Preview

Obstetrics, Gynecology and Reproduction

Advanced search

Immunological testing for female infertility: a modern view on the problem

https://doi.org/10.17749/2313-7347/ob.gyn.rep.2024.532

Abstract

Introduction. According to various estimates, in Russia 10 to 20 % of people of reproductive age are infertile. Changes in the immune system play a key role in the etiology and treatment of various infertility forms. The active introduction of immunological testing into clinical practice can potentially improve the results of infertility diagnostics and treatment.

Aim: to analyze the current literature data on immunological testing in female infertility, as well as to assess its potential role in infertility diagnostics and treatment.

Materials and Methods. There was conducted a search for publications in the electronic databases PubMed and eLibrary by using the following keywords and their combinations: "infertility", "immunology", "immune system", "immunological testing", "diagnostics", "treatment". The articles were evaluated in accordance with the PRISMA recommendations. Ultimately, 88 publications were included in the review.

Results. Testing for antiphospholipid antibodies (APA) may be useful for women undergoing assisted reproductive technology (ART) therapy, as these antibodies increase the risk of pregnancy complications and thrombotic risks associated with ovarian stimulation, but studies assessing AFA effect on in vitro fertilization (IVF) outcomes have ambiguous results. The presence of antithyroid antibodies (ATA) may be associated with infertility, so their assessment is indeed important to determine treatment tactics. It has been suggested that antinuclear antibodies (ANA) may affect reproductive function by disrupting trophoblast cell development and interfering with RNA transcription, which may lead to lowered reproductive success. Studies have shown that patients with a positive ANA data have a lower incidence of pregnancy and a higher rate of miscarriages after IVF procedure. The human herpes virus type 6 (HHV-6) affects female fertility and is often the cause of spontaneous termination of pregnancy. B-cell lymphoma protein 6 (BCL-6) can serve as an important prognostic biomarker to identify individuals with endometriosis and related reproductive disorders, including idiopathic infertility. Evaluation of endometrial decidualization can be a useful tool to assess readiness for endometrial implantation and provide opportunities for targeted therapeutic interventions. The issue of testing for NK-cells in patients undergoing infertility screening remains controversial due to the difficulties of standardizing testing recommendations.

Conclusion. To date, there is a limited number of reliable data on the role of various immunological tests in infertility diagnostics and treatment. With the exception of testing for AFA in patients with RPL, as well as for thyroid-stimulating hormone (TSH) and anti-thyroperoxidase antibodies (TPOAb) in patients undergoing therapy using various types of assisted reproductive technologies, the remaining immunological tests provide scant data to justify their routine use in clinical practice. The major limitations of existing studies are coupled to a small patient sample, as well as heterogeneity of inclusion criteria, patient groups and research methods.

About the Authors

A. V. Konkina
Stavropol State Medical University, Health Ministry of Russian Federation
Russian Federation

Anastasia V. Konkina.

310 Mira Str., Stavropol 355017



L. A. Blikyan
Stavropol State Medical University, Health Ministry of Russian Federation
Russian Federation

Lilit A. Blikyan.

310 Mira Str., Stavropol 355017



D. E. Aleynikova
Stavropol Regional Center of Specialized Types of Medical Care No. 1
Russian Federation

Daria E. Aleynikova - MD.

2 Kalinin Avenue, Budyonnovsk 356800



I. R. Abubakarov
Stavropol State Medical University, Health Ministry of Russian Federation
Russian Federation

Ilzanur R. Abubakarov.

310 Mira Str., Stavropol 355017



A. S.-M. Dzhumanyazova
Stavropol State Medical University, Health Ministry of Russian Federation
Russian Federation

Aida S.-M. Dzhumanyazova.

310 Mira Str., Stavropol 355017



A. V. Abramian
Stavropol State Medical University, Health Ministry of Russian Federation
Russian Federation

Alexandra V. Abramian.

310 Mira Str., Stavropol 355017



L. G. Gafurova
Stavropol State Medical University, Health Ministry of Russian Federation
Russian Federation

Liana G. Gafurova.

310 Mira Str., Stavropol 355017



D. A. Lobko
Stavropol State Medical University, Health Ministry of Russian Federation
Russian Federation

Daria A. Lobko.

