Neuro-inflammatory Disorders in Women

  • Ivana VodopivecEmail author


Many neuro-inflammatory disorders have a predilection for women; even if there is no female predominance, neuro-inflammatory conditions in women pose a management challenge for several reasons. Disease activity of these conditions may change during pregnancy and commonly increases in the postpartum period. Immunomodulating agents that are used to suppress the disease activity may have a negative impact on fertility, pregnancy, and fetal outcomes, and on infants who are breastfed. Adverse effects of immunosuppressants extend beyond the reproductive issues and may include bone loss, increased risk of cancers, and infectious complications. The successful management of women with these disorders not only involves understanding and early recognition of the adverse effects of immunosuppressants but also active prevention of the adverse outcomes through counseling about contraceptive choices, safety monitoring, risk surveillance, and other strategies.


Neuro-inflammatory disorders Multiple sclerosis Immunosuppressants Adverse effects Fertility Pregnancy Lactation Glucocorticoid-induced osteoporosis Cervical cancer 


  1. 1.
    Xanthos DN, Sandkuhler J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci. 2014;15(1):43–53.PubMedCrossRefGoogle Scholar
  2. 2.
    Hohlfeld R, Kerschensteiner M, Meinl E. Dual role of inflammation in CNS disease. Neurology. 2007;68(22 Suppl 3):S58–63; discussion S91–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74(4):691–705.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Armangue T, Moris G, Cantarin-Extremera V, Conde CE, Rostasy K, Erro ME, et al. Autoimmune post-herpes simplex encephalitis of adults and teenagers. Neurology. 2015;85(20):1736–43.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Beeson PB. Age and sex associations of 40 autoimmune diseases. Am J Med. 1994;96(5):457–62.PubMedCrossRefGoogle Scholar
  6. 6.
    Whitacre CC. Sex differences in autoimmune disease. Nat Immunol. 2001;2(9):777–80.PubMedCrossRefGoogle Scholar
  7. 7.
    Fish EN. The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol. 2008;8(9):737–44.PubMedCrossRefGoogle Scholar
  8. 8.
    Liang Y, Tsoi LC, Xing X, Beamer MA, Swindell WR, Sarkar MK, et al. A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases. Nat Immunol. 2017;18(2):152–60.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Panchanathan R, Choubey D. Murine BAFF expression is up-regulated by estrogen and interferons: implications for sex bias in the development of autoimmunity. Mol Immunol. 2013;53(1–2):15–23.PubMedCrossRefGoogle Scholar
  10. 10.
    Bove R, McHenry A, Hellwig K, Houtchens M, Razaz N, Smyth P, et al. Multiple sclerosis in men: management considerations. J Neurol. 2016;263(7):1263–73.PubMedCrossRefGoogle Scholar
  11. 11.
    Bove R, Chitnis T. The role of gender and sex hormones in determining the onset and outcome of multiple sclerosis. Mult Scler. 2014;20(5):520–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Bielecki B, Mattern C, Ghoumari AM, Javaid S, Smietanka K, Abi Ghanem C, et al. Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin. Proc Natl Acad Sci U S A. 2016;113(51):14829–34.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Koelman DL, Chahin S, Mar SS, Venkatesan A, Hoganson GM, Yeshokumar AK, et al. Acute disseminated encephalomyelitis in 228 patients: a retrospective, multicenter US study. Neurology. 2016;86(22):2085–93.PubMedCrossRefGoogle Scholar
  14. 14.
    Tenembaum S, Chitnis T, Ness J, Hahn JS, International Pediatric MSSG. Acute disseminated encephalomyelitis. Neurology. 2007;68(16 Suppl 2):S23–36.PubMedCrossRefGoogle Scholar
  15. 15.
