD but stopped 64 days prior to conception d births fathered by men with relapsing-onset MS (including secondary progressive MS) who were exposed within 64 days prior to conception  120  9.3  Discussion This study is one of the first North American studies to report on the use of  paternal MS DMD use before and at conception and its effect on birth outcomes. Among men with MS in BC treated with a DMD prior to conception, 76% of them were exposed to a DMD within 64 days of conception of their newborn, a rate much higher than the incidence of periconceptional DMD exposure (21%) in mothers with MS residing in BC.132 This finding is not surprising as fathers with MS are not commonly advised to stop DMD use prior to conception. In contrast to large number of research initiatives and established frameworks such as the FDA pregnancy risk categories to guide recommendations for maternal medication use during pregnancy, little data is available to inform guidelines on drug use for men planning to conceive offspring. Nonetheless, there is value in researching birth outcomes following paternal use of medications because these agents can cause adverse birth outcomes by altering the genetic material or the motility and morphology of sperm, inducing abnormal gene expression in sperm or having toxic effects on the developing fetus when the medication is excreted into sperm and the father continues to have intercourse with his pregnant partner.173 Paternal DMD use in men with MS was not found to be associated with an increased risk of lower mean birth weight or gestational age in this study; exposed and unexposed newborns fathered by men with MS had growth parameters within the normal range for the general population.83 This finding is in agreement with a German study – the only other reported study of birth outcomes in MS fathers using DMDs.77 The authors of the exploratory German study recognized that their data were collected  121  via voluntary recruitment and surveys77 – an approach that is susceptible to selection and recall bias. This limitation was overcome in this present study by linking several large, comprehensive population-based databases as well as obtaining additional information on demographics, maternal social and obstetrical history. In addition, data in this study had minimal surveillance bias because they were largely generated prospectively without a priori knowledge of the research question. This study is not without limitations. The association between MS DMD use in fathers and pregnancy loss was not investigated because data on spontaneous abortions were unavailable, although men are often unaware of a pregnancy loss in their partner.174 Another limitation is that the use of other prescription and over-thecounter medications used by fathers was not accounted for in this study, but existing literature suggests that in general paternal medication use does not significantly increase the risk of adverse birth outcomes in the general population.170 Nonetheless, with new medications such as teriflunomide – a recently licensed oral DMD for MS – which has been found to have teratogenic effects in animal studies and be detectable in human sperm,45 it is important to remain vigilant about possible adverse fetal outcomes caused by paternal preconceptional and conceptional medication use.  122  CHAPTER 10 – CONCLUSIONS The overall contribution of this dissertation to knowledge in the broader discipline. 10.1  Analysis and integration of findings Although having MS still carries the prospect of an unpredictable and potentially  debilitating prognosis, it is becoming increasingly clear that MS is not associated with adverse perinatal outcomes for women with MS or the offspring of those with MS compared to the general population – albeit the rate of epidural use in multiparous women with MS is higher than that of multiparous women in the general population (Chapter 4). There is evidence that among people with MS, there was a greater likelihood of labor induction in women with greater disability (Chapter 3), decreased likelihood of epidural anesthesia in women with longer disease duration (Chapter 4) and lower mean birth weight babies fathered by men with greater disability (Chapter 8). Nonetheless, these newborns with lower mean birth weight were still within the normal range of the general population. Likewise, the use of procedures during labor/delivery is by no means compelling enough to discourage women with MS from having children. These findings add to the growing body of literature suggesting that, overall, parents with MS disease are not at greater risk for adverse perinatal outcomes compared to