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Live birth in women with multiple sclerosis receiving assisted reproduction
Assisted reproduction in multiple sclerosis
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Live birth in women with multiple sclerosis receiving assisted reproduction Line Riis Jølving MHSc, Ph.D. , Michael Due Larsen MSc. Pharm, Ph.D. Associate professor , Jens Fedder MD, DMSc, Ph.D. Professor , ˚ MD, DMSc, Ph.D. Professor Bente Mertz Nørgard PII: DOI: Reference:
S1472-6483(20)30066-3 https://doi.org/10.1016/j.rbmo.2020.01.013 RBMO 2336
To appear in:
Reproductive BioMedicine Online
Received date: Revised date: Accepted date:
28 October 2019 20 January 2020 21 January 2020
Please cite this article as: Line Riis Jølving MHSc, Ph.D. , Michael Due Larsen MSc. Pharm, Ph.D. Associate profe ˚ MD, DMSc, Ph.D. Professor , Live Jens Fedder MD, DMSc, Ph.D. Professor , Bente Mertz Nørgard birth in women with multiple sclerosis receiving assisted reproduction, Reproductive BioMedicine Online (2020), doi: https://doi.org/10.1016/j.rbmo.2020.01.013
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Live birth in women with multiple sclerosis receiving assisted reproduction Short running title: Assisted reproduction in multiple sclerosis Line Riis Jølving, MHSc, Ph.D.1, Michael Due Larsen, MSc. Pharm, Ph.D., associate professor1, Jens Fedder, MD, DMSc, Ph.D., Professor2, Bente Mertz Nørgård, MD, DMSc, Ph.D., Professor1 1
Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark and Research
Unit of Clinical Epidemiology, Department of Clinical Research, University of Southern Denmark, Odense, Denmark. 2
Centre of Andrology and Fertility Clinic, Odense University Hospital, Odense Denmark and
Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Words: Abstract: 246, body text: 4222. Tables: 4. Keywords: Assisted reproductive technology, in vitro fertilization, multiple sclerosis, clinical epidemiology, chronic disease.
Corresponding author: Line Riis Jølving, MHSc, Ph.D., Center for Clinical Epidemiology and Research Unit of Clinical Epidemiology, Odense University Hospital, Kløvervænget 30, Entrance 216, Odense C DK-5000, Denmark; +45 2462 9638 [email protected].
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ABSTRACT Research question Multiple sclerosis (MS) is predominant in women during the childbearing years and in case of problems with conceiving naturally, assisted reproductive technology (ART) becomes relevant. The efficacy of ART treatment in women MS has not previously been studied. Our aim was to examine the chance of a live-born child after an embryo transfer in women with MS and to examine whether corticosteroids prior to embryo transfer had a beneficial effect. Design This cohort study is based on nationwide Danish health registries, including all women with embryo transfers from 1 January 1995 through 31 December 2017. The exposed cohort comprised 2,267 embryo transfers in women with MS and 200,684 in women without MS (unexposed). We used multilevel logistic regression analysis to compute the crude and the adjusted risk estimates. Results A total of 21.97% of the embryo transfers in women with MS resulted in a live born child compared to 24.17% in women without MS, and the adjusted odds ratio (aOR) was 0.91 (95% CI 0.81 - 1.02). The aOR of live birth in women with MS using corticosteroids prior to embryo transfer was 0.90 (95% CI 0.49 – 1.68), compared to women with MS receiving no corticosteroids. Conclusion The chance of a live birth was not decreased, in women with MS undergoing ART, compared to women without MS. The use of corticosteroids had no impact on the result. These novel results on ART treatment are useful when counseling women with MS undergoing assisted reproduction.
INTRODUCTION
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Multiple sclerosis (MS) is a chronic autoimmune disease that causes progressive damage to the myelin sheaths with an array of symptoms (Compston A. and Coles A., 2002; Poser S., Raun N. E. and Poser W., 1982; Stenager E., 2019). The disease is one of the most common neurological demyelinating disease (Love S., 2006) and is predominant in women with a peak incidence during the childbearing years from 20-45 (Poser S., Raun N. E. and Poser W., 1982). Whether fertility is impaired in MS is still a subject for debate (Cavalla P., Rovei V., Masera S., Vercellino M., Massobrio M., Mutani R. and Revelli A., 2006; Jalkanen A., Alanen A., Airas L., Finnish Multiple Sclerosis and Pregnancy Study Group, 2010; McCombe P. A. and Stenager E., 2015; Moberg J. Y., Laursen B., Thygesen L. C. and Magyari M., 2019) but in case of problems with conceiving naturally, assisted reproductive technology (ART) becomes relevant. In this study we aimed to examine the efficacy of ART in women with MS. Previous studies have focused on which impact ART treatment has on the MS symptoms and the disease course, and a number of putative mechanisms involved in MS have been suggested to worsen after ART treatment resulting in an increased relapse rate of the MS symptoms (Cavalla P., Rovei V., Masera S., Vercellino M., Massobrio M., Mutani R. and Revelli A., 2006; Correale J., Farez M. F. and Ysrraelit M. C., 2012; Hellwig K. and Correale J., 2013; Hellwig K., Schimrigk S., Beste C., Muller T. and Gold R., 2009; Laplaud D. A., Leray E., Barriere P., Wiertlewski S. and Moreau T., 2006; Michel L., Foucher Y., Vukusic S., Confavreux C., de Seze J., Brassat D., Clanet M., Clavelou P., Ouallet J. C., Brochet B., Pelletier J., Labauge P., Lebrun C., Lepage E., Le Frere F., Jacq-Foucher M., Barriere P., Wiertlewski S., Laplaud D. A. and Club Francophone de la Sclerose En Plaques, 2012). Furthermore, corticosteroids may be used to treat relapses in multiple sclerosis, but prednisolone or related drugs have also been proposed to improve the embryo implantation rate after ART treatment in general, and to protect against miscarriage when administrated from embryo implantation through the early placentation phase (Robertson S. A., Jin M., Yu D., Moldenhauer L. M., Davies
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M. J., Hull M. L. and Norman R. J., 2016; van Mourik M. S., Macklon N. S. and Heijnen C. J., 2009). Whether there is a beneficial effect of corticosteroids at embryo transfer in women with MS is so far unsettled (Boomsma C. M., Keay S. D. and Macklon N. S., 2012). Therefore, based on nationwide Danish registries on all embryo transfers for a period of 23 years, we examined the chance of a live born child after ART treatment (the primary outcome) in women with MS compared to all other women receiving ART. Secondary outcomes were a biochemical pregnancy (a positive human chorionic gonadotropin (hCG) measurement) and a clinical pregnancy (positive ultrasound), and lastly a potential impact of treatment with corticosteroids prior to embryo transfer was examined.
MATERIAL AND METHODS Setting In Denmark, all citizens have free access to a tax-supported health care system including an offer of ART treatment to all infertile couples and single women referred to infertility treatment before the age of 41 years. In the private sector, fertility treatments are permitted until the woman’s age is 46 years (Glazer C. H., Tottenborg S. S., Giwercman A., Brauner E. V., Eisenberg M. L., Vassard D., Magyari M., Pinborg A., Schmidt L. and Bonde J. P., 2017). The Danish population of approximately 5.6 million inhabitants has a unique civil registration number assigned at birth, and this unique number is used across all Danish health registers for valid record linkage at an individual level. Therefore, the Danish registers are unique for population-based study design using nationwide information across data sources. Study population
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We obtained the following data: i) data related to all ART procedures and causes of infertility, and data on the outcomes of biochemical and clinical pregnancy from the Danish ART register (Nyboe Andersen A. and Erb K., 2006; Westergaard H. B., Johansen A. M., Erb K. and Andersen A. N., 2000), ii) data on the outcome of the ART treatment in terms of a live-born child from the Danish Medical Birth Register (DMBR) (Bliddal M., Broe A., Pottegard A., Olsen J. and Langhoff-Roos J., 2018), iii) data on diagnoses of MS, and comorbidity from The Danish National Patient Register (DNPR) (Schmidt M., Schmidt S. A., Sandegaard J. L., Ehrenstein V., Pedersen L. and Sorensen H. T., 2015), iv) data on prescriptions of corticosteroids from The Danish National Prescription Register according to the Anatomical Therapeutic Chemical (ATC) Classification system in women with MS (Kildemoes H. W., Sorensen H. T. and Hallas J., 2011), and finally v) data on death and emigration, based on the civil registration number from The Civil Registration System (CRS) (Thygesen L. C., Daasnes C., Thaulow I. and Bronnum-Hansen H., 2011). The study population comprised all women with a valid civil registration number, who were available for at least 9 months of follow-up after any ART treatment in Denmark, and who started ART treatment with one or several embryo transfers during the study period of 1 January 1995 to 31 December 2017. All ART treatment cycles are mandatorily recorded in the Danish ART register. The register was established on 1 January 1994 and includes data from both public and private clinics (Westergaard H. B., Johansen A. M., Erb K. and Andersen A. N., 2000). For the purpose of this study, all embryo transfers could be a result of in vitro fertilization (IVF), with or without fertilization with intracytoplasmic sperm injection (ICSI) and transfer of frozen-thawed embryo replacement (FER). The exposed cohort All women in the study population, with diagnoses of MS before the embryo transfer, were identified in the DNPR. The DNPR has recorded all discharges from Danish hospitals since 1977 5
and all outpatient visits since 1994 (Schmidt M., Schmidt S. A., Sandegaard J. L., Ehrenstein V., Pedersen L. and Sorensen H. T., 2015). The exposed cohort is constituted by all embryo transfers in women who had at least one discharge diagnosis of MS from any hospital in Denmark before the date of embryo transfer (ICD-8 code: 340, 349; ICD-10 codes: G35).(Boesen M. S., Magyari M., Born A. P. and Thygesen L. C., 2018; Mason K., Thygesen L. C., Stenager E., Bronnum-Hansen H. and Koch-Henriksen N., 2012). The ICD-9 classifications were never used in Denmark. Women with MS could have several embryo transfers during the study period and we thus used the embryo transfer as the observation unit (Fedder J., Loft A., Parner E. T., Rasmussen S. and Pinborg A., 2013). The unexposed cohort The unexposed cohort comprised all embryo transfers where the woman did not have a diagnosis of MS before the date of embryo transfer; and similarly to the exposed cohort, the observation unit was the embryo transfer. Primary and secondary outcomes The outcome was a live born child recorded in the DMBR within a period of 124-292 days after each embryo transfer. Live birth was considered to be a result of a particular ART treatment if the difference was 140-308 days (corresponding to 20-44 weeks) from the last menstruation start or 124-292 days after each embryo transfer (Norgard B. M., Larsen M. D., Friedman S., Knudsen T. and Fedder J., 2019; Norgard B. M., Larsen P. V., Fedder J., de Silva P. S., Larsen M. D. and Friedman S., 2016; Petersen G. L., Schmidt L., Pinborg A. and Kamper-Jorgensen M., 2013). The DMBR holds information on all births in Denmark since 1 January 1973 and includes information on the mother, the child, and birth-related information such as date of birth, gestational age, birth weight and mode of delivery (Bliddal M., Broe A., Pottegard A., Olsen J. and Langhoff-Roos J.,
