Pregnancy and multiple sclerosis: from molecular mechanisms to clinical application

Seminars in Immunopathology

Volumn 38, Issue 6, 2016, Pages 709-718

  Gold, Stefan M ^a,b   Voskuhl, Rhonda R ^c  

^a UNIVERSITY MEDICAL CENTER HAMBURG EPPENDORF   (Germany)

^b CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^c UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BETA1A INTERFERON; DESOGESTREL PLUS ETHINYLESTRADIOL; ESTRADIOL; ESTRIOL; GONADORELIN AGONIST; GONADORELIN ANTAGONIST; PLACEBO; PROGESTERONE;

AUTOIMMUNITY; DISEASE ACTIVITY; DISEASE COURSE; DRUG MEGADOSE; HUMAN; IMMUNOMODULATION; IMMUNOPATHOLOGY; INFERTILITY THERAPY; INFLAMMATION; LOW DRUG DOSE; MULTICENTER STUDY (TOPIC); MULTIPLE SCLEROSIS; PARITY; PHASE 2 CLINICAL TRIAL (TOPIC); PREGNANCY; PRIORITY JOURNAL; PROGENY; PUERPERIUM; RANDOMIZED CONTROLLED TRIAL (TOPIC); RELAPSE; REVIEW; RISK FACTOR; TREATMENT OUTCOME; UNSPECIFIED SIDE EFFECT; CLINICAL TRIAL (TOPIC); DISEASE PREDISPOSITION; FEMALE; INCIDENCE; PREGNANCY COMPLICATION; RECURRENT DISEASE; REPRODUCTIVE HISTORY; RISK; TRANSLATIONAL RESEARCH;

CLINICAL TRIALS AS TOPIC; DISEASE SUSCEPTIBILITY; ESTRIOL; FEMALE; HUMANS; INCIDENCE; MULTIPLE SCLEROSIS; PREGNANCY; PREGNANCY COMPLICATIONS; RECURRENCE; REPRODUCTIVE HISTORY; REPRODUCTIVE TECHNIQUES, ASSISTED; RISK; TRANSLATIONAL MEDICAL RESEARCH; TREATMENT OUTCOME;

EID: 84981285536     PISSN: 18632297     EISSN: 18632300     Source Type: Journal    
DOI: 10.1007/s00281-016-0584-y     Document Type: Review

References (85)

