SYSTEMATIC REVIEW published: 31 January 2022 doi: 10.3389/fneur.2021.812147 Women’s Health in Multiple Sclerosis: A Scoping Review Lindsay Ross 1 , Huah Shin Ng 2 , Julia O’Mahony 3 , Maria Pia Amato 4,5 , Jeffrey A. Cohen 1 , Mary Pat Harnegie 6 , Kerstin Hellwig 7 , Mar Tintore 8 , Sandra Vukusic 9,10,11 and Ruth Ann Marrie 3,12* on behalf of the International Advisory Committee on Clinical Trials in MS 1 Department of Neurology, Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States, 2 Division of Neurology and the Djavad Mowafaghian Centre for Brain Health, Department of Medicine, University of British Columbia, Vancouver, BC, Canada, 3 Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada, 4 Department Neurofarba, Section of Neurosciences, University of Florence, Florence, Italy, 5 Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione Don Carlo Gnocchi, Florence, Italy, 6 Cleveland Clinic, Cleveland, OH, United States, 7 Department of Neurology, Ruhr University, Bochum, Germany, 8 Multiple Sclerosis Centre of Catalonia, Department of Neurology-Neuroimmunology, Hospital Universitari Vall d’Hebron, Universitat Autonoma de Barcelona, Universitat de Vic - Universitat Central de Catalunya, Barcelona, Spain, 9 Service de Neurologie A et Fondation Eugène Devic EDMUS pour la Sclérose en Plaques, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon, France, 10 Centre des Neurosciences de Lyon, INSERM 1028 et CNRS UMR5292, Observatoire Français de la Sclérose en Plaques, Lyon, France, 11 Université Claude Bernard Lyon 1, Villeurbanne, France, 12 Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada Edited by: Background: Women with multiple sclerosis (MS) may face challenges related to Jodie Burton, managing reproduction, pregnancy, and menopause while simultaneously managing University of Calgary, Canada their disease. The purpose of this scoping review was to map the literature broadly Reviewed by: Patricia Coyle, related to topics relevant to women’s health in MS to inform the clinical and research Stony Brook University, United States communities about the existing types and sources of evidence and knowledge gaps. Sandra Leanne Neate, The University of Melbourne, Australia Apart from coverage of topics within the field of women’s health, we were interested in Rhonda Voskuhl, potential gaps related to geographic and racial and ethnic diversity. We also aimed to UCLA Department of Medicine, understand the degree of inclusion of women with progressive MS in this research. United States *Correspondence: Methods: We searched the EMBASE and Ovid Medline databases from 1980 until Ruth Ann Marrie November 23, 2020. We included case-control and cohort studies, clinical trials and rmarrie@hsc.mb.ca case series published in any language, conducted in women with MS, clinically isolated Specialty section: syndrome, or radiologically isolated syndrome, that addressed women’s health. Two This article was submitted to reviewers independently screened abstracts and full-text reports for study inclusion, and Multiple Sclerosis and Neuroimmunology, completed data extraction. a section of the journal Results: Of 112,106 citations screened, 1,041 underwent full-text review and Frontiers in Neurology 353 met the inclusion criteria. The number of studies regarding women’s health Received: 09 November 2021 Accepted: 15 December 2021 has increased exponentially over time. Almost half of the studies were conducted Published: 31 January 2022 (at least in part) in Europe, while 21.7% were conducted in North America; only Citation: one study was conducted in Africa. Most studies did not report the race or Ross L, Ng HS, O’Mahony J, ethnicity of their participants (n = 308, 87.2%). Among the 353 studies, 509 topics Amato MP, Cohen JA, Harnegie MP, Hellwig K, Tintore M, Vukusic S and were reported as some studies addressed more than one topic. Over one-third Marrie RA (2022) Women’s Health in of these focused on pregnancy (n = 201, 37.2%), followed by fetal/neonatal Multiple Sclerosis: A Scoping Review. Front. Neurol. 