Skip to main content
Log in

Fertility, Pregnancy and Childbirth in Patients with Multiple Sclerosis: Impact of Disease-Modifying Drugs

  • Review Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

In recent decades, pregnancy-related issues in multiple sclerosis (MS) have received growing interest. MS is more frequent in women than in men and typically starts during child-bearing age. An increasing number of disease-modifying drugs (DMDs) for the treatment of MS are becoming available. Gathering information on their influences on pregnancy-related issues is of crucial importance for the counselling of MS patients. As for the immunomodulatory drugs (interferons and glatiramer acetate), accumulating evidence points to the relative safety of pregnancy exposure in terms of maternal and foetal outcomes. In case of higher clinical disease activity before pregnancy, these drugs could be continued until conception. As for the ‘newer’ drugs (fingolimod, natalizumab, teriflunomide, dimethyl fumarate and alemtuzumab), the information is more limited. Whereas fingolimod and teriflunomide are likely associated with an increased risk of foetal malformations, the effects of natalizumab, dimethyl fumarate and alemtuzumab still need to be ascertained. This article provides a review of the available information on the use of DMDs during pregnancy, with a specific focus on fertility, foetal development, delivery and breast-feeding.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502–17.

    CAS  PubMed  Google Scholar 

  2. Niedziela N, Adamczyk-Sowa M, Pierzchala K. Epidemiology and clinical record of multiple sclerosis in selected countries: a systematic review. Int J Neurosci. 2013;124(5):322–30.

    PubMed  Google Scholar 

  3. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996;46(4):907–11.

    CAS  PubMed  Google Scholar 

  4. Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sorensen PS, Thompson AJ, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278–86.

    PubMed Central  PubMed  Google Scholar 

  5. Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J, et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain. 1989;112(Pt 1):133–46.

    PubMed  Google Scholar 

  6. Rieckmann P, Toyka KV, Bassetti C, Beer K, Beer S, Buettner U, et al. Escalating immunotherapy of multiple sclerosis—new aspects and practical application. J Neurol. 2004;251(11):1329–39.

    CAS  PubMed  Google Scholar 

  7. Sorensen PS. New management algorithms in multiple sclerosis. Curr Opin Neurol. 2014;27(3):246–59.

    PubMed  Google Scholar 

  8. Havrdova E, Galetta S, Stefoski D, Comi G. Freedom from disease activity in multiple sclerosis. Neurology. 2010;74(Suppl 3):S3–7.

    PubMed  Google Scholar 

  9. Interferon beta-1b is effective in relapsing–remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology. 1993;43(4):655–61.

  10. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet. 1998;352(9139):1498–504.

  11. Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. 1996;39(3):285–94.

    CAS  PubMed  Google Scholar 

  12. Calabresi PA, Kieseier BC, Arnold DL, Balcer LJ, Boyko A, Pelletier J, et al. Pegylated interferon beta-1a for relapsing–remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol. 2014;13(7):657–65.

    CAS  PubMed  Google Scholar 

  13. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing–remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995;45(7):1268–76.

    CAS  PubMed  Google Scholar 

  14. Portaccio E, Amato MP. Improving compliance with interferon-beta therapy in patients with multiple sclerosis. CNS Drugs. 2009;23(6):453–62.

    PubMed  Google Scholar 

  15. Sorensen PS, Deisenhammer F, Duda P, Hohlfeld R, Myhr KM, Palace J, et al. Guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis: report of an EFNS task force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol. 2005;12(11):817–27.

    CAS  PubMed  Google Scholar 

  16. Larochelle C, Grand’maison F, Bernier GP, Latour M, Cailhier JF, Prat A. Thrombotic thrombocytopenic purpura–hemolytic uremic syndrome in relapsing–remitting multiple sclerosis patients on high-dose interferon beta. Mult Scler. 2014;20(13):1783–7.

    CAS  PubMed  Google Scholar 

  17. Nerrant E, Charif M, Ramay AS, Perrochia H, Patrier L, de Champfleur NM, et al. Hemolytic uremic syndrome: an unusual complication of interferon-beta treatment in a MS patient. J Neurol. 2013;260(7):1915–6.

    PubMed  Google Scholar 

  18. Claussen MC, Korn T. Immune mechanisms of new therapeutic strategies in MS: teriflunomide. Clin Immunol. 2012;142(1):49–56.

    CAS  PubMed  Google Scholar 

  19. O’Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293–303.

    PubMed  Google Scholar 

  20. Confavreux C, O’Connor P, Comi G, Freedman MS, Miller AE, Olsson TP, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(3):247–56.