    Granerod J, Ambrose HE, Davies NW, Clewley JP, Walsh AL, Morgan D, et al. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis. 2010;10(12):835–44.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA. The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project. Clin Infect Dis. 2012;54(7):899–904.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Svensson-Arvelund J, Mehta RB, Lindau R, Mirrasekhian E, Rodriguez-Martinez H, Berg G, et al. The human fetal placenta promotes tolerance against the semiallogeneic fetus by inducing regulatory T cells and homeostatic M2 macrophages. J Immunol. 2015;194(4):1534–44.PubMedCrossRefGoogle Scholar
  18. 18.
    Tilburgs T, Evans JH, Crespo AC, Strominger JL. The HLA-G cycle provides for both NK tolerance and immunity at the maternal-fetal interface. Proc Natl Acad Sci U S A. 2015;112(43):13312–7.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Fu B, Li X, Sun R, Tong X, Ling B, Tian Z, et al. Natural killer cells promote immune tolerance by regulating inflammatory TH17 cells at the human maternal-fetal interface. Proc Natl Acad Sci U S A. 2013;110(3):E231–40.PubMedCrossRefGoogle Scholar
  20. 20.
    Santner-Nanan B, Peek MJ, Khanam R, Richarts L, Zhu E, Fazekas de St Groth B, et al. Systemic increase in the ratio between Foxp3+ and IL-17-producing CD4+ T cells in healthy pregnancy but not in preeclampsia. J Immunol. 2009;183(11):7023–30.PubMedCrossRefGoogle Scholar
  21. 21.
    Arck PC, Hecher K. Fetomaternal immune cross-talk and its consequences for maternal and offspring’s health. Nat Med. 2013;19(5):548–56.PubMedCrossRefGoogle Scholar
  22. 22.
    Zenclussen AC. Adaptive immune responses during pregnancy. Am J Reprod Immunol. 2013;69(4):291–303.PubMedCrossRefGoogle Scholar
  23. 23.
    Saito S, Nakashima A, Shima T, Ito M. Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy. Am J Reprod Immunol. 2010;63(6):601–10.PubMedCrossRefGoogle Scholar
  24. 24.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Fabian M. Pregnancy in the setting of multiple sclerosis. Continuum (Minneap Minn). 2016;22(3):837–50.Google Scholar
  26. 26.
    Kim W, Kim SH, Nakashima I, Takai Y, Fujihara K, Leite MI, et al. Influence of pregnancy on neuromyelitis optica spectrum disorder. Neurology. 2012;78(16):1264–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Fragoso YD, Adoni T, Bichuetti DB, Brooks JB, Ferreira ML, Oliveira EM, et al. Neuromyelitis optica and pregnancy. J Neurol. 2013;260(10):2614–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Shimizu Y, Fujihara K, Ohashi T, Nakashima I, Yokoyama K, Ikeguch R, et al. Pregnancy-related relapse risk factors in women with anti-AQP4 antibody positivity and neuromyelitis optica spectrum disorder. Mult Scler. 2016;22(11):1413–20.PubMedCrossRefGoogle Scholar
  29. 29.
    Norwood F, Dhanjal M, Hill M, James N, Jungbluth H, Kyle P, et al. Myasthenia in pregnancy: best practice guidelines from a U.K. multispecialty working group. J Neurol Neurosurg Psychiatry. 2014;85(5):538–43.PubMedCrossRefGoogle Scholar
  30. 30.
    Boldingh MI, Maniaol AH, Brunborg C, Weedon-Fekjaer H, Verschuuren JJ, Tallaksen CM. Increased risk for clinical onset of myasthenia gravis during the postpartum period. Neurology. 2016;87(20):2139–45.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Gayed M, Gordon C. Pregnancy and rheumatic diseases. Rheumatology (Oxford). 2007;46(11):1634–40.CrossRefGoogle Scholar
  32. 32.
    Andersen SL, Olsen J, Carle A, Laurberg P. Hyperthyroidism incidence fluctuates widely in and around pregnancy and is at variance with some other autoimmune diseases: a Danish population-based study. J Clin Endocrinol Metab. 2015;100(3):1164–71.PubMedCrossRefGoogle Scholar
  33. 33.
    de Man YA, Dolhain RJ, van de Geijn FE, Willemsen SP, Hazes JM. Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Rheum. 2008;59(9):1241–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Buchel E, Van Steenbergen W, Nevens F, Fevery J. Improvement of autoimmune hepatitis during pregnancy followed by flare-up after delivery. Am J Gastroenterol. 2002;97(12):3160–5.PubMedCrossRefGoogle Scholar
  35. 35.