1. Libert C, Dejager L, Pinheiro I (2010) The X chromosome in immune functions: when a chromosome makes the difference. Nat Rev Immunol 10(8):594–604
2. Whitacre CC, Reingold SC, O'Looney PA (1999) A gender gap in autoimmunity. Science 283(5406):1277–1278
3. Hellwig K, Haghikia A, Gold R (2010) Parenthood and immunomodulation in patients with multiple sclerosis. J Neurol 257(4):580–583
4. Vukusic S, Marignier R (2015) Multiple sclerosis and pregnancy in the ‘treatment era’. Nat Rev Neurol 11(5):280–289
5. Coyle PK (2016) Management of women with multiple sclerosis through pregnancy and after childbirth. Ther Adv Neurol Disord 9(3):198–210
6. Sawcer S, Franklin RJ, Ban M (2014) Multiple sclerosis genetics. Lancet Neurol 13(7):700–709
7. Ascherio A (2013) Environmental factors in multiple sclerosis. Expert Rev Neurother 13(12 Suppl):3–9
8. Dendrou CA, Fugger L, Friese MA (2015) Immunopathology of multiple sclerosis. Nat Rev Immunol 15(9):545–558
9. Friese MA, Schattling B, Fugger L (2014) Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat Rev Neurol 10(4):225–238
10. B. Runmarker, O. Andersen, (1995) Pregnancy is associated with a lower risk of onset and a better prognosis in multiple sclerosis [see comments], Brain 118(Pt 1)(10):253–61
11. Villard-Mackintosh L, Vessey MP (1993) Oral contraceptives and reproductive factors in multiple sclerosis incidence. Contraception 47(2):161–168
12. Thorogood M, Hannaford PC (1998) The influence of oral contraceptives on the risk of multiple sclerosis. Br J Obstet Gynaecol 105(12):1296–1299
13. Alonso A, Jick SS, Olek MJ, Ascherio A, Jick H, Hernan MA (2005) Recent use of oral contraceptives and the risk of multiple sclerosis. Arch Neurol 62(9):1362–1365
14. Hernan MA, Hohol MJ, Olek MJ, Spiegelman D, Ascherio A (2000) Oral contraceptives and the incidence of multiple sclerosis. Neurology 55(6):848–854
15. Weinshenker BG, Hader W, Carriere W, Baskerville J, Ebers GC (1989) The influence of pregnancy on disability from multiple sclerosis: a population-based study in Middlesex County, Ontario. Neurology 39(11):1438–1440
16. Ponsonby AL, Lucas RM, van der Mei IA, Dear K, Valery PC, Pender MP, Taylor BV, Kilpatrick TJ, Coulthard A, Chapman C, Williams D, McMichael AJ, Dwyer T (2012) Offspring number, pregnancy, and risk of a first clinical demyelinating event: the AusImmune Study. Neurology 78(12):867–874
17. Laplaud DA, Leray E, Barriere P, Wiertlewski S, Moreau T (2006) Increase in multiple sclerosis relapse rate following in vitro fertilization. Neurology 66(8):1280–1281
18. 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 (2012) Club Francophone de la Sclerose En, increased risk of multiple sclerosis relapse after in vitro fertilisation. J Neurol Neurosurg Psychiatry 83(8):796–802
19. Hellwig K, Beste C, Brune N, Haghikia A, Muller T, Schimrigk S, Gold R (2008) Increased MS relapse rate during assisted reproduction technique. J Neurol 255(4):592–593
20. Hellwig K, Schimrigk S, Beste C, Muller T, Gold R (2009) Increase in relapse rate during assisted reproduction technique in patients with multiple sclerosis. Eur Neurol 61(2):65–68
21. Correale J, Farez MF, Ysrraelit MC (2012) Increase in multiple sclerosis activity after assisted reproduction technology. Ann Neurol 72(5):682–694
22. Pasch LA, Gregorich SE, Katz PK, Millstein SG, Nachtigall RD, Bleil ME, Adler NE (2012) Psychological distress and in vitro fertilization outcome. Fertil Steril 98(2):459–464
23. Mohr DC, Hart SL, Julian L, Cox D, Pelletier D (2004) Association between stressful life events and exacerbation in multiple sclerosis: a meta-analysis. BMJ 328(7442):731
24. Golan D, Somer E, Dishon S, Cuzin-Disegni L, Miller A (2008) Impact of exposure to war stress on exacerbations of multiple sclerosis. Ann Neurol 64(2):143–148
25. Gold SM, Sasidhar MV, Lagishetty V, Spence RD, Umeda E, Ziehn MO, Krieger T, Schulz KH, Heesen C, Hewison M, Voskuhl RR (2012) Dynamic development of glucocorticoid resistance during autoimmune neuroinflammation. J Clin Endocrinol Metab 97(8):E1402–E1410