parents without MS. DMDs remain a key component for long-term disease management in men and women with MS. The data from BC yielded no strong evidence of an increased risk of adverse birth outcomes following IFNβ and GA exposure in either men or women with MS (Chapters 6 and 9). However, in light of the small sample sizes of available studies investigating exposure to different types of DMDs (with the largest prospective cohort 123  study having 88 cases of IFNβ exposure), a systematic review of births to women with DMD exposure was conducted (Chapter 7). This review found a potential risk for prematurity and decreased fetal growth associated with IFNβ exposure – albeit identified preterm births were close to term and growth parameters were still within the normal range for the general population.175  10.2  Significance and contribution of findings This dissertation contributes to the existing knowledge on the relationship  between MS and perinatal outcomes by examining several important yet understudied outcomes in women with MS. Studies on labor induction and augmentation (Chapter 3), obstetrical anesthesia (Chapter 4) and birth outcomes in pregnancies fathered by men with MS exposed to DMD (Chapter 9) are the first of their kind in North America. In addition, the study on birth outcomes in pregnancies fathered by men with MS (Chapter 8) is one of the first in the World. The novel linkage strategy for the MS father studies will likely be useful and applicable to investigating birth outcomes in children fathered by men with other chronic conditions. In addition, studies outside our research group did not report the association of disease duration and disability with outcomes of interest; studies in this dissertation were the first to do so. By investigating the role of these MS clinical factors, the likelihood of certain outcomes that people with more severe MS may be at greater risk for could be better evaluated; this will allow clinicians to provide MS patients with evidence-based advice on when to start a family. Lastly, studies on DMD exposure during pregnancy in mothers with MS and preconceptionally in fathers with MS could contribute to future meta-analysis.  124  10.3  Strengths and limitations of study design The studies in this dissertation have several methodological strengths that  minimize key threats to validity including bias, type I and II errors, confounders and interactions. By linking several large comprehensive population-based databases such as the BCPDR (with full provincial coverage of births in BC since 2000, including home births) and the BCMS database (patients from 4 specialized MS clinics), methodological challenges of previous studies were overcome; potential selection bias from using voluntary or self-reported surveys was eliminated.90 Population-based databases have been demonstrated to have good validity.176,177 Specifically, surveillance reports of the BCPDR have found a high concordance rate between the database registry and medical charts.178 Although data linkage using unique personal identifiers has been found to have an estimated error rate of 5-9%,179 greater accuracy is achieved when additional demographic data are used for linkage.180 Patients with MS were identified via neurologist-confirmed diagnoses rather than by a single ICD code (an unvalidated method)42 which increased the validity of studies in this dissertation and reduced the bias of selecting certain MS patients that may be preferentially identified by a single ICD code (i.e. patients with active MS disease). The data collection process can be considered reliable because researchers gathered data from medical charts generated by trained healthcare professionals using common definitions of health conditions in clinical practice as opposed to ICD codes alone (which may be prone to miscoding and misclassification if appropriate ICD codes are not selected).181,182 Recall bias was minimized because the data used were based largely  125  on prospectively generated data from office, clinic, and labour/delivery admissions.90 These data were also collected without a priori knowledge of a specific research question, effectively avoiding surveillance and reporting bias90 as well as the possibility of Type I errors (i.e. false positive findings).88 Specific to studies of DMD exposure, DMD costs are prohibitively expensive for patients with MS in BC unless they receive a prescription from an MS specialist neurologist that is eligible for government subsidies. Hence, clinical data on virtually all MS patients who used a DMD prior to 2005 (a fifth MS clinic opened in Burnaby in 2005, but is not part of the BCMS