310 Mira Str., Stavropol 355017



A. A. Pozoyan
Stavropol State Medical University, Health Ministry of Russian Federation
Russian Federation

Anna A. Pozoyan.

310 Mira Str., Stavropol 355017



K. M. Thagapsova
Stavropol State Medical University, Health Ministry of Russian Federation
Russian Federation

Kamila M. Thagapsova.

310 Mira Str., Stavropol 355017



M. S. Golubeva
Pavlov First Saint Petersburg State Medical University, Health Ministry of Russian Federation
Russian Federation

Maya S. Golubeva.

197022 Saint Petersburg, Lev Tolstoy Str., 6–8



E. E. Shvanova
Pavlov Ryazan State Medical University, Health Ministry of Russian Federation
Russian Federation

Evgeniya E. Shvanova.

390026 Ryazan, Vysokovoltnaya, 9



E. O. Ryzhov
Vernadsky Crimean Federal University
Russian Federation

Evgeniy O. Ryzhov.

5/7 Lenin Boulevard, Simferopol 295051



References

1. Korneeva I.E., Nazarenko T.A., Perminova S.G. et al. Medical and social factors of infertility in Russia. [Mediko-social'nye faktory besplodiya v Rossii]. Akusherstvo i ginekologiya. 2023;(3):65-72. (In Russ.). https://doi.org/10.18565/aig.2022.279.

2. Federal State Statistics Service. [Federal'naya sluzhba gosudarstvennoj statistiki]. (In Russ.). Available at: https://rosstat.gov.ru/folder/313/document/94975. [Accessed: 13.04.2024].

3. Savina A.A., Feiginova S.I., Kuraeva V.M., Armashevskaya O.V. The challenge of incomparability of male and female infertility incidence among adult population in the Russian Federation. [Problema nesopostavimosti urovnej zabolevaemosti muzhskim i zhenskim besplodiem vzroslogo naseleniya v Rossijskoj Federacii]. Social'nye aspekty zdorov'ya naseleniya. 2020;(4):7. (In Russ.). https://doi.org/10.21045/2071-5021-2020-66-4-7.

4. Tsakhilova S.G., Kuznetsov V.P., Khmelnitskaya A.V. et al. The influence of the immune status of the mother on fetal development and the health of the newborn (a review). [Vliyanie immunnogo statusa materi na razvitie ploda i zdorov'e novorozhdennogo (obzor literatury)]. Problemy reprodukcii. 2016;22(6):38-43. (In Russ.). https://doi.org/10.17116/repro201622638-43.

5. Practice Committee of the American Society for Reproductive Medicine. Evidence-based treatments for couples with unexplained infertility: a guideline. Fertil Steril. 2020;113(2):305-22. https://doi.org/10.1016/j.fertnstert.2019.10.014.

6. Shabanova A.A., Shitova M.S. Habitual miscarriage of pregnancy - a modern view of the problem. [Privychnoe nevynashivanie beremennosti - sovremennyj vzglyad na problem]. Stolypinskij vestnik. 2022;(3):1192-203. (In Russ.).

7. Ma J., Gao W., Li D. Recurrent implantation failure: a comprehensive summary from etiology to treatment. Front Endocrinol (Lausanne). 2023;13:1061766. https://doi.org/10.3389/fendo.2022.1061766.

8. Mityurina E.V., Perminova S.G., Amyan T.S. Causes of repeated implantation failures in an in vitro fertilization program. [Prichiny povtornyh neudach implantacii v programme ekstrakorporal'nogo oplodotvoreniya]. Akusherstvo i ginekologiya. 2016;(11):34-40. (In Russ.). https://doi.org/10.18565/aig.2016.11.34-40.

9. Tkachenko O.Yu., Lapin S.V., Shmonin A.A. et al. Ranging of antiphospolipid antibodies in the patients with thrombophilia and recurrent miscarriage. [Analiz spektra antifosfolipidnyh antitel u pacientov s trombozami i privychnym nevynashivaniem beremennosti]. Medicinskaya immunologiya. 2018;20(5):753-62. (In Russ.). https://doi.org/10.15789/1563-0625-2018-5-753-762.