26. Gold SM, Mohr DC, Huitinga I, Flachenecker P, Sternberg EM, Heesen C (2005) The role of stress-response systems for the pathogenesis and progression of MS. Trends Immunol 26(12):644–652
27. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T (1998) Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in multiple sclerosis group [see comments]. N Engl J Med 339(5):285–291
28. Finkelsztejn A, Brooks JB, Paschoal FM Jr, Fragoso YD (2011) What can we really tell women with multiple sclerosis regarding pregnancy? A systematic review and meta-analysis of the literature. BJOG 118(7):790–797
29. Hutchinson M (2013) One can prevent post-partum MS relapses by exclusive breast feeding: commentary. Mult Scler 19(12):1569–1570
30. Langer-Gould A, Hellwig K (2013) One can prevent post-partum MS relapses by exclusive breast feeding: yes. Mult Scler 19(12):1567–1568
31. Vukusic S, Confavreux C (2013) One can prevent post-partum MS relapses by exclusive breast feeding: no. Mult Scler 19(12):1565–1566
32. Vukusic S, Hutchinson M, Hours M, Moreau T, Cortinovis-Tourniaire P, Adeleine P, Confavreux C (2004) The pregnancy in multiple sclerosis, pregnancy and multiple sclerosis (the PRIMS study): clinical predictors of post-partum relapse. Brain 127(Pt 6):1353–1360
33. Nelson LM, Franklin GM, Jones MC (1988) Risk of multiple sclerosis exacerbation during pregnancy and breast-feeding. JAMA 259(23):3441–3443
34. Airas L, Jalkanen A, Alanen A, Pirttila T, Marttila RJ (2010) Breast-feeding, postpartum and prepregnancy disease activity in multiple sclerosis. Neurology 75(5):474–476
35. Portaccio E, Ghezzi A, Hakiki B, Martinelli V, Moiola L, Patti F, La Mantia L, Mancardi GL, Solaro C, Tola MR, Pozzilli C, De Giglio L, Totaro R, Lugaresi A, De Luca G, Paolicelli D, Marrosu MG, Comi G, Trojano M, Amato MP (2011) Breastfeeding is not related to postpartum relapses in multiple sclerosis. Neurology 77(2):145–150
36. A. Langer-Gould, S.M. Huang, R. Gupta, A.D. Leimpeter, E. Greenwood, K.B. Albers, S.K. Van Den Eeden, L.M. Nelson (2009) Exclusive breastfeeding and the risk of postpartum relapses in women with multiple sclerosis. Arch Neurol 66(8):958–963
37. Hellwig K, Haghikia A, Agne H, Beste C, Gold R (2009) Protective effect of breastfeeding in postpartum relapse rate of mothers with multiple sclerosis. Arch Neurol 66(12):1580–1581 author reply 1581
38. Hellwig K, Rockhoff M, Herbstritt S, Borisow N, Haghikia A, Elias-Hamp B, Menck S, Gold R, Langer-Gould A (2015) Exclusive breastfeeding and the effect on postpartum multiple sclerosis relapses. JAMA Neurol 72(10):1132–1138
39. Patas K, Engler JB, Friese MA, Gold SM (2013) Pregnancy and multiple sclerosis: feto-maternal immune cross talk and its implications for disease activity. J Reprod Immunol 97(1):140–146
40. Langer-Gould A, Garren H, Slansky A, Ruiz PJ, Steinman L (2002) Late pregnancy suppresses relapses in experimental autoimmune encephalomyelitis: evidence for a suppressive pregnancy-related serum factor. J Immunol 169(2):1084–1091
41. Abramsky O, Brenner T, Mizrachi R, Soffer D (1982) Alpha-fetoprotein suppresses experimental allergic encephalomyelitis. J Neuroimmunol 2(1):1–7
42. Laffont S, Garnier L, Lelu K, Guery JC (2015) Estrogen-mediated protection of experimental autoimmune encephalomyelitis: lessons from the dissection of estrogen receptor-signaling in vivo. Biomed J 38(3):194–205
43. Kim S, Liva SM, Dalal MA, Verity MA, Voskuhl RR (1999) Estriol ameliorates autoimmune demyelinating disease: implications for multiple sclerosis. Neurology 52(6):1230–1238
44. Yates MA, Li Y, Chlebeck P, Proctor T, Vandenbark AA, Offner H (2010) Progesterone treatment reduces disease severity and increases IL-10 in experimental autoimmune encephalomyelitis. J Neuroimmunol 220(1–2):136–139
45. Hoffman GE, Le WW, Murphy AZ, Koski CL (2001) Divergent effects of ovarian steroids on neuronal survival during experimental allergic encephalitis in Lewis rats. Exp Neurol 171(2):272–284
