Multiple sclerosis impact on pregnancy: An update on management issues
DOI:
https://doi.org/10.31661/gmj.v11i.2703Keywords:
Multiple Sclerosis, Pregnancy, Disease-Modifying Treatments, Relapsing-remitting, Primary ProgressiveAbstract
Women with multiple sclerosis (MS) of reproductive age are becoming pregnant at an alarmingly high rate. Disease control is required during the preconception, prenatal, and postpartum periods to reduce the likelihood of relapses of MS while minimizing hazards to the mother and fetus. It has long been understood that the disease activity of MS noticeably decreases in the third trimester of pregnancy, then noticeably increases in the first three months after delivery before returning to its pre-pregnancy baseline. Relapse during pregnancy and high rates of relapse before becoming pregnant have both been linked to an increased risk of postpartum attacks. In patients with relapse MS, recent results continue to support the notion that pregnancy does not affect long-term disease progression (and may even have the opposite effect); the situation is less clear for patients with progressive MS. It is comforting to know that none of the MS disease-modifying medications have been shown to cause teratogenic consequences. This review discusses the effects of pregnancy on disease activity and how to handle relapses when pregnant and breastfeeding.
References
Jafarinia M, Sadeghi E, Alsahebfosoul F, Etemadifar M, Jahanbani-Ardakani H. Evaluation of plasma Osteopontin level in relapsing-remitting multiple sclerosis patients compared to healthy subjects in Isfahan Province. Int J Neurosci. 2020;130(5):493-8. https://doi.org/10.1080/00207454.2019.1694925PMid:31795798 Parnell GP, Booth DR. The multiple sclerosis (MS) genetic risk factors indicate both acquired and innate immune cell subsets contribute to MS pathogenesis and identify novel therapeutic opportunities. Front Immunol. 2017;8:425. https://doi.org/10.3389/fimmu.2017.00425PMid:28458668 PMCid:PMC5394466 Jafarinia M, Amoon M, Javid A, Vakili S, Sadeghi E, Azadi D, et al. Male microchimerism in peripheral blood from women with multiple sclerosis in Isfahan Province. Int J Immunogenet. 2020;47(2):175-9. https://doi.org/10.1111/iji.12465PMid:31833227 Kyritsis AP, Boussios S, Pavlidis N. Cancer specific risk in multiple sclerosis patients. Crit Rev Oncol Hematol. 2016;98:29-34. https://doi.org/10.1016/j.critrevonc.2015.10.002PMid:26481954 Jafarinia M, Ashja-Arvan M, Hosseininasab F, Vakili S, Sadeghi E, Etemadifar M, et al. Evaluation of plasma soluble CD137 level in relapsing-remitting multiple sclerosis patients in comparison with healthy controls in Isfahan Province, Iran. Neurol Asia. 2020;25(3):361-5. Cree BA. Multiple Sclerosis Therapy: Are We Ready for a One-Size-Fits-All Approach? J Neuroophthalmol. 2018;38(2):258-62. https://doi.org/10.1097/WNO.0000000000000640PMid:29750736 Langer-Gould A, Smith JB, Albers KB, Xiang AH, Wu J, Kerezsi EH, et al. Pregnancy-related relapses and breastfeeding in a contemporary multiple sclerosis cohort. Neurology. 2020;94(18):e1939-49. https://doi.org/10.1212/WNL.0000000000009374PMid:32284359 PMCid:PMC7274922 Bilbao MM, Durán SB, Llona JB, Rodriguez-Antigüedad A. Multiple sclerosis: pregnancy and women's health issues. Neurologia (English Edition). 2019;34(4):259-69. https://doi.org/10.1016/j.nrleng.2016.06.014 Mansuori E, Alihemmati A, Mesbahi A. An overview on the effects of power frequency electromagnetic field exposure on the female reproduction system, pregnancy outcome and fetal development. J Med Chem Sci. 2020;3(1):60-70. Voskuhl R, Momtazee C. Pregnancy: effect on multiple sclerosis, treatment considerations, and breastfeeding. Neurotherapeutics. 