12:812147. outcomes (14.4%) and sexual dysfunction (10%). Among the 201 studies that doi: 10.3389/fneur.2021.812147 focused on pregnancy, only 51 (25.4%) included participants with progressive MS. Frontiers in Neurology | www.frontiersin.org 1 January 2022 | Volume 12 | Article 812147 Ross et al. Women’s Health in MS Conclusions: This review identifies important knowledge gaps related to women’s health in MS and particularly the need for future studies to include participants with a broader range of races and ethnicities, with progressive MS, and living in Asia-Pacific and African regions. Keywords: multiple sclerosis, scoping review, pregnancy, menopause, women’s health INTRODUCTION We report this review according to the PRISMA Extension for Scoping Reviews (12). Historically, there was a paucity of research on women’s health concerns, severely limiting the information available to women and their healthcare providers (1). More recently, there has been Identification of Relevant Literature a substantial shift, with growing support from governmental Lists of potential key words were developed by neurologists and non-governmental institutions for women’s health research specializing in MS, with expertise in epidemiology, systematic accompanied by organization structural changes and policy reviews, and women’s health in MS based on group discussion, revisions. The result has been an influx of women’s health and review of relevant systematic and scoping review search research, which is starting to fill the previous void (2). One area strategies in other chronic diseases. Subsequently, a medical where women’s health research is of particular importance is librarian (MPH) with expertise in systematic reviews and within the context of chronic disease management. scoping reviews developed the formal search strategy and Multiple sclerosis (MS) is a chronic disease of the central searched the literature for records including the concepts of nervous system affecting nearly three million people worldwide MS and women’s health. The librarian created search strategies (3). Two to three times as many women as men are affected by MS using a combination of keywords and controlled vocabulary (4, 5). Women with MS may face challenges related to managing in Ovid Medline and EMBASE for the period 1980 onward; reproduction, pregnancy, and menopause while simultaneously 1980 was chosen to coincide with the 1983 Poser criteria for managing their disease. For example, multiple physiologic MS (13) and focus the review on contemporary research of changes occur during pregnancy, including hypercoagulability, women’s health issues for persons with MS. The searches were insulin resistance, immunotolerance to the fetoplacental unit and completed on November 23, 2020 without language limits. increased plasma volume. Adaptation to these changes may be Appendix I shows the full search strategies. We also manually harder in the context of chronic disease (6). Also, numerous searched the references lists of included articles. All database disease-modifying therapies have emerged for the management search results were imported into EndnoteTM and de-duplicated of MS, but most are not recommended for use during pregnancy. before screening. Thus, women with MS must balance management of their disease with the health of the fetus. While research surrounding the experience and management of women’s health issues in MS Inclusion and Exclusion Criteria We included studies that met the following criteria: (i) case- has increased over time, women living with MS, clinicians, and control, cohort, clinical trial, and case series (14); (ii) published researchers recognize that knowledge gaps remain. in any language (studies that were not published in English We aimed to conduct a scoping review. Scoping reviews were translated using Google Translate); (iii) conducted constitute a newer form of evidence synthesis which provides an in women with MS, clinically isolated syndrome (CIS), or overview of available research evidence, in contrast to systematic radiologically isolated syndrome (RIS); and (iv) addressed one reviews which summarize evidence related to a focused question of the following women’s health topics of interest: birth control, (7). The purpose of this scoping review was to map the literature pregnancy, menstruation, breastfeeding, fertility, assisted broadly related to topics relevant to women’s health in MS to reproduction, fetal/neonatal outcomes, menopause, children’s inform the clinical and research communities about the existing health/developmental milestones, gynecologic cancer or related types and sources of evidence and knowledge gaps. Apart from screening activities/prevention, sexually transmitted infections, coverage of topics within the field of women’s health, given the sexual dysfunction, gender identity or sexual orientation, and sex relative lack of diversity in clinical trials at large (8) as well within hormones. Studies that included MS and non-MS populations the MS field (9, 10), we were particularly interested in potential were included provided that they reported results