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2018; Knudsen L. B. and Olsen J., 1998; Kristensen J., Langhoff-Roos J., Skovgaard L. T. and Kristensen F. B., 1996). From the ART register we extracted information on the secondary outcomes biochemical pregnancies (a positive hCG test at day 14-16 after embryo transfer), and a clinical pregnancy (a positive ultrasound examination approximately 7-8 weeks after embryo transfer) from 2010 and onwards (Westergaard H. B., Johansen A. M., Erb K. and Andersen A. N., 2000). Finally, we examined the impact of the use of corticosteroids within three months prior to the embryo transfer based on prescriptions obtained from the nationwide Danish Database of Reimbursed Prescriptions where data on outpatient drug prescriptions has been available since 1995 (Kildemoes H. W., Sorensen H. T. and Hallas J., 2011). Confounders Confounders included in the statistical models were selected a priori and counts information from the different registries. From the DNPR we obtained information on comorbidity in the study population, and a comorbidity index score adapted from Charlson was conducted, covering 19 disease categories weighted according to their prognostic impact (Charlson M. E., Pompei P., Ales K. L. and MacKenzie C. R., 1987). The scores were calculated for each treatment cycle of each woman in two index levels: no comorbidity (index 0), and some comorbidity (index 1). From the ART register we extracted information on parity in two categories (0, 1+), women’s age at the time of embryo transfer (as a continuous variable), year of infertility treatment in four categories (19952000, 2001-2006, 2007-2012, and 2013-2017), type of ART treatment (IVF, ICSI or FER), and the cause of infertility (female factor, male factor, or a mixture of factors/idiopathic). Since 2006, the ART register further includes data on the following potential confounders: partners age (as a continuous variable), alcohol intake (yes/no), smoking at the time of embryo transfer and body mass index (BMI), categorized according to the World Health Organization (World Health Organization.,
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2000) in four categories (underweight: <18.5 kg/m2, normal weight: 18.5-24.9 kg/m2, overweight: 25.0-29.9 kg/m2, and obese: ≥30 kg/m2). Statistical analyses Main analyses for the primary and secondary outcomes We conducted contingency tables on the main study variables according to the exposed and the unexposed cohort, and the duration of MS was calculated from the date of the first occurring diagnosis of MS in the DNPR until the date of the first embryo transfer. We used multilevel logistic regression analyses to compute the crude and the confounder-adjusted relative risk estimates as odds ratios (OR), with the corresponding 95% confidence intervals (CI), for a live birth following embryo transfer in women with MS relative to women without MS, undergoing ART treatment. Likewise, analyses were conducted on the outcomes of biochemical pregnancy, and clinical pregnancy following embryo transfer on a restricted period from 2010 and onwards. The models accounted for multiple embryo transfers. In the adjusted analyses we included the comorbidity index, women’s age at the time of embryo transfer, calendar year of infertility treatment, type of ART treatment, and the cause of infertility. In sub-analysis, we examined a potential impact of the partner’s age, alcohol intake, and BMI using data from a restricted period from 2006, but the inclusion of these factors did not change the results and was omitted from the final model. Sub-analysis of the impact of corticosteroids and weight on the primary outcome In a sub-analysis we examined a possible impact of use of corticosteroid within 3 months prior to embryo transfer in women with MS. We obtained the prescription history of each woman with MS by corticosteroid use according to ATC codes: H02AB02 (Dexamethasone), H02AB04 (Methylprednisolone), H02AB06 (Prednisolone), H02AB07 (Prednisone), and H02AB09 (Hydrocortisone). Based on this information, we stratified the population of women with MS 8
undergoing ART treatment into two cohorts, the exposed cohort was the embryo transfers in women with MS, who had at least one prescription for corticosteroids within a period of 3 months before the date of embryo transfer, and the unexposed cohort was embryo transfers in women with MS, who had no prescriptions for corticosteroids 3 months before embryo transfer. Live births in the exposed cohort were compared to live births in women with MS without the use of corticosteroids. In another sub-analysis, we examined by stratified analyses the chance of a live born child in categories of women’s weight (normal weighted women, and overweight and obesity). Approvals and ethical considerations The study is notified at the Danish Data Protection Agency under the current joint notification of the Region of Southern Denmark (ref.no. 2012-58-0018). In Denmark, record linkage studies that only use information already recorded in the health registries do not require informed patient consent. All data was in encrypted form so that no individuals could be identified by the researchers, and data was stored and linked at a secure server at the Danish Health Data Authority, and all statistical analyses were conducted using Stata v. 15.0 software (StataCorp LP, College Station, Texas, USA).
RESULTS Patient characteristics A total of 2,267 embryo transfers (in 815 women with MS) constituted the exposed cohort, and 200,684 embryo transfers (in 66,960 women without MS) constituted the unexposed cohort. The median age at onset of ART treatment, the cause of infertility and type of preceding treatment were similar in the two cohorts, whereas women in the exposed cohort were slightly more overweight
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than women in the unexposed cohort 28.6% versus 23.0% and obese with 12.3% versus 9.8% (Table 1). Similarly, women in the exposed cohort had more comorbid diseases compared to the unexposed cohort, 14.8% versus 9.3%, whereas alcohol consumption was more frequent in the unexposed cohort with 44.7% compared to 35.6% in the exposed cohort. The median duration of MS at the time of embryo transfer was 18 years (25-75 percentile; 9-26 years). Primary and secondary outcomes A total of 21.97% of the embryo transfers in women with MS resulted in a live born child, compared to 24.17% in women without MS (Table 2). The crude OR of live birth was 0.85 (95 % CI, 0.76 - 0.96), and the confounder adjusted OR 0.91 (95% CI, 0.81 – 1.02). The chance of a biochemical pregnancy and a clinical pregnancy after embryo transfer is shown in Table 3. The adjusted OR of a positive hCG measurement in women with MS, relative to women without MS, was 0.92 (95% CI, 0.78 – 1.08), and the adjusted OR for a clinical pregnancy in women with MS was 0.89 (95% CI, 0.64 – 1.25) (Table 3). Sub-analysis on the use of corticosteroids prior to embryo transfer In the analyses of a potential impact of corticosteroid prior to embryo transfer, the adjusted OR of a live birth in women with MS using corticosteroids was 0.90 (95% CI, 0.49 – 1.68) compared to women with MS receiving no prescription of corticosteroids (Table 4). Sub-analysis on the impact of weight In women with normal weight, the adjusted OR of a live birth in women with MS, compared to women without MS, was 0.89 (95% CI 0.72-1.09) and in those being obese and overweight the results were identical.
DISCUSSION
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In this nationwide cohort study including data from 23 years of ART treatment, we found no statistically significantly reduced chance of a live birth in women with MS, receiving ART treatment compared to other women receiving ART treatment. The use of corticosteroids up to 3 months before embryo transfer did not seem to have a positive impact on the chance of a live birth. To the best of our knowledge, these findings are novel, and because this is the first study to examine the chance of live birth in women with MS receiving ART treatment, we cannot compare our results to others. However, several studies on women with MS receiving ART treatment have tended to pivot around the medical treatment related to both MS and ART, on the MS disease course (Hellwig K. and Correale J., 2013; Hellwig K., Schimrigk S., Beste C., Muller T. and Gold R., 2009; Laplaud D. A., Leray E., Barriere P., Wiertlewski S. and Moreau T., 2006; Pozzilli C., Pugliatti M. and Paradig M. S. Group, 2015; Vukusic S. and Marignier R., 2015). Besides being novel, this study is important for a number of reasons: i) the number of women with MS in their fertile years is increasing (Harbo H. F., Gold R. and Tintore M., 2013; Jolving L. R., Nielsen J., Kesmodel U. S., Nielsen R. G., Beck-Nielsen S. S. and Norgard B. M., 2016; Stenager E., 2019), and the questions related to the efficacy of ART in MS may become increasingly frequent, ii) the results on ART treatment in women with other autoimmune diseases have suggested a reduced chance of a live birth which could therefore also be the case in MS. Thus the ORs of a live birth after ART treatment in women with ulcerative colitis and Crohn’s disease were 0.78 (95% CI 0.67 – 0.91), and 0.61 (95% CI 0.47 – 0.79), respectively (Norgard B. M., Larsen P. V., Fedder J., de Silva P. S., Larsen M. D. and Friedman S., 2016) and the OR for a live birth in women with rheumatoid arthritis was OR 0.78 (95% CI 0.65 – 0.92) (Norgard B. M., Larsen M. D., Friedman S., Knudsen T. and Fedder J., 2019) in recent studies. The mechanisms behind these findings so far are unknown (Friedman S., Larsen P. V., Fedder J. and Norgard B. M., 2017; Norgard B. M., Larsen M. D., Friedman S., Knudsen T. and Fedder J., 2019), but the live birth rate