10. Bagdasarova Yu.S., Zainulina M.S., Nikolaeva M.G. Complications and outcomes of pregnancy in patients with antiphospholipid antibodies during various treatment methods. [Oslozhneniya i iskhody beremennosti u pacientok s nositel'stvom antifosfolipidnyh antitel pri razlichnyh metodah lecheniya]. Obstetrics, Gynecology and Reproduction. 2023;17(2):176-87. (In Russ.). https://doi.org/10.17749/2313-7347/ob.gyn.rep.2023.414.

11. 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.

12. Del Porto F., Ferrero S., Cifani N. et al. Antiphospholipid antibodies and idiopathic infertility. Lupus. 2022;31(3):347-53. https://doi.org/10.1177/09612033221076735.

13. Motak-Pochrzest H., Malinowski A. Does autoimmunity play a role in the risk of implantation failures? Neuro Endocrinol Lett. 2018;38(8):575-8.

14. Hong Y.H., Kim S.J., Moon K.Y. et al. Impact of presence of antiphospholipid antibodies on in vitro fertilization outcome. Obstet Gynecol Sci. 2018;61(3):359-66. https://doi.org/10.5468/ogs.2018.61.3.359.

15. Simopoulou M., Sfakianoudis K., Maziotis E. et al. The impact of autoantibodies on IVF treatment and outcome: a systematic review. Int J Mol Sci. 2019;20(4):892. https://doi.org/10.3390/ijms20040892.

16. Wu L., Fang X., Lu F. et al. Anticardiolipin and/or anti-e2-glycoprotein-I antibodies are associated with adverse IVF outcomes. Front Immunol. 2022;13:986893. https://doi.org/10.3389/fimmu.2022.986893.

17. Chen X., Mo M.-L., Huang C.-Y. et al. Association of serum autoantibodies with pregnancy outcome of patients undergoing first IVF/ICSI treatment: a prospective cohort study. J Reprod Immunol. 2017;122:14-20. https://doi.org/10.1016/j.jri.2017.08.002.

18. Gao R., Zeng R., Qing P. et al. Antiphospholipid antibodies and pregnancy outcome of assisted reproductive treatment: a systematic review and meta-analysis. Am J Reprod Immunol. 2021;86(4):e13470. https://doi.org/10.1111/aji.13470.

19. Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98(5):1103-11. https://doi.org/10.1016/j.fertnstert.2012.06.048.

20. ESHRE Guideline Group on RPL; Atik R.B., Christiansen O.B., Elson J. et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018;2018(2):hoy004. https://doi.org/10.1093/hropen/hoy004.

21. Platonova N.M., Makolina N.P., Rybakova A.A., Troshina E.A. Autoimmune thyroiditis and pregnancy: changes in the modern diagnostic and therapeutic paradigms. [Autoimmunnyj tireoidit i beremennost': izmeneniya v sovremennyh lechebno-diagnosticheskih paradigmah]. Problemy reprodukcii. 2020;26(1):29-38. (In Russ.). https://doi.org/10.17116/repro20202601129.

22. Zhu Q., Xu Q.-H., Xie T. et al. Recent insights into the impact of immune dysfunction on reproduction in autoimmune thyroiditis. Clin Immunol. 2021;224:108663. https://doi.org/10.1016/j.clim.2020.108663.

23. Bastos D.C.D.S., Chiamolera M.I., Silva R.E. et al. Metabolomic analysis of follicular fluid from women with Hashimoto thyroiditis. Sci Rep. 2003;13(1):12497. https://doi.org/10.1038/s41598-023-39514-7.

24. Xie J., Gu A., He H. et al. Autoimmune thyroid disease disrupts immune homeostasis in the endometrium of unexplained infertility women - a single-cell RNA transcriptome study during the implantation window. Front Endocrinol (Lausanne). 2023;14:1185147. https://doi.org/10.3389/fendo.2023.1185147.

25. Venables A., Wong W., Way M., Homer H.A. Thyroid autoimmunity and IVF/ICSI outcomes in euthyroid women: a systematic review and meta-analysis. Reprod Biol Endocrinol. 2020;18(1):120. https://doi.org/10.1186/s12958-020-00671-3.