separately in gaps related to geographic and racial and ethnic diversity. We women with MS. Studies that included men and women with also aimed to understand the degree of inclusion of women with MS were included provided that they reported results separately progressive MS in this research (11). We expected that this effort in women. We excluded studies: (i) in animals or conducted would inform future research efforts and policy. in-vitro; (ii) study protocols, opinion documents, editorials, or commentaries; (iii) case reports; (iv) systematic reviews or METHODS meta-analyses; (v) limited to populations with neuromyelitis optica spectrum disorders (NMOSD) or myelin oligodendrocyte We used the methods for scoping reviews delineated by Arksey glycoprotein antibody disease (MOGAD); and (vi) limited to and O’Malley, as updated by the Joanna Briggs Institute (7). men with MS. Frontiers in Neurology | www.frontiersin.org 2 January 2022 | Volume 12 | Article 812147 Ross et al. Women’s Health in MS Study Selection and women’s health topic (see Appendix II for data extraction We used a multistep process to select the studies and conduct the tool). Three reviewers tested the data extraction tool on the first data extraction. Titles and abstracts were screened independently 30 articles, following which adjustments were made to clarify data for inclusion by pairs of team members for relevance using element descriptors or add additional options (e.g., not reported) EPPI-Reviewer software (15). Disagreements were resolved by were added for specific data elements. consensus between the two members of the pair; if consensus The focus of this scoping review was on what topics had been could not be reached a third member was engaged. Subsequently, studied and who participated in those studies. Therefore, we did the selected articles underwent full-text review for relevance by not extract information about study results or assess the quality two team members using a similar process. At each step in the of the included studies. process the reviewers used a standardized form in EPPI-Reviewer that delineated the a priori inclusion and exclusion criteria. Synthesis and Presentation of Results We summarized the literature according to the data elements Data Extraction extracted using descriptive statistics. One reviewer extracted data from the selected articles using a data collection tool implemented in Eppi-Reviewer software, and the RESULTS extraction was verified by a second reviewer. The data elements extracted included title, author (year), language, sample size, Results of Search region where the study was performed, data source, study design, The searches identified a total of 137,913 citations, of which characteristics of the study population, diagnostic criteria used, 15,807 were duplicates, resulting in 112,106 citations for review. FIGURE 1 | PRISMA flow diagram. Frontiers in Neurology | www.frontiersin.org 3 January 2022 | Volume 12 | Article 812147 Ross et al. Women’s Health in MS FIGURE 2 | Number of publications regarding women’s health in multiple sclerosis by year. Of these, 111,065 were excluded at the title/abstract review stage with MS, and 39 (11%) also included men or those with (Figure 1). Of 1,041 articles selected for full-text review, we non-binary gender identities with MS. The remaining excluded 685. We could not locate full-text articles for one. After 22 (6%) articles studied MS as well as least one other full-text review, we retained 353 articles for data extraction. disease including NMOSD, epilepsy, spinal cord injury, and headache. Study Characteristics Study sample sizes ranged from 2 to 96,937. The mean (SD) Appendix III shows details of the included studies. Consistent sample size was 466 (920) with a median of 130. Participants with our search parameters, study publication years ranged from ranged in age from 12 to 81 years. 1983 (n = 1) to 2020 (n = 45). The number of studies regarding Most studies did not report the race or ethnicity of women’s health has increased exponentially over time (model R2 their participants (n = 308, 87.2%); the races and ethnicities = 0.80, Figure 2). Nearly all studies were published in English captured among reporting studies is shown in Figure 5. The (n = 350, 99.2%); the remainder were published in Spanish (2) or proportion of studies that reported race and ethnicity was Turkish (1). Almost half of the studies were conducted (at least in higher in North America (38.4%) than in all other regions part) in Europe, while 21.7% were conducted in North America; (Australia/New Zealand: 20%, South America: 5.9%, Europe only one study was conducted in Africa (Figure 3). 