Advertisement

Patient awareness about family planning represents a major knowledge gap in multiple sclerosis

Open AccessPublished:June 14, 2018DOI:https://doi.org/10.1016/j.msard.2018.06.006

      Highlights

      • Survey revealed low awareness of teratogenic risk during disease modifying therapy.
      • Knowledge of potential exposure to healthy partners of male patients was absent.
      • 10% of female multiple sclerosis patients had experienced unplanned pregnancies.
      • The internet and the neurologist were key sources of information on family planning.

      Abstract

      Background

      The purpose of the survey was to assess the knowledge of family planning issues associated with disease modifying therapies (DMTs) among patients diagnosed with multiple sclerosis (MS).

      Methods

      590 Danish MS patients responded to an online questionnaire about family planning in MS, collecting demographics, disease characteristics, disease modifying treatment, knowledge of potential teratogenic effects in DMTs, number of children, occurrence of unplanned pregnancies and outcome, and sources of information.

      Results

      488 females and 102 males, mean age 40 years, responded. On average, it was 6.5 and 10.9 years since diagnosis and first symptoms, respectively. 16% of female and 19% of male respondents did not receive DMT at the time of responding to the survey. 30% of all had received only one DMT, 37%, 19%, 8%, and 5% had received two, three, four, and five different treatments, respectively. 42% of female and 74% of male respondents said they did not know if the medication they were taking had teratogenic risks. 83% of females and 85% of males responded that they did not know, whether DMT in male MS patients may expose healthy partners to teratogenic risks; hereto, 13% and 10%, respectively, answered that no transmission occurs. On average respondents had two children; three of four children reported in the study were born prior to the respondents being diagnosed with MS. 50% of both female and male respondents without children wanted a family and 25% of females and 16% of males wanted to start a family within the next two years. 91% of female respondents would discontinue DMT during pregnancy. Among male respondents 32% would continue treatment during a partner's pregnancy and 47% did not know whether they would continue or discontinue treatment. 10% of the female patients had had unplanned pregnancies during MS treatment, of these 49% chose to have an abortion. 53% of all felt they were well informed about MS treatment and family planning. 22% and 41% of the respondents received information from the neurologist about teratogenic risks in female MS patients and about teratogenic risks in women with male MS patients as partners, respectively; 27% and 34%% retrieved information from the internet on these two issues.

      Conclusion

      This survey uncovered a low level of knowledge about DMTs’ teratogenic risks among MS patients irrespective of sex. Knowledge about potential teratogenic risks for male MS patients receiving DMTs while planning to start a family was largely absent. 10% of female patients had experienced unplanned pregnancies on MS treatment. In general, patients use the internet and their neurologist to the same extent for information on parenthood planning.