database) were captured effectively. In addition, with data available on the obstetrical history as well as demographic and clinical characteristics of study participants, many important confounders were adjusted for. Clustering effect from multiple births to the same parent and potential two-way interactions between MS and confounders have also been accounted for. Lastly, the possibility of Type II errors (i.e. false negative finding) were minimized by having sample sizes with sufficient power88 for several studies of this dissertation. Based on all these factors, there is greater confidence in the study findings of this dissertation; stronger inferences on the causal effect of MS and related clinical factors on outcomes could be made. Study limitations in this dissertation included the limited applicability of the findings to MS patients with progressive and/or severe disease as the majority of MS patients have a relapsing-onset MS. The BCMS database is estimated to capture 80% of all MS patients in BC; the exact reason for why the other 20% do not attend MS clinics remains unknown, but it has been suspected that patients with very mild (benign) or severe MS disease (i.e. bedbound or severely disabled patients) may be  126  underrepresented in this MS cohort. In addition, administrative and logistical challenges may have prevented the Burnaby clinic from formally participating in the BCMS database, potentially contributing to the missing 20% of MS patients. Despite approximately 20% of MS patients not being captured by the BCMS database, women with more severe MS may be less likely to give birth to offspring due to medical and personal reasons.174 Given that the MS is more common in Caucasians,16 which compose the majority of the BC population,183 the results of this dissertation may not be generalizable to MS populations that are not predominantly Caucasian as they often have markedly different presentations and/or disease courses.184 There were also limitations regarding the data collected in studies of this dissertation. Although it is the recognized gold standard for measuring disability, the EDSS is an imperfect measure of disability in MS with considerable intra/inter-rater variability.185 The EDSS has been criticized for giving excessive weight to the assessment of ambulation186 when other factors such as pelvic organ dysfunction or fatigue may have a larger adverse effect on perinatal outcomes. Ideally, this dissertation would have incorporated EDSS data on women with MS only at the time of delivery and men with MS at the time of conception; however, since disability was not assessed annually or at every clinic visit for each patient, the date range was broaden to include EDSS scores within 3 years of delivery/conception in order to capture more subjects and better represent this cohort. This extended window for EDSS scores was not believed to have substantially affected the conclusions of this study as EDSS scores have been found to be fairly stable, even over a whole decade.187 When baseline characteristics between subjects with and without an EDSS score available within 3  127  years of delivery/conception were compared, subjects without an EDSS score available had a longer MS disease duration than those with an EDSS score – albeit the comparison of investigated outcomes between those with and without EDSS score was not statistically significant (see Tables A.3.1, A.4.1, A.4.2, A.8.1, Appendices). Although it is unclear why some MS patients did not have an EDSS score recorded, it is possible that some of these patients had not yet been diagnosed with MS at the time of delivery or conception. Of MS subjects with EDSS scores available, approximately 80% had an EDSS of 3.0 or less (i.e. mild disability), limiting the applicability of findings for subjects with more severe disability. In addition, studies in this dissertation did not examine the association between perinatal outcomes and relapse activity because data on relapse are not collected prospectively, which could influence the accuracy to identifying a relapse that occurred before conception, during pregnancy or in the postpartum period. However, EDSS scores were collected prospectively and could be used as an alternative measure for inferring disease severity. Compared to existing studies, studies in this dissertation have included considerably more demographic and clinical characteristics of subjects. However, there were still unmeasured or difficult to ascertain paternal and maternal demographic and clinical characteristics that were not captured. The MS father studies lack data on paternal factors including paternal ethnic