5.7%, Asia 1.9%). Whereas, reporting of race and ethnicity The most common design observed was a cohort study appeared to demonstrate diversity at the study level, within (51.4%), followed by cross-sectional studies (26.8%, Figure 4). North America, where reporting of race and ethnicity was most Slightly more than half of the studies included a prospective common, we found that 90% of participants enrolled were component (n = 209, 57.3%); some studies included prospective White. While numbers or percentages of White participants and retrospective components. With respect to data sources used, were given in all studies reporting race or ethnicity, reporting the most common was primary data collection (n = 255, 66.2%), for all other groups was varied. Often race and ethnicity followed by use of a clinical registry (n = 63, 16.4%), medical reporting included “other” or “unknown categories.” As a result, records review (n = 40, 10.4%), and use of administrative data assessment of true participation from most racial and ethnic (n = 26, 6.7%); some studies used more than one data source. groups was difficult to accurately determine. Notably, there were 6 participants clearly identified as Native or Indigenous persons Study Populations and 148 Asian persons in comparison to 29,812 clearly identified Overall, 278 (78%) publications for which data were White participants. extracted focused exclusively on women with MS. An Overall, 143 (39.7%) studies did not report the criteria additional 15 (4%) focused on children born to parents used to establish the diagnosis of MS in study participants. Frontiers in Neurology | www.frontiersin.org 4 January 2022 | Volume 12 | Article 812147 Ross et al. Women’s Health in MS FIGURE 3 | Distribution of included studies by geographic region. FIGURE 5 | Racial and ethnic categories reported by study where reported (n FIGURE 4 | Types of study designs. = 45 studies). Only a small number of the studies that did not report secondary progressive MS (SPMS) (n = 88, 16.2%) and primary the diagnostic criteria used had exclusively employed progressive MS (PPMS) (n = 75, 13.8%). administrative data sources (n = 10) where such information is typically unavailable. Study Topics Most studies reported the subtype of MS that were enrolled Among the 353 studies, 509 topics were reported as some (n = 334, 94.6%). These studies frequently included participants studies addressed more than one topic. Over one-third of these with multiple subtypes of MS thus the number of subtypes focused on pregnancy (n = 201, 37.2%) (Figure 6). Studies of reported was 543. At the study level, participants most often had pregnancy often focused on more than one aspect, the most relapsing remitting MS (RRMS) (n = 215, 39.6%), followed by common subtopics of interest being relapses (24.1%), pregnancy Frontiers in Neurology | www.frontiersin.org 5 January 2022 | Volume 12 | Article 812147 Ross et al. Women’s Health in MS FIGURE 6 | Frequency of topics studied. complications (23.1%), and disease-modifying therapy exposure DISCUSSION (23.1%). Disability outcomes (14.2%) and mechanisms of pregnancy-related reductions in disease activity (8%) received In this scoping review of women’s health research in MS we less attention. The second most common topic was fetal/neonatal reviewed 353 studies fulfilling our inclusion criteria. We found outcomes (14.4%) which is closely related to the topic of an increase in the focus on women’s health research in MS pregnancy, and sexual dysfunction was the third most common over time but with variable coverage across different topics; by topic (10%). Most other topics, including menopause, birth geographic location, racial, and ethnic group; and by MS subtype. control, assisted reproduction, cancer screening, and gender Nonetheless, our findings also highlight important gaps. identity, received little attention (Figure 6). We found limited coverage of women’s health issues in MS by Among studies that enrolled individuals with progressive MS, year until around the turn of the millennium. In 2004 for the first pregnancy, fetal/neonatal outcomes and sexual dysfunction were time the number of studies relating to women’s health issues in the most common topics, similar in overall frequency. Among the MS reached 10; this rose sharply thereafter until 2020, where 45 201 studies that focused on pregnancy, only 51 (25.4%) studies studies on women’s health issues in MS were identified in a single included participants with progressive MS. Collectively, the