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may be affected by numerous factors related to the different stages of fertilization, implantation and to the ability to maintain a pregnancy throughout the trimesters. When it comes to use of medications, MS disease-modifying therapies is not recommended during infertility treatment, pregnancy and lactation (Bove R., Alwan S., Friedman J. M., Hellwig K., Houtchens M., Koren G., Lu E., McElrath T. F., Smyth P., Tremlett H. and Sadovnick A. D., 2014) but an applicant drug in pregnancies is corticosteroids with a broad-spectrum anti-inflammatory and immunosuppressive property. A possible positive impact of corticosteroids on embryo implantation in women with MS is however uncertain though a beneficial impact on ART treatment in general, is discussed (Robertson S. A., Jin M., Yu D., Moldenhauer L. M., Davies M. J., Hull M. L. and Norman R. J., 2016). However, the use of corticosteroids in women undergoing standard IVF treatment was associated with an increased pregnancy rate, suggesting that amongst unselected women there may be subsets with undiagnosed immune disorders that benefit from immunosuppressive therapy (Boomsma C. M., Keay S. D. and Macklon N. S., 2012; Robertson S. A., Jin M., Yu D., Moldenhauer L. M., Davies M. J., Hull M. L. and Norman R. J., 2016). We, nevertheless did not detect a clear beneficial impact of the use of corticosteroids among women with MS and the statistical power in our analyses was limited. Patient characteristics with respect to the cause of infertility did not seem to differ between women with, and women without MS. A potential decreased relapse rate during pregnancy has been suggested in the literature, though a rebound effect can occur postpartum (Confavreux C., Hutchinson M., Hours M. M., Cortinovis-Tourniaire P. and Moreau T., 1998). Hormones supplied as a part of the ART treatment may also alter the short-term course of the disease, although the exact mechanism for the increase in relapse risk of women with MS after ART treatment is not fully understood (Confavreux C., Hutchinson M., Hours M. M., Cortinovis-Tourniaire P. and Moreau T., 1998; Harbo H. F., Gold R. and Tintore M., 2013). Additionally, the number of new or enlarging T
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lesions and gadolinium-enhancing lesions up to three months after ART treatment has been described (Correale J., Farez M. F. and Ysrraelit M. C., 2012) and a recent review from Vukusic and colleagues concludes that it may be wise to undergo the ART treatment during a period when the disease is not active (Vukusic S. and Marignier R., 2015). Corticosteroids could be prescribed for a number of reasons in our study, including a potentially positive role of an improved chance of implementation of the egg and corticosteroids may be prescribed by fertility doctors (Boomsma C. M., Keay S. D. and Macklon N. S., 2012). However, therapeutic strategies in MS could also include corticosteroid treatment of relapses and immunomodulatory or immunosuppressive treatment to prevent new relapses and progression of disability (Filippini G., Brusaferri F., Sibley W. A., Citterio A., Ciucci G., Midgard R. and Candelise L., 2000; Jonsson B., Von Reis G. and Sahlgren E., 1954; Myhr K. M. and Mellgren S. I., 2009). The underlying reason for prescribing corticosteroids can nevertheless, not be established in our data. This study has several strengths, including the large nationwide study population, accurate classification of the exposure, high validity of the assessed outcome data, and the ability to consider a number of important confounders. Factors such as comorbidity, women’s age at embryo transfer, calendar year of ART treatment, type of ART treatment, cause of infertility and smoking are also included. The considerable amount of data also provided statistical models with robustness for the main results. The study population comprises an unselected population of all patients with embryo transfers during a long time period, and information on ART procedures was based on complete and valid data from the Danish ART register which is based on statutory documentation of all treatments in all public and private clinics (Westergaard H. B., Johansen A. M., Erb K. and Andersen A. N., 2000) with extensive completeness and validity (Bliddal M., Broe A., Pottegard A., Olsen J. and Langhoff-Roos J., 2018; Knudsen L. B. and Olsen J., 1998; Schmidt M., Schmidt S. A., Sandegaard J. L., Ehrenstein V., Pedersen L. and Sorensen H. T., 2015). In order to ensure
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accurate exposure assessments (i.e. the diagnoses of MS), we included patients with at least one diagnose of MS recorded in the DNPR. In a Danish study on the validity of MS diagnoses in DNPR, the validity was high with 96.3%, using ICD-10 diagnoses (Mason K., Thygesen L. C., Stenager E., Bronnum-Hansen H. and Koch-Henriksen N., 2012). Regarding the outcome measurements, data from the DMBR provides both high completeness and validity, as all new-born children in Denmark are registered in the DMBR (Knudsen L. B. and Olsen J., 1998; Kristensen J., Langhoff-Roos J., Skovgaard L. T. and Kristensen F. B., 1996). Finally, the study design allows complete follow-up of the study cohorts and importantly, the outcomes of interest were retrieved independently of the exposure status, thereby preventing selection bias and differential misclassification of the outcome measurement. This study also has limitations. We did not have detailed clinical information on the use of MS medication, disease activity, and patient disability score as a patient chart review was not obtainable. Nonetheless, we do have reasons to believe that the majority of the women in our cohort must not be in a relapse phase during the ART treatment according to the review from Vukusic and colleagues (Vukusic S. and Marignier R., 2015). Also, our data did not provide us with information on the underlying reason for prescribing corticosteroids or the dosage of the corticosteroids. One could further speculate on a possible confounding impact of socioeconomics, but we have no reason to believe that such factors have an impact on our results, and as in other observational studies, an impact of unknown confounding can never be excluded. In Denmark there are more than 18,000 annual ART treatments corresponding to 8.0% of the childbirths in 2016 (Sundhedsdatastyrelsen and Sundhedsdatastyrelsen, 2017). Because of an increasing incidence of MS during the reproductive years (Gleicher N. and Barad D. H., 2007; Jolving L. R., Nielsen J., Kesmodel U. S., Nielsen R. G., Beck-Nielsen S. S. and Norgard B. M., 2016), physicians can foresee to treat increasingly more women with MS, counsel these women in 14
reproductive questions in general, but also to counsel them regarding the efficacy of ART treatment. We conclude that the chance of a live birth is not statistically significantly decreased in women with MS undergoing ART, compared to women without MS. These findings are novel, and replication is needed.
ACKNOWLEDGEMENTS The study received support from the Danish Multiple Sclerosis Society, Kong Christian den Tiendes Fond, the Region of Southern Denmark and Odense University Hospital.
CONTRIBUTERS LRJ: Funding, design, data collection, interpretation of results, manuscript drafting and editing, critical revision of the manuscript for important intellectual contents, approved the final version. MDL: Data analysis, interpretation of results, manuscript editing, critical revision of the manuscript for important intellectual contents, approved the final version. JF: Interpretation of results, manuscript editing, critical revision of the manuscript for important intellectual contents, approved the final version. BMN: Funding, conception of study, design, data collection, supervision of data analysis, interpretation of data, manuscript drafting and editing, critical revision of the manuscript for important intellectual contents, approved the final version. REFERENCES Bliddal M, Broe A, Pottegard A, Olsen J, and Langhoff-Roos J: The Danish Medical Birth Register, Eur J Epidemiol 33, 27-36.
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Boesen MS, Magyari M, Born AP, and Thygesen LC: Pediatric acquired demyelinating syndromes: a nationwide validation study of the Danish National Patient Register, Clin Epidemiol 10, 391-399. Boomsma CM, Keay SD, and Macklon NS: Peri-implantation glucocorticoid administration for assisted reproductive technology cycles, Cochrane Database Syst Rev, CD005996. Bove R, Alwan S, Friedman JM, Hellwig K, Houtchens M, Koren G, Lu E, McElrath TF, Smyth P, Tremlett H, and Sadovnick AD: Management of multiple sclerosis during pregnancy and the reproductive years: a systematic review, Obstet Gynecol 124, 1157-1168. Cavalla P, Rovei V, Masera S, Vercellino M, Massobrio M, Mutani R, and Revelli A: Fertility in patients with multiple sclerosis: current knowledge and future perspectives, Neurol Sci 27, 231-239. Charlson ME, Pompei P, Ales KL, and MacKenzie CR: A new method of classifying prognostic comorbidity in longitudinal studies: development and validation, J Chronic Dis 40, 373-383. Compston A, and Coles A: Multiple sclerosis, Lancet 359, 1221-1231. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, and Moreau T: Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group, N Engl J Med 339, 285-291. Correale J, Farez MF, and Ysrraelit MC: Increase in multiple sclerosis activity after assisted reproduction technology, Ann Neurol 72, 682-694. Fedder J, Loft A, Parner ET, Rasmussen S, and Pinborg A: Neonatal outcome and congenital malformations in children born after ICSI with testicular or epididymal sperm: a controlled national cohort study, Hum Reprod 28, 230-240. Filippini G, Brusaferri F, Sibley WA, Citterio A, Ciucci G, Midgard R, and Candelise L: Corticosteroids or ACTH for acute exacerbations in multiple sclerosis, Cochrane Database Syst Rev, CD001331. Friedman S, Larsen PV, Fedder J, and Norgard BM: The reduced chance of a live birth in women with IBD receiving assisted reproduction is due to a failure to achieve a clinical pregnancy, Gut 66, 556-558. Glazer CH, Tottenborg SS, Giwercman A, Brauner EV, Eisenberg ML, Vassard D, Magyari M, Pinborg A, Schmidt L, and Bonde JP: Male factor infertility and risk of multiple sclerosis: A register-based cohort study, Multiple sclerosis (Houndmills, Basingstoke, England), 1352458517734069. Gleicher N, and Barad DH: Gender as risk factor for autoimmune diseases, J Autoimmun 28, 1-6. Harbo HF, Gold R, and Tintore M: Sex and gender issues in multiple sclerosis, Ther Adv Neurol Disord 6, 237248. Hellwig K, and Correale J: Artificial reproductive techniques in multiple sclerosis, Clin Immunol 149, 219224. Hellwig K, Schimrigk S, Beste C, Muller T, and Gold R: Increase in relapse rate during assisted reproduction technique in patients with multiple sclerosis, Eur Neurol 61, 65-68. Jalkanen A, Alanen A, Airas L, Finnish Multiple S, and Pregnancy Study G: Pregnancy outcome in women with multiple sclerosis: results from a prospective nationwide study in Finland, Multiple sclerosis (Houndmills, Basingstoke, England) 16, 950-955. Jolving LR, Nielsen J, Kesmodel US, Nielsen RG, Beck-Nielsen SS, and Norgard BM: Prevalence of maternal chronic diseases during pregnancy - a nationwide population based study from 1989 to 2013, Acta Obstet Gynecol Scand 95, 1295-1304. Jonsson B, Von Reis G, and Sahlgren E: ACTH and cortisone in the treatment of multiple sclerosis, Acta Psychiatr Neurol Scand 29, 53. Kildemoes HW, Sorensen HT, and Hallas J: The Danish National Prescription Registry, Scand J Public Health 39, 38-41. Knudsen LB, and Olsen J: The Danish Medical Birth Registry, Dan Med Bull 45, 320-323. Kristensen J, Langhoff-Roos J, Skovgaard LT, and Kristensen FB: Validation of the Danish Birth Registration, J Clin Epidemiol 49, 893-897. Laplaud DA, Leray E, Barriere P, Wiertlewski S, and Moreau T: Increase in multiple sclerosis relapse rate following in vitro fertilization, Neurology 66, 1280-1281. Love S: Demyelinating diseases, J Clin Pathol 59, 1151-1159.