    CAS  PubMed  Google Scholar 

  21. Vermersch P, Czlonkowska A, Grimaldi LM, Confavreux C, Comi G, Kappos L, et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler. 2014;20(6):705–16.

    CAS  PubMed  Google Scholar 

  22. Phillips JT, Fox RJ. BG-12 in multiple sclerosis. Semin Neurol. 2012;33(1):56–65.

    Google Scholar 

  23. Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12):1087–97.

    CAS  PubMed  Google Scholar 

  24. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12):1098–107.

    CAS  PubMed  Google Scholar 

  25. Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899–910.

    CAS  PubMed  Google Scholar 

  26. Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):911–23.

    CAS  PubMed  Google Scholar 

  27. Hartung HP. New cases of progressive multifocal leukoencephalopathy after treatment with natalizumab. Lancet Neurol. 2009;8(1):28–31.

    PubMed  Google Scholar 

  28. Sorensen PS, Bertolotto A, Edan G, Giovannoni G, Gold R, Havrdova E, et al. Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab. Mult Scler. 2012;18(2):143–52.

    PubMed  Google Scholar 

  29. Plavina T, Subramanyam M, Bloomgren G, Richman S, Pace A, Lee S, et al. Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol. 2014;76(6):802–12.

    CAS  PubMed  Google Scholar 

  30. Massberg S, von Andrian UH. Fingolimod and sphingosine-1-phosphate—modifiers of lymphocyte migration. N Engl J Med. 2006;355(11):1088–91.

    CAS  PubMed  Google Scholar 

  31. Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387–401.

    CAS  PubMed  Google Scholar 

  32. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402–15.

    CAS  PubMed  Google Scholar 

  33. Laroni A, Brogi D, Morra VB, Guidi L, Pozzilli C, Comi G, et al. Safety of the first dose of fingolimod for multiple sclerosis: results of an open-label clinical trial. BMC Neurol. 2014;14:65.

    PubMed Central  PubMed  Google Scholar 

  34. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing–remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012;380(9856):1819–28.

    CAS  PubMed  Google Scholar 

  35. Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012;380(9856):1829–39.

    CAS  PubMed  Google Scholar 

  36. Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, et al. Alemtuzumab more effective than interferon beta-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology. 2012;78(14):1069–78.

    CAS  PubMed  Google Scholar 

  37. Hartung HP, Gonsette R, Konig N, Kwiecinski H, Guseo A, Morrissey SP, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002;360(9350):2018–25.

    PubMed  Google Scholar 

  38. Cocco E, Sardu C, Gallo P, Capra R, Amato MP, Trojano M, et al. Frequency and risk factors of mitoxantrone-induced amenorrhea in multiple sclerosis: the FEMIMS study. Mult Scler. 2008;14(9):1225–33.

    CAS  PubMed  Google Scholar 

  39. Le Page E, Leray E, Edan G. Long-term safety profile of mitoxantrone in a French cohort of 802 multiple sclerosis patients: a 5-year prospective study. Mult Scler. 2011;17(7):867–75.

    PubMed  Google Scholar 

  40. Martinelli V, Cocco E, Capra R, Salemi G, Gallo P, Capobianco M, et al. Acute myeloid leukemia in Italian patients with multiple sclerosis treated with mitoxantrone. Neurology. 2011;77(21):1887–95.

    CAS  PubMed  Google Scholar 

  41. Marriott JJ, Miyasaki JM, Gronseth G, O’Connor PW. Evidence report: the efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2010;74(18):1463–70.

    PubMed Central  CAS  PubMed  Google Scholar 

  42. Awad A, Stuve O. Cyclophosphamide in multiple sclerosis: scientific rationale, history and novel treatment paradigms. Ther Adv Neurol Disord. 2009;2(6):50–61.

    PubMed Central  PubMed  Google Scholar 

  43. Zipoli V, Portaccio E, Hakiki B, Siracusa G, Sorbi S, Amato MP. Intravenous mitoxantrone and cyclophosphamide as second-line therapy in multiple sclerosis: an open-label comparative study of efficacy and safety. J Neurol Sci. 2008;266(1–2):25–30.

    CAS  PubMed  Google Scholar 

  44. Portaccio E, Zipoli V, Siracusa G, Piacentini S, Sorbi S, Amato MP. Safety and tolerability of cyclophosphamide ‘pulses’ in multiple sclerosis: a prospective study in a clinical cohort. Mult Scler. 2003;9(5):446–50.