2017;14(4):974-84. https://doi.org/10.1007/s13311-017-0562-7PMid:28766273 PMCid:PMC5722767 Patas K, Engler JB, Friese MA, Gold SM. Pregnancy and multiple sclerosis: feto-maternal immune cross talk and its implications for disease activity. J Reprod Immunol. 2013;97(1):140-6. https://doi.org/10.1016/j.jri.2012.10.005PMid:23432880 Zenclussen AC. Adaptive immune responses during pregnancy. Am J Reprod Immunol. 2013;69(4):291-303. https://doi.org/10.1111/aji.12097PMid:23418773 Yamazaki S, Morita A. Dendritic cells in the periphery control antigen-specific natural and induced regulatory T cells. Front Immunol. 2013;4:151. https://doi.org/10.3389/fimmu.2013.00151PMid:23801989 PMCid:PMC3689032 Mor G, Cardenas I. The immune system in pregnancy: a unique complexity. Am J Reprod Immunol. 2010;63(6):425-33. https://doi.org/10.1111/j.1600-0897.2010.00836.xPMid:20367629 PMCid:PMC3025805 Coyle PK. Management of women with multiple sclerosis through pregnancy and after childbirth. Ther Adv Neurol Disord. 2016;9(3):198-210. https://doi.org/10.1177/1756285616631897PMid:27134675 PMCid:PMC4811012 Coyle PK, Oh J, Magyari M, Oreja-Guevara C, Houtchens M. Management strategies for female patients of reproductive potential with multiple sclerosis: an evidence-based review. Mult Scler Relat Disord. 2019;32:54-63. https://doi.org/10.1016/j.msard.2019.04.003PMid:31030020 Thöne J, Kollar S, Nousome D, Ellrichmann G, Kleiter I, Gold R, Hellwig K. Serum anti-Müllerian hormone levels in reproductive-age women with relapsing-remitting multiple sclerosis. Mult Scler. 2015;21(1):41-7. https://doi.org/10.1177/1352458514540843PMid:25145691 Nazari F, Shaygannejad V, Mohammadi Sichani M, Mansourian M, Hajhashemi V. Sexual dysfunction in women with multiple sclerosis: prevalence and impact on quality of life. BMC Urol. 2020;20(1):15. https://doi.org/10.1186/s12894-020-0581-2 Al Abdali FH, Gowri V. The Etiology of Infertility and Treatment Outcome in Couples Aged 40 Years or more in a Non-IVF Setting. J Infertil Reprod Biol. 2021;9(2):87-92. Ojoawo AO, Bamidele OO, Akinsomisoye SO, Adeyemi BA. Menstrual Period and Anthropometric Characteristics of Women with Secondary Infertility and Age Matched Control. J Infertil Reprod Biol. 2020;8(4):84-9. Lengfeld J, Cutforth T, Agalliu D. The role of angiogenesis in the pathology of multiple sclerosis. Vascular Cell. 2014;6(1):1-6. https://doi.org/10.1186/s13221-014-0023-6PMid:25473485 PMCid:PMC4253611 Kaplan TB. Management of demyelinating disorders in pregnancy. Neurol Clin. 2019;37(1):17-30. https://doi.org/10.1016/j.ncl.2018.09.007PMid:30470273 Sintzel MB, Rametta M, Reder AT. Vitamin D and multiple sclerosis: a comprehensive review. Neurol Ther. 2018;7(1):59-85. https://doi.org/10.1007/s40120-017-0086-4PMid:29243029 PMCid:PMC5990512 Munger KL, Ã…ivo J, Hongell K, Soilu-Hänninen M, Surcel H-M, Ascherio A. Vitamin D status during pregnancy and risk of multiple sclerosis in offspring of women in the Finnish Maternity Cohort. JAMA Neurol. 2016;73(5):515-9. https://doi.org/10.1001/jamaneurol.2015.4800PMid:26953778 PMCid:PMC4861670 Alwan S, Yee I, Dybalski M, Guimond C, Dwosh E, Greenwood T, et al. Reproductive decision making after the diagnosis of multiple sclerosis (MS). Mult Scler. 2013;19(3):351-8. https://doi.org/10.1177/1352458512452920PMid:22760102 Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T, Group PiMS. Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med. 1998;339(5):285-91. https://doi.org/10.1056/NEJM199807303390501PMid:9682040 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. https://doi.org/10.1177/1352458513507816PMid:24107309 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. https://doi.org/10.1016/j.clineuro.2012.04.024PMid:22633835 Nguyen A-L, Havrdova EK, Horakova D, Izquierdo G, Kalincik T, Van Der Walt A, et al. Incidence of pregnancy and disease-modifying therapy exposure trends in women with multiple sclerosis: a contemporary cohort study. Mult Scler Relat Disord. 2019;28:235-43. https://doi.org/10.1016/j.msard.2019.01.003PMid:30623864 Houtchens MK, Edwards NC, Schneider G, Stern K, Phillips AL. Pregnancy rates and outcomes in women with and without MS in the United States. Neurology. 2018;91(17):e1559-69. https://doi.org/10.1212/WNL.0000000000006384PMid:30266889 PMCid:PMC6205683 Moberg JY, Laursen B, Thygesen LC, Magyari M. Reproductive history of the Danish multiple sclerosis population: a register-based study. Mult Scler. 2020;26(8):902-11. https://doi.org/10.1177/1352458519851245PMid:31144565 Benoit A, Durand-Dubief F, Amato M-P, Portaccio E, Casey R, Roggerone S, et al. History of multiple sclerosis in 2 successive pregnancies: a French and Italian cohort. Neurology. 2016;87(13):1360-7. https://doi.org/10.1212/WNL.0000000000003036PMid:27466470 D'hooghe MB, Nagels G. Long-term effects of childbirth in MS. J Neurol Neurosurg Psychiatry. 2010;81(1):38-41. https://doi.org/10.1136/jnnp.2008.163816PMid:19939856 Zuluaga MI, Otero-Romero S, Rovira A, Perez-Hoyos S, Arrambide G, Negrotto L, et al. Menarche, pregnancies, and breastfeeding do not modify long-term prognosis in multiple sclerosis. Neurology. 2019;92(13):e1507-16. https://doi.org/10.1212/WNL.0000000000007178PMid:30824557 PMCid:PMC6453769 Runmarker B, Andersen O. Pregnancy is associated with a lower risk of onset and a better prognosis in multiple sclerosis. Brain. 1995;118(1):253-61. https://doi.org/10.1093/brain/118.1.253PMid:7895009 Ebers G, Yee I, Sadovnick A, Duquette P. Conjugal multiple sclerosis: Populationâ€based prevalence and recurrence risks in offspring. Ann Neurol. 2000;48(6): 927-31. https://doi.org/10.1002/1531-8249(200012)48:6PMid:11117550 Fiddes B, Wason J, Kemppinen A, Ban M, Compston A, Sawcer S. Confounding underlies the apparent month of birth effect in multiple sclerosis. Ann Neurol. 2013;73(6):714-20. https://doi.org/10.1002/ana.23925PMid:23744589 PMCid:PMC3748787 Mirzaei F, Michels KB, Munger K, O'Reilly E, Chitnis T, Forman MR, et al. Gestational vitamin D and the risk of multiple sclerosis in offspring. Ann Neurol. 2011;70(1):30-40. https://doi.org/10.1002/ana.22456PMid:21786297 PMCid:PMC3205990 Riley M, Dobson M, Jones E, Kirst N. Health maintenance in women. Am Fam Physician. 2013;87(1):30-7. Paavilainen T, Kurki T, Färkkilä M, Salonen O, Parkkola R, Airas L. Lower brain diffusivity in postpartum period compared to late pregnancy: results from a prospective imaging study of multiple sclerosis patients. Neuroradiology. 2012;54(8):823-8. https://doi.org/10.1007/s00234-011-0994-4PMid:22160148 Ponsonby A-L, Lucas R, Van Der Mei I, Dear K, Valery P, Pender M, et al. Offspring number, pregnancy, and risk of a first clinical demyelinating event: the AusImmune Study. Neurology. 2012;78(12):867-74. https://doi.org/10.1212/WNL.0b013e31824c4648PMid:22402857 Lebrun C, Le Page E, Kantarci O, Siva A, Pelletier D, Okuda D, et al. Impact of pregnancy on conversion to clinically isolated syndrome in a radiologically isolated syndrome cohort. Mult Scler. 