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Mason K, Thygesen LC, Stenager E, Bronnum-Hansen H, and Koch-Henriksen N: Evaluating the use and limitations of the Danish National Patient Register in register-based research using an example of multiple sclerosis, Acta Neurol Scand 125, 213-217. McCombe PA, and Stenager E: Female infertility and multiple sclerosis: is this an issue?, Multiple sclerosis (Houndmills, Basingstoke, England) 21, 5-7. Michel L, Foucher Y, Vukusic S, Confavreux C, de Seze J, Brassat D, Clanet M, Clavelou P, Ouallet JC, Brochet B, Pelletier J, Labauge P, Lebrun C, Lepage E, Le Frere F, Jacq-Foucher M, Barriere P, Wiertlewski S, Laplaud DA, and Club Francophone de la Sclerose En P: Increased risk of multiple sclerosis relapse after in vitro fertilisation, J Neurol Neurosurg Psychiatry 83, 796-802. Moberg JY, Laursen B, Thygesen LC, and Magyari M: Reproductive history of the Danish multiple sclerosis population: A register-based study, Multiple sclerosis (Houndmills, Basingstoke, England), 1352458519851245. Myhr KM, and Mellgren SI: Corticosteroids in the treatment of multiple sclerosis, Acta Neurol Scand Suppl, 73-80. Norgard BM, Larsen MD, Friedman S, Knudsen T, and Fedder J: Decreased chance of a live born child in women with rheumatoid arthritis after assisted reproduction treatment: a nationwide cohort study, Ann Rheum Dis. Norgard BM, Larsen PV, Fedder J, de Silva PS, Larsen MD, and Friedman S: Live birth and adverse birth outcomes in women with ulcerative colitis and Crohn's disease receiving assisted reproduction: a 20-year nationwide cohort study, Gut 65, 767-776. Nyboe Andersen A, and Erb K: Register data on Assisted Reproductive Technology (ART) in Europe including a detailed description of ART in Denmark, Int J Androl 29, 12-16. Petersen GL, Schmidt L, Pinborg A, and Kamper-Jorgensen M: The influence of female and male body mass index on live births after assisted reproductive technology treatment: a nationwide register-based cohort study, Fertil Steril 99, 1654-1662. Poser S, Raun NE, and Poser W: Age at onset, initial symptomatology and the course of multiple sclerosis, Acta Neurol Scand 66, 355-362. Pozzilli C, Pugliatti M, and Paradig MSG: An overview of pregnancy-related issues in patients with multiple sclerosis, Eur J Neurol 22 Suppl 2, 34-39. Robertson SA, Jin M, Yu D, Moldenhauer LM, Davies MJ, Hull ML, and Norman RJ: Corticosteroid therapy in assisted reproduction - immune suppression is a faulty premise, Hum Reprod 31, 2164-2173. Schmidt M, Schmidt SA, Sandegaard JL, Ehrenstein V, Pedersen L, and Sorensen HT: The Danish National Patient Registry: a review of content, data quality, and research potential, Clin Epidemiol 7, 449490. Stenager E: A global perspective on the burden of multiple sclerosis, Lancet Neurol. Sundhedsdatastyrelsen, and Sundhedsdatastyrelsen: Assisteret reproduktion 2016, 1.0, 12. Thygesen LC, Daasnes C, Thaulow I, and Bronnum-Hansen H: Introduction to Danish (nationwide) registers on health and social issues: structure, access, legislation, and archiving, Scand J Public Health 39, 12-16. van Mourik MS, Macklon NS, and Heijnen CJ: Embryonic implantation: cytokines, adhesion molecules, and immune cells in establishing an implantation environment, J Leukoc Biol 85, 4-19. Vukusic S, and Marignier R: Multiple sclerosis and pregnancy in the 'treatment era', Nat Rev Neurol 11, 280289. Westergaard HB, Johansen AM, Erb K, and Andersen AN: Danish National IVF Registry 1994 and 1995. Treatment, pregnancy outcome and complications during pregnancy, Acta Obstet Gynecol Scand 79, 384-389. World Health Organization.: Obesity : preventing and managing the global epidemic Geneva, 2000, World Health Organization.
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Biography LRJ has a PhD. in clinical epidemiology from University of Southern Denmark in 2018. She is affiliated at University of Southern Denmark as a postdoctoral researcher and at Center for Clinical Epidemiology at Odense University Hospital. She takes advantages of the Danish nationwide registries in her research on different areas within human reproduction, fetal programming hypothesis and the impact of maternal chronic disease on assisted reproductive technology, pregnancy and offspring morbidity.
Key message In women with other autoimmune diseases, we have previously found statistically significant reduced chances of a live birth after assisted reproduction. In this study, however, we did not find a statistically significantly decreased chance of a livebirth in women with multiple sclerosis, compared to other women. Besides being novel, our results further suggests that women with multiple sclerosis using steroids aroud the time of embryo transfer did not have an alterd chance of a live birth.
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Table 1 Descriptive characteristic of study cohort of assisted reproductive technology (ART) treatment (embryo transfers) in women with multiple sclerosis (MS) and in women without MS, during the study period of 1 January 1995 to 31 December 2017 Exposed cohort (embryo transfers in women with MS)a, b N=2,267
Unexposed cohort (embryo transfers in women without MS)a, c N=200,684
Characteristics Age at embryo transfer Median (25%-75% percentiles) 34 (31-38) 34 (30-37) Partner’s age at embryo transfer Median (25%-75% percentiles) 35 (33-39) 36 (32-40) Cause of infertility Female factor, N (%) 545 (25.5) 44,642 (23.6) Male factor, N (%) 711 (33.3) 60,417 (32.0) Mixture of factors/idiopathic, N (%) 879 (41.2) 83,824 (44.4) Type of preceding treatment* IVF, N (%) 977 (43.6) 88,378 (44.3) ICSI, N (%) 821 (36.6) 70,231 (35.2) FER, N (%) 444 (19.8) 40,721 (20.4) Body mass index BMI <18.5 (underweight), N (%) 24 (2.1) 3,514 (3.4) 18.5-24.9 (normal), N (%) 664 (56.9) 66,899 (63.8) 25.0-29.9 (overweight), N (%) 334 (28.6) 24,116 (23.0) ≥30.0 (obese) N (%) 144 (12.3) 10,323 (9.8) Smoking at the time of embryo transfer Non-smoker, N (%) 1,028 (89.9) 95,237 (91.6) Smoker, N (%) 115 (10.1) 8,760 (8.4) Alcohol No, N (%) 711 (64.4) 55,233 (55.3) Yes, N (%) 393 (35.6) 44,625 (44.7) Calendar year of infertility treatment 1995-2000 N (%) 412 (18.2) 34,109 (17.0) 2001-2006 N (%) 568 (25.1) 47,424 (23.6) 2007-2012 N (%) 695 (30.7) 61,789 (30.8) 2013-2017 N (%) 592 (26.1) 57,362 (28.6) Parity 0, N (%) 323 (66.1) 32,134 (67.6) 1+, N (%) 166 (33.9) 15,418 (32.4) Comorbidity at embryo transfers No comorbidity, N (%) 1,932 (85.2) 181,969 (90.7) Some comorbidity, N (%) 335 (14.8) 18,715 (9.3) Duration of multiple sclerosis at the time of embryo transfer (years) Median (25-75 percentiles) 18 (9-26) a Number of women in exposed 815 and in the unexposed cohort: 66,960 b Missing (%), women with multiple sclerosis: Age of partner (43.8), fertility factor (5.8), ART treatment (1.1), parity (78.4), BMI (48.6), smoking at the time of embryo transfer (49.6), alcohol (51.3) c Missing (%), women without multiple sclerosis: Age of partner (40.4), fertility factor (5.9), ART treatment (0.7), parity (76.3), BMI (48.6), smoking at the time of embryo transfer (48,2), alcohol (50,2) * IVF: In vitro fertilization, ICSI: Intracytoplasmic sperm injection, FER: frozen-thawed embryo replacement.
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Table 2 The chance of live birth in women with multiple sclerosis (MS) after assisted reproductive technology (ART) treatment (embryo transfer), during the study period of 1 January 1995 to 31 December 2017 Exposed cohort (embryo transfers in women MS) N=2,267a
Unexposed cohort (embryo transfers in women without MS) N=200,684b
Crude OR (95% CI)
Adjusted ORc (95% CI)
Live birth Yes, N (%) 498 (21.97) 48,503 (24.17) 0.85 (0.76-0.96) 0.91 (0.81-1.02) No, N (%) 1,769 (78.03) 152,181 (75.83) a Number of women in the exposed cohort: 815 b Number of women in the unexposed cohort: 66,960 c Adjusted for comorbidity, women’s age, calendar year of treatment, type of treatment (in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), frozen-thawed embryo replacement (FER), cause of infertility (female factor, male factor, or mixture of factors/idiopathic). Number of observations=189,649 number of women: 66,628.
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Table 3 Biochemical and clinical pregnancies in women with multiple sclerosis (MS), in the study cohorts of assisted reproductive technology (ART) treatments during the study period of 1 January 2010 through 31 December 2017 Exposed cohort Unexposed cohort (embryo transfers (embryo transfers Crude OR Adjusted OR in women with in women without (95% CI) (95% CI)a MS) MS) Biochemical pregnancy (hCG) b Yes, N (%) 318 (34.12) 32,243 (36.65) 0.88 (0.75-1.03) 0.92 (0.78-1.08) No, N (%) 614 (65.88) 55,733 (63.35) Clinical Pregnancy (ultra sound) c Yes, N (%) 259 (82.22) 26,594 (83.52) 0.91 (0.66-1,27) 0.89 (0.64-1.25) No, N (%) 56 (17.78) 5,248 (16.48) a Adjusted for comorbidity, women’s age, calendar year of treatment, type of treatment (in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), frozen-thawed embryo replacement (FER), cause of infertility (female factor, male factor, or a mixture of factors/idiopathic) and partner´s age. b Number of embryo transfers in the exposed cohort: 932 (number of women: 354). Number of embryo transfers in the unexposed cohort: 87,976 (number of women: 31,094). c Number of embryo transfers in the exposed cohort: 315 (number of women: 213). Number of embryo transfers in the unexposed cohort: 31,842 (number of women: 22,320).
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Table 4 The chance of live birth in women with multiple sclerosis (MS), who had prescriptions for corticosteroids 3 months prior to embryo transfer, compared with women with MS, who did not have prescriptions for corticosteroids 3 months prior to embryo transfer. The study period of 1 January 1995 to 31 December 2017
Exposed cohort (embryo transfers in women with MS, with prescriptions for corticosteroids prior to embryo transfer) N=100a
Unexposed cohort (embryo transfers in women with MS who did not have prescriptions for corticosteroids prior to embryo transfer) N=2,167b
Crude OR (95% CI)
Adjusted ORc (95% CI)
Live birth Yes, N (%) 18 (18.00) 480 (22.15) 0.87 (0.49-1.52) 0.90 (0.49-1.68) No, N (%) 82 (82.00) 1,687 (77.85) a Number of women in the exposed cohort: 52 b Number of women in the unexposed cohort: 810 c Adjusted for comorbidity, women’s age, calendar year of treatment, type of treatment (in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), frozen-thawed embryo replacement (FER), and cause of infertility (female factor, male factor, or mixture of factors/idiopathic).