    CAS  PubMed  Google Scholar 

  45. Miller DH, Fazekas F, Montalban X, Reingold SC, Trojano M. Pregnancy, sex and hormonal factors in multiple sclerosis. Mult Scler. 2014;20(5):527–36.

    CAS  PubMed  Google Scholar 

  46. Ghezzi A, Annovazzi P, Portaccio E, Cesari E, Amato MP. Current recommendations for multiple sclerosis treatment in pregnancy and puerperium. Expert Rev Clin Immunol. 2013;9(7):683–91 (quiz 692).

    CAS  PubMed  Google Scholar 

  47. Houtchens MK, Kolb CM. Multiple sclerosis and pregnancy: therapeutic considerations. J Neurol. 2013;260(5):1202–14.

    CAS  PubMed  Google Scholar 

  48. Orton SM, Herrera BM, Yee IM, Valdar W, Ramagopalan SV, Sadovnick AD, et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol. 2006;5(11):932–6.

    PubMed  Google Scholar 

  49. Alonso A, Hernan MA. Temporal trends in the incidence of multiple sclerosis: a systematic review. Neurology. 2008;71(2):129–35.

    PubMed Central  PubMed  Google Scholar 

  50. Trojano M, Lucchese G, Graziano G, Taylor BV, Simpson S Jr, Lepore V, et al. Geographical variations in sex ratio trends over time in multiple sclerosis. PLoS One. 2012;7(10):e48078.

    PubMed Central  CAS  PubMed  Google Scholar 

  51. Sellner J, Kraus J, Awad A, Milo R, Hemmer B, Stuve O. The increasing incidence and prevalence of female multiple sclerosis—a critical analysis of potential environmental factors. Autoimmun Rev. 2011;10(8):495–502.

    PubMed  Google Scholar 

  52. Chao MJ, Ramagopalan SV, Herrera BM, Orton SM, Handunnetthi L, Lincoln MR, et al. MHC transmission: insights into gender bias in MS susceptibility. Neurology. 2011;76(3):242–6.

    PubMed Central  CAS  PubMed  Google Scholar 

  53. Marrie RA, Cutter G, Tyry T, Hadjimichael O, Campagnolo D, Vollmer T. Changes in the ascertainment of multiple sclerosis. Neurology. 2005;65(7):1066–70.

    CAS  PubMed  Google Scholar 

  54. Cavalla P, Rovei V, Masera S, Vercellino M, Massobrio M, Mutani R, et al. Fertility in patients with multiple sclerosis: current knowledge and future perspectives. Neurol Sci. 2006;27(4):231–9.

    CAS  PubMed  Google Scholar 

  55. Nortvedt MW, Riise T, Myhr KM, Landtblom AM, Bakke A, Nyland HI. Reduced quality of life among multiple sclerosis patients with sexual disturbance and bladder dysfunction. Mult Scler. 2001;7(4):231–5.

    CAS  PubMed  Google Scholar 

  56. Ghezzi A. Sexual dysfunction in multiple sclerosis. Int MS J. 1999;5:44–53.

    Google Scholar 

  57. Zorzon M, Zivadinov R, Bosco A, Bragadin LM, Moretti R, Bonfigli L, et al. Sexual dysfunction in multiple sclerosis: a case-control study. I. Frequency and comparison of groups. Mult Scler. 1999;5(6):418–27.

    CAS  PubMed  Google Scholar 

  58. Borello-France D, Leng W, O’Leary M, Xavier M, Erickson J, Chancellor MB, et al. Bladder and sexual function among women with multiple sclerosis. Mult Scler. 2004;10(4):455–61.

    PubMed  Google Scholar 

  59. Dewis ME, Thornton NG. Sexual dysfunction in multiple sclerosis. J Neurosci Nurs. 1989;21(3):175–9.

    CAS  PubMed  Google Scholar 

  60. Grinsted L, Heltberg A, Hagen C, Djursing H. Serum sex hormone and gonadotropin concentrations in premenopausal women with multiple sclerosis. J Intern Med. 1989;226(4):241–4.

    CAS  PubMed  Google Scholar 

  61. Falaschi P, Martocchia A, Proietti A, D’Urso R, Antonini G. High incidence of hyperandrogenism-related clinical signs in patients with multiple sclerosis. Neuro Endocrinol Lett. 2001;22(4):248–50.

    CAS  PubMed  Google Scholar 

  62. Thone J, Kollar S, Nousome D, Ellrichmann G, Kleiter I, Gold R, et al. Serum anti-Mullerian hormone levels in reproductive-age women with relapsing–remitting multiple sclerosis. Mult Scler. 2015;21(1):41–7.