      Keywords

      1. Introduction

      Multiple sclerosis (MS) is a chronic, inflammatory and neurodegenerative disease affecting the central nervous system (CNS). As MS tends to become apparent during fertile and childbearing age, the diagnosis may raise concerns in the individual patient as well as his or her partner about consequences for family planning. These concerns include thoughts on the heredity of MS, the effect of MS on the course of pregnancy, how the pregnancy may affect the disease, and considerations involving the potential teratogenic risks associated with disease modifying therapies (DMTs) (
      • Alwan S.
      • Yee I.M.
      • Dybalski M.
      • et al.
      Reproductive decision making after the diagnosis of multiple sclerosis (MS).
      ). Whereas MS only has a small impact on the course of the pregnancy, if at all, pregnancy, itself, seems to affect the disease by lowering the frequency of relapses, especially in the third trimester (
      • Bove R.
      • Alwan S.
      • Friedman J.M.
      • et al.
      Management of multiple sclerosis during pregnancy and the reproductive years: a systematic review.
      ,
      • Confavreux C.
      • Hutchinson M.
      • Hours M.M.
      • Cortinovis-Tourniaire P.
      • Moreau T.
      Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in multiple sclerosis group.
      ). However, this trend can be followed, by a subsequent increase in relapse rate in the first months postpartum (
      • Bove R.
      • Alwan S.
      • Friedman J.M.
      • et al.
      Management of multiple sclerosis during pregnancy and the reproductive years: a systematic review.
      ,
      • Confavreux C.
      • Hutchinson M.
      • Hours M.M.
      • Cortinovis-Tourniaire P.
      • Moreau T.
      Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in multiple sclerosis group.
      ). Furthermore, children of patients with MS have a slightly higher risk of developing MS (
      • O'Gorman C.
      • Lin R.
      • Stankovich J.
      • Broadley S.A.
      Modelling genetic susceptibility to multiple sclerosis with family data.
      ,
      • Nielsen N.M.
      • Westergaard T.
      • Rostgaard K.
      • et al.
      Familial risk of multiple sclerosis: a nationwide cohort study.
      ,
      • Munger K.L.
      • Aivo J.
      • Hongell K.
      • Soilu-Hanninen M.
      • Surcel H.M.
      • Ascherio A.
      Vitamin D status during pregnancy and risk of multiple sclerosis in offspring of women in the finnish maternity cohort.
      ). The treatment possibilities in MS have expanded over the last decade with approval of a series of highly potent DMTs. However, DMTs have potential adverse effects on fertility and pregnancy outcomes which vary among the different therapies (
      • Amato M.P.
      • Portaccio E.
      Fertility, pregnancy and childbirth in patients with multiple sclerosis: impact of disease-modifying drugs.
      ,
      • Pozzilli C.
      • Pugliatti M.
      An overview of pregnancy-related issues in patients with multiple sclerosis.
      ).
      A systematic review of studies showed that compared with unexposed pregnancies interferon-beta (Avonex, Rebif, Betaseron, Extavia) exposure was associated with lower mean birth weight, shorter mean birth length, preterm birth but was not associated with birth weights <2500 g, caesarean delivery, congenital anomaly (including malformation), or spontaneous abortion (
      • Lu E.
      • Wang B.W.
      • Guimond C.
      • Synnes A.
      • Sadovnick D.
      • Tremlett H.
      Disease-modifying drugs for multiple sclerosis in pregnancy: a systematic review.
      ). Glatiramer acetate (Copaxone) exposure was not associated with lower mean birth weight, congenital anomaly, preterm birth, or spontaneous abortion (
      • Herbstritt S.
      • Langer-Gould A.
      • Rockhoff M.
      • et al.
      Glatiramer acetate during early pregnancy: a prospective cohort study.
      ). Natalizumab (Tysabri) exposure appeared not to be associated with shorter mean birth length, lower mean birth weight, or lower mean gestational age, (
      • Lu E.
      • Wang B.W.
      • Guimond C.
      • Synnes A.
      • Sadovnick D.
      • Tremlett H.
      Disease-modifying drugs for multiple sclerosis in pregnancy: a systematic review.
      ) and observational follow-up data on birth outcome suggested no specific pattern of malformations or increased rate of abortion that would suggest a drug effect of natalizumab (
      • Friend S.
      • Richman S.
      • Bloomgren G.
      • Cristiano L.M.
      • Wenten M.
      Evaluation of pregnancy outcomes from the Tysabri(R) (natalizumab) pregnancy exposure registry: a global, observational, follow-up study.
      ). Another study found no difference in the rate of spontaneous abortions in pregnancies where the fathers had MS and received either interferon-beta or glatiramer acetate compared to a group of pregnancies where the fathers with MS were unexposed to either of the two DMTs (
      • Pecori C.
      • Giannini M.
      • Portaccio E.
      • et al.
      Paternal therapy with disease modifying drugs in multiple sclerosis and pregnancy outcomes: a prospective observational multicentric study.
      ). Concerning the effects of newer oral DMT exposure during pregnancy e.g. fingolimod (Gilenya), teriflunomide (Aubagio) and dimethyl fumarate (Tecfidera) the safety data regarding cases of human pregnancy exposure remain inconclusive since interventional clinical trials with DMT in MS generally exclude pregnancies by means of the study protocol, and long term real world observations are still limited (
      • Gold R.
      • Phillips J.T.
      • Havrdova E.
      • et al.
      Delayed-release dimethyl fumarate and pregnancy: preclinical studies and pregnancy outcomes from clinical trials and postmarketing experience.
      ,
      • Karlsson G.
      • Francis G.
      • Koren G.
      • et al.
      Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis.
      ). With DMTs for MS only animal studies have confirmed the teratogenic risks to the offspring, leaving the potential risks in humans to be speculative (
      • Amato M.P.
      • Portaccio E.
      Fertility, pregnancy and childbirth in patients with multiple sclerosis: impact of disease-modifying drugs.
      ). Nonetheless – and based on animal reproductive studies – some of the newer DMTs are clearly contraindicated in female patients during pregnancy and some even carry a risk of being transmitted via semen from a male patient to his female partner onto the foetus. As the teratogenic risk seems to vary greatly among the DMTs, the need for patient awareness and appropriate information to MS patients planning parenthood and receiving DMT is imperative. Studies about the knowledge on family planning among MS patients are scarce, hence the purpose of this survey is to investigate the knowledge of family planning issues and in particular knowledge on potential teratogenic risks associated with the use of DMTs among MS patients and uncover the sources of information in order to provide data to guide healthcare professionals for improved patient information and care.