origin, height, paternal birth weight and the degree of paternal involvement during pregnancy, which are known to influence birth outcomes.65,66 In addition, no data was available on whether the pregnancy was intended or not;65,75 it is known that planned pregnancies are associated with fewer adverse pregnancy outcomes (potentially due to increased parental precaution  128  regarding recreational substance use, better nutrition, as well as better management of comorbid medical conditions).75 Furthermore, other than maternal hypertension, diabetes, and obesity (considered in studies of this dissertation), there were comorbidities in MS mothers and fathers that may have been confounders in the analysis of birth outcomes. Data from population-based studies suggest that some diseases including epilepsy, migraines, irritable bowel syndrome, systemic lupus erythematosus, depression, anemia, and rheumatoid arthritis are more prevalent among individuals with MS compared to the general population.70,188 For pregnant mothers with MS, comorbid lupus may increase the risk of preeclampsia, preterm birth, and fetal growth restriction and maternal epilepsy is associated with an increased risk of seizures during pregnancy.189 A potential solution to identify parental comorbidities is to further link existing population-based databases with medical service databases that contain ICD codes. Lastly, some characteristics may have been underreported for different reasons; data on the use of cigarettes, alcohol and drug during pregnancy are selfreported, which may be influenced by social stigma. In addition, documentation on the number of antenatal visits may be unclear in medical charts or lost during transfer of care. Congenital anomalies were identified in the BCPDR only during a newborn’s stay in acute care, transfer or readmission episode. Given that previous studies of in utero exposure to IFNβ revealed a potentially higher risk of spontaneous abortion,120,121 this dissertation would have been even more clinically useful if it was possible to analyze the risk of spontaneous abortions associated with DMD exposure. The BCPDR contained data on births of ≥20 weeks gestational age or newborns with birth weight ≥500 grams, preventing the potential  129  identification of many cases of spontaneous abortion which, by definition, is <20 weeks gestational age.190 In addition, no data were available on spontaneous and therapeutic abortions, which have important implications for the analysis of congenital malformations. Given that embryos and fetuses that were spontaneously aborted often have genetic and/or structural defects,190 this dissertation may have underestimated the true risk of congenital anomalies associated with parental MS disease or DMD use. In addition, while significant effort was made to make the research questions in this dissertation as clinically relevant as possible, the available sample size prevented us from investigating the most clinically meaningful outcomes; for instance, in the MS father and DMD studies, mean birth weight and mean gestational age were chosen as outcomes despite low birth weight (<2500 grams) and preterm birth (gestational age <37 weeks) being more clinically important; low birth weight and preterm birth are strongly associated with an increased risk of perinatal morbidity and mortality.59 Lastly, a limitation common to epidemiological studies is that even if an association is found between MS and the outcome, the identified association might not be causal. Classifying births to mother and fathers with MS as being exposed or unexposed was challenging due to the uncertainty regarding the bioavailability and pharmacodynamics properties of DMDs. It is possible that even when a DMD is discontinued, the biological actions of the drug may persist for weeks to months afterwards156 and still exert harmful effects on the fetus. Arbitrary washout periods were incorporated in the studies of DMD exposure based on best available evidence. Furthermore, patients may become non-adherent to their prescribed DMDs,191 something that further complicates the accurate identification of DMD exposed and  130  unexposed births. For studies in this dissertation, extensive chart reviews have been performed to validate drug start and stop dates. However, women with MS may be taking medications including corticosteroids for MS relapses, baclofen or tizanidine for spasticity, as well as modafinil or amantadine for fatigue.192 They may also be taking medications for non-MS comorbidities including antidepressants for depressive disorders as well as analgesics for migraines, all which could potentially adversely affect