    PubMed  Google Scholar 

  63. Foster SC, Daniels C, Bourdette DN, Bebo BF Jr. Dysregulation of the hypothalamic–pituitary–gonadal axis in experimental autoimmune encephalomyelitis and multiple sclerosis. J Neuroimmunol. 2003;140(1–2):78–87.

    CAS  PubMed  Google Scholar 

  64. Wei T, Lightman SL. The neuroendocrine axis in patients with multiple sclerosis. Brain. 1997;120(Pt 6):1067–76.

    PubMed  Google Scholar 

  65. Dohle GR, Smit M, Weber RF. Androgens and male fertility. World J Urol. 2003;21(5):341–5.

    CAS  PubMed  Google Scholar 

  66. Hellwig K, Correale J. Artificial reproductive techniques in multiple sclerosis. Clin Immunol. 2013;149(2):219–24.

    CAS  PubMed  Google Scholar 

  67. Hellwig K, Schimrigk S, Beste C, Muller T, Gold R. Increase in relapse rate during assisted reproduction technique in patients with multiple sclerosis. Eur Neurol. 2009;61(2):65–8.

    PubMed  Google Scholar 

  68. Michel L, Foucher Y, Vukusic S, Confavreux C, de Seze J, Brassat D, et al. Increased risk of multiple sclerosis relapse after in vitro fertilisation. J Neurol Neurosurg Psychiatry. 2013;83(8):796–802.

    Google Scholar 

  69. Correale J, Farez MF, Ysrraelit MC. Increase in multiple sclerosis activity after assisted reproduction technology. Ann Neurol. 2012;72(5):682–94.

    CAS  PubMed  Google Scholar 

  70. Dahl J, Myhr KM, Daltveit AK, Hoff JM, Gilhus NE. Pregnancy, delivery, and birth outcome in women with multiple sclerosis. Neurology. 2005;65(12):1961–3.

    CAS  PubMed  Google Scholar 

  71. Kelly VM, Nelson LM, Chakravarty EF. Obstetric outcomes in women with multiple sclerosis and epilepsy. Neurology. 2009;73(22):1831–6.

    PubMed  Google Scholar 

  72. van der Kop ML, Pearce MS, Dahlgren L, Synnes A, Sadovnick D, Sayao AL, et al. Neonatal and delivery outcomes in women with multiple sclerosis. Ann Neurol. 2011;70(1):41–50.

    PubMed Central  PubMed  Google Scholar 

  73. Lu E, Zhao Y, Zhu F, van der Kop ML, Synnes A, Dahlgren L, et al. Birth hospitalization in mothers with multiple sclerosis and their newborns. Neurology. 2013;80(5):447–52.

    PubMed Central  PubMed  Google Scholar 

  74. Sadovnick AD, Eisen K, Hashimoto SA, Farquhar R, Yee IM, Hooge J, et al. Pregnancy and multiple sclerosis. A prospective study. Arch Neurol. 1994;51(11):1120–4.

    CAS  PubMed  Google Scholar 

  75. Jalkanen A, Alanen A, Airas L. Pregnancy outcome in women with multiple sclerosis: results from a prospective nationwide study in Finland. Mult Scler. 2010;16(8):950–5.

    CAS  PubMed  Google Scholar 

  76. Lu E, Dahlgren L, Sadovnick A, Sayao A, Synnes A, Tremlett H. Perinatal outcomes in women with multiple sclerosis exposed to disease-modifying drugs. Mult Scler. 2012;18(4):460–7.

    CAS  PubMed  Google Scholar 

  77. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med. 1998;339(5):285–91.

    CAS  PubMed  Google Scholar 

  78. Finkelsztejn A, Brooks JB, Paschoal FM Jr, Fragoso YD. What can we really tell women with multiple sclerosis regarding pregnancy? A systematic review and meta-analysis of the literature. BJOG. 2011;118(7):790–7.

    CAS  PubMed  Google Scholar 

  79. McCombe PA, Greer JM. Female reproductive issues in multiple sclerosis. Mult Scler. 2012;19(4):392–402.

    PubMed  Google Scholar 

  80. Gilli F, Lindberg RL, Valentino P, Marnetto F, Malucchi S, Sala A, et al. Learning from nature: pregnancy changes the expression of inflammation-related genes in patients with multiple sclerosis. PLoS One. 2010;5(1):e8962.

    PubMed Central  PubMed  Google Scholar 

  81. Vukusic S, Hutchinson M, Hours M, Moreau T, Cortinovis-Tourniaire P, Adeleine P, et al. Pregnancy and multiple sclerosis (the PRIMS study): clinical predictors of post-partum relapse. Brain. 2004;127(Pt 6):1353–60.