2012;18(9):1297-302. https://doi.org/10.1177/1352458511435931PMid:22300971 Krysko KM, Bove R, Dobson R, Jokubaitis V, Hellwig K. Treatment of women with multiple sclerosis planning pregnancy. Curr Treat Options Neurol. 2021;23(4):1-19. https://doi.org/10.1007/s11940-021-00666-4PMid:33814892 PMCid:PMC8008016 Neuhaus O, Kieseier BC, Hartung H-P. Pharmacokinetics and pharmacodynamics of the interferon-betas, glatiramer acetate, and mitoxantrone in multiple sclerosis. J Neurol Sci. 2007;259(1-2):27-37. https://doi.org/10.1016/j.jns.2006.05.071PMid:17391705 Hellwig K, Geissbuehler Y, Sabidó M, Popescu C, Adamo A, Klinger J, et al. Pregnancy outcomes in interferon-beta-exposed patients with multiple sclerosis: results from the European Interferon-beta Pregnancy Registry. J Neurol. 2020;267(6):1715-23. https://doi.org/10.1007/s00415-020-09762-yPMid:32100126 PMCid:PMC7293672 Hakkarainen KM, Juuti R, Burkill S, Geissbühler Y, Sabidó M, Popescu C, et al. Pregnancy outcomes after exposure to interferon beta: a register-based cohort study among women with MS in Finland and Sweden. Ther Adv Neurol Disord. 2020;13:1756286420951072. https://doi.org/10.1177/1756286420951072PMid:33101459 PMCid:PMC7549181 Hale TW, Siddiqui AA, Baker TE. Transfer of interferon β-1a into human breastmilk. Breastfeed Med. 2012;7(2):123-5. https://doi.org/10.1089/bfm.2011.0044PMid:21988602 Ciplea AI, Langer-Gould A, Stahl A, Thiel S, Queisser-Wahrendorf A, Gold R, et al. Safety of potential breast milk exposure to IFN-β or glatiramer acetate: one-year infant outcomes. Neurol Neuroimmunol Neuroinflamm. ;7(4):e757. Cassina M, Johnson D, Robinson L, Braddock S, Xu R, Jimenez J, et al. Pregnancy outcome in women exposed to leflunomide before or during pregnancy. Arthritis Rheum. 2012;64(7):2085-94. https://doi.org/10.1002/art.34419PMid:22307734 Correale J, Abad P, Alvarenga R, Alves-Leon S, Armas E, Barahona J, et al. Management of relapsing-remitting multiple sclerosis in Latin America: Practical recommendations for treatment optimization. J Neurol Sci. 2014;339(1-2):196-206. https://doi.org/10.1016/j.jns.2014.02.017PMid:24607335 Buraga I, Popovici RE. Multiple sclerosis and pregnancy: current considerations. Scientific World Journal. 2014;2014:513160. https://doi.org/10.1155/2014/513160PMid:24977202 PMCid:PMC3997075 VarytÄ— G, ArlauskienÄ— A, RamaÅ¡auskaitÄ— D. Pregnancy and multiple sclerosis: an update. Curr Opin Obstet Gynecol. 2021;33(5):378. https://doi.org/10.1097/GCO.0000000000000731PMid:34310364 PMCid:PMC8452312 Bodiguel E, Bensa C, Brassat D, Laplaud D, Le Page E, Ouallet J-C, et al. Multiple sclerosis and pregnancy. Rev Neurol (Paris). 2014;170(4):247-65. https://doi.org/10.1016/j.neurol.2013.09.010PMid:24684929 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. https://doi.org/10.1212/WNL.0000000000000137PMid:24463630 PMCid:PMC3945658 Lu E, Wang BW, Guimond C, Synnes A, Sadovnick AD, Dahlgren L, et al. Safety of disease-modifying drugs for multiple sclerosis in pregnancy: current challenges and future considerations for effective pharmacovigilance. Expert Rev Neurother. 2013;13(3):251-61. https://doi.org/10.1586/ern.13.12PMid:23448215 Landi D, Portaccio E, Bovis F, Annovazzi P, Morra V, Bucello S, et al. Continuation of natalizumab versus interruption is associated with lower risk of relapses during pregnancy and postpartum in women with MS. Mult Scler. 2019;25:892-4. Dobson R, Dassan P, Roberts M, Giovannoni G, Nelson-Piercy C, Brex PA. UK consensus on pregnancy in multiple sclerosis:'Association of British Neurologists' guidelines. Pract Neurol. 