the fetus.150 A potential solution to identify DMD adherence and non-DMD medication use is to further link existing population databases with a national or regional drug use, which contains records of dispensed prescription drugs used in outpatient settings; however, such databases do not confirm actual medication administration or capture non-prescription medication use. Moreover, when investigating drug exposure in fathers, only mothers have FDA recommendations regarding the potential harm of in utero drug exposure; no corresponding recommendations exist for men. Hence, it may be difficult to control for the wide array of drugs taken by fathers, although one population-based study did not find paternal drug use to be associated with adverse birth outcomes.170 There exists the possibility that a small proportion of newborns may have been linked to non-biological fathers as the birth records in the BC Vital Statistics Birth Registry does not distinguish between biological and non-biological fathers. However, according to a recent meta-analysis, the non-paternity rate is estimated to be 2-3% in the Western World;172 Furthermore, even if the linked individual is not the biological father, non-genetic paternal characteristics can have a substantial effect on birth outcomes; paternal family involvement has a positive influence on the likelihood of  131  mother and fetus receiving prenatal care while paternal smoking and lack of paternal financial support are associated with adverse birth outcomes.76 Even without a biological relationship, there is value to investigating at newborns fathered by men with MS.  10.4  Potential applications and future directions Although people with MS do not have an increased risk of outcomes examined in  this dissertation compared to the general population, there is evidence that those with greater disease severity (disease duration and disability) have a higher likelihood of experiencing certain outcomes. Healthcare providers are encouraged to consider each pregnancy in people with MS on a case-by-case basis to ensure optimum care throughout pregnancy, delivery and the postpartum period. Women with MS planning to conceive are still advised to discontinue DMD use, in consultation with their health care providers, to minimize potential adverse effects from in utero DMD exposure. The potential adverse effects of exposure to DMDs, especially ones that have only recently been approved for MS such as fingolimod and teriflunomide, remain largely unknown. However, mitoxantrone and terflunomide aside, accidental exposure to other DMD does not strongly warrant the consideration of pregnancy termination. In addition, for people with MS, the optimal period to discontinue specific DMDs prior to conceiving offspring is unknown. Stopping DMD therapy too early could potentially increase the risk of relapse; however, remaining on DMD therapy too close to conception increases the risk of in utero exposure. Future studies should investigate the optimal period prior to conception that DMDs can be safely discontinued.  132  More data are needed to ascertain the risk of rarer outcomes such as specific congenital anomalies with in utero exposure to virtually all DMDs. Comprehensive postmarketing surveillance efforts, likely requiring multicentre cooperation, should be pursued to assess the safety of newer agents and the longer-term outcomes in offspring exposed to DMDs. Although there exist databases in Europe such as the Danish MS Treatment Registry193 and the Danish Medical Birth Registry194 which if combined with data from BC could strengthen findings; however, linking fathers to their offspring is not a straightforward process and usually involves linkage of multiple registries similar to the BC Vital Statistics Birth Registry. DNA testing is an objective alternative approach to confirm biological relationships between father and their offspring. The linkage strategy involving multiple population-based databases in the study of fathers with MS could be a model for investigating birth outcomes in men with other chronic diseases. In addition, future studies should strive to take into account important maternal and paternal confounders not commonly adjusted for in existing studies. Biological factors such as maternal and paternal birth weight and body measurements are relevant to include in future studies. Maternal and paternal ethnicity, socioeconomic status, comorbidities, substance use, and medication should also be considered. The degree of paternal involvement in the pregnancy as well as the intentional or accidental nature of the pregnancy should also be accounted for. Increased surveillance for pregnancy loss are critical in future studies, especially those investigating the effects of parental disease or parental medication use. It is encouraging to find growing recognition of longer-term developmental and behavioral outcomes in DMD-exposed newborns in recent studies of maternal DMD  133  exposure;113,114,122 future research should continue to include these outcomes in order to provide a comprehensive investigation of potential adverse effects associated with in utero drug exposures.  