    PubMed  Google Scholar 

  82. Portaccio E, Ghezzi A, Hakiki B, Sturchio A, Martinelli V, Moiola L, et al. Postpartum relapses increase the risk of disability progression in multiple sclerosis: the role of disease modifying drugs. J Neurol Neurosurg Psychiatry. 2014;85(8):845–50.

    PubMed  Google Scholar 

  83. Amato MP, Portaccio E, Ghezzi A, Hakiki B, Zipoli V, Martinelli V, et al. Pregnancy and fetal outcomes after interferon-beta exposure in multiple sclerosis. Neurology. 2010;75(20):1794–802.

    CAS  PubMed  Google Scholar 

  84. Hughes SE, Spelman T, Gray OM, Boz C, Trojano M, Lugaresi A, et al. Predictors and dynamics of postpartum relapses in women with multiple sclerosis. Mult Scler. 2014;20(6):739–46.

    PubMed  Google Scholar 

  85. Ramagopalan S, Yee I, Byrnes J, Guimond C, Ebers G, Sadovnick D. Term pregnancies and the clinical characteristics of multiple sclerosis: a population based study. J Neurol Neurosurg Psychiatry. 2012;83(8):793–5.

    PubMed  Google Scholar 

  86. D’Hooghe MB, Haentjens P, Nagels G, D’Hooghe T, De Keyser J. Menarche, oral contraceptives, pregnancy and progression of disability in relapsing onset and progressive onset multiple sclerosis. J Neurol. 2011;259(5):855–61.

    PubMed  Google Scholar 

  87. Stenager E, Stenager EN, Jensen K. Effect of pregnancy on the prognosis for multiple sclerosis. A 5-year follow up investigation. Acta Neurol Scand. 1994;90(5):305–8.

    CAS  PubMed  Google Scholar 

  88. Runmarker B, Andersen O. Pregnancy is associated with a lower risk of onset and a better prognosis in multiple sclerosis. Brain. 1995;118(Pt 1):253–61.

    PubMed  Google Scholar 

  89. Pasto L, Portaccio E, Ghezzi A, Hakiki B, Giannini M, Razzolini L, et al. Epidural analgesia and cesarean delivery in multiple sclerosis post-partum relapses: the Italian cohort study. BMC Neurol. 2012;12:165.

    PubMed Central  PubMed  Google Scholar 

  90. Hellwig K, Haghikia A, Rockhoff M, Gold R. Multiple sclerosis and pregnancy: experience from a nationwide database in Germany. Ther Adv Neurol Disord. 2012;5(5):247–53.

    PubMed Central  PubMed  Google Scholar 

  91. Langer-Gould A, Huang SM, Gupta R, Leimpeter AD, Greenwood E, Albers KB, et al. Exclusive breastfeeding and the risk of postpartum relapses in women with multiple sclerosis. Arch Neurol. 2009;66(8):958–63.

    PubMed  Google Scholar 

  92. Langer-Gould A, Gupta R, Huang S, Hagan A, Atkuri K, Leimpeter AD, et al. Interferon-gamma-producing T cells, pregnancy, and postpartum relapses of multiple sclerosis. Arch Neurol. 2010;67(1):51–7.

    PubMed  Google Scholar 

  93. Airas L, Jalkanen A, Alanen A, Pirttila T, Marttila RJ. Breast-feeding, postpartum and prepregnancy disease activity in multiple sclerosis. Neurology. 2011;75(5):474–6.

    Google Scholar 

  94. Portaccio E, Ghezzi A, Hakiki B, Martinelli V, Moiola L, Patti F, et al. Breastfeeding is not related to postpartum relapses in multiple sclerosis. Neurology. 2011;77(2):145–50.

    CAS  PubMed  Google Scholar 

  95. Food and Drug Administration. Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling. 2014. http://federalregister.gov/a/2014-28241. Accessed 16 Feb 2015.

  96. Quality review of documents human product-information annotated template (English) version 9. http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2009/10/WC500004368.pdf. Accessed 17 Feb 2015.

  97. Sandberg-Wollheim M, Frank D, Goodwin TM, Giesser B, Lopez-Bresnahan M, Stam-Moraga M, et al. Pregnancy outcomes during treatment with interferon beta-1a in patients with multiple sclerosis. Neurology. 2005;65(6):802–6.

