Pregnancy and autoimmune diseases: from immunological tolerance to placenta-associated complications

Autoimmune diseases and pregnancy represent a complex interplay among the immune, vascular, and endocrine systems. Physiological pregnancy is accompanied by dynamic immune adaptation, including the establishment of immunological tolerance, modulation of the Th1/Th2/Th17/Treg balance, and activation of innate immune mechanisms. In autoimmune diseases, these processes may become dysregulated, contributing to endothelial dysfunction, thromboinflammation, complement activation, and placental insufficiency. This review summarizes current concepts on the mechanisms of immune adaptation during pregnancy and the roles of innate and adaptive immunity, microchimerism, the complement system, and neutrophil extracellular traps in the pathogenesis of autoimmune and placenta-associated complications. It also examines the impact of autoantibodies on pregnancy outcomes, including antiphospholipid antibodies as well as anti-Ro/SSA (Ro/Sjögren syndrome-related antigen A), anti-La/SSB (La/Sjögren syndrome-related antigen B), anti-thyroid peroxidase, ANCA (antineutrophil cytoplasmic antibodies), and anti-tissue transglutaminase antibodies. The review discusses the mechanisms underlying preeclampsia, fetal growth restriction, pregnancy loss, and preterm birth, including impaired placentation, endothelial dysfunction, and immunoinflammatory activation. The influence of pregnancy on the course of autoimmune diseases is also considered, including the immunological changes observed in rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, as well as the role of postpartum reactivation of autoimmune inflammation. Current principles of multidisciplinary pregnancy management for women with autoimmune diseases are presented, including preconception counseling, control of disease activity, safe therapy, and postpartum follow-up. Unresolved issues in reproductive immunology, prospects for identifying biomarkers of pregnancy complications, and the development of personalized approaches to managing patients with autoimmune pathology are also discussed.

1. Merz W.M., Fischer-Betz R., Hellwig K. et al. Pregnancy and autoimmune disease. Dtsch Arztebl Int. 2022;119(9):145–56. https://doi.org/10.3238/arztebl.m2021.0353.

2. Singh M., Phillips K., Wang J. et al. Trends in the prevalence of autoimmune diseases during pregnancy in the UK, 2000-21: a retrospective cohort study. Lancet Rheumatol. 2025;7(7):e495–e504. https://doi.org/10.1016/S2665-9913(25)00039-6.

3. Tincani A., Nalli C., Khizroeva J. et al. Autoimmune diseases and pregnancy. Best Pract Res Clin Endocrinol Metab. 2019;33(6):101322. https://doi.org/10.1016/j.beem.2019.101322.

4. Williams A., Grantz K., Seeni I. et al. Obstetric and neonatal complications among women with autoimmune disease. J Autoimmun. 2019;103:102287. 10.1016/j.jaut.2019.05.015.

5. Wang J., Han T., Zhu X. Role of maternal-fetal immune tolerance in the establishment and maintenance of pregnancy. Chin Med J (Engl). 2024;137(12):1399–406. https://doi.org/10.1097/CM9.0000000000003114.

6. Vargas-Rojas M.I., Solleiro-Villavicencio H., Soto-Vega E. Th1, Th2, Th17 and Treg levels in umbilical cord blood in preeclampsia. J Matern Fetal Neonatal Med. 2016;29(10):1642–5. https://doi.org/10.3109/14767058.2015.1057811.

7. Antonova A.S., Khizroeva J.Kh., Kalashnikova I.S. et al. The complement system in pregnant women with severe preeclampsia. [Sistema komplementa u beremennyh s tyazheloj preeklampsiej]. Obstetrics, Gynecology and Reproduction. 2025;19(3):443–52. (In Russ.). https://doi.org/10.17749/2313-7347/ob.gyn.rep.2025.626.

8. Antonova A.S., Tretyakova M.V., Khizroeva J.Kh. et al. The role of complement components (C1q, C3a, MAC) activation in earlyand late-onset preeclampsia and fetal growth restriction. [Rol' aktivacii komponentov sistemy komplementa (C1q, C3a, MAC) pri rannej i pozdnej preeklampsii i sindrome zaderzhki rosta ploda]. Obstetrics, Gynecology and Reproduction. 2026;20(1):67–81. (In Russ.). https://doi.org/10.17749/2313-7347/ob.gyn.rep.2026.703.