      2. Methods

      An online survey was conducted from December 2016 through June 2017 by Incentive, a health economic consultancy company, amongst Danish patients self-reported with a diagnosis of clinically isolated syndrome (CIS) or relapsing-remitting MS (hereafter referred to as MS). The questionnaire was designed in collaboration with two MS experts, both physicians. Patients signed up for the survey voluntarily and did not receive payment for participating. A pilot study consisting of 31 patients self-reported with a diagnosis of MS was carried out prior to the main survey. Only minor changes to the wording were made based on the pilot testing. The final questionnaire consisted of 34 closed-ended questions, starting with screening questions on demographics and disease characteristics. In the introduction to the questionnaire, respondents were informed that the questionnaire would take about eight minutes to complete and were also provided a statement explaining that the survey followed appropriate ethical guidelines, that their answers were anonymous, and that data was handled and organized according to the Danish legislation. Respondents had to actively indicate that they agreed on these terms and conditions but could also drop out of the survey at any time.
      Besides querying about demographics and disease characteristics, the 34 questions asked for information about respondents’ MS treatment, their level of knowledge on DMTs for MS, the potential teratogenic effect of DMTs, and the source(s) of information on MS and treatment that the patients turned to. Furthermore, information about the occurrence of unplanned pregnancies and outcomes was collected.
      The sampling strategy was aimed at MS patients aged 18–49. Data was collected using online advertisements, as well as links at the webpage of the patient organization Danish Multiple Sclerosis Society.
      Descriptive statistics were applied to the sample, and testing for differences between proportions were done, using a chi-square test.

      3. Results

      The results of the survey are divided into two sections: a general section describing the characteristics of the sample, the general level of knowledge that the respondents have, and where they search for information on the disease; the second section contains more specific information on respondents’ knowledge of potential teratogenic effects of using DMT to treat MS.

      3.1 Response from the internet survey panel

      A total of 1227 patients were recruited through the online data sources described above. Most of the respondents (N = 848/1227, 69%) self-reported that they were diagnosed as having either CIS or relapsing-remitting MS, while the remaining 31% (N = 379/1227) responded that they were diagnosed with either primary progressive or secondary progressive MS. Of the 848 respondents having the diagnosis of interest (CIS or relapsing-remitting MS), 765 were in the target population of 18–49 years old. This age group was chosen due to the study's focus on MS from a family planning perspective. From the target population, 590 responses were completed.
      The sample consisted of 488 females and 102 males (Table 1). On average, respondents had their first clinical symptoms 10.9 years ago (10.8 for females and 11.2 for males). Time since diagnosis was 6.5 years on average (6.4 for women and 7.2 for men). 16% of females and 18% of males reported that they were not currently receiving any DMT for MS. 67% of the patients had been treated with one or two DMTs since diagnosis.
      Table 1Distribution of respondents; age and time with MS, number of DMTs prescribed in the past.
      AllFemalesMales
      N590488102
      Age
      <30 years13%14%10%
      30–39 years32%35%22%
      40–49 years54%51%69%
      Mean age393841
      Time with MS
      Years since first symptoms10.910.811.2
      Years since diagnosis6.56.47.2
      Treatment
      Number of DMTs tried
      130%30%33%
      237%38%36%
      319%19%21%
      48%8%5%
      5 or more5%6%5%
      Note: Rounding decimals off in some cases left the sum of integers ≠ 100; DMTs, disease modifying therapies.
      Among the 590 respondents, 417 (71%) had children, 2.0 children on average (SD 0.79; range 0–5). On average 1.5 children (SD 1.06; range 0–5) were born before the MS diagnosis had been established. Among both female and male respondents who had not yet had any children, 50% wanted to start a family. A subset of this group (25% of females and 16% of males without children) was specifically planning to conceive within the next two years.