    CAS  PubMed  Google Scholar 

  98. Waubant E, Sadovnick AD. Interferon beta babies. Neurology. 2005;65(6):788–9.

    PubMed  Google Scholar 

  99. Pecori C, Giannini M, Portaccio E, Ghezzi A, Hakiki B, Pasto L, et al. Paternal therapy with disease modifying drugs in multiple sclerosis and pregnancy outcomes: a prospective observational multicentric study. BMC Neurol. 2014;14:114.

    PubMed Central  PubMed  Google Scholar 

  100. Lu E, Zhu F, Zhao Y, van der Kop M, Sadovnick A, Synnes A, et al. Birth outcomes of pregnancies fathered by men with multiple sclerosis. Mult Scler. 2014;20(9):1260–4.

    CAS  PubMed  Google Scholar 

  101. Lu E, Wang BW, Guimond C, Synnes A, Sadovnick D, Tremlett H. Disease-modifying drugs for multiple sclerosis in pregnancy: a systematic review. Neurology. 2012;79(11):1130–5.

    PubMed Central  CAS  PubMed  Google Scholar 

  102. Sandberg-Wollheim M, Alteri E, Moraga MS, Kornmann G. Pregnancy outcomes in multiple sclerosis following subcutaneous interferon beta-1a therapy. Mult Scler. 2011;17(4):423–30.

    CAS  PubMed  Google Scholar 

  103. Weber-Schoendorfer C, Schaefer C. Multiple sclerosis, immunomodulators, and pregnancy outcome: a prospective observational study. Mult Scler. 2009;15(9):1037–42.

    CAS  PubMed  Google Scholar 

  104. Fragoso YD, Boggild M, Macias-Islas MA, Carra A, Schaerer KD, Aguayo A, et al. The effects of long-term exposure to disease-modifying drugs during pregnancy in multiple sclerosis. Clin Neurol Neurosurg. 2013;115(2):154–9.

    PubMed  Google Scholar 

  105. Boskovic R, Wide R, Wolpin J, Bauer DJ, Koren G. The reproductive effects of beta interferon therapy in pregnancy: a longitudinal cohort. Neurology. 2005;65(6):807–11.

    CAS  PubMed  Google Scholar 

  106. Fragoso YD, Finkelsztejn A, Comini-Frota ER, da Gama PD, Grzesiuk AK, Khouri JM, et al. Pregnancy and multiple sclerosis: the initial results from a Brazilian database. Arq Neuropsiquiatr. 2009;67(3A):657–60.

    PubMed  Google Scholar 

  107. Hellwig K, Haghikia A, Gold R. Parenthood and immunomodulation in patients with multiple sclerosis. J Neurol. 2010;257(4):580–3.

    CAS  PubMed  Google Scholar 

  108. Finkelsztejn A, Fragoso YD, Ferreira ML, Lana-Peixoto MA, Alves-Leon SV, Gomes S, et al. The Brazilian database on pregnancy in multiple sclerosis. Clin Neurol Neurosurg. 2011;113(4):277–80.

    CAS  PubMed  Google Scholar 

  109. Fernandez Liguori N, Klajn D, Acion L, Caceres F, Calle A, Carra A, et al. Epidemiological characteristics of pregnancy, delivery, and birth outcome in women with multiple sclerosis in Argentina (EMEMAR study). Mult Scler. 2009;15(5):555–62.

    CAS  PubMed  Google Scholar 

  110. Giannini M, Portaccio E, Ghezzi A, Hakiki B, Pasto L, Razzolini L, et al. Pregnancy and fetal outcomes after glatiramer acetate exposure in patients with multiple sclerosis: a prospective observational multicentric study. BMC Neurol. 2012;12:124.

    PubMed Central  CAS  PubMed  Google Scholar 

  111. Salminen HJ, Leggett H, Boggild M. Glatiramer acetate exposure in pregnancy: preliminary safety and birth outcomes. J Neurol. 2010;257(12):2020–3.

    CAS  PubMed  Google Scholar 

  112. Dahl J, Myhr KM, Daltveit AK, Gilhus NE. Planned vaginal births in women with multiple sclerosis: delivery and birth outcome. Acta Neurol Scand Suppl. 2006;183:51–4.

    CAS  PubMed  Google Scholar 

  113. Hale TW, Siddiqui AA, Baker TE. Transfer of interferon beta-1a into human breastmilk. Breastfeed Med. 2012;7(2):123–5.

    PubMed  Google Scholar 

  114. Fragoso YD, Finkelsztejn A, Kaimen-Maciel DR, Grzesiuk AK, Gallina AS, Lopes J, et al. Long-term use of glatiramer acetate by 11 pregnant women with multiple sclerosis: a retrospective, multicentre case series. CNS Drugs. 2010;24(11):969–76.