year. This trend is consistent with recent updates specifically studies focused on pregnancy that reported number of women focused on the women’s health information available to treating and not simply number of pregnancies included 155,295 women, clinicians and persons with MS. The American College of of whom only 1,316 (0.85%) were reported to be women with Obstetricians and Gynecologists (16), Multiple Sclerosis Society progressive MS. After excluding women for whom the subtype of Canada (17), and National Multiple Sclerosis Society (18) have was not recorded, including from one large administrative data all issued updates specifically focused on women’s health in MS study (n = 96,937), 5.3% of women included in pregnancy studies and MS Australia has become a sponsoring partner of a national had progressive MS. Women’s Health Week (19). Ten studies assessed issues related to menopause. Of these, The current literature landscape is dominated by pregnancy- nine enrolled a total of 1,779 participants of whom 17% had related studies with one-third of reviewed studies focusing SPMS, PPMS, or progressive relapsing MS (PRMS). The last on pregnancy and one in seven focusing on fetal/neonatal study enrolled 148 participants and it was uncertain if they had outcomes. Perhaps this observation is unsurprising given RRMS or SPMS. Figure 7 details inclusion at the study level of the pivotal social importance of pregnancy in a woman’s life participants with each disease subtype for all topic areas. and the established intersection with the healthcare system Frontiers in Neurology | www.frontiersin.org 6 January 2022 | Volume 12 | Article 812147 Ross et al. Women’s Health in MS FIGURE 7 | Frequency of study topics according to type of multiple sclerosis. for pregnancy (20). Additionally, the typical onset of MS large topic area. While menopause tends to hold less perceived during childbearing years (11), disproportionate likelihood social importance, 94% of women in the general population to affect women (4, 5), and changes in disease course during experience menopause symptoms, and 63% of those women and after pregnancy (21) lead to a wide range questions to feel that their symptoms would benefit from medical care researchers surrounding the topic. Correspondingly, we saw (25). However only three studies were identified relating to that all pregnancy subtopics of interest received attention with menopause and symptoms in women with MS. Moreover, more than 10 studies touching on each subtopic. Despite this despite the growing recognition of the importance of hormonal attention, gaps remain surrounding pregnancy for women influences in MS, the impact of menopause, use of hormone with MS. Particularly, consistent with the lack of inclusion replacement therapies, as well as hormonal therapies unrelated of pregnant women in clinical trials in general (22), pregnant to menopause on relapses, disability, and MRI outcomes women with MS were excluded from the recent clinical trials in MS remains understudied (26, 27). There remains an of new disease-modifying therapies (DMTs) (23, 24). Further, opportunity to further the understanding of interactions of observational information surrounding use of DMTs approved MS and menopause to help guide women with MS and in the period 2017 to date in pregnancy, including ocrelizumab, provide additional insights about hormonal influences in MS ofatumumab, cladribine, diroximel fumarate, siponimod, and at large. other spingosine-1-phosphate receptor modulators (ozanimod, Many other women’s health topics also received little attention ponesimod) remains limited. The exclusion of pregnant and over the review period with nine topic areas having fewer breastfeeding women from clinical trials, while customary in than 15 relevant studies. While all these topics merit additional situations where there are prominent concerns for teratogenicity, attention, we will briefly note three here. First, many women continues to limit the type of evidence and timing of available with MS are encouraged to use contraception because numerous information to clinicians and persons with MS surrounding DMTs and symptomatic agents potentially pose fetal harm. pregnancy and breastfeeding. Additionally, 48% of reproductive age women worldwide use Conversely, given that women with MS have a long contraception (28). Yet, only 10 studies were identified evaluating life expectancy, menopause—a health topic that all women birth control in women with MS. Second, more than 5 million encounter if they live long enough—has received surprisingly