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Journal Pre-proof
Live birth in women with multiple sclerosis receiving assisted reproduction Line Riis Jølving MHSc, Ph.D. , Michael Due Larsen MSc. Pharm, Ph.D. Associate professor , Jens Fedder MD, DMSc, Ph.D. Professor , ˚ MD, DMSc, Ph.D. Professor Bente Mertz Nørgard PII: DOI: Reference:
S1472-6483(20)30066-3 https://doi.org/10.1016/j.rbmo.2020.01.013 RBMO 2336
To appear in:
Reproductive BioMedicine Online
Received date: Revised date: Accepted date:
28 October 2019 20 January 2020 21 January 2020
Please cite this article as: Line Riis Jølving MHSc, Ph.D. , Michael Due Larsen MSc. Pharm, Ph.D. Associate profe ˚ MD, DMSc, Ph.D. Professor , Live Jens Fedder MD, DMSc, Ph.D. Professor , Bente Mertz Nørgard birth in women with multiple sclerosis receiving assisted reproduction, Reproductive BioMedicine Online (2020), doi: https://doi.org/10.1016/j.rbmo.2020.01.013
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Live birth in women with multiple sclerosis receiving assisted reproduction Short running title: Assisted reproduction in multiple sclerosis Line Riis Jølving, MHSc, Ph.D.1, Michael Due Larsen, MSc. Pharm, Ph.D., associate professor1, Jens Fedder, MD, DMSc, Ph.D., Professor2, Bente Mertz Nørgård, MD, DMSc, Ph.D., Professor1 1
Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark and Research
Unit of Clinical Epidemiology, Department of Clinical Research, University of Southern Denmark, Odense, Denmark. 2
Centre of Andrology and Fertility Clinic, Odense University Hospital, Odense Denmark and
Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Words: Abstract: 246, body text: 4222. Tables: 4. Keywords: Assisted reproductive technology, in vitro fertilization, multiple sclerosis, clinical epidemiology, chronic disease.
Corresponding author: Line Riis Jølving, MHSc, Ph.D., Center for Clinical Epidemiology and Research Unit of Clinical Epidemiology, Odense University Hospital, Kløvervænget 30, Entrance 216, Odense C DK-5000, Denmark; +45 2462 9638 [email protected].
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ABSTRACT Research question Multiple sclerosis (MS) is predominant in women during the childbearing years and in case of problems with conceiving naturally, assisted reproductive technology (ART) becomes relevant. The efficacy of ART treatment in women MS has not previously been studied. Our aim was to examine the chance of a live-born child after an embryo transfer in women with MS and to examine whether corticosteroids prior to embryo transfer had a beneficial effect. Design This cohort study is based on nationwide Danish health registries, including all women with embryo transfers from 1 January 1995 through 31 December 2017. The exposed cohort comprised 2,267 embryo transfers in women with MS and 200,684 in women without MS (unexposed). We used multilevel logistic regression analysis to compute the crude and the adjusted risk estimates. Results A total of 21.97% of the embryo transfers in women with MS resulted in a live born child compared to 24.17% in women without MS, and the adjusted odds ratio (aOR) was 0.91 (95% CI 0.81 - 1.02). The aOR of live birth in women with MS using corticosteroids prior to embryo transfer was 0.90 (95% CI 0.49 – 1.68), compared to women with MS receiving no corticosteroids. Conclusion The chance of a live birth was not decreased, in women with MS undergoing ART, compared to women without MS. The use of corticosteroids had no impact on the result. These novel results on ART treatment are useful when counseling women with MS undergoing assisted reproduction.
INTRODUCTION
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Multiple sclerosis (MS) is a chronic autoimmune disease that causes progressive damage to the myelin sheaths with an array of symptoms (Compston A. and Coles A., 2002; Poser S., Raun N. E. and Poser W., 1982; Stenager E., 2019). The disease is one of the most common neurological demyelinating disease (Love S., 2006) and is predominant in women with a peak incidence during the childbearing years from 20-45 (Poser S., Raun N. E. and Poser W., 1982). Whether fertility is impaired in MS is still a subject for debate (Cavalla P., Rovei V., Masera S., Vercellino M., Massobrio M., Mutani R. and Revelli A., 2006; Jalkanen A., Alanen A., Airas L., Finnish Multiple Sclerosis and Pregnancy Study Group, 2010; McCombe P. A. and Stenager E., 2015; Moberg J. Y., Laursen B., Thygesen L. C. and Magyari M., 2019) but in case of problems with conceiving naturally, assisted reproductive technology (ART) becomes relevant. In this study we aimed to examine the efficacy of ART in women with MS. Previous studies have focused on which impact ART treatment has on the MS symptoms and the disease course, and a number of putative mechanisms involved in MS have been suggested to worsen after ART treatment resulting in an increased relapse rate of the MS symptoms (Cavalla P., Rovei V., Masera S., Vercellino M., Massobrio M., Mutani R. and Revelli A., 2006; Correale J., Farez M. F. and Ysrraelit M. C., 2012; Hellwig K. and Correale J., 2013; Hellwig K., Schimrigk S., Beste C., Muller T. and Gold R., 2009; Laplaud D. A., Leray E., Barriere P., Wiertlewski S. and Moreau T., 2006; Michel L., Foucher Y., Vukusic S., Confavreux C., de Seze J., Brassat D., Clanet M., Clavelou P., Ouallet J. C., Brochet B., Pelletier J., Labauge P., Lebrun C., Lepage E., Le Frere F., Jacq-Foucher M., Barriere P., Wiertlewski S., Laplaud D. A. and Club Francophone de la Sclerose En Plaques, 2012). Furthermore, corticosteroids may be used to treat relapses in multiple sclerosis, but prednisolone or related drugs have also been proposed to improve the embryo implantation rate after ART treatment in general, and to protect against miscarriage when administrated from embryo implantation through the early placentation phase (Robertson S. A., Jin M., Yu D., Moldenhauer L. M., Davies
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M. J., Hull M. L. and Norman R. J., 2016; van Mourik M. S., Macklon N. S. and Heijnen C. J., 2009). Whether there is a beneficial effect of corticosteroids at embryo transfer in women with MS is so far unsettled (Boomsma C. M., Keay S. D. and Macklon N. S., 2012). Therefore, based on nationwide Danish registries on all embryo transfers for a period of 23 years, we examined the chance of a live born child after ART treatment (the primary outcome) in women with MS compared to all other women receiving ART. Secondary outcomes were a biochemical pregnancy (a positive human chorionic gonadotropin (hCG) measurement) and a clinical pregnancy (positive ultrasound), and lastly a potential impact of treatment with corticosteroids prior to embryo transfer was examined.
MATERIAL AND METHODS Setting In Denmark, all citizens have free access to a tax-supported health care system including an offer of ART treatment to all infertile couples and single women referred to infertility treatment before the age of 41 years. In the private sector, fertility treatments are permitted until the woman’s age is 46 years (Glazer C. H., Tottenborg S. S., Giwercman A., Brauner E. V., Eisenberg M. L., Vassard D., Magyari M., Pinborg A., Schmidt L. and Bonde J. P., 2017). The Danish population of approximately 5.6 million inhabitants has a unique civil registration number assigned at birth, and this unique number is used across all Danish health registers for valid record linkage at an individual level. Therefore, the Danish registers are unique for population-based study design using nationwide information across data sources. Study population
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We obtained the following data: i) data related to all ART procedures and causes of infertility, and data on the outcomes of biochemical and clinical pregnancy from the Danish ART register (Nyboe Andersen A. and Erb K., 2006; Westergaard H. B., Johansen A. M., Erb K. and Andersen A. N., 2000), ii) data on the outcome of the ART treatment in terms of a live-born child from the Danish Medical Birth Register (DMBR) (Bliddal M., Broe A., Pottegard A., Olsen J. and Langhoff-Roos J., 2018), iii) data on diagnoses of MS, and comorbidity from The Danish National Patient Register (DNPR) (Schmidt M., Schmidt S. A., Sandegaard J. L., Ehrenstein V., Pedersen L. and Sorensen H. T., 2015), iv) data on prescriptions of corticosteroids from The Danish National Prescription Register according to the Anatomical Therapeutic Chemical (ATC) Classification system in women with MS (Kildemoes H. W., Sorensen H. T. and Hallas J., 2011), and finally v) data on death and emigration, based on the civil registration number from The Civil Registration System (CRS) (Thygesen L. C., Daasnes C., Thaulow I. and Bronnum-Hansen H., 2011). The study population comprised all women with a valid civil registration number, who were available for at least 9 months of follow-up after any ART treatment in Denmark, and who started ART treatment with one or several embryo transfers during the study period of 1 January 1995 to 31 December 2017. All ART treatment cycles are mandatorily recorded in the Danish ART register. The register was established on 1 January 1994 and includes data from both public and private clinics (Westergaard H. B., Johansen A. M., Erb K. and Andersen A. N., 2000). For the purpose of this study, all embryo transfers could be a result of in vitro fertilization (IVF), with or without fertilization with intracytoplasmic sperm injection (ICSI) and transfer of frozen-thawed embryo replacement (FER). The exposed cohort All women in the study population, with diagnoses of MS before the embryo transfer, were identified in the DNPR. The DNPR has recorded all discharges from Danish hospitals since 1977 5
and all outpatient visits since 1994 (Schmidt M., Schmidt S. A., Sandegaard J. L., Ehrenstein V., Pedersen L. and Sorensen H. T., 2015). The exposed cohort is constituted by all embryo transfers in women who had at least one discharge diagnosis of MS from any hospital in Denmark before the date of embryo transfer (ICD-8 code: 340, 349; ICD-10 codes: G35).(Boesen M. S., Magyari M., Born A. P. and Thygesen L. C., 2018; Mason K., Thygesen L. C., Stenager E., Bronnum-Hansen H. and Koch-Henriksen N., 2012). The ICD-9 classifications were never used in Denmark. Women with MS could have several embryo transfers during the study period and we thus used the embryo transfer as the observation unit (Fedder J., Loft A., Parner E. T., Rasmussen S. and Pinborg A., 2013). The unexposed cohort The unexposed cohort comprised all embryo transfers where the woman did not have a diagnosis of MS before the date of embryo transfer; and similarly to the exposed cohort, the observation unit was the embryo transfer. Primary and secondary outcomes The outcome was a live born child recorded in the DMBR within a period of 124-292 days after each embryo transfer. Live birth was considered to be a result of a particular ART treatment if the difference was 140-308 days (corresponding to 20-44 weeks) from the last menstruation start or 124-292 days after each embryo transfer (Norgard B. M., Larsen M. D., Friedman S., Knudsen T. and Fedder J., 2019; Norgard B. M., Larsen P. V., Fedder J., de Silva P. S., Larsen M. D. and Friedman S., 2016; Petersen G. L., Schmidt L., Pinborg A. and Kamper-Jorgensen M., 2013). The DMBR holds information on all births in Denmark since 1 January 1973 and includes information on the mother, the child, and birth-related information such as date of birth, gestational age, birth weight and mode of delivery (Bliddal M., Broe A., Pottegard A., Olsen J. and Langhoff-Roos J.,