9. Krivonos M.I., Khizroeva J.Kh., Zainulina M.S. et al. The role of lymphocytic cells in infertility and reproductive failures in women with antiphospholipid antibodies. J Matern Fetal Neonatal Med. 2022;35(5):871–7. https://doi.org/10.1080/14767058.2020.1732343.

10. Makatsariya A.D., Slukhanchuk E.V., Bitsadze V.O. et al. Neutrophil extracellular traps: a role in inflammation and dysregulated hemostasis as well as in patients with COVID-19 and severe obstetric pathology. [Vnekletochnye lovushki nejtrofilov uchastie v processah vospaleniya i dizregulyacii gemostaza, v tom chisle u pacientov s COVID-19 i tyazheloj akusherskoj patologiej]. Obstetrics, Gynecology and Reproduction. 2021;15(4):335–50. https://doi.org/10.17749/2313-7347/ob.gyn.rep.2021.238.

11. Aslanova Z.D., Khizroeva J.Kh., Solopova A.G. et al. Clinical significance of determining neutrophil extracellular traps in women with oncogynecological neoplasms. [Klinicheskoe znachenie opredeleniya vnekletochnyh lovushek nejtrofilov u zhenshchin s onkoginekologicheskimi zabolevaniyami]. Obstetrics, Gynecology and Reproduction. 2023;17(6):751–68. (In Russ.). https://doi.org/10.17749/2313-7347/ob.gyn.rep.2023.447.

12. Urbschat C., Arck P.C. Micro-chimerism: from evolution to revolution. Semin Immunopathol. 2025;47(1):33. https://doi.org/10.1007/s00281-025-01060-x.

13. Cómitre-Mariano B., Martínez-García M., García-Gálvez B. et al. Feto-maternal microchimerism: Memories from pregnancy. iScience. 2021;25(1):103664. https://doi.org/10.1016/j.isci.2021.103664.

14. Jacobsen D.P., Fjeldstad H.E., Olsen M.B. et al. Microchimerism and pregnancy complications with placental dysfunction. Semin Immunopathol. 2025;47(1):21. https://doi.org/10.1007/s00281-025-01045-w.

15. Nelson J.L. Microchimerism and human autoimmune diseases. Lupus. 2002;11(10):651–4. https://doi.org/10.1191/0961203302lu271oa.

16. Lepez T., Vandewoestyne M., Deforce D. Fetal microchimeric cells in autoimmune thyroid diseases: harmful, beneficial or innocent for the thyroid gland? Chimerism. 2013;4(4):111–8. https://doi.org/10.4161/chim.25055.

17. Alaverdova M.V., Troshina E.A. The role of microchimerism in the development of endocrine diseases (using autoimmune thyroid diseases and type 1 diabetes mellitus as examples). [Rol' mikrohimerizma v razvitii endokrinnyh zabolevanij (na primere autoimmunnyh zabolevanij shchitovidnoj zhelezy i saharnogo diabeta 1 tipa)]. Problemy endokrinologii. 2026;72(1):38–47. (In Russ.). https://doi.org/10.14341/probl13636.

18. Miech R.P. The role of fetal microchimerism in autoimmune disease. Int J Clin Exp Med. 2010;3(2):164–8.

19. Chee Y.J., Dalan R., Cheung C. The interplay between immunity, inflammation and endothelial dysfunction. Int J Mol Sci. 2025;26(4):1708. https://doi.org/10.3390/ijms26041708.

20. Maynard S.E., Min J.Y., Merchan J. et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111(5):649–58. https://doi.org/10.1172/JCI17189.

21. Schrottmaier W.C., Assinger A. The concept of thromboinflammation. Hamostaseologie. 2024;44(1):21–30. https://doi.org/10.1055/a-2178-6491.

22. Knight J.S., Kanthi Y. Mechanisms of immunothrombosis and vasculopathy in antiphospholipid syndrome. Semin Immunopathol. 2022;44(3):347–62. https://doi.org/10.1007/s00281-022-00916-w.