      3.2 Information

      The patients’ source of information about MS is shown in Table 2. General information is collected from three main sources: patients’ MS neurologist (70%), patients’ MS nurse (64%), and internet sources (60%). Very little information is gathered from patients’ GP (7%). The pattern is almost the same for men and women.
      Table 2Distribution of where general information on MS was collected.
      AllFemalesMales
      My GP7%7%10%
      My MS neurologist70%71%64%
      My MS nurse64%64%65%
      Other people within healthcare (e.g. nurse, gynaecologist, midwife)2%2%3%
      Patient associations (e.g. meetings, telephone lines)32%32%30%
      Internet (e.g. organization home pages)60%62%52%
      Social media (e.g. Facebook)41%42%33%
      Other sources8%7%14%
      Note: More than one answer option for a question.
      Table 3 shows sources of specific information related to potential teratogenic effects of DMTs. 41% of the females get their information from their MS neurologist. The second largest sources of information were the MS nurse and the internet, both with 34% of females turning to these sources. For males, ‘Other sources’ were most frequently used (51%), followed by the internet (27%).
      Table 3Sources of specific information regarding potential effects on the foetus from the MS treatment.
      FemalesMales
      My GP2%1%
      My MS neurologist41%22%
      My MS nurse34%17%
      Other people within healthcare (e.g. nurse, gynaecologist, midwife)5%5%
      Patient associations (e.g. meetings, telephone lines)7%9%
      Internet (e.g. organization home pages)34%27%
      Social media (e.g. Facebook)16%13%
      Other sources21%51%
      Note: More than one answer option for a question.
      In a subset of respondents (n = 130; 82% females and 18% males) who had had children after their MS diagnosis, half (53%) felt they were well informed (to a large or very large extent) about treatment possibilities and treatment choices after conception or during pregnancy. Moreover, 47% felt they had easy access to information (to a large or very large extent) regarding the treatment possibilities. There were no differences between genders.

      3.3 Respondents’ knowledge of teratogenic effects of using DMTs

      Questions were asked to uncover whether respondents differentiated between DMTs with respect to the potential teratogenic effects. Questions were directed specifically to female MS patients being treated with DMTs (Fig. 1), and to male MS patients being treated with DMT with regard to risk of transmission of the DMT to the female partner and onto the foetus (Fig. 2).
      Fig 1
      Fig. 1Question: Are you aware of any DMT for MS which affect the foetus if a pregnant woman with MS is in treatment?
      Fig 2
      Fig. 2Question: Do you know if drugs used for MS can be transmitted from a male partner with MS to a female partner without MS and thus affect the foetus?
      Fig. 1 shows that 74% of male respondents and 42% of female respondents answered that they did not know whether any DMT could affect the foetus, if a pregnant woman with MS was undergoing treatment. 4% of male and 14% of female respondents stated that all drugs used for MS would affect a foetus equally, while 7% of the males and 25% of females responded that the risk differs across drugs used, but that all drugs to some extent affect the foetus. 2% of male and 0.4% of female respondents stated that no drugs used for MS would affect the foetus. Finally, 14% of male and 18% of female respondents stated that some drugs would affect the foetus, while other drugs would not.
      With respect to the risk of transmission of the DMT from a male MS patient to his healthy female partner and onto the foetus (Fig. 2), 85% of male and 83% of female respondents stated that they did not know whether such transmission could occur. 10% of male and 13% of female respondents stated that such a transmission could not take place, while no male and 2% female respondents stated that such a transmission could take place independently of the DMT. 1% male and 0.6% female respondents stated that all drugs used for MS treatment could be transmitted equally. Finally, 4% of the male and 1% of the female respondents stated that transmission from a male MS patient to a healthy female partner and the foetus could only take place for some DMTs, while it would not be possible for other DMTs.
      Respondents were asked to state to what extent a drug's effect on a foetus would matter in their choice of DMT during a pregnancy. Overall, 61% found that it does matter, while 27% stated that it is not an important factor at all. Males and females had different perspectives on this; female respondents found it significantly more important (64%) than male respondents (48%) (p-value < 0.001).
      In the survey, the female respondents were asked whether they had experienced an unplanned pregnancy while receiving treatment for MS with DMTs. Among 468 female respondents, 10% (n = 47) had experienced unplanned pregnancies. Out of the 47 experiencing unplanned pregnancies, 23 of them tried to carry through the pregnancy with varying outcomes. 23 of the remaining respondents had a medical or a surgical abortion – one did not want to answer the question. Among the 23 females who tried to carry through the pregnancy, 15 stopped the treatment and completed the pregnancy, four continued the treatment but had a spontaneous abortion, and four stopped the treatment but had a spontaneous abortion.