134  BIBLIOGRAPHY 1. Hassan-Smith G, Douglas MR. Epidemiology and diagnosis of multiple sclerosis. Br J Hosp Med (Lond) 2011;72(10):M146-151. 2. Conway D, Cohen JA. 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New York, USA: The McGraw-Hill Companies, Inc., 2010.  154  191. Caon C, Saunders C, Smrtka J et al. Injectable disease-modifying therapy for relapsing-remitting multiple sclerosis: A review of adherence data. J Neurosci Nurs 2010;42(5 Suppl):S5-9. 192. Calabresi PA. Diagnosis and management of multiple sclerosis. Am Fam Physician 2004;70(10):1935-1944. 193. Hurwitz BJ. Analysis of current multiple sclerosis registries. Neurology 2011;76(1 Suppl 1):S7-13. 194. Knudsen LB, Olsen J. The Danish medical birth registry. Dan Med Bull 1998;45(3):320-323. 195. International Liaison Committee on Resuscitation. Instructions for completion of the C2010 evidence evaluation worksheet [online]. Available at: www.heart.org/idc/groups/heartpublic/@wcm/@private/@ecc/documents/downloadable/ucm_308196.pdf (accessed 19 Sep 2012).  155  APPENDICES Table A.1.1. Kurtzke Expanded Disability Status Scale.6 Score Definition 0 Normal Neurological Exam 1.0 No disability, minimal signs on 1 FS 1.5 No disability, minimal signs on 2 of 7 FS 2.0 Minimal disability in 1 of 7 FS 2.5 Minimal disability in 2 FS 3.0 Moderate disability in 1 FS; or mild disability in 3 - 4 FS, though fully ambulatory 3.5 Fully ambulatory but with moderate disability in 1 FS and mild disability in 1 or 2 FS; or moderate disability in 2 FS; or mild disability in 5 FS 4.0 Fully ambulatory without aid, up and about 12hrs a day despite relatively severe disability. Able to walk without aid 500 meters 4.5 Fully ambulatory without aid, up and about much of day, able to work a full day, may otherwise have some limitations of full activity or require minimal assistance. Relatively severe disability. Able to walk without aid 300 meters 5.0 Ambulatory without aid for about 200 meters. Disability impairs full daily activities 5.5 Ambulatory for 100 meters, disability precludes full daily activities 6.0 Intermittent or unilateral constant assistance (cane, crutch or brace) required to walk 100 meters with or without resting 6.5 Constant bilateral support (cane, crutch or braces) required to walk 20 meters without resting 7.0 Unable to walk beyond 5 meters even with aid, essentially restricted to wheelchair, wheels self, transfers alone; active in wheelchair about 12 hours a day 7.5 Unable to take more than a few steps, restricted to wheelchair, may need aid to transfer; wheels self, but may require motorized chair for full day's activities 8.0 Essentially restricted to bed, chair, or wheelchair, but may be out of bed much of day; retains self care functions, generally effective use of arms 8.5 Essentially restricted to bed much of day, some effective use of arms, retains some self care functions 9.0 Helpless bed patient, can communicate and eat 9.5 Unable to communicate effectively or eat/swallow 10.0 Death due to MS FS, functional system; MS, multiple sclerosis Adapted from Kurtzke JF. Rating Neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33(11):1444-1452.  156  Table A.1.2. FDA pregnancy risk categories.50 Category Definition A No fetal risk in all trimesters of adequate, well-controlled human studies B No fetal risk in animal studies, but no adequate, well-controlled human studies C Fetal risk in animal studies and no adequate, well-controlled human studies D Fetal risk in human studies X Fetal abnormalities in animal/human studies; risk outweighs potential benefits FDA, Food and Drug Administration Adapted from US FDA. Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling. [online] Availabe at: www.gpo.gov/fdsys/pkg/FR-2008-05-29/pdf/E8-11806.pdf (accessed Sep 19 2012).  