    CAS  PubMed  Google Scholar 

  115. Hellwig K, Gold R. Glatiramer acetate and interferon-beta throughout gestation and postpartum in women with multiple sclerosis. J Neurol. 2011;258(3):502–3.

    PubMed  Google Scholar 

  116. Tysabri (natalizumab) prescribing information FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/125104s033lbl.pdf. Accessed 16 Feb 2015.

  117. Tysabri (natalizumab) prescribing information EMA. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000603/WC500044686.pdf. Accessed 16 Feb 2015.

  118. Wehner NG, Shopp G, Rocca MS, Clarke J. Effects of natalizumab, an alpha4 integrin inhibitor, on the development of Hartley guinea pigs. Birth Defects Res B Dev Reprod Toxicol. 2009;86(2):98–107.

    CAS  PubMed  Google Scholar 

  119. Fox RJ, Cree BA, De Seze J, Gold R, Hartung HP, Jeffery D, et al. MS disease activity in RESTORE: a randomized 24-week natalizumab treatment interruption study. Neurology. 2014;82(17):1491–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  120. Fagius J, Burman J. Normal outcome of pregnancy with ongoing treatment with natalizumab. Acta Neurol Scand. 2014;129(6):e27–9.

    CAS  PubMed  Google Scholar 

  121. Schneider H, Weber CE, Hellwig K, Schroten H, Tenenbaum T. Natalizumab treatment during pregnancy—effects on the neonatal immune system. Acta Neurol Scand. 2013;127(1):e1–4.

    CAS  PubMed  Google Scholar 

  122. Haghikia A, Langer-Gould A, Rellensmann G, Schneider H, Tenenbaum T, Elias-Hamp B, et al. Natalizumab use during the third trimester of pregnancy. JAMA Neurol. 2014;71(7):891–5.

    PubMed  Google Scholar 

  123. Ebrahimi N, Herbstritt S, Gold R, Amezcua L, Koren G, Hellwig K. Pregnancy and fetal outcomes following natalizumab exposure in pregnancy. A prospective, controlled observational study. Mult Scler. 2015;21(2):198–205.

    CAS  PubMed  Google Scholar 

  124. Gilenya (fingolimod) prescribing information FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022527s009lbl.pdf. Accessed 16 Feb 2015.

  125. Gilenya (fingolimod) prescribing information EMA. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002202/WC500104528.pdf. Accessed 16 Feb 2015.

  126. Karlsson G, Francis G, Koren G, Heining P, Zhang X, Cohen JA, et al. Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis. Neurology. 2014;82(8):674–80.

    PubMed Central  PubMed  Google Scholar 

  127. Meistrich ML, Wilson G, Mathur K, Fuller LM, Rodriguez MA, McLaughlin P, et al. Rapid recovery of spermatogenesis after mitoxantrone, vincristine, vinblastine, and prednisone chemotherapy for Hodgkin’s disease. J Clin Oncol. 1997;15(12):3488–95.

    CAS  PubMed  Google Scholar 

  128. Watson AR, Rance CP, Bain J. Long term effects of cyclophosphamide on testicular function. Br Med J (Clin Res Ed). 1985;291(6507):1457–60.

    CAS  Google Scholar 

  129. Rivkees SA, Crawford JD. The relationship of gonadal activity and chemotherapy-induced gonadal damage. JAMA. 1988;259(14):2123–5.

    CAS  PubMed  Google Scholar 

  130. Novantrone (mitoxantrone) prescribing information FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019297s035lbl.pdf. Accessed 16 Feb 2015.

  131. De Santis M, Straface G, Cavaliere AF, Rosati P, Batocchi AP, Caruso A. The first case of mitoxantrone exposure in early pregnancy. Neurotoxicology. 2007;28(3):696–7.

    PubMed  Google Scholar 

  132. Baumgartner AK, Oberhoffer R, Jacobs VR, Ostermayer E, Menzel H, Voigt M, et al. Reversible foetal cerebral ventriculomegaly and cardiomyopathy under chemotherapy for maternal AML. Onkologie. 2009;32(1–2):40–3.

    PubMed  Google Scholar 

  133. Hellwig K, Schimrigk S, Chan A, Epplen J, Gold R. A newborn with Pierre Robin sequence after preconceptional mitoxantrone exposure of a female with multiple sclerosis. J Neurol Sci. 2011;307(1–2):164–5.