26. Toulis K.A., Goulis D.G., Venetis C.A. et al. Risk of spontaneous miscarriage in euthyroid women with thyroid autoimmunity undergoing IVF: a meta-analysis. Eur J Endocrinol. 2010;162(4):643-52. https://doi. org/10.1530/EJE-09-0850.

27. Busnelli A., Paffoni A., Fedele L., Somigliana E. The impact of thyroid autoimmunity on IVF/ICSI outcome: a systematic review and metaanalysis. Hum Reprod Update. 2016;22(6):775-90. https://doi.org/10.1093/humupd/dmw019.

28. Zhang S., Yang M., Li T. et al. High level of thyroid peroxidase antibodies as a detrimental risk of pregnancy outcomes in euthyroid women undergoing ART: a meta-analysis. Mol Reprod Dev. 2023;90(4):218-26. https://doi.org/10.1002/mrd.23677.

29. Alexander E.K., Pearce E.N., Brent G.A. et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017;27(3):315-89. https://doi.org/10.1089/thy.2016.0457.

30. Clinical guidelines - Female infertility - 2021-2022-2023 (24.06.2021). [Klinicheskie rekomendacii - Zhenskoe besplodie - 2021-2022-2023 (24.06.2021)]. Moscow: Ministerstvo zdravoohraneniya Rossijskoj Federacii, 2021. 50 p. (In Russ.). Available at: https://moniiag.ru/wp-content/uploads/2019/07/Klinicheskie-rekomendatsii.-ZHenskoe-besplodie.pdf. [Accessed: 13.04.2024].

31. Wu S., Zhang L., Liu X. et al. Antinuclear antibodies in follicular fluid may be a risk factor in vitro fertilization and embryo transfer. Am J Reprod Immunol. 2022;88(1):e13560. https://doi.org/10.1111/aji.13560.

32. Chighizola C.B., Pregnolato F., Raschi E. et al. Antiphospholipid antibodies and infertility: a gene expression study in decidual stromal cells. Isr Med Assoc J. 2016;18(3-4):146-9.

33. Molazadeh M., Karimzadeh H., Azizi M.R. Prevalence and clinical significance of antinuclear antibodies in Iranian women with unexplained recurrent miscarriage. Iran J Reprod Med. 2014;12(3):221-6.

34. Ying Y., Zhong Y., Zhou C. et al. Antinuclear antibodies predicts a poor IVF-ET outcome: impaired egg and embryo development and reduced pregnancy rate. Immunol Invest. 2012;41(5):458-68. https://doi.org/10.3109/08820139.2012.660266.

35. Li Y., Wang Y., Lan Y. et al. Antinuclear antibodies in follicular fluid may reduce efficacy of in vitro fertilization and embryo transfer by invading endometrium and granular cells. Am J Reprod Immunol. 2020;84(4):e13289. https://doi.org/10.1111/aji.13289.

36. Ticconi C., Inversetti A., Logruosso E. et al. Antinuclear antibodies positivity in women in reproductive age: from infertility to adverse obstetrical outcomes - a meta-analysis. J Reprod Immunol. 2023;155:103794. https://doi.org/10.1016/j.jri.2022.103794.

37. Zheleznikova G.F., Scripchenko N.V., Ivanova G.P. et al. Gerpes viruses and multiple sclerosis. [Gerpes-virusy i rasseyannyj skleroz]. Zhurnal nevrologii i psihiatrii imeni S.S. Korsakova. 2016;116(9):133-43. (In Russ.). https://doi.org/10.17116/jnevro201611691133-143.

38. Tian N.S., Goleva O.V., Babachenko I.V. Clinical and etiological aspects of human Betaherpesvirus infection 6: a review. [Kliniko-etiologicheskie aspekty beta-gerpes-virusnoj infekcii cheloveka 6: obzor literatury]. Zhurnal infektologii. 2022;14(2):55-64. (In Russ.). https://doi.org/10.22625/2072-6732-2022-14-2-55-64.

39. Marci R., Gentili V., Bortolotti D. et al. Presence of HHV-6A in endometrial epithelial cells from women with primary unexplained infertility. PLoS One. 2016;11(7):e0158304. https://doi.org/10.1371/journal

40. Bortolotti D., Gentili V., Rotola A. et al. HHV-6A infection of endometrial epithelial cells affects immune profile and trophoblast invasion. Am J Reprod Immunol. 2019;82(4):e13174. https://doi.org/10.1111/aji.13174.