157  Table A.3.1. Baseline characteristics of MS mothers with EDSS scores available and unavailable closest to the time of delivery (±3 years) for attempted vaginal deliveries. Mothers with MS Births to mothers with MS Unavailable Available p value Unavailable Available p value n=84 n=206 n=119 n=262 Disease duration at delivery – years 0.01 0.18 n 76 203 108 256 Median (range) 7.3 (<1-28) 6.1 (<1-21) 8.5 (<1-28) 6.8 (<1-21) Maternal age – years 0.59 0.84 Median (range) 32 (22-41) 32 (19-44) 32 (22-44) 32 (19-44) Nullipara 0.49 0.13 n (%) 54 (64) 141 (68) 54 (45) 141 (54) Labor induction 0.58 0.93 n (%) 23 (27) 50 (24) 29 (24) 65 (25) Labor Augmentation 0.67 0.81 n (%) 30 (36) 79 (38) 47 (39) 100 (38) MS, multiple sclerosis; EDSS, Expanded Disability Status Scale  158  Table A.4.1. Baseline characteristics of MS mothers with EDSS scores available and unavailable closest to the time of delivery (±3 years) for all births. Mothers with MS Births to mothers with MS Unavailable Available p value Unavailable Available p value n=69 n=252 n=102 n=330 Disease duration at delivery – years 0.05 0.001 n 61 248 91 323 Median (range) 8.5 (<1-21) 6.0 (<1-28) 9.6 (<1-21) 6.8 (<1-28) Maternal age – years 0.41 0.16 Median (range) 32 (22-41) 32 (19-44) 33 (22-44) 32 (19-44) Nullipara 0.26 0.06 n (%) 41 (59) 168 (67) 41 (40) 168 (51) Epidural anesthesia 0.23 0.26 n (%) 17 (25) 81 (32) 23 (23) 93 (28) Maternal hospitalization – hours 0.54 0.56 n 69 250 102 327 Median (range) 53.8 (2-184) 57.5 (2-361) 48.5 (2-184) 51.9 (2-361) Newborn hospitalization – hours 0.42 0.44 n 69 250 101 327 Median (range) 53.8 (2-481) 58.8 (<1-973) 48.7 (2-481) 53.7 (<1-973) MS, multiple sclerosis; EDSS, Expanded Disability Status Scale  159  Table A.4.2. Baseline characteristics of MS mothers with EDSS scores available and unavailable closest to the time of delivery (±3 years) for cesarean deliveries. Mothers with MS Births to mothers with MS Unavailable Available p value Unavailable Available p value n=29 n=68 n=43 n=85 Disease duration at delivery – years 0.04 0.001 n 28 67 41 84 Median (range) 9.5 (1-18) 5.8 (<1-21) 10 (1-18) 6.5 (<1-21) Maternal age – years 0.31 0.16 Median (range) 35 (24-41) 33 (23-42) 35 (24-42) 33 (23-42) Nullipara 0.34 0.09 n (%) 19 (66) 51 (75) 19 (44) 51 (60) Spinal anesthesia 0.41 0.18 n (%) 18 (66) 36 (53) 31 (72) 51 (60) MS, multiple sclerosis; EDSS, Expanded Disability Status Scale  160  Table A.7.1. Level of evidence for studies.195 Level of Definitions Evidence 1 Randomized clinical trials or meta-analyses of multiple clinical trials with substantial treatment effects 2 Randomized clinical trials with smaller or less significant treatment effects 3 Prospective, controlled, non-randomized, cohort studies 4 Historic, non-randomized, cohort or case-control studies 5 Case-series: patients compiled in serial fashion, lacking a control group 6 Animal studies or mechanical model studies 7 Extrapolations from existing data collected for other purposes, theoretical analyses 8 Rational conjecture (common sense); common practices accepted before evidence-based guidelines  161  Table A.7.2. Quality of evidence for studies.195 Component of Design & Methods Study and Rating Excellent Highly appropriate sample or model, randomized, proper controls AND Outstanding accuracy, precision, and data collection in its class Good Highly appropriate sample or model, randomized, proper controls OR Outstanding accuracy, precision, and data collection in its class Fair Adequate, design, but possibly biased OR Adequate under the circumstances Poor Small or clearly biased population or model Weakly defensible in its class, limited data or measures Unsatisfactory Anecdotal, no controls, off target end-points Not defensible in its class, insufficient data or measures  162  Table A.7.3. Class of recommendation.195 Class Clinical Definition I:  Always acceptable, safe Definitely  Definitely useful recommended.  Proven in both efficacy & Definitive, excellent effectiveness evidence provides  Must be used in the support. intended manner for  proper clinical indications. IIa:  Safe, acceptable Acceptable and  Clinically useful useful  Considered treatments of Good evidence choice provides support  Not yet confirmed definitively  IIb: Acceptable and useful Fair evidence provides support       Safe, acceptable Clinically useful Considered optional or alternative treatments Not yet confirmed definitively  Required Level of Evidence  One or more Level 1 studies are present (with rare exceptions)  Study results consistently positive and compelling           III: Not acceptable, not useful, may be harmful  Indeterminate       Unacceptable Not useful clinically May be harmful Research just getting started    Continuing area of research No recommendations until further research            Generally higher levels of evidence Results are consistently positive Most evidence is positive Level 1 studies are absent, or inconsistent, or lack power No evidence of harm Generally lower or intermediate levels of evidence Generally, but