46. Garay L, Gonzalez Deniselle MC, Gierman L, Meyer M, Lima A, Roig P, De Nicola AF (2008) Steroid protection in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Neuroimmunomodulation 15(1):76–83
47. Garay L, Deniselle MC, Lima A, Roig P, De Nicola AF (2007) Effects of progesterone in the spinal cord of a mouse model of multiple sclerosis. J Steroid Biochem Mol Biol 107(3–5):228–237
48. Garay L, Deniselle MC, Meyer M, Costa JJ, Lima A, Roig P, De Nicola AF (2009) Protective effects of progesterone administration on axonal pathology in mice with experimental autoimmune encephalomyelitis. Brain Res 1283:177–185
49. Voskuhl RR, Gold SM (2012) Sex-related factors in multiple sclerosis susceptibility and progression. Nat Rev Neurol 8(5):255–263
50. Nashold FE, Spach KM, Spanier JA, Hayes CE (2009) Estrogen controls vitamin D3-mediated resistance to experimental autoimmune encephalomyelitis by controlling vitamin D3 metabolism and receptor expression. J Immunol 183(6):3672–3681
51. Spanier JA, Nashold FE, Mayne CG, Nelson CD, Hayes CE (2015) Vitamin D and estrogen synergy in Vdr-expressing CD4(+) T cells is essential to induce Helios(+)FoxP3(+) T cells and prevent autoimmune demyelinating disease. J Neuroimmunol 286:48–58
52. Gilli F, Lindberg RL, Valentino P, Marnetto F, Malucchi S, Sala A, Capobianco M, di Sapio A, Sperli F, Kappos L, Calogero RA, Bertolotto A (2010) Learning from nature: pregnancy changes the expression of inflammation-related genes in patients with multiple sclerosis. PLoS One 5(1):e8962
53. Al-Shammri S, Rawoot P, Azizieh F, AbuQoora A, Hanna M, Saminathan TR, Raghupathy R (2004) Th1/Th2 cytokine patterns and clinical profiles during and after pregnancy in women with multiple sclerosis. J Neurol Sci 222(1–2):21–27
54. Gilmore W, Arias M, Stroud N, Stek A, McCarthy KA, Correale J (2004) Preliminary studies of cytokine secretion patterns associated with pregnancy in MS patients. J Neurol Sci 224(1–2):69–76
55. Lopez C, Comabella M, Tintore M, Sastre-Garriga J, Montalban X (2006) Variations in chemokine receptor and cytokine expression during pregnancy in multiple sclerosis patients. Mult Scler 12(4):421–427
56. Airas L, Saraste M, Rinta S, Elovaara I, Huang YH, Wiendl H (2008) Immunoregulatory factors in multiple sclerosis patients during and after pregnancy: relevance of natural killer cells. Clin Exp Immunol 151(2):235–243
57. Langer-Gould A, Gupta R, Huang S, Hagan A, Atkuri K, Leimpeter AD, Albers KB, Greenwood E, Van Den Eeden SK, Steinman L, Nelson LM (2010) Interferon-gamma-producing T cells, pregnancy, and postpartum relapses of multiple sclerosis. Arch Neurol 67(1):51–57
58. Neuteboom RF, Verbraak E, Voerman JS, van Meurs M, Steegers EA, de Groot CJ, Laman JD, Hintzen RQ (2009) First trimester interleukin 8 levels are associated with postpartum relapse in multiple sclerosis. Mult Scler 15(11):1356–1358
59. Sanchez-Ramon S, Navarro AJ, Aristimuno C, Rodriguez-Mahou M, Bellon JM, Fernandez-Cruz E, de Andres C (2005) Pregnancy-induced expansion of regulatory T-lymphocytes may mediate protection to multiple sclerosis activity. Immunol Lett 96(2):195–201
60. Neuteboom RF, Verbraak E, Wierenga-Wolf AF, van Meurs M, Steegers EA, de Groot CJ, Laman JD, Hintzen RQ (2010) Pregnancy-induced fluctuations in functional T-cell subsets in multiple sclerosis patients. Mult Scler 16(9):1073–1078
61. Clark DA (2016) The importance of being a regulatory T cell in pregnancy. J Reprod Immunol 116:60–69
62. Erlebacher A (2013) Mechanisms of T cell tolerance towards the allogeneic fetus. Nat Rev Immunol 13(1):23–33
63. M.J. Polanczyk, C. Hopke, J. Huan, A.A. Vandenbark, H. Offner, (2005) Enhanced FoxP3 expression and Treg cell function in pregnant and estrogen-treated mice. J Neuroimmunol 170(1–2):85–92
64. Munoz-Suano A, Kallikourdis M, Sarris M, Betz AG (2012) Regulatory T cells protect from autoimmune arthritis during pregnancy. J Autoimmun 38(2–3):J103–J108