41. Ando Y., Kakimoto K., Ekuni Y., Ichijo M. HHV-6 infection during pregnancy and spontaneous abortion. Lancet. 1992;340(8830):1289. https://doi.org/10.1016/0140-6736(92)92990-w.

42. Drago F., Broccolo F., Zaccaria E. et al. Pregnancy outcome in patients with pityriasis rosea. J Am Acad Dermatol. 2008;58(5 Suppl 1):S78-83. https://doi.org/10.1016/j.jaad.2007.05.030.

43. Drago F., Broccolo F., Javor S. et al. Evidence of human herpesvirus-6 and -7 reactivation in miscarrying women with pityriasis rosea. J Am Acad Dermatol. 2014;71(1):198-9. https://doi.org/10.1016/j.jaad.2014.02.023.

44. Miura H., Kawamura Y., Ohye T. et al. Inherited chromosomally integrated human herpes virus 6 is a risk factor for spontaneous abortion. J Infect Dis. 2021;223(10):1717-23. https://doi.org/10.1093/infdis/jiaa606.

45. Coulam C.B., Bilal M., Salazar Garcia M.D. et al. Prevalence of HHV-6 in endometrium from women with recurrent implantation failure. Am J Reprod Immunol. 2018;80(1):e12862. https://doi.org/10.1111/aji.12862.

46. Klimczak A.M., Herlihy N.S., Scott C.S. et al. B-cell lymphoma 6 expression is not associated with live birth in a normal responder in vitro fertilization population. Fertil Steril. 2022;117(2):351-8. https://doi.org/10.1016/j.fertnstert.2021.09.036.

47. Louwen F., Kreis N.N., Ritter A. et al. BCL6, a key oncogene, in the placenta, pre-eclampsia and endometriosis. Hum Reprod Update. 2022;28(6):890-909. https://doi.org/10.1093/humupd/dmac027.

48. Matsuzaki S., Pouly J.L., Canis M. Persistent activation of signal transducer and activator of transcription 3 via interleukin-6 trans-signaling is involved in fibrosis of endometriosis. Hum Reprod. 2022;37(7):1489-504. https://doi.org/10.1093/humrep/deac098.

49. Lin S.C., Li Y.H., Wu M.H. et al. Suppression of COUP-TFII by proinflammatory cytokines contributes to the pathogenesis of endometriosis. J Clin Endocrinol Metab. 2014;99(3):427-37. https://doi.org/10.1210/jc.2013-3717.

50. Nezhat C., Rambhatla A., Miranda-Silva C. et al. BCL-6 overexpression as a predictor for endometriosis in patients undergoing in vitro fertilization. JSLS. 2020;24(4):e2020.00064. https://doi.org/10.4293/JSLS.2020.

51. Almquist L.D., Likes C.E., Stone B. et al. Endometrial BCL6 testing for the prediction of in vitro fertilization outcomes: a cohort study. Fertil Steril. 2017;108(6):1063-9. https://doi.org/10.1016/j.fertnstert.2017.09.017.

52. Likes C.E., Cooper L.J., Efird J. et al. Medical or surgical treatment before embryo transfer improves outcomes in women with abnormal endometrial BCL6 expression. J Assist Reprod Genet. 2019;36(3):483-90. https://doi.org/10.1007/s10815-018-1388-x.

53. Dambaeva S., Bilal M., Schneiderman S. et al. Decidualization score identifies an endometrial dysregulation in samples from women with recurrent pregnancy losses and unexplained infertility. F S Rep. 2020;2(1):95-103. https://doi.org/10.1016/j.xfre.2020.12.

54. Vrhovac Madunic I., Karin-Kujundzic V., Madunic J. et al. Endometrial glucose transporters in health and disease. Front Cell Dev Biol. 2021;9:703671. https://doi.org/10.3389/fcell.2021.703671.

55. von Wolff M., Ursel S., Hahn U. et al. Glucose transporter proteins (GLUT) in human endometrium: expression, regulation, and function throughout the menstrual cycle and in early pregnancy. J Clin Endocrinol Metab. 2003;88(8):3885-92. https://doi.org/10.1210/jc.2002-021890.