      4. Discussion

      The onset of MS typically occurs at an age where people consider planning a family. For MS patients, family planning may prompt concerns about the effects of pregnancy on the course of the disease, about the heredity of MS, and about foetal and paediatric safety when taking medications at time of conception, during pregnancy, and while breastfeeding (
      • Alwan S.
      • Yee I.M.
      • Dybalski M.
      • et al.
      Reproductive decision making after the diagnosis of multiple sclerosis (MS).
      ,
      • Albrecht P.
      • Fischer D.
      • Moser A.
      Multiple sclerosis and pregnancy: what does the patient think? A questionnaire study.
      ). While the treatment possibilities in MS have expanded with a series of highly potent DMTs, information and studies on the knowledge among MS patients of the potential impact that DMTs may have on their plans to start a family are lacking. The data presented uncovers number of children, hereunder unplanned pregnancies and outcomes, and wish to start a family within two years among MS patients aged 18–49 years. Moreover, the study investigated sources of information MS patients employ and how they rate it, and the level of knowledge of potential teratogenic risks related to DMTs.
      Among the 590 respondents, 417 had children (71%). Among both female and male respondents who had not yet had any children, 50% wanted to start a family. While the majority of patients had received one or two DMTs (Table 1), the remainder of respondents had received three-five different DMTs. Using the number of DMT as a marker of disease activity, a further breakdown of data demonstrated no significant difference with respect to respondents with high disease activity being less likely to want to start a family than respondents with lower disease activity. Furthermore, there was no significant difference with regards to knowledge about the teratogenic risk among respondents with presumed high or low disease activity (data not shown).
      About 10% of female MS patients reported having had an unplanned pregnancy, of which 49% led to medical/surgical termination of the pregnancy and an additional 18% ended with a spontaneous abortion. It is, however, unclear from this survey whether the 23 medical/surgical abortions were related to the respondents’ fear of teratogenic risk or other reasons. The above number of unplanned pregnancies in MS patients coincides with another Danish study, in which contraceptive failure was seen among 9% of women who became pregnant during the study period (
      • Rasch V.
      Contraceptive failure–results from a study conducted among women with accepted and unaccepted pregnancies in Denmark.
      ). Hence, regardless of contraceptive use, a significant proportion of pregnancies are unplanned, i.e. in women with no imminent pregnancy wish. This highlights the need for careful consideration of choice of DMT not only in women planning pregnancy but in all fertile women.
      In the subset of respondents (n = 130) who had children after the diagnosis of MS, 47% responded that they felt inadequately informed about treatment possibilities for MS while planning to start a family, and 53% did not feel that they had easy access to information about the treatment possibilities. This highlights the need for valid sources of information that are accessed by MS patients. Healthcare professionals (the neurologist and the MS nurse) represented the most frequently used and important sources of information about MS in general (Table 2) but for the knowledge about information related to potential teratogenic effects of DMT, the respondents turned to the internet, social media, and other sources (Table 3) just as often as to their healthcare professionals. Thus, the large proportion of respondents, who were looking to other sources of information than their healthcare professionals, points to an unmet need for very specific information related to family planning.
      The responses in this survey concerning the knowledge of DMTs potential teratogenic effects reveal a knowledge gap. When asked about their knowledge of teratogenic risks related to DMT given to a female patient, 42% of females and 74% of males responded that they did not know, and just 43% and 21%, females and males, respectively, responded that all DMTs/or some DMTs could affect the foetus, but that the risk differs across DMTs (Fig. 1). Similarly, very few had knowledge on the risk of transmitting teratogenic DMT to a female partner via semen, i.e. 95% and 96% responding either ‘don't know’ or ‘that there is no risk for the foetus’, male and female patients, respectively (Fig. 2). This low level of knowledge poses a potential for inadvertent conception during treatment and emphasizes an impending teratogenic risk in MS patients treated with DMTs. Notably, the European Medicines Agency has recently published a paper on how the European pharmacovigilance system works in order to guide clinical decision making in cases where human medicines expose patients or their partners to a teratogenic risk in the offspring (
      • Santoro A.
      • Genov G.
      • Spooner A.
      • Raine J.
      • Arlett P.
      Promoting and protecting public health: how the European union pharmacovigilance system works.
      ). The paper points to the need for increasing awareness among prescribers and patients on the risk of teratogenicity and the need for specific measures in monitoring to mitigate the risk (
      • Santoro A.
      • Genov G.
      • Spooner A.
      • Raine J.
      • Arlett P.
      Promoting and protecting public health: how the European union pharmacovigilance system works.
      ). This survey shows that the awareness on the potential teratogenic effect of DMT does matter to the respondents’ decision in regard to treatment choice, since 61% of all (male and female) responded that it would matter to a very large or large extent. At the same time, the potential teratogenic effects did not matter at all to 27% of the respondents. Further breakdown of the 27% shows that only 6% of these respondents wished to have (more) children. The data also revealed a difference between genders on this matter, as the female respondents found the teratogenic risk to be significantly more important than male respondents.
      The survey represents a large sample of MS patients and holds information about the level of knowledge of DMTs’ potential teratogenic risk with both the female and male MS population. This is a strength to the survey as very little information is currently available on this subject. Furthermore, the information about the sources of information yields valuable input as to specific future channels of information but also gives rise to the need for healthcare professionals to proactively and directly address the issues of DMTs in connection to family planning when engaging with MS patients.
      The enrolment in the study was conducted through online advertisements and by using The Danish MS Society as an information source where patients tend to look up information. The sample of respondents expectedly enclosed more female than males in reflection of the higher incidence rates of MS among females than males; therefore, it required additional efforts to enrol an adequate number of male respondents. This is a limitation to the study. Furthermore, it is a limitation that the extent to which the sample is representative of the general MS population remains unknown; information about the respondents was a self-reported diagnosis, number of drugs used, and years since first symptoms and since diagnosis.