children have been born following assisted reproduction (29), little attention, with just 10 studies identified covering this including up to 5% of all children in some countries (30). Frontiers in Neurology | www.frontiersin.org 7 January 2022 | Volume 12 | Article 812147 Ross et al. Women’s Health in MS However, persons with MS and clinicians must make decisions having access to natalizumab (44). The field needs further about the growing availability of assisted reproduction with studies with participants outside of North America and Europe limited data. Third, there is a rising incidence of breast cancer to help understand potential regional differences in women’s globally (31), and cancers are of increasing concern in MS health issues in MS, and to support the development of as cancer risks may increase during treatment with strong health care policies and services that meet the needs in immunosuppressive therapies are used (32). However, relatively each region. little attention has been focused on addressing disparities and Most studies focused on relapsing remitting MS. Studies barriers related to screening for breast and cervical cancers, that included participants with progressive MS were clustered which are recognized in the general population (33) as well predominantly in two topics, pregnancy and sexual dysfunction. as those related to physical impairments. It is important to Even among the studies that focused on menopause, which understand more about how persons with MS are affected by typically occurs around age 50 years, by which age when a higher breast and gynecological cancer as well as their participation and proportion of women with MS will have progressive MS than experience with screening. at earlier ages, fewer than one in five participants enrolled had In the last decade there have been changes reported in progressive MS. Additional focus on the women’s health issues the demographics of persons with MS worldwide (34–36). for patients with progressive MS is needed. There is known clinical variability in MS across racial and The field has also largely not examined women’s health ethnic groups including differences in age of onset of disease, issues among women with MS who are lesbian, bisexual, and/or environmental and genetic risk factors, disease severity and transgender. In the general population, lesbians are known to progression, and health outcomes (37). Additionally, there is be less likely to receive cancer preventive services (45, 46) and established variability in women’s health issues by race and transgender women are at higher risk of sexually transmitted ethnicity including in age of pubertal onset, outcomes with infections (47). Given the potential additional risks of malignancy assisted reproduction, perimenopausal symptoms, hormonal and infections with some DMTs (32), understanding how these changes through menopause (38), and incidence and time and other women’s health issues affect persons with MS who have to diagnosis and treatment of cervical cancer (39). Despite a non-binary gender identities and those with non-heterosexual the importance of understanding the effects of race and orientation is vital to adequately advise these individuals. ethnicity on health outcomes, the generalizability of the current Our review has several limitations. First, although scoping literature across diverse racial and ethnic groups remains reviews typically include a broader spectrum of evidence such as largely unknown since 87% of studies did not report these from electronic databases and gray literature (that is, information data. Most studies reporting racial and ethnic participant data produced outside traditional publishing routes), we limited this were conducted in North America and it is unlikely that search to electronic databases and peer-reviewed journal articles this generalizes globally given geographic differences in racial given the enormity of the search conducted. Next, we did and ethnic distribution. Even within North America study not include single case reports which might be informative findings cannot be well-extrapolated beyond the community for issues such as adverse effects related to drug exposure in self-identifying as White given that 9 out of 10 participants pregnancy, since our goal was to broadly identify research gaps. in reporting studies identified as White. This mirrors the Articles published prior to 1980 were not reviewed, as our inadequate representation of minority racial and ethnic groups focus was to evaluate the scope of contemporary knowledge of reported in recent