23. Coss S.L., Zhou D., Chua G.T. et al. The complement system and human autoimmune diseases. J Autoimmun. 2023;137:102979. https://doi.org/10.1016/j.jaut.2022.102979.

24. Castellanos Gutierrez A.S., Figueras F., Morales-Prieto D.M. et al. Placental damage in pregnancies with systemic lupus erythematosus: A narrative review. Front Immunol. 2022;13:941586. https://doi.org/10.3389/fimmu.2022.941586.

25. Yamanaka R., Ichii O., Nakamura T. et al. Effects of autoimmune abnormalities on fertility and placental morphology in mice. Autoimmunity. 2024;57(1):2319209. https://doi.org/10.1080/08916934.2024.2319209.

26. Krause M.L., Makol A. Management of rheumatoid arthritis during pregnancy: challenges and solutions. Open Access Rheumatol. 2016;8:23–36. https://doi.org/10.2147/OARRR.S85340.

27. Logoteta A., Piccioni M.G., Nistri R. et al. Potential Protective role of pregnancy and breastfeeding in delaying onset symptoms related to multiple sclerosis. Medicina (Kaunas). 2023;59(3):619. https://doi.org/10.3390/medicina59030619.

28. Confavreux C., Hutchinson M., Hours M.M. et al. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med. 199830;339(5):285–91. https://doi.org/10.1056/NEJM199807303390501.

29. de Man Y.A., Dolhain R.J., van de Geijn F.E. et al. Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Rheum. 2008;59(9):1241–8. https://doi.org/10.1002/art.24003.

30. Hemmer B, Archelos JJ, Hartung HP. New concepts in the immunopathogenesis of multiple sclerosis. Nat Rev Neurosci. 2002;3:291–301. https://doi.org/10.1038/nrn784.

31. Arkema E.V., Palmsten K., Sjöwall C. et al. What to expect when expecting with systemic lupus erythematosus (SLE): A population-based study of maternal and fetal outcomes in SLE and pre-SLE. Arthritis Care Res (Hoboken). 2016;68(7):988–94. https://doi.org/10.1002/acr.22791.

32. Gerede A., Oikonomou E., Stavros S. et al. Systemic lupus erythematosus in pregnancy. Med Sci (Basel). 202513(3):174. https://doi.org/10.3390/medsci13030174.

33. Moyer A., Edens C.. Impact of systemic lupus erythematosus on conception: insights into infertility, fertility preservation, assisted reproductive technology, and pregnancy outcomes. Semin Reprod Med. 202442(3):209–27. https://doi.org/10.1055/s-0044-1793827.

34. Yang Y., Zhou Y., Zhang X. et al. Risk and protective factors of disease flare during pregnancy in systemic lupus erythematosus: a systematic review and meta-analysis. Clin Rheumatol. 2025;44(3):887–99. https://doi.org/10.1007/s10067-025-07341-y.

35. Wu X., Jin R. Effects of postpartum hormonal changes on the immune system and their role in recovery. Acta Biochim Pol. 2025;72:14241. https://doi.org/10.3389/abp.2025.14241.

36. Zucchi D., Tani C., Cascarano G. et al. Postpartum challenges in women with systemic autoimmune diseases. Front Lupus. 2026;4:1788752. https://doi.org/10.3389/flupu.2026.1788752.

37. Bitsadze V.O., Khizroeva J.Kh., Makatsariya N.A. et al. Antiphospholipid antibodies, their pathogenetic and diagnostic issues in obstetric practice. [Antifosfolipidnye antitela, ih patogeneticheskoe i diagnosticheskoe znachenie pri akusherskoj patologii]. Obstetrics, Gynecology and Reproduction. 2014;8(2):39–60. (In Russ.).

38. Mulla M.J., Weel I.C., Potter J.A. et al. Antiphospholipid antibodies inhibit trophoblast Toll-like receptor and inflammasome negative regulators. Arthritis Rheumatol. 2018;70(6):891–902. https://doi.org/10.1002/art.40416.