not consistently, positive results Most evidence is positive Level 1 studies are absent, or inconsistent, or lack power No evidence of harm No positive high level data Some studies suggest or confirm harm Minimal evidence is available Higher studies in progress Results inconsistent, contradictory Results not compelling  163  Table A.8.1. Baseline characteristics of MS fathers with EDSS scores available and unavailable closest to the time of conception (±3 years). Unavailable n=36  Fathers with MS Available n=105  Disease duration at conception – years n 35 101 Median (range) 8.4 (<1-24) 5.5 (<1-19) Paternal age – years Median (range) 34 (24-58) 34 (25-51) Neighborhood income quintile (year of conception) n 35 104 first (lowest income) – n (%) 3 (6) 23 (21) second – n (%) 9 (21) 22 (16) third – n (%) 8 (29) 22 (20) fourth – n (%) 11 (23) 20 (22) fifth (highest income) – n (%) 4 (21) 17 (19) Birth weight – grams Median (range) 3,338 (1,500-4,795) 3,483 (1,492-4,704) Gestational age – weeks Median (range) 39 (30-42) 39 (29-43) MS, multiple sclerosis; EDSS, Expanded Disability Status Scale  p value 0.04  0.31 0.29  0.14 0.90  Births fathered by men with MS Unavailable Available p value n=54 n=148 0.002 52 144 8.6 (<1-26) 6.1 (<1-25) 0.06 35 (24-58) 34 (25-54) 0.46 53 145 7 (13) 30 (21) 12 (23) 27 (19) 15 (28) 30 (21) 13 (25) 32 (22) 6 (11) 26 (18) 0.41 3,445 (1,500-4,795) 3,505 (1,492-4,996) 0.62 39 (30-42) 39 (29-43)  164  Table A.9.1. Birth outcomes of newborns with IFNβ-exposed, GA-exposed and unexposed (excluding previously treated) relapsing-onset MS fathers.a Factor  n  Mean ± SD Median (range)  Unadjusted β  Birth weight – grams Unexposedc 117 IFNβ-exposedd  41  GA-exposedd  18  3,524 ± 559 3,465 (1,726-4,996) 3442 ± 592 3,574 (1,492-4,680) 3,483 ± 347 3,503 (2,882-4,230)  95% CI  p value  Reference  Adjusted for Clustering and Confounding Effectsb β 95% CI p value Reference  -81.3  -275.3 – 112.8  0.41  -178.6  -464.5 – 107.2  0.22  -40.7  -311.4 – 230.1  0.77  -24.1  -284.3 – 236.2  0.86  Gestational age – weeks Unexposedc 117  39.2 ± 1.6 Reference Reference 39 (30-42) IFNβ-exposedd 41 38.6 ± 2.1 -0.65 -1.26 – -0.05 0.04 -0.87 -1.85 – 0.11 0.08 39 (29-42) GA-exposedd 18 39.1 ± 1.4 -0.10 -0.95 – 0.74 0.81 -0.23 -1.08 – 0.62 0.60 39 (37-43) IFNβ, interferon-beta; GA, glatiramer acetate; MS, multiple sclerosis; SD, standard deviation; β, regression coefficient; CI, confidence interval a 8 men had children belonging to different DMD groups during the study period: 6 men had 1 DMD unexposed and 1 IFNβ-exposed births; 1 man had 1 DMD unexposed and 1 GA-exposed births; 1 man had 1 DMD unexposed and 2 GAexposed births b adjustments: sex of the newborn and duration of DMD use before conception c births fathered by men with relapsing-onset MS (including secondary progressive MS) who never used a DMD before conception d births fathered by men with relapsing-onset MS (including secondary progressive MS) who were exposed within 64 days prior to conception  165  Table A.9.2. Birth outcomes of newborns with IFNβ-exposed, GA-exposed and unexposed relapsing-remitting MS fathers.a Factor  n  Mean ± SD Median (range)  Unadjusted β  Birth weight – grams Unexposedc 131 IFNβ-exposedd  39  GA-exposedd  18  3,527 ± 524 3,485 (1,726-4,996) 3,467 ± 597 3,617 (1,492-4,680) 3,483 ± 347 3,503 (2,882-4,230)  95% CI  p value  Reference  Adjusted for Clustering and Confounding Effectsb β 95% CI p value Reference  -59.9  -246.6 – 126.8  0.53  -102.1  -355.8 – 151.7  0.43  -44.2  -301.4 – 213.1  0.74  10.9  -232.7 – 254.5  0.93  Gestational age – weeks Unexposedc 131  39.2 ± 1.6 Reference Reference 39 (30-42) IFNβ-exposedd 39 38.7 ± 2.1 -0.44 -1.03 – 0.15 0.15 -0.36 -1.26 – 0.55 0.44 39 (29-42) GA-exposedd 18 39.1 ± 1.4 -0.02 -0.83 – 0.80 0.96 0.08 -0.71 – 0.86 0.84 39 (37-43) IFNβ, interferon-beta; GA, glatiramer acetate; MS, multiple sclerosis; SD, standard deviation; β, regression coefficient; CI, confidence interval a 10 men had children belonging to different DMD groups during the study period: 8 men had 1 DMD unexposed and 1 IFNβ-exposed births; 1 man had 1 DMD unexposed and 1 GA-exposed births; 1 man had 1 DMD unexposed and 2 GAexposed births b adjustments: sex of the newborn and duration of DMD use at conception c births fathered by relapsing-remitting MS men who never used a DMD before conception or previously treated with a DMD but stopped 64 days prior to conception d births fathered by relapsing-remitting MS men who were exposed within 64 days prior to conception  166  Figure A.2. Formulae used for sample size calculation in univariate analyses.88  167  

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