clinical trials of DMT (23, 40–42). Race women’s health issues for persons with MS. Additionally, while and ethnicity are social constructs without biologic meaning, animal and in vitro studies may provide important insights into but they intersect with social determinants of health and mechanistic issues underlying women’s health concerns these inequities associated with health outcomes. It is imperative were not reviewed as we aimed to delineate the landscape of that the field reports the racial and ethnic characteristics clinical knowledge as presently established in persons with MS. of study participants, and addresses barriers to enrollment Finally, there are other issues relevant to women living with of underrepresented groups so that we can understand MS that we did not consider in our review such as domestic differences across these groups, clarify generalizability, and violence particularly in the context of women with physical or reduce health disparities. cognitive impairments. Another threat to generalizability is the limited number of Although the number of studies regarding women’s health studies including participants from outside of North America in MS has increased exponentially over time, greater than and Europe; only one study included participants from Africa. one-third of these studies focused on pregnancy. This review Women’s health issues vary by geographic region. For example, also identifies important knowledge gaps related to women’s the incidence of breast cancer in Australia and New Zealand health in MS. Future studies are needed that focus more is 94 cases per 1,000,000 female population but is substantially on understudied topics such as menopause, sex hormones lower, at 26 cases per 100,000 female population, in Middle and cancer screening. All studies addressing women’s health Africa (43). Furthermore, the evaluation and treatment of should seek to include participants with a broader range of MS differs globally. One illustration of these differences is races and ethnicities, with progressive MS, and to clearly that 82% of high income countries reported patients having report these participant characteristics. Studies are also needed access to natalizumab whereas only 10% of lower middle that include individuals with MS living in Asia-Pacific and income and 0% of low income countries reported patients African regions. Frontiers in Neurology | www.frontiersin.org 8 January 2022 | Volume 12 | Article 812147 Ross et al. Women’s Health in MS DATA AVAILABILITY STATEMENT University Amsterdam), Jeremy Chataway (University College London), Tanuja Chitnis (Brigham and Women’s Hospital), The original contributions presented in the study are included Timothy Coetzee (National MS Society), Giancarlo Comi in the article/Supplementary Material, further inquiries can be (University Vita-Salute San Raffaele), Jorge Correale (Raul directed to the corresponding author. Carrea Institute for Neurological Research), Tobias Derfuss (University Basel), Marcia Finlayson (Queen’s University), AUTHOR CONTRIBUTIONS Ari Green (University of California at San Francisco), Myla Goldman (Virginia Commonwealth University), KH (Ruhr LR, HN, JO’M, MA, JC, KH, MT, SV, and RM conceived of the University), Daphne Kos (University of Leuven), RM (University study, developed the protocol, and selected studies for review. of Manitoba), Aaron Miller (Mount Sinai School of Medicine), MH developed the search strategies and conducted the search. Xavier Montalban (Vall d’Hebron University Hospital), LR, HN, JO’M, and RM extracted the study data. LR and RM Ellen Mowry (Johns Hopkins University), Jiwon Oh (St. drafted the manuscript. LR, HN, JO’M, MA, JC, KH, MT, SV, Michael’s Hospital), Daniel Reich (NIH-National Institute of MH, and RM revised the manuscript and approved the final Neurological Disorders and Stroke), Amber Salter (University version. All authors contributed to the article and approved the of Texas Southwestern), Maria Pia Sormani (University of submitted version. Genoa), Alan J Thompson (University College London), MT (Vall d’Hebron University Hospital), Helen Tremlett FUNDING (University of British Columbia), Anneke van der Walt (Monash University), SV (Hopital Neurologique Pierre Werthemier— LR was supported by a Sylvia Lawry Fellowship Grant ID#: FP- GHE), Emmanuelle Waubant (University of California 190634172 from the National MS Society. RM was supported by San Francisco). the Waugh Family Chair in Multiple Sclerosis and by Research Manitoba. The International Advisory Committee on Clinical Trials in MS is sponsored by the European Committee for SUPPLEMENTARY MATERIAL Treatments and Research in MS and the National Multiple The Supplementary Material for this article can be found Sclerosis Society. online at: https://www.frontiersin.org/articles/10.3389/fneur. 