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2018; Knudsen L. B. and Olsen J., 1998; Kristensen J., Langhoff-Roos J., Skovgaard L. T. and Kristensen F. B., 1996). From the ART register we extracted information on the secondary outcomes biochemical pregnancies (a positive hCG test at day 14-16 after embryo transfer), and a clinical pregnancy (a positive ultrasound examination approximately 7-8 weeks after embryo transfer) from 2010 and onwards (Westergaard H. B., Johansen A. M., Erb K. and Andersen A. N., 2000). Finally, we examined the impact of the use of corticosteroids within three months prior to the embryo transfer based on prescriptions obtained from the nationwide Danish Database of Reimbursed Prescriptions where data on outpatient drug prescriptions has been available since 1995 (Kildemoes H. W., Sorensen H. T. and Hallas J., 2011). Confounders Confounders included in the statistical models were selected a priori and counts information from the different registries. From the DNPR we obtained information on comorbidity in the study population, and a comorbidity index score adapted from Charlson was conducted, covering 19 disease categories weighted according to their prognostic impact (Charlson M. E., Pompei P., Ales K. L. and MacKenzie C. R., 1987). The scores were calculated for each treatment cycle of each woman in two index levels: no comorbidity (index 0), and some comorbidity (index 1). From the ART register we extracted information on parity in two categories (0, 1+), women’s age at the time of embryo transfer (as a continuous variable), year of infertility treatment in four categories (19952000, 2001-2006, 2007-2012, and 2013-2017), type of ART treatment (IVF, ICSI or FER), and the cause of infertility (female factor, male factor, or a mixture of factors/idiopathic). Since 2006, the ART register further includes data on the following potential confounders: partners age (as a continuous variable), alcohol intake (yes/no), smoking at the time of embryo transfer and body mass index (BMI), categorized according to the World Health Organization (World Health Organization.,
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2000) in four categories (underweight: <18.5 kg/m2, normal weight: 18.5-24.9 kg/m2, overweight: 25.0-29.9 kg/m2, and obese: ≥30 kg/m2). Statistical analyses Main analyses for the primary and secondary outcomes We conducted contingency tables on the main study variables according to the exposed and the unexposed cohort, and the duration of MS was calculated from the date of the first occurring diagnosis of MS in the DNPR until the date of the first embryo transfer. We used multilevel logistic regression analyses to compute the crude and the confounder-adjusted relative risk estimates as odds ratios (OR), with the corresponding 95% confidence intervals (CI), for a live birth following embryo transfer in women with MS relative to women without MS, undergoing ART treatment. Likewise, analyses were conducted on the outcomes of biochemical pregnancy, and clinical pregnancy following embryo transfer on a restricted period from 2010 and onwards. The models accounted for multiple embryo transfers. In the adjusted analyses we included the comorbidity index, women’s age at the time of embryo transfer, calendar year of infertility treatment, type of ART treatment, and the cause of infertility. In sub-analysis, we examined a potential impact of the partner’s age, alcohol intake, and BMI using data from a restricted period from 2006, but the inclusion of these factors did not change the results and was omitted from the final model. Sub-analysis of the impact of corticosteroids and weight on the primary outcome In a sub-analysis we examined a possible impact of use of corticosteroid within 3 months prior to embryo transfer in women with MS. We obtained the prescription history of each woman with MS by corticosteroid use according to ATC codes: H02AB02 (Dexamethasone), H02AB04 (Methylprednisolone), H02AB06 (Prednisolone), H02AB07 (Prednisone), and H02AB09 (Hydrocortisone). Based on this information, we stratified the population of women with MS 8
undergoing ART treatment into two cohorts, the exposed cohort was the embryo transfers in women with MS, who had at least one prescription for corticosteroids within a period of 3 months before the date of embryo transfer, and the unexposed cohort was embryo transfers in women with MS, who had no prescriptions for corticosteroids 3 months before embryo transfer. Live births in the exposed cohort were compared to live births in women with MS without the use of corticosteroids. In another sub-analysis, we examined by stratified analyses the chance of a live born child in categories of women’s weight (normal weighted women, and overweight and obesity). Approvals and ethical considerations The study is notified at the Danish Data Protection Agency under the current joint notification of the Region of Southern Denmark (ref.no. 2012-58-0018). In Denmark, record linkage studies that only use information already recorded in the health registries do not require informed patient consent. All data was in encrypted form so that no individuals could be identified by the researchers, and data was stored and linked at a secure server at the Danish Health Data Authority, and all statistical analyses were conducted using Stata v. 15.0 software (StataCorp LP, College Station, Texas, USA).
RESULTS Patient characteristics A total of 2,267 embryo transfers (in 815 women with MS) constituted the exposed cohort, and 200,684 embryo transfers (in 66,960 women without MS) constituted the unexposed cohort. The median age at onset of ART treatment, the cause of infertility and type of preceding treatment were similar in the two cohorts, whereas women in the exposed cohort were slightly more overweight
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than women in the unexposed cohort 28.6% versus 23.0% and obese with 12.3% versus 9.8% (Table 1). Similarly, women in the exposed cohort had more comorbid diseases compared to the unexposed cohort, 14.8% versus 9.3%, whereas alcohol consumption was more frequent in the unexposed cohort with 44.7% compared to 35.6% in the exposed cohort. The median duration of MS at the time of embryo transfer was 18 years (25-75 percentile; 9-26 years). Primary and secondary outcomes A total of 21.97% of the embryo transfers in women with MS resulted in a live born child, compared to 24.17% in women without MS (Table 2). The crude OR of live birth was 0.85 (95 % CI, 0.76 - 0.96), and the confounder adjusted OR 0.91 (95% CI, 0.81 – 1.02). The chance of a biochemical pregnancy and a clinical pregnancy after embryo transfer is shown in Table 3. The adjusted OR of a positive hCG measurement in women with MS, relative to women without MS, was 0.92 (95% CI, 0.78 – 1.08), and the adjusted OR for a clinical pregnancy in women with MS was 0.89 (95% CI, 0.64 – 1.25) (Table 3). Sub-analysis on the use of corticosteroids prior to embryo transfer In the analyses of a potential impact of corticosteroid prior to embryo transfer, the adjusted OR of a live birth in women with MS using corticosteroids was 0.90 (95% CI, 0.49 – 1.68) compared to women with MS receiving no prescription of corticosteroids (Table 4). Sub-analysis on the impact of weight In women with normal weight, the adjusted OR of a live birth in women with MS, compared to women without MS, was 0.89 (95% CI 0.72-1.09) and in those being obese and overweight the results were identical.
DISCUSSION
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In this nationwide cohort study including data from 23 years of ART treatment, we found no statistically significantly reduced chance of a live birth in women with MS, receiving ART treatment compared to other women receiving ART treatment. The use of corticosteroids up to 3 months before embryo transfer did not seem to have a positive impact on the chance of a live birth. To the best of our knowledge, these findings are novel, and because this is the first study to examine the chance of live birth in women with MS receiving ART treatment, we cannot compare our results to others. However, several studies on women with MS receiving ART treatment have tended to pivot around the medical treatment related to both MS and ART, on the MS disease course (Hellwig K. and Correale J., 2013; Hellwig K., Schimrigk S., Beste C., Muller T. and Gold R., 2009; Laplaud D. A., Leray E., Barriere P., Wiertlewski S. and Moreau T., 2006; Pozzilli C., Pugliatti M. and Paradig M. S. Group, 2015; Vukusic S. and Marignier R., 2015). Besides being novel, this study is important for a number of reasons: i) the number of women with MS in their fertile years is increasing (Harbo H. F., Gold R. and Tintore M., 2013; Jolving L. R., Nielsen J., Kesmodel U. S., Nielsen R. G., Beck-Nielsen S. S. and Norgard B. M., 2016; Stenager E., 2019), and the questions related to the efficacy of ART in MS may become increasingly frequent, ii) the results on ART treatment in women with other autoimmune diseases have suggested a reduced chance of a live birth which could therefore also be the case in MS. Thus the ORs of a live birth after ART treatment in women with ulcerative colitis and Crohn’s disease were 0.78 (95% CI 0.67 – 0.91), and 0.61 (95% CI 0.47 – 0.79), respectively (Norgard B. M., Larsen P. V., Fedder J., de Silva P. S., Larsen M. D. and Friedman S., 2016) and the OR for a live birth in women with rheumatoid arthritis was OR 0.78 (95% CI 0.65 – 0.92) (Norgard B. M., Larsen M. D., Friedman S., Knudsen T. and Fedder J., 2019) in recent studies. The mechanisms behind these findings so far are unknown (Friedman S., Larsen P. V., Fedder J. and Norgard B. M., 2017; Norgard B. M., Larsen M. D., Friedman S., Knudsen T. and Fedder J., 2019), but the live birth rate