      5. Conclusions

      In conclusion, this survey uncovered a low level of knowledge about the teratogenic risks of DMTs among MS patients irrespective of sex. Knowledge about potential teratogenic risks for male MS patients receiving DMTs while planning to start a family was largely absent. 10% of female patients had experienced unplanned pregnancies on MS treatment. In general, patients use the internet and their neurologist to the same extent for information on parenthood planning. The increasing number of potent DMTs and the low-level knowledge among patients calls for increased focus on the topic from the healthcare professionals.

      Acknowledgements

      This survey was conducted by Incentive and funded by Biogen. The authors thank Charlotte Strøm, M.D., Ph.D., for writing assistance with this paper. This service was financially supported by Biogen.

      Author disclosures

      Peter Vestergaard Rasmussen has acted/is acting in one or several roles as an investigator, expert on advisory board, a lecturer, or consultant with Novartis Healthcare A/S, Sanofi-Aventis Denmark A/S; Biogen Denmark A/S, Roche A/S, Allergan A/S, Merck A/S; Teva Denmark A/S, and Sanofi Genzyme Denmark. Melinda Magyari has acted/is acting in one or several roles as a lecturer, consultant, speaker, or an expert on advisory board with Biogen Denmark A/S, Novartis Healthcare A/S, Teva Denmark A/S, Merck A/S, Sanofi-Aventis Denmark A/S, Roche Products Ltd., Genzyme Europe B.V., Genzyme Therapeutics Ltd. Julie Yoon Moberg has received travel and educational grants from Biogen Denmark A/S, Sanofi Genzyme Denmark, Merck A/S, and Teva Denmark A/S and has acted as a speaker for Biogen Denmark A/S, Sanofi Genzyme Denmark, and Teva Denmark A/S. Mette Bøgelund is CEO and Partner at Incentive. Ulla Fie Appel Jensen and Klaus Gregaard Madsen are employees at Biogen Denmark A/S.