39. Dragoutsos G., Tsiggalou C., Oikonomou E. et al. Association of anti-Ro/SSA and anti-La/SSB autoantibodies with pregnancy outcome in the general population. Mater Sociomed. 2024;36(1):47–53. https://doi.org/10.5455/msm.2024.36.47-53.

40. Niafar M., Samaie V., Soltani-Zangbar M.S. et al. The association of Treg and Th17 cells development factors and anti-TPO autoantibodies in patients with recurrent pregnancy loss. BMC Res Notes. 2023;16(1):302. https://doi.org/10.1186/s13104-023-06579-6.

41. Borodina E., Gzgzyan A.M., Dzhemlikhanova L.K. et al. Anti-TPO-mediated specific features of the placenta immunohistochemical profile and possible mechanisms for fetal loss. Clin Exp Immunol. 2023;213(2):235–42. https://doi.org/10.1093/cei/uxad057.

42. Partalidou S., Mamopoulos A., Dimopoulou D. et al. Pregnancy outcomes in ANCA-associated vasculitis patients: A systematic review and meta-analysis. Joint Bone Spine. 2023;90(6):105609. https://doi.org/10.1016/j.jbspin.2023.105609.

43. Di Simone N., Silano M., Castellani R. et al. Anti-tissue transglutaminase antibodies from celiac patients are responsible for trophoblast damage via apoptosis in vitro. Am J Gastroenterol. 2010;105(10):2254–61. https://doi.org/10.1038/ajg.2010.233.

44. Chasan-Taber L. It is time to view pregnancy as a stress test. J Womens Health (Larchmt). 2016;25(1):2–3. https://doi.org/10.1089/jwh.2015.5653.

45. Geldenhuys J., Rossouw T.M., Lombaard H.A. et al. Disruption in the regulation of immune responses in the placental subtype of preeclampsia. Front Immunol. 2018;9:1659. https://doi.org/10.3389/fimmu.2018.01659.

46. Wu P., Haththotuwa R., Kwok C.S. et al. Preeclampsia and future cardiovascular health: A systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2017;10(2):e003497. https://doi.org/10.1161/CIRCOUTCOMES.116.003497.

47. Singh M., Fayaz F.F.A., Wang J. et al.; MuM-PreDiCT. Pregnancy complications and autoimmune diseases in women: systematic review and meta-analysis. BMC Med. 2024;22(1):339. https://doi.org/10.1186/s12916-024-03550-5.

48. Sattar N., Greer I.A. Pregnancy complications and maternal cardiovascular risk: opportunities for intervention and screening? BMJ. 2002;325(7356):157–60. https://doi.org/10.1136/bmj.325.7356.157.

49. Fernández-Buhigas I. Obstetric management of the most common autoimmune diseases: A narrative review. Front Glob Womens Health. 2022;3:1031190. https://doi.org/10.3389/fgwh.2022.1031190.

50. Garufi C., Rizzo F., Matys V. et al. Evolution of therapy for autoimmune diseases in pregnancy: a retrospective study from 2000 to 2023. Front Med (Lausanne). 2026;13:1716385. https://doi.org/10.3389/fmed.2026.1716385.

51. Sammaritano L.R., Bermas B.L., Chakravarty E.E. et al. 2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases. Arthritis Rheumatol. 2020;72(4):529–56. https://doi.org/10.1002/art.41191.

52. Flint J., Panchal S., Hurrell A. et al; BSR and BHPR Standards, Guidelines and Audit Working Group. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding –Part II: analgesics and other drugs used in rheumatology practice. Rheumatology (Oxford). 2016;55(9):1698–702. https://doi.org/10.1093/rheumatology/kev405.

53. Götestam Skorpen C., Hoeltzenbein M., Tincani A. 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. https://doi.org/10.1136/annrheumdis-2015-208840.

54. Burton G.J., Redman C.W., Roberts J.M., Moffett A. Pre-eclampsia: pathophysiology and clinical implications. BMJ. 2019;366:l2381. https://doi.org/10.1136/bmj.l2381.

55. Menzies F.M. The placenta as an immunological environment. Br J Biomed Sci. 2025;82:14910. https://doi.org/10.3389/bjbs.2025.14910.