2021.812147/full#supplementary-material ACKNOWLEDGMENTS Appendix I | Search strategies. Women’s health and multiple sclerosis (ovid medline)-1980-2021. Members of the International Advisory Committee on Clinical Appendix II | Data extraction [standard]. Trials in MS include MA (University of Florence), Brenda Banwell (University of Pennsylvania), Frederik Barkhof (VU Appendix III | Characteristics of studies included in the scoping review. REFERENCES 9. Mateen FJ. Is It Time for quotas to achieve racial and ethnic representation in multiple sclerosis trials? Front Neurol. (2021) 12:751. 1. Kirschstein RL, Merritt DH. Women’s Health. 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Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi speaker honoraria from Biogen, Merck, Sanofi Genzyme, Roche, Novartis and G, et al. Ocrelizumab versus placebo in primary progressive multiple Teva; received research grants for her Institution from Biogen, Merck, Sanofi sclerosis. N Engl J Med. (2017) 376:209–20. doi: 10.1056/NEJMoa16 Genzyme, Novartis and Roche. She is co-editor of the Multiple Sclerosis Journal. 06468 JC received personal compensation for consulting for Biogen, Bristol-Myers 33. Buskwofie A, David-West G, Clare CA. A review of cervical cancer: Squibb, Convelo, Genentech, Janssen, NervGen, Novartis, and PSI; speaking for incidence and disparities. J Natl Med Assoc. (2020) 112:229–32. H3 Communications; and serving as an Editor of Multiple Sclerosis Journal. KH doi: 10.1016/j.jnma.2020.03.002 received personal compensation as a speaker for Biogen, Bristol-Myers Squibb, 34. Langer-Gould A, Brara SM, Beaber BE, Zhang JL. Incidence of multiple Roche, Teva, Novartis, Bayer, Sanofi-Genzyme and Merck. She receives currently sclerosis in multiple racial and ethnic groups. Neurology. (2013) 80:1734–9. funding by the Innovationsfonds, the national MS society, Biogen, Teva, Novartis, doi: 10.1212/WNL.0b013e3182918cc2 Roche, Sanofi-Genzyme and Merck. MT has received compensation for consulting 35. Lee JD, Guimond C, Yee IM, Vilariño-Güell C, Wu ZY, Traboulsee AL, et al. services, speaking honoraria and research support from Almirall, Bayer Schering Incidence of multiple sclerosis and related disorders in Asian populations of Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi- British Columbia. Can J Neurol Sci Le J Can des Sci Neurol. (2015) 42:235–41. Aventis, Viela Bio and Teva Pharmaceuticals. SV received consulting and lecture doi: 10.1017/cjn.2015.36 fees, travel grants and research support from Biogen, Celgène/BMS, Novartis, 36. Chinea A, Ríos-Bedoya CF, Vicente I, Rubí C, García G, Rivera A, et al. Merck, Roche, Sanofi Genzyme and Teva Pharma. RM receives research funding Increasing incidence and prevalence of multiple sclerosis in Puerto Rico from CIHR, the MS Society of Canada, the National MS Society, the Consortium (2013-2016). Neuroepidemiology. (2017) 49:106–12. doi: 10.1159/000484090 of MS Centers, the US Department of Defense, Research Manitoba and Crohn’s Frontiers in Neurology | www.frontiersin.org 10 January 2022 | Volume 12 | Article 812147 Ross et al. Women’s Health in MS and Colitis Canada. She was supported by the Waugh Family Chair in Multiple this article, or claim that may be made by its manufacturer, is not guaranteed or Sclerosis. She is a co-investigator on studies funded by Biogen Idec and Roche. endorsed by the publisher. The remaining authors declare that the research was conducted in the absence of Copyright © 2022 Ross, Ng, O’Mahony, Amato, Cohen, Harnegie, Hellwig, Tintore, any commercial or financial relationships that could be construed as a potential Vukusic and Marrie. This is an open-access article distributed under the terms conflict of interest. of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the Publisher’s Note: All claims expressed in this article are solely those of the authors copyright owner(s) are credited and that the original publication in this journal and do not necessarily represent those of their affiliated organizations, or those of is cited, in accordance with accepted academic practice. No use, distribution or the publisher, the editors and the reviewers. Any product that may be evaluated in reproduction is permitted which does not comply with these terms. Frontiers in Neurology | www.frontiersin.org 11 January 2022 | Volume 12 | Article 812147