      Appendix. Supplementary materials

      References

      1. 1
        • Alwan S.
        • Yee I.M.
        • Dybalski M.
        • et al.
        Reproductive decision making after the diagnosis of multiple sclerosis (MS).
        Mult. Scler. 2013; 19: 351-358
      2. 2
        • Bove R.
        • Alwan S.
        • Friedman J.M.
        • et al.
        Management of multiple sclerosis during pregnancy and the reproductive years: a systematic review.
        Obstet. Gynecol. 2014; 124: 1157-1168
      3. 3
        • Confavreux C.
        • Hutchinson M.
        • Hours M.M.
        • Cortinovis-Tourniaire P.
        • Moreau T.
        Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in multiple sclerosis group.
        N. Engl. J. Med. 1998; 339: 285-291
      4. 4
        • O'Gorman C.
        • Lin R.
        • Stankovich J.
        • Broadley S.A.
        Modelling genetic susceptibility to multiple sclerosis with family data.
        Neuroepidemiology. 2013; 40: 1-12
      5. 5
        • Nielsen N.M.
        • Westergaard T.
        • Rostgaard K.
        • et al.
        Familial risk of multiple sclerosis: a nationwide cohort study.
        Am. J. Epidemiol. 2005; 162: 774-778
      6. 6
        • Munger K.L.
        • Aivo J.
        • Hongell K.
        • Soilu-Hanninen M.
        • Surcel H.M.
        • Ascherio A.
        Vitamin D status during pregnancy and risk of multiple sclerosis in offspring of women in the finnish maternity cohort.
        JAMA Neurol. 2016; 73: 515-519
      7. 7
        • Amato M.P.
        • Portaccio E.
        Fertility, pregnancy and childbirth in patients with multiple sclerosis: impact of disease-modifying drugs.
        CNS Drugs. 2015; 29: 207-220
      8. 8
        • Pozzilli C.
        • Pugliatti M.
        An overview of pregnancy-related issues in patients with multiple sclerosis.
        Eur. J. Neurol. 2015; 22: 34-39
      9. 9
        • Lu E.
        • Wang B.W.
        • Guimond C.
        • Synnes A.
        • Sadovnick D.
        • Tremlett H.
        Disease-modifying drugs for multiple sclerosis in pregnancy: a systematic review.
        Neurology. 2012; 79: 1130-1135
      10. 10
        • Herbstritt S.
        • Langer-Gould A.
        • Rockhoff M.
        • et al.
        Glatiramer acetate during early pregnancy: a prospective cohort study.
        Mult. Scler. 2016; 22: 810-816
      11. 11
        • Friend S.
        • Richman S.
        • Bloomgren G.
        • Cristiano L.M.
        • Wenten M.
        Evaluation of pregnancy outcomes from the Tysabri(R) (natalizumab) pregnancy exposure registry: a global, observational, follow-up study.
        BMC Neurol. 2016; 16: 150
      12. 12
        • Pecori C.
        • Giannini M.
        • Portaccio E.
        • et al.
        Paternal therapy with disease modifying drugs in multiple sclerosis and pregnancy outcomes: a prospective observational multicentric study.
        BMC Neurol. 2014; 14: 114
      13. 13
        • Gold R.
        • Phillips J.T.
        • Havrdova E.
        • et al.
        Delayed-release dimethyl fumarate and pregnancy: preclinical studies and pregnancy outcomes from clinical trials and postmarketing experience.
        Neurol. Ther. 2015; 4: 93-104
      14. 14
        • Karlsson G.
        • Francis G.
        • Koren G.
        • et al.
        Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis.
        Neurology. 2014; 82: 674-680
      15. 15
        • Albrecht P.
        • Fischer D.
        • Moser A.
        Multiple sclerosis and pregnancy: what does the patient think? A questionnaire study.
        BMC Res. Notes. 2010; 3: 91
      16. 16
        • Rasch V.
        Contraceptive failure–results from a study conducted among women with accepted and unaccepted pregnancies in Denmark.
        Contraception. 2002; 66: 109-116
      17. 17
        • Santoro A.
        • Genov G.
        • Spooner A.
        • Raine J.
        • Arlett P.
        Promoting and protecting public health: how the European union pharmacovigilance system works.
        Drug Saf. 2017; 40: 855-869