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may be affected by numerous factors related to the different stages of fertilization, implantation and to the ability to maintain a pregnancy throughout the trimesters. When it comes to use of medications, MS disease-modifying therapies is not recommended during infertility treatment, pregnancy and lactation (Bove R., Alwan S., Friedman J. M., Hellwig K., Houtchens M., Koren G., Lu E., McElrath T. F., Smyth P., Tremlett H. and Sadovnick A. D., 2014) but an applicant drug in pregnancies is corticosteroids with a broad-spectrum anti-inflammatory and immunosuppressive property. A possible positive impact of corticosteroids on embryo implantation in women with MS is however uncertain though a beneficial impact on ART treatment in general, is discussed (Robertson S. A., Jin M., Yu D., Moldenhauer L. M., Davies M. J., Hull M. L. and Norman R. J., 2016). However, the use of corticosteroids in women undergoing standard IVF treatment was associated with an increased pregnancy rate, suggesting that amongst unselected women there may be subsets with undiagnosed immune disorders that benefit from immunosuppressive therapy (Boomsma C. M., Keay S. D. and Macklon N. S., 2012; Robertson S. A., Jin M., Yu D., Moldenhauer L. M., Davies M. J., Hull M. L. and Norman R. J., 2016). We, nevertheless did not detect a clear beneficial impact of the use of corticosteroids among women with MS and the statistical power in our analyses was limited. Patient characteristics with respect to the cause of infertility did not seem to differ between women with, and women without MS. A potential decreased relapse rate during pregnancy has been suggested in the literature, though a rebound effect can occur postpartum (Confavreux C., Hutchinson M., Hours M. M., Cortinovis-Tourniaire P. and Moreau T., 1998). Hormones supplied as a part of the ART treatment may also alter the short-term course of the disease, although the exact mechanism for the increase in relapse risk of women with MS after ART treatment is not fully understood (Confavreux C., Hutchinson M., Hours M. M., Cortinovis-Tourniaire P. and Moreau T., 1998; Harbo H. F., Gold R. and Tintore M., 2013). Additionally, the number of new or enlarging T
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lesions and gadolinium-enhancing lesions up to three months after ART treatment has been described (Correale J., Farez M. F. and Ysrraelit M. C., 2012) and a recent review from Vukusic and colleagues concludes that it may be wise to undergo the ART treatment during a period when the disease is not active (Vukusic S. and Marignier R., 2015). Corticosteroids could be prescribed for a number of reasons in our study, including a potentially positive role of an improved chance of implementation of the egg and corticosteroids may be prescribed by fertility doctors (Boomsma C. M., Keay S. D. and Macklon N. S., 2012). However, therapeutic strategies in MS could also include corticosteroid treatment of relapses and immunomodulatory or immunosuppressive treatment to prevent new relapses and progression of disability (Filippini G., Brusaferri F., Sibley W. A., Citterio A., Ciucci G., Midgard R. and Candelise L., 2000; Jonsson B., Von Reis G. and Sahlgren E., 1954; Myhr K. M. and Mellgren S. I., 2009). The underlying reason for prescribing corticosteroids can nevertheless, not be established in our data. This study has several strengths, including the large nationwide study population, accurate classification of the exposure, high validity of the assessed outcome data, and the ability to consider a number of important confounders. Factors such as comorbidity, women’s age at embryo transfer, calendar year of ART treatment, type of ART treatment, cause of infertility and smoking are also included. The considerable amount of data also provided statistical models with robustness for the main results. The study population comprises an unselected population of all patients with embryo transfers during a long time period, and information on ART procedures was based on complete and valid data from the Danish ART register which is based on statutory documentation of all treatments in all public and private clinics (Westergaard H. B., Johansen A. M., Erb K. and Andersen A. N., 2000) with extensive completeness and validity (Bliddal M., Broe A., Pottegard A., Olsen J. and Langhoff-Roos J., 2018; Knudsen L. B. and Olsen J., 1998; Schmidt M., Schmidt S. A., Sandegaard J. L., Ehrenstein V., Pedersen L. and Sorensen H. T., 2015). In order to ensure
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accurate exposure assessments (i.e. the diagnoses of MS), we included patients with at least one diagnose of MS recorded in the DNPR. In a Danish study on the validity of MS diagnoses in DNPR, the validity was high with 96.3%, using ICD-10 diagnoses (Mason K., Thygesen L. C., Stenager E., Bronnum-Hansen H. and Koch-Henriksen N., 2012). Regarding the outcome measurements, data from the DMBR provides both high completeness and validity, as all new-born children in Denmark are registered in the DMBR (Knudsen L. B. and Olsen J., 1998; Kristensen J., Langhoff-Roos J., Skovgaard L. T. and Kristensen F. B., 1996). Finally, the study design allows complete follow-up of the study cohorts and importantly, the outcomes of interest were retrieved independently of the exposure status, thereby preventing selection bias and differential misclassification of the outcome measurement. This study also has limitations. We did not have detailed clinical information on the use of MS medication, disease activity, and patient disability score as a patient chart review was not obtainable. Nonetheless, we do have reasons to believe that the majority of the women in our cohort must not be in a relapse phase during the ART treatment according to the review from Vukusic and colleagues (Vukusic S. and Marignier R., 2015). Also, our data did not provide us with information on the underlying reason for prescribing corticosteroids or the dosage of the corticosteroids. One could further speculate on a possible confounding impact of socioeconomics, but we have no reason to believe that such factors have an impact on our results, and as in other observational studies, an impact of unknown confounding can never be excluded. In Denmark there are more than 18,000 annual ART treatments corresponding to 8.0% of the childbirths in 2016 (Sundhedsdatastyrelsen and Sundhedsdatastyrelsen, 2017). Because of an increasing incidence of MS during the reproductive years (Gleicher N. and Barad D. H., 2007; Jolving L. R., Nielsen J., Kesmodel U. S., Nielsen R. G., Beck-Nielsen S. S. and Norgard B. M., 2016), physicians can foresee to treat increasingly more women with MS, counsel these women in 14
reproductive questions in general, but also to counsel them regarding the efficacy of ART treatment. We conclude that the chance of a live birth is not statistically significantly decreased in women with MS undergoing ART, compared to women without MS. These findings are novel, and replication is needed.
ACKNOWLEDGEMENTS The study received support from the Danish Multiple Sclerosis Society, Kong Christian den Tiendes Fond, the Region of Southern Denmark and Odense University Hospital.
CONTRIBUTERS LRJ: Funding, design, data collection, interpretation of results, manuscript drafting and editing, critical revision of the manuscript for important intellectual contents, approved the final version. MDL: Data analysis, interpretation of results, manuscript editing, critical revision of the manuscript for important intellectual contents, approved the final version. JF: Interpretation of results, manuscript editing, critical revision of the manuscript for important intellectual contents, approved the final version. BMN: Funding, conception of study, design, data collection, supervision of data analysis, interpretation of data, manuscript drafting and editing, critical revision of the manuscript for important intellectual contents, approved the final version. REFERENCES Bliddal M, Broe A, Pottegard A, Olsen J, and Langhoff-Roos J: The Danish Medical Birth Register, Eur J Epidemiol 33, 27-36.
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Boesen MS, Magyari M, Born AP, and Thygesen LC: Pediatric acquired demyelinating syndromes: a nationwide validation study of the Danish National Patient Register, Clin Epidemiol 10, 391-399. Boomsma CM, Keay SD, and Macklon NS: Peri-implantation glucocorticoid administration for assisted reproductive technology cycles, Cochrane Database Syst Rev, CD005996. Bove R, Alwan S, Friedman JM, Hellwig K, Houtchens M, Koren G, Lu E, McElrath TF, Smyth P, Tremlett H, and Sadovnick AD: Management of multiple sclerosis during pregnancy and the reproductive years: a systematic review, Obstet Gynecol 124, 1157-1168. Cavalla P, Rovei V, Masera S, Vercellino M, Massobrio M, Mutani R, and Revelli A: Fertility in patients with multiple sclerosis: current knowledge and future perspectives, Neurol Sci 27, 231-239. Charlson ME, Pompei P, Ales KL, and MacKenzie CR: A new method of classifying prognostic comorbidity in longitudinal studies: development and validation, J Chronic Dis 40, 373-383. Compston A, and Coles A: Multiple sclerosis, Lancet 359, 1221-1231. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, and Moreau T: Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group, N Engl J Med 339, 285-291. Correale J, Farez MF, and Ysrraelit MC: Increase in multiple sclerosis activity after assisted reproduction technology, Ann Neurol 72, 682-694. Fedder J, Loft A, Parner ET, Rasmussen S, and Pinborg A: Neonatal outcome and congenital malformations in children born after ICSI with testicular or epididymal sperm: a controlled national cohort study, Hum Reprod 28, 230-240. Filippini G, Brusaferri F, Sibley WA, Citterio A, Ciucci G, Midgard R, and Candelise L: Corticosteroids or ACTH for acute exacerbations in multiple sclerosis, Cochrane Database Syst Rev, CD001331. Friedman S, Larsen PV, Fedder J, and Norgard BM: The reduced chance of a live birth in women with IBD receiving assisted reproduction is due to a failure to achieve a clinical pregnancy, Gut 66, 556-558. Glazer CH, Tottenborg SS, Giwercman A, Brauner EV, Eisenberg ML, Vassard D, Magyari M, Pinborg A, Schmidt L, and Bonde JP: Male factor infertility and risk of multiple sclerosis: A register-based cohort study, Multiple sclerosis (Houndmills, Basingstoke, England), 1352458517734069. Gleicher N, and Barad DH: Gender as risk factor for autoimmune diseases, J Autoimmun 28, 1-6. Harbo HF, Gold R, and Tintore M: Sex and gender issues in multiple sclerosis, Ther Adv Neurol Disord 6, 237248. Hellwig K, and Correale J: Artificial reproductive techniques in multiple sclerosis, Clin Immunol 149, 219224. Hellwig K, Schimrigk S, Beste C, Muller T, and Gold R: Increase in relapse rate during assisted reproduction technique in patients with multiple sclerosis, Eur Neurol 61, 65-68. Jalkanen A, Alanen A, Airas L, Finnish Multiple S, and Pregnancy Study G: Pregnancy outcome in women with multiple sclerosis: results from a prospective nationwide study in Finland, Multiple sclerosis (Houndmills, Basingstoke, England) 16, 950-955. Jolving LR, Nielsen J, Kesmodel US, Nielsen RG, Beck-Nielsen SS, and Norgard BM: Prevalence of maternal chronic diseases during pregnancy - a nationwide population based study from 1989 to 2013, Acta Obstet Gynecol Scand 95, 1295-1304. Jonsson B, Von Reis G, and Sahlgren E: ACTH and cortisone in the treatment of multiple sclerosis, Acta Psychiatr Neurol Scand 29, 53. Kildemoes HW, Sorensen HT, and Hallas J: The Danish National Prescription Registry, Scand J Public Health 39, 38-41. Knudsen LB, and Olsen J: The Danish Medical Birth Registry, Dan Med Bull 45, 320-323. Kristensen J, Langhoff-Roos J, Skovgaard LT, and Kristensen FB: Validation of the Danish Birth Registration, J Clin Epidemiol 49, 893-897. Laplaud DA, Leray E, Barriere P, Wiertlewski S, and Moreau T: Increase in multiple sclerosis relapse rate following in vitro fertilization, Neurology 66, 1280-1281. Love S: Demyelinating diseases, J Clin Pathol 59, 1151-1159.