    Airas L, Saraste M, Rinta S, Elovaara I, Huang YH, Wiendl H, et al. Immunoregulatory factors in multiple sclerosis patients during and after pregnancy: relevance of natural killer cells. Clin Exp Immunol. 2008;151(2):235–43.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Lateef A, Petri M. Management of pregnancy in systemic lupus erythematosus. Nat Rev Rheumatol. 2012;8(12):710–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Davoudi V, Keyhanian K, Bove RM, Chitnis T. Immunology of neuromyelitis optica during pregnancy. Neurol Neuroimmunol Neuroinflamm. 2016;3(6):e288.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Shosha E, Pittock SJ, Flanagan E, Weinshenker BG. Neuromyelitis optica spectrum disorders and pregnancy: interactions and management. Mult Scler. 2017;23(14):1808–17.PubMedCrossRefGoogle Scholar
  39. 39.
    Jones BG, Penkert RR, Xu B, Fan Y, Neale G, Gearhart PJ, et al. Binding of estrogen receptors to switch sites and regulatory elements in the immunoglobulin heavy chain locus of activated B cells suggests a direct influence of estrogen on antibody expression. Mol Immunol. 2016;77:97–102.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Weinstein RS. Clinical practice. Glucocorticoid-induced bone disease. N Engl J Med. 2011;365(1):62–70.PubMedCrossRefGoogle Scholar
  41. 41.
    Compston J. Management of glucocorticoid-induced osteoporosis. Nat Rev Rheumatol. 2010;6(2):82–8.PubMedCrossRefGoogle Scholar
  42. 42.
    van Staa TP, Leufkens HG, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int. 2002;13(10):777–87.PubMedCrossRefGoogle Scholar
  43. 43.
    Allen CS, Yeung JH, Vandermeer B, Homik J. Bisphosphonates for steroid-induced osteoporosis. Cochrane Database Syst Rev. 2016;10:CD001347.PubMedGoogle Scholar
  44. 44.
    Overman RA, Toliver JC, Yeh JY, Gourlay ML, Deal CL. United States adults meeting 2010 American College of Rheumatology criteria for treatment and prevention of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken). 2014;66(11):1644–52.CrossRefGoogle Scholar
  45. 45.
    Grossman JM, Gordon R, Ranganath VK, Deal C, Caplan L, Chen W, et al. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken). 2010;62(11):1515–26.CrossRefGoogle Scholar
  46. 46.
    Mok CC, Ho LY, Ma KM. Switching of oral bisphosphonates to denosumab in chronic glucocorticoid users: a 12-month randomized controlled trial. Bone. 2015;75:222–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Santana IU, Gomes Ado N, Lyrio LD, Rios Grassi MF, Santiago MB. Systemic lupus erythematosus, human papillomavirus infection, cervical pre-malignant and malignant lesions: a systematic review. Clin Rheumatol. 2011;30(5):665–72.PubMedCrossRefGoogle Scholar
  48. 48.
    Nguyen ML, Flowers L. Cervical cancer screening in immunocompromised women. Obstet Gynecol Clin N Am. 2013;40(2):339–57.CrossRefGoogle Scholar
  49. 49.
    Curtis KM, Tepper NK, Jatlaoui TC, Berry-Bibee E, Horton LG, Zapata LB, et al. U.S. medical eligibility criteria for contraceptive use, 2016. MMWR Recomm Rep. 2016;65(3):1–103.PubMedCrossRefGoogle Scholar
  50. 50.
    Vukusic S, Marignier R. Multiple sclerosis and pregnancy in the ‘treatment era’. Nat Rev Neurol. 2015;11(5):280–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Gotestam Skorpen C, Hoeltzenbein M, Tincani A, Fischer-Betz R, Elefant E, Chambers C, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis. 2016;75(5):795–810.PubMedCrossRefGoogle Scholar
  52. 52.
    Hellwig K, Rockhoff M, Herbstritt S, Borisow N, Haghikia A, Elias-Hamp B, et al. Exclusive breastfeeding and the effect on postpartum multiple sclerosis relapses. JAMA Neurol. 2015;72(10):1132–8.PubMedCrossRefGoogle Scholar
  53. 53.
    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.PubMedCrossRefGoogle Scholar
  54. 54.
    Westerlind H, Ramanujam R, Uvehag D, Kuja-Halkola R, Boman M, Bottai M, et al. Modest familial risks for multiple sclerosis: a registry-based study of the population of Sweden. Brain. 2014;137(Pt 3):770–8.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of NeurologyBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA

Personalised recommendations