{"paper_id":"a0e024ab-10b1-4bab-bc21-63644de8c286","body_text":"Multiple sclerosis (MS) preferentially affects women with the clinical onset usually\noccurring during the reproductive years. Historically, women with MS were advised\nagainst pregnancy. The current situation with respect to disease modifying therapies (DMTs) \n 1 \n  and revised diagnostic criteria \n 2 \n  have led to diagnosis earlier in the disease course. Thus, it appears that\nthe number of women considering reproduction has increased in many geographic regions. \n 3 \n  Family planning has now become a major topic of interest to the MS\ncommunity. 4 , 5\nThere is a recognized need for population-based MS-specific pregnancy\nregistries 6 , 7 \nand this is the goal of the “Canadian Multiple Sclerosis Pregnancy Study (CANPREG-MS)”. \n 8\nIdeally women with MS should plan pregnancies 9 , 10  but the “road to conception”\ncan be daunting and has not been systematically prospectively studied in a “real\nworld” scenario. Most women planning a pregnancy seek information from various\nsources including their neurologists, MS nurses, and social media. There are no\ndefinitive guidelines for DMT safety during pregnancy. Product information, United\nStates Food and Drug Administration (FDA) postings, pharma pregnancy registries and\ncommittee guidelines can be outdated, confusing and/or contradictory. 11 – 21  The current consensus in many\nregions is that for most DMTs, continuation during conception and gestation is\npermissible if the benefits to the mother outweigh the risks to the fetus. 9 , 10  Final decisions made by woman\nmay or may not concur with the advising source(s).\nHere we present data on Canadian women with MS who were identified as “planning a\npregnancy” as part of CANPREG-MS. \n 8 \n  The data are preliminary as the study is ongoing and sample size will\nincrease. Nevertheless, we feel that this sample of 44 women provides important real\nworld information on challenges faced by women with MS in making reproductive\ndecisions.\n\nCANPREG-MS rationale and methodology have been detailed elsewhere. \n 8 \n  Ethics approval was given by the University of British Columbia Clinical\nResearch Ethics Board and Vancouver Coastal Health Research Institute.\nCANPREG-MS was designed to include women with MS who were either pregnant or planning\na pregnancy at the time of enrollment. This paper focuses on women planning to\nconceive. Upon conception, the woman is transferred to the “pregnancy” arm of\nCANPREG-MS.\nParticipants are followed longitudinally. Data is collected through telephone\ninterviews using standardized questionnaires. A secure web-based application REDCap\n(Research Electronic Data Capture) designed exclusively to support data capture for\nresearch studies was used to develop data entry forms. \n 22 \n  Each woman’s self-reported information on MS history (MS course, DMT, etc.)\nhas been confirmed by her neurologist after she signed a “release of information” form. \n 8\nData presented here have a cut-off date of April 30, 2020. All results are truncated\nfor this date as given the size of the dataset, it is impossible to conduct analyses\nwithout a firm cut-off.\n\nForty-four women planning a pregnancy were consented and enrolled. The average age at\nthe initial interview was 31.91 years (SD = 2.96). Thirty-nine of the 44 women\n(88.64%) had European ancestry. Thirty of the 44 women (68.18%) had post-secondary\neducation, 40/44 (90.91%) were employed and 42/44 (95.45%) were in a stable\nrelationship (see  Table\n1 ).\nDemographics of women with MS with “planning pregnancy” status at initial\ninterview.\nThe average age of MS onset was 26.05 years (SD= 5.39). The average age of diagnosis\nwas 27.20 years (SD= 4.34) with 29/44 (65.91%) diagnosed within a year of clinical\nonset. The majority experienced sensory or visual symptoms at onset. See  Table 2  for clinical\ncharacteristics of this cohort.\nClinical characteristics of women with MS with “planning pregnancy” status at\ninitial interview.\na 11 participants only had Initial Interview at the cut-off\ndate.\nb 7 participants only started trying.\nReported comorbidities in these women are shown in  Table 3 . Few, other than reproductive\nconditions, affect the ability to conceive.\nComorbid diseases reported by the 44 participants.\nPhysician correspondence relevant to CANPREG-MS \n 8 \n  tend not to give recent EDSS. \n 23 \n  However, at each study interview, Patient Determined Disease Steps (PDDS)\nvalidated for MS are scored. 2 , 24 , 25  As done by others, (e.g. see 24 , 26 ) PDDS scores were classified\ninto 3 distinctive disability groups as follows: no or mild (PDDS 0-1), moderate\n(PDDS 2-3) and severe (PDDS 4 or higher).