    PubMed  Google Scholar 

  134. Cytoxan (cyclophosphamide) prescribing information FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012141s090,012142s112lbl.pdf. Accessed 16 Feb 2015.

  135. Meirow D, Epstein M, Lewis H, Nugent D, Gosden RG. Administration of cyclophosphamide at different stages of follicular maturation in mice: effects on reproductive performance and fetal malformations. Hum Reprod. 2001;16(4):632–7.

    CAS  PubMed  Google Scholar 

  136. Gupta R, Deepanjali S, Thabah MM, Kaur P, Gupta S. Successful twin pregnancy while on cyclophosphamide therapy in a patient with lupus nephritis. Rheumatol Int. 2009;29(12):1503–5.

    PubMed  Google Scholar 

  137. Paladini D, Vassallo M, D’Armiento MR, Cianciaruso B, Martinelli P. Prenatal detection of multiple fetal anomalies following inadvertent exposure to cyclophosphamide in the first trimester of pregnancy. Birth Defects Res A Clin Mol Teratol. 2004;70(2):99–100.

    CAS  PubMed  Google Scholar 

  138. Patti F, Messina S, D’Amico E, Lo Fermo S, Zappia M. Pregnancy outcomes in multiple sclerosis patients previously treated with cyclophosphamide. Acta Neurol Scand. 2014;130(4):e41–4.

    CAS  PubMed  Google Scholar 

  139. Ramsey-Goldman R, Mientus JM, Kutzer JE, Mulvihill JJ, Medsger TA Jr. Pregnancy outcome in women with systemic lupus erythematosus treated with immunosuppressive drugs. J Rheumatol. 1993;20(7):1152–7.

    CAS  PubMed  Google Scholar 

  140. Aubagio (teriflunomide) prescribing information FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202992s001lbl.pdf. Accessed 16 Feb 2015.

  141. Aubagio (teriflunomide) prescribing information EMA. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002514/WC500148682.pdf. Accessed 16 Feb 2015.

  142. Tecfidera (dimethyl fumarate) prscribing information FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204063lbl.pdf. Accessed 16 Feb 2015.

  143. Tecfidera (dimethyl fumarate) prescribing information EMA. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002601/WC500162069.pdf. Accessed 16 Feb 2015.

  144. Campath (alemtuzumab) prescribing information FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/103948s5070lbl.pdf. Accessed 16 Feb 2015.

  145. Lemtrada (alemtuzumab) prescribing information EMA. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003718/WC500150521.pdf. Accessed 16 Feb 2015.

  146. Davenport L, Czich A, Turpault S. Teriflunomide: non-clinical evaluation demonstrates no effect on sperm DNA or male fertility [abstract]. Neurology. 2014;82(10 Suppl):P2.233.

  147. Henson LJ, Benamor M, Truffinet P, Kieseier BC. Updated pregnancy outcomes in patients and partners of patients in the teriflunomide clinical trial program [abstract]. Neurology. 2014;82(10 Suppl):P4.161.

  148. Gold R, Phillips JT, Havrdova E, Bar-Or A, Kappos L, Kim N, et al., editors. Delayed-release demethyl fumarate and pregnancy: preclinical studies and pregnancy outcomes from clinical trials and postmarketing experience [abstract]. Joint ACTRIMS-ECTRIMS Congress; 2014. Boston, US, September 10–13 2014.

  149. McCombe P, Achiron A, Giovannoni G, Brinar V, Margolin DH, Palmer J, et al., editors. Pregnancy outcomes in the alemtuzumab multiple sclerosis clinical development program [abstract]. Joint ACTRIMS-ECTRIMS Congress; 2014. Boston, US, September 10–13 2014.

Download references

Acknowledgments

Maria Pia Amato has served on scientific advisory boards for and received speaker’s honoraria from Biogen Idec, Merck Serono, Novartis, Genzyme, and Teva; received research grants from Biogen Idec, Merck Serono, Novartis, and Teva; and received speaker’s honoraria from Almirall. Emilio Portaccio has served on scientific advisory boards for Biogen Idec, Merck Serono, Bayer and Genzyme; received speaker’s honoraria from Biogen Idec, Teva, Novartis and Genzyme; and received research support from Merck Serono. No source of funding was received to assist with the preparation of this review.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Maria Pia Amato.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Amato, M.P., Portaccio, E. Fertility, Pregnancy and Childbirth in Patients with Multiple Sclerosis: Impact of Disease-Modifying Drugs. CNS Drugs 29, 207–220 (2015). https://doi.org/10.1007/s40263-015-0238-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-015-0238-y

Keywords

Navigation