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Mason K, Thygesen LC, Stenager E, Bronnum-Hansen H, and Koch-Henriksen N: Evaluating the use and limitations of the Danish National Patient Register in register-based research using an example of multiple sclerosis, Acta Neurol Scand 125, 213-217. McCombe PA, and Stenager E: Female infertility and multiple sclerosis: is this an issue?, Multiple sclerosis (Houndmills, Basingstoke, England) 21, 5-7. Michel L, Foucher Y, Vukusic S, Confavreux C, de Seze J, Brassat D, Clanet M, Clavelou P, Ouallet JC, Brochet B, Pelletier J, Labauge P, Lebrun C, Lepage E, Le Frere F, Jacq-Foucher M, Barriere P, Wiertlewski S, Laplaud DA, and Club Francophone de la Sclerose En P: Increased risk of multiple sclerosis relapse after in vitro fertilisation, J Neurol Neurosurg Psychiatry 83, 796-802. Moberg JY, Laursen B, Thygesen LC, and Magyari M: Reproductive history of the Danish multiple sclerosis population: A register-based study, Multiple sclerosis (Houndmills, Basingstoke, England), 1352458519851245. Myhr KM, and Mellgren SI: Corticosteroids in the treatment of multiple sclerosis, Acta Neurol Scand Suppl, 73-80. Norgard BM, Larsen MD, Friedman S, Knudsen T, and Fedder J: Decreased chance of a live born child in women with rheumatoid arthritis after assisted reproduction treatment: a nationwide cohort study, Ann Rheum Dis. Norgard BM, Larsen PV, Fedder J, de Silva PS, Larsen MD, and Friedman S: Live birth and adverse birth outcomes in women with ulcerative colitis and Crohn's disease receiving assisted reproduction: a 20-year nationwide cohort study, Gut 65, 767-776. Nyboe Andersen A, and Erb K: Register data on Assisted Reproductive Technology (ART) in Europe including a detailed description of ART in Denmark, Int J Androl 29, 12-16. Petersen GL, Schmidt L, Pinborg A, and Kamper-Jorgensen M: The influence of female and male body mass index on live births after assisted reproductive technology treatment: a nationwide register-based cohort study, Fertil Steril 99, 1654-1662. Poser S, Raun NE, and Poser W: Age at onset, initial symptomatology and the course of multiple sclerosis, Acta Neurol Scand 66, 355-362. Pozzilli C, Pugliatti M, and Paradig MSG: An overview of pregnancy-related issues in patients with multiple sclerosis, Eur J Neurol 22 Suppl 2, 34-39. Robertson SA, Jin M, Yu D, Moldenhauer LM, Davies MJ, Hull ML, and Norman RJ: Corticosteroid therapy in assisted reproduction - immune suppression is a faulty premise, Hum Reprod 31, 2164-2173. Schmidt M, Schmidt SA, Sandegaard JL, Ehrenstein V, Pedersen L, and Sorensen HT: The Danish National Patient Registry: a review of content, data quality, and research potential, Clin Epidemiol 7, 449490. Stenager E: A global perspective on the burden of multiple sclerosis, Lancet Neurol. Sundhedsdatastyrelsen, and Sundhedsdatastyrelsen: Assisteret reproduktion 2016, 1.0, 12. Thygesen LC, Daasnes C, Thaulow I, and Bronnum-Hansen H: Introduction to Danish (nationwide) registers on health and social issues: structure, access, legislation, and archiving, Scand J Public Health 39, 12-16. van Mourik MS, Macklon NS, and Heijnen CJ: Embryonic implantation: cytokines, adhesion molecules, and immune cells in establishing an implantation environment, J Leukoc Biol 85, 4-19. Vukusic S, and Marignier R: Multiple sclerosis and pregnancy in the 'treatment era', Nat Rev Neurol 11, 280289. Westergaard HB, Johansen AM, Erb K, and Andersen AN: Danish National IVF Registry 1994 and 1995. Treatment, pregnancy outcome and complications during pregnancy, Acta Obstet Gynecol Scand 79, 384-389. World Health Organization.: Obesity : preventing and managing the global epidemic Geneva, 2000, World Health Organization.
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Biography LRJ has a PhD. in clinical epidemiology from University of Southern Denmark in 2018. She is affiliated at University of Southern Denmark as a postdoctoral researcher and at Center for Clinical Epidemiology at Odense University Hospital. She takes advantages of the Danish nationwide registries in her research on different areas within human reproduction, fetal programming hypothesis and the impact of maternal chronic disease on assisted reproductive technology, pregnancy and offspring morbidity.
Key message In women with other autoimmune diseases, we have previously found statistically significant reduced chances of a live birth after assisted reproduction. In this study, however, we did not find a statistically significantly decreased chance of a livebirth in women with multiple sclerosis, compared to other women. Besides being novel, our results further suggests that women with multiple sclerosis using steroids aroud the time of embryo transfer did not have an alterd chance of a live birth.
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Table 1 Descriptive characteristic of study cohort of assisted reproductive technology (ART) treatment (embryo transfers) in women with multiple sclerosis (MS) and in women without MS, during the study period of 1 January 1995 to 31 December 2017 Exposed cohort (embryo transfers in women with MS)a, b N=2,267
Unexposed cohort (embryo transfers in women without MS)a, c N=200,684
Characteristics Age at embryo transfer Median (25%-75% percentiles) 34 (31-38) 34 (30-37) Partner’s age at embryo transfer Median (25%-75% percentiles) 35 (33-39) 36 (32-40) Cause of infertility Female factor, N (%) 545 (25.5) 44,642 (23.6) Male factor, N (%) 711 (33.3) 60,417 (32.0) Mixture of factors/idiopathic, N (%) 879 (41.2) 83,824 (44.4) Type of preceding treatment* IVF, N (%) 977 (43.6) 88,378 (44.3) ICSI, N (%) 821 (36.6) 70,231 (35.2) FER, N (%) 444 (19.8) 40,721 (20.4) Body mass index BMI <18.5 (underweight), N (%) 24 (2.1) 3,514 (3.4) 18.5-24.9 (normal), N (%) 664 (56.9) 66,899 (63.8) 25.0-29.9 (overweight), N (%) 334 (28.6) 24,116 (23.0) ≥30.0 (obese) N (%) 144 (12.3) 10,323 (9.8) Smoking at the time of embryo transfer Non-smoker, N (%) 1,028 (89.9) 95,237 (91.6) Smoker, N (%) 115 (10.1) 8,760 (8.4) Alcohol No, N (%) 711 (64.4) 55,233 (55.3) Yes, N (%) 393 (35.6) 44,625 (44.7) Calendar year of infertility treatment 1995-2000 N (%) 412 (18.2) 34,109 (17.0) 2001-2006 N (%) 568 (25.1) 47,424 (23.6) 2007-2012 N (%) 695 (30.7) 61,789 (30.8) 2013-2017 N (%) 592 (26.1) 57,362 (28.6) Parity 0, N (%) 323 (66.1) 32,134 (67.6) 1+, N (%) 166 (33.9) 15,418 (32.4) Comorbidity at embryo transfers No comorbidity, N (%) 1,932 (85.2) 181,969 (90.7) Some comorbidity, N (%) 335 (14.8) 18,715 (9.3) Duration of multiple sclerosis at the time of embryo transfer (years) Median (25-75 percentiles) 18 (9-26) a Number of women in exposed 815 and in the unexposed cohort: 66,960 b Missing (%), women with multiple sclerosis: Age of partner (43.8), fertility factor (5.8), ART treatment (1.1), parity (78.4), BMI (48.6), smoking at the time of embryo transfer (49.6), alcohol (51.3) c Missing (%), women without multiple sclerosis: Age of partner (40.4), fertility factor (5.9), ART treatment (0.7), parity (76.3), BMI (48.6), smoking at the time of embryo transfer (48,2), alcohol (50,2) * IVF: In vitro fertilization, ICSI: Intracytoplasmic sperm injection, FER: frozen-thawed embryo replacement.
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Table 2 The chance of live birth in women with multiple sclerosis (MS) after assisted reproductive technology (ART) treatment (embryo transfer), during the study period of 1 January 1995 to 31 December 2017 Exposed cohort (embryo transfers in women MS) N=2,267a
Unexposed cohort (embryo transfers in women without MS) N=200,684b
Crude OR (95% CI)
Adjusted ORc (95% CI)
Live birth Yes, N (%) 498 (21.97) 48,503 (24.17) 0.85 (0.76-0.96) 0.91 (0.81-1.02) No, N (%) 1,769 (78.03) 152,181 (75.83) a Number of women in the exposed cohort: 815 b Number of women in the unexposed cohort: 66,960 c Adjusted for comorbidity, women’s age, calendar year of treatment, type of treatment (in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), frozen-thawed embryo replacement (FER), cause of infertility (female factor, male factor, or mixture of factors/idiopathic). Number of observations=189,649 number of women: 66,628.
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Table 3 Biochemical and clinical pregnancies in women with multiple sclerosis (MS), in the study cohorts of assisted reproductive technology (ART) treatments during the study period of 1 January 2010 through 31 December 2017 Exposed cohort Unexposed cohort (embryo transfers (embryo transfers Crude OR Adjusted OR in women with in women without (95% CI) (95% CI)a MS) MS) Biochemical pregnancy (hCG) b Yes, N (%) 318 (34.12) 32,243 (36.65) 0.88 (0.75-1.03) 0.92 (0.78-1.08) No, N (%) 614 (65.88) 55,733 (63.35) Clinical Pregnancy (ultra sound) c Yes, N (%) 259 (82.22) 26,594 (83.52) 0.91 (0.66-1,27) 0.89 (0.64-1.25) No, N (%) 56 (17.78) 5,248 (16.48) a Adjusted for comorbidity, women’s age, calendar year of treatment, type of treatment (in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), frozen-thawed embryo replacement (FER), cause of infertility (female factor, male factor, or a mixture of factors/idiopathic) and partner´s age. b Number of embryo transfers in the exposed cohort: 932 (number of women: 354). Number of embryo transfers in the unexposed cohort: 87,976 (number of women: 31,094). c Number of embryo transfers in the exposed cohort: 315 (number of women: 213). Number of embryo transfers in the unexposed cohort: 31,842 (number of women: 22,320).
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Table 4 The chance of live birth in women with multiple sclerosis (MS), who had prescriptions for corticosteroids 3 months prior to embryo transfer, compared with women with MS, who did not have prescriptions for corticosteroids 3 months prior to embryo transfer. The study period of 1 January 1995 to 31 December 2017
Exposed cohort (embryo transfers in women with MS, with prescriptions for corticosteroids prior to embryo transfer) N=100a
Unexposed cohort (embryo transfers in women with MS who did not have prescriptions for corticosteroids prior to embryo transfer) N=2,167b
Crude OR (95% CI)
Adjusted ORc (95% CI)
Live birth Yes, N (%) 18 (18.00) 480 (22.15) 0.87 (0.49-1.52) 0.90 (0.49-1.68) No, N (%) 82 (82.00) 1,687 (77.85) a Number of women in the exposed cohort: 52 b Number of women in the unexposed cohort: 810 c Adjusted for comorbidity, women’s age, calendar year of treatment, type of treatment (in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), frozen-thawed embryo replacement (FER), and cause of infertility (female factor, male factor, or mixture of factors/idiopathic).
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