\nThirty-seven of the 44 (84.09%) had a consistent “no” or “mild” disability (PDDS= 0\nor 1) from the initial interview until the last interview before the cut-off. Seven\nentered the study with moderate disability (5 had a PDDS = 2; 2 had PDDS = 3). No\nwoman had a PDDS score ≥ 4 on enrollment.\n\nDMTs are discussed here using generic names as well as the trade name to reflect the\ninformation conveyed by participants. Physician information provided to the study\nused trade names, generic names, or both. We did not find any discrepancies between\nthe patient information and that of the neurologist with respect to any specific DMT\nusage.\nDMTs can be administered as injections, oral medications, or infusions.\nParticipant DMT treatment choice was often influenced by how the DMT is\nadministered.\nSee  Table 4  for the\nnumber of women on each DMT (or naïve to therapy) and PDDS at enrollment, pregnancy\nstatus by cut-off date and the use of assisted reproductive technology (ART). A\ntotal of 7 women used ART.\nNumber of women on each disease modifying therapy (or therapy naïve) and PDDS\nat initial interview (Total = 44), status by cut-off date of April 30, 2020,\nand the use of ART.\na Neurologist records and patient reports vary in using trade\nand generic names. This also provides clarity if there is more than 1\ntrade name for a generic (e.g. interferon beta 1-a).\nb Disability groups: No or mild – PDDS= 0,1; Moderate – PDDS=\n2,3 (see literature 24 , 25 ).\nc Number includes 1 woman who used assisted reproductive\ntechnology (ART).\nd Includes one woman lost to follow-up before cut-off date.\nTo truly reflect the information as collected, we decided to show results for DMT\nnaïve women first followed by those who have used DMTs prior to or during the period\nwhen they were planning to conceive. DMTs are listed by the number of study\nparticipants on each (see  Table 4 ).\nSix participants were DMT naïve at enrollment. Three were recently diagnosed and\nwanted to conceive as soon as possible. Over time, one newly diagnosed woman\nstopped trying to conceive because of MS severity and began her first DMT\n(ocrelizumab). At cut-off, 2 woman are still trying to conceive and 3 were able\nto conceive.\nAt study enrollment, 10 women were either on a washout or actively trying to\nconceive. Washout periods suggested by their neurologists ranged from 2 months\nto 12 months. At enrollment, one woman made the decision to remain on dimethyl\nfumarate until conception, i.e., no washout. She is currently pregnant and only\ndiscontinued dimethyl fumarate once the pregnancy was confirmed. As of the study\ncut-off date, no concerns have been raised by prenatal testing. One woman had\nplanned a 3-month washout but her MS became aggressive. She stopped trying to\nconceive and resumed the DMT. Seven women have had no or mild disability (PDDS=\n0,1) despite having stopped the DMT. Four of the 7 women achieved pregnancy\nincluding one early miscarriage before cut-off. One woman had moderate\ndisability (PDDS = 2) which has remained stable despite her being off DMT as she\nis still trying to conceive.\nSix women were on glatiramer acetate and all had no or mild disability (PDDS = 0\nor 1). Three have achieved pregnancy (one had an early miscarriage and 2 are\nstill pregnant) by the cut-off date; 2 are still trying to conceive; and one has\nstopped trying due to fertility issues. No washouts were recommended by\nneurologists but 2 women decided on their own to take the DMT “sporadically”\nwhile trying to conceive.\nFive women were on ocrelizumab at or prior to enrollment. Initial PDDS for these\nwomen were 0 (N = 2), 1 (N = 1), 2 (N = 1) and 3 (N = 1). Washout periods\nvaried. Washouts of 2 and 3 months were recommended to 2 women. One achieved\npregnancy but had an early miscarriage; and the other is pregnant at cut-off. No\ninformation on the fetus is available at this time.\nOne woman became pregnant 6 weeks after her second dose of ocrelizumab. Another\nwoman is trying to conceive after her first dose. The final woman in this cohort\nhad a six-month washout followed by 2 months of intense trying to conceive\nbefore having a second dose of ocrelizumab. At cut-off, she is pregnant, having\nconceived 8 months after her last dose.\nFive women were on alemtuzumab. Four had no or mild disability (PDDS 0,1) and one\nhad moderate disability (PDDS = 2). All had the required washout and 3 became\npregnant by cut-off. One woman is still trying to conceive. One woman was\ndiagnosed as “infertile” based on her inability to conceive but no etiology was\nknown. She and her partner decided to adopt rather than undergo in vitro\nfertilization (IVF) as suggested by her specialist.\nThree women, all with no disability (PDDS = 0), were on fingolimod. One had a\n2-month washout and the other a 3-month washout, as suggested by their\nneurologists. The third woman had stopped fingolimod and was about to start\nocrelizumab when she decided it was time to try to conceive. To date, she is off\nany DMT. No woman had a rebound relapse after stopping fingolimod.