65. D'Hooghe MB, De Keyser J (2014) Multiparity in women with multiple sclerosis causes less long-term disability: yes. Mult Scler 20(11):1432–1434
66. Hutchinson M (2014) Multiparity in women with multiple sclerosis causes less long-term disability: commentary. Mult Scler 20(11):1437–1438
67. McCombe PA, Callaway LK (2014) Multiparity in women with multiple sclerosis causes less long-term disability: no. Mult Scler 20(11):1435–1436
68. Roullet E, Verdier-Taillefer MH, Amarenco P, Gharbi G, Alperovitch A, Marteau R (1993) Pregnancy and multiple sclerosis: a longitudinal study of 125 remittent patients. J Neurol Neurosurg Psychiatry 56(10):1062–1065
69. Damek DM, Shuster EA (1997) Pregnancy and multiple sclerosis. Mayo Clin Proc 72(10):977–989
70. Verdru P, Theys P, D'Hooghe MB, Carton H (1994) Pregnancy and multiple sclerosis: the influence on long term disability. Clin Neurol Neurosurg 96(1):38–41
71. D'Hooghe BM, Nagels G, Uitdehaag BM (2010) Long-term effects of childbirth in MS. J Neurol Neurosurg Psychiatry 81(1):38–41
72. Masera S, Cavalla P, Prosperini L, Mattioda A, Mancinelli CR, Superti G, Chiavazza C, Vercellino M, Pinessi L, Pozzilli C (2015) Parity is associated with a longer time to reach irreversible disability milestones in women with multiple sclerosis. Mult Scler 21(10):1291–1297
73. Rowe JH, Ertelt JM, Xin L, Way SS (2012) Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. Nature 490:102–106
74. Spence RD, Voskuhl RR (2012) Neuroprotective effects of estrogens and androgens in CNS inflammation and neurodegeneration. Front Neuroendocrinol 33(1):105–115
75. Munger KL, Aivo J, Hongell K, Soilu-Hanninen M, Surcel HM, Ascherio A (2016) Vitamin D status during pregnancy and risk of multiple sclerosis in offspring of women in the Finnish maternity cohort. JAMA Neurol 73(5):515–519
76. Lauritzen C (1987) Results of a 5 years prospective study of estriol succinate treatment in patients with climacteric complaints. Horm Metab Res 19(11):579–584
77. Schiff I, Wentworth B, Koos B, Ryan KJ, Tulchinsky D (1978) Effect of estriol administration on the hypogonadal woman. Fertil Steril 30(3):278–282
78. Sicotte NL, Liva SM, Klutch R, Pfeiffer P, Bouvier S, Odesa S, Wu TC, Voskuhl RR (2002) Treatment of multiple sclerosis with the pregnancy hormone estriol. Ann Neurol 52(4):421–428
79. Soldan SS, Retuerto AI, Sicotte NL, Voskuhl RR (2003) Immune modulation in multiple sclerosis patients treated with the pregnancy hormone estriol. J Immunol 171(11):6267–6274
80. Gold SM, Sasidhar MV, Morales LB, Du S, Sicotte NL, Tiwari-Woodruff SK, Voskuhl RR (2009) Estrogen treatment decreases matrix metalloproteinase (MMP)-9 in autoimmune demyelinating disease through estrogen receptor alpha (ERalpha). Lab Investig 89(10):1076–1083
81. Voskuhl RR, Wang H, Wu TC, Sicotte NL, Nakamura K, Kurth F, Itoh N, Bardens J, Bernard JT, Corboy JR, Cross AH, Dhib-Jalbut S, Ford CC, Frohman EM, Giesser B, Jacobs D, Kasper LH, Lynch S, Parry G, Racke MK, Reder AT, Rose J, Wingerchuk DM, MacKenzie-Graham AJ, Arnold DL, Tseng CH, Elashoff R (2016) Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol 15(1):35–46
82. Voskuhl R, Wang H, Elashoff RM (2016) Why use sex hormones in relapsing-remitting multiple sclerosis?—Authors’ reply. Lancet Neurol 15(8):790–791
83. Pozzilli C, De Giglio L, Barletta VT, Marinelli F, Angelis FD, Gallo V, Pagano VA, Marini S, Piattella MC, Tomassini V, Pantano P (2015) Oral contraceptives combined with interferon β in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2(4):e120
84. Schumacher M, Mattern C, Ghoumari A, Oudinet JP, Liere P, Labombarda F, Sitruk-Ware R, De Nicola AF, Guennoun R (2014) Revisiting the roles of progesterone and allopregnanolone in the nervous system: resurgence of the progesterone receptors. Prog Neurobiol 113:6–39
85. Voskuhl RR (2012) Assisted reproduction technology in multiple sclerosis: giving birth to a new avenue of research in hormones and autoimmunity. Ann Neurol 72(5):631–632