2019;19(2):106-14. https://doi.org/10.1136/practneurol-2018-002060PMid:30612100 Friend S, Richman S, Bloomgren G, Cristiano LM, Wenten M. Evaluation of pregnancy outcomes from the Tysabri®(natalizumab) pregnancy exposure registry: a global, observational, follow-up study. BMC Neurol. 2016;16(1):1-9. https://doi.org/10.1186/s12883-016-0674-4PMid:27552976 PMCid:PMC4995778 Haghikia A, Langer-Gould A, Rellensmann G, Schneider H, Tenenbaum T, Elias-Hamp B, Menck S, Zimmermann J, Herbstritt S, Marziniak M, Kümpfel T, Meinl I, Plavina T, Gold R, Hellwig K. Natalizumab use during the third trimester of pregnancy. JAMA Neurol. 2014;71(7):891-5. https://doi.org/10.1001/jamaneurol.2014.209PMid:24821217 Alroughani R, Altintas A, Al Jumah M, Sahraian M, Alsharoqi I, AlTahan A, et al. Pregnancy and the Use of Disease-Modifying Therapies in Patients with Multiple Sclerosis: Benefits versus Risks. Mult Scler Int. 2016;2016:1034912. https://doi.org/10.1155/2016/1034912PMid:28078140 PMCid:PMC5203912 Simone IL, Tortorella C, Ghirelli A. Influence of Pregnancy in Multiple Sclerosis and Impact of Disease-Modifying Therapies. Front Neurol. 2021;12:697974. https://doi.org/10.3389/fneur.2021.697974PMid:34276545 PMCid:PMC8280312 Decallonne B, Bartholomé E, Delvaux V, D'haeseleer M, El Sankari S, Seeldrayers P, et al. Thyroid disorders in alemtuzumab-treated multiple sclerosis patients: a Belgian consensus on diagnosis and management. Acta Neurol Belg. 2018;118(2):153-9. https://doi.org/10.1007/s13760-018-0883-2PMid:29372482 PMCid:PMC5971042 Rehman N, Ghotekar S, Izharullah M, Zaheer J, Akram M, Khan M. Prevalence and Treatment of Hypertension in District Bhimber, Azad Jammu and Kashmir. J Med Chem. 2021;4(1):75-83. Moreno Torres I, GarcÃa-Merino A. Anti-CD20 monoclonal antibodies in multiple sclerosis. Expert Rev Neurother. 2017;17(4):359-71. https://doi.org/10.1080/14737175.2017.1245616PMid:27718747 Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes after maternal exposure to rituximab. Blood. 2011;117(5):1499-506. https://doi.org/10.1182/blood-2010-07-295444PMid:21098742 Giovannoni G, Galazka A, Schick R, Leist T, Comi G, Montalban X, et al. Pregnancy outcomes during the clinical development program of cladribine in multiple sclerosis: an integrated analysis of safety. Drug Saf. 2020;43(7):635-43. https://doi.org/10.1007/s40264-020-00948-xPMid:32447743 PMCid:PMC7305061 Milad S, Ehsan J, Farzad MS, Mohsen R, Ahmad B, Shahram M, et al. Effects of Dimethyl Fumarate on the Karnofsky Performance Status and Serum S100β Level in Newly Glioblastoma Patients: A Randomized, Phase-II, Placebo, Triple Blinded, Controlled Trial: Effect of DMF On the Serum S100β Level and KPS Score of GBM Patients. GMJ. 2022;10:1-10. Hellwig K, Rog D, McGuigan C, Houtchens MK, Bruen DR, Mokliatchouk O, et al. Interim Analysis of Pregnancy Outcomes After Exposure to Dimethyl Fumarate in a Prospective International Registry. Neurol Neuroimmunol Neuroinflamm. 2021;9(1):e1114. https://doi.org/10.1212/NXI.0000000000001114PMid:34815321 PMCid:PMC8611504 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. https://doi.org/10.1177/1352458513519840PMid:24446387 PMCid:PMC5458871 Pakpoor J, Disanto G, Lacey MV, Hellwig K, Giovannoni G, Ramagopalan SV. Breastfeeding and multiple sclerosis relapses: a meta-analysis. J Neurol. 2012;259(10):2246-8. https://doi.org/10.1007/s00415-012-6553-zPMid:22619059 Hellwig K. Pregnancy in multiple sclerosis. Eur Neurol. 2014;72(Suppl 1):39-42. https://doi.org/10.1159/000367640PMid:25278125 Haas J, Hommes OR. A dose comparison study of IVIG in postpartum relapsing-remitting multiple sclerosis. Mult Scler. 2007;13(7):900-8. https://doi.org/10.1177/1352458506075654PMid:17881400