\nTwo women were on natalizumab (one initially with no or mild disability (PDDS = 0\nor 1) and one with moderate disability (PDDS = 2). They reduced the frequency of\nnatalizumab while trying to conceive (to 6 weeks from 4 week intervals). At\ncut-off, one is still trying to conceive, and her disability has progressed from\nmild (PDDS = 1) to moderate (PDDS = 2). The other woman did not take natalizumab\nonce pregnancy was confirmed despite her neurologist suggested a dose before\ndelivery. She resumed the DMT at 1-month postpartum.\nTwo women in this study, both with no or mild disability (PDDS = 0 or 1), were on\ninterferon beta 1-a. One woman decided on a 1-month washout (did not speak with\nher neurologist), eventually became pregnant and stayed off DMT. The other woman\nstayed on the DMT while trying to conceive on the advice of her neurologist. She\nsubsequently became pregnant and had an early miscarriage. She continued to\nparticipate in CANPREG-MS and did not take any DMT during her second attempt to\nconceive. She is now pregnant.\nTwo women with no or mild disability (PDDS = 0,1) were on oral cladribine. One\nhad a single course followed by an 11-month washout and she became pregnant at\ncut-off. The other had a 6-month washout after her second course before trying\nto conceive and is still trying.\nOne woman was on interferon beta 1-a (Avonex) and no washout was planned. She is\nstill on the DMT and trying to conceive.\nOne woman on teriflunomide did an accelerated (4 month) washout using activated charcoal \n 27 \n  and is pregnant at the cut-off date.\nOne woman was on this (PDDS = 1) and is continuing her therapy while trying to\nconceive. She has no plans for a washout or discontinuation if she\nconceives.\n\nCANPREG-MS is the first prospective, real world study on women with MS who are\nactively planning a pregnancy. Women use various sources for information about the\nsafety of DMT usage at conception. Even with the relatively small numbers presented\nhere, we found that 6 women discontinued their DMTs while trying to conceive against\nthe advice of their neurologists because of disease activity. Another 6 women\ninterrupted/stopped trying to conceive because of a major clinical relapse, a\nMRI-detected inflammation or limited “windows of opportunity” between DMT\ncourses.\nThe data presented here are preliminary, but they show how complex the road to\nconception can be for women with MS. Further potentially complicating the path to\npregnancy is the fact that there is no single authority or roadmap on what to do for\nany woman with MS with respect to therapy and disease course if she wishes to\nconceive. It is imperative to remind health care professionals (most often MS\nneurologists or MS nurses) that one must always ask female patients about\nreproductive plans at each visit (until pregnancy is no longer an option). This must\nbe done regardless of whether or not a therapy is changed. Assumptions about\nreproductive plans based on facts presumably known to the health care professional\nsuch as age, relationship status and MS disability cannot be made. Decisions can be\nvery surprising (e.g. a wish to be a surrogate, MS diagnosis not disclosed to\npartners, etc.).\nGiven the small sample, it is not possible to draw definitive conclusions on\nfertility. However, the percentage of our participants who used ARTs is similar to\nreports for the general Canadian population. 28 , 29  It is important to consider\nthat counseling should be given about the possibility of an increased risk for MS\nrelapse after ART. 29 , 30\nAs with most research, CANPREG-MS has benefits and limitations. As previously stated,\nthis is a real world scenario with no restrictions on a woman’s age, disability, MS\nduration, therapy, etc. There are however certain caveats to be recognized in\naddition to the fact that the results are preliminary. Numbers will increase as\nCANPREG-MS continues. All participants were actively trying to conceive; no\nunplanned pregnancies were included. No participant had a PDDS of 4 or higher.\nEuropean ancestry predominated. Most women (42/44) were in a stable relationship and\nwere relatively highly educated. The Canadian healthcare system supposedly provides\nequal access but this is not the case regarding DMTs. Access to MS neurologist and\nnurses, especially in some remote communities, remains problematic in Canada. \n 31\nNevertheless, as the data are presented with sufficient demographics, the study\npopulation is well defined and thus can be applied to the general comparable MS\npopulations internationally.","source_license":"CC-BY-4.0","license_restricted":false}