56. Salker M.S., Christian M., Steel J.H. et al. Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure. Nat Med. 2011;17(11):1509-13. https://doi.org/10.1038/nm.2498.

57. Ruan Y.C., Guo J.H., Liu X. et al. Activation of the epithelial Na. channel triggers prostaglandin E(2) release and production required for embryo implantation. Nat Med. 2012;18(7):1112-7. https://doi.org/10.1038/nm.2771.

58. Kolesnikova N.V., Filippov E.F. Immunological aspects of infertility in chronic endometritis. [Immunologicheskie aspekty besplodiya pri hronicheskom endometrite]. RMZh. Medicinskoe obozrenie. 2024;8(3):155-62. (In Russ.). https://doi.org/10.32364/2587-6821-2024-8-3-6.

59. Lédée N., Petitbarat M., Prat-Ellenberg L. et al. The uterine immune profile: a method for individualizing the management of women who have failed to implant an embryo after IVF/ICSI. J Reprod Immunol. 2020;142:103207. https://doi.org/10.1016/j.jri.2020.103207.

60. Lédée N., Prat-Ellenberg L., Chevrier L. et al. Uterine immune profiling for increasing live birth rate: a one-to-one matched cohort study. J Reprod Immunol. 2017;119:23-30. https://doi.org/10.1016/j.jri.2016.11.007.

61. Tamura I., Doi-Tanaka Y., Takasaki A. et al. High incidence of decidualization failure in infertile women. Reprod Med Biol. 2024;23(1):e12580. https://doi.org/10.1002/rmb2.12580.

62. Lédée N., Petitbarat M., Prat-Ellenberg L. et al. Endometrial immune profiling: a method to design personalized care in assisted reproductive medicine. Front Immunol. 2020;4(11):1032. https://doi.org/10.3389/fimmu.2020.01032.

63. Mikhailova V.A., Belyakova K.L., Selkov S.A., Sokolov D.I. Peculiarities of NK cells differentiation: CD56dim and CD56bright NK cells at pregnancy and in non-pregnant state. [Osobennosti differencirovki NK-kletok: CD56dim i CD56bright NK-kletki vo vremya i vne beremennosti]. Medicinskaya immunologiya. 2017;19(1):19-26. (In Russ.). https://doi.org/10.15789/1563-0625-2017-1-19-26.

64. Agnaeva A.O., Bespalova O.N., Sokolov D.I. et al. Role of natural killer cells in reproductive failure. [Rol' estestvennyh killerov (NK-kletok) v reproduktivnyh poteryah]. Zhurnal akusherstva i zhenskih boleznej. 2017;66(3):143-56. (In Russ.). https://doi.org/10.17816/JOWD663143-156.

65. Hao F., Zhou X., Jin L. Natural killer cells: functional differences in recurrent spontaneous abortion. Biol Reprod. 2020;102(3):524-31. https://doi.org/10.1093/biolre/ioz203

66. Yang X., Yang Y., Yuan Y. et al. The roles of uterine natural killer (NK) cells and KIR/HLA-C combination in the development of preeclampsia: a systematic review. Biomed Res Int. 2020;2020:4808072. https://doi.org/10.1155/2020/4808072.

67. Shojaei Z., Jafarpour R., Mehdizadeh S. et al. Functional prominence of natural killer cells and natural killer T cells in pregnancy and infertility: a comprehensive review and update. Pathol Res Pract. 2022;238:154062. https://doi.org/10.1016/j.prp.2022.154062.

68. Azargoon A., Mirrasouli Y., Barough M.S. et al. The state of peripheral blood natural killer cells and cytotoxicity in women with recurrent pregnancy loss and unexplained infertility. Int J Fertil Steril. 2019;13(1):12-7. https://doi.org/10.22074/ijfs.2019.5503.

69. Glover L.E., Crosby D., Thiruchelvam U. et al. Uterine natural killer cell progenitor populations predict successful implantation in women with endometriosis-associated infertility. Am J Reprod Immunol. 2018;79(3). https://doi.org/10.1111/aji.12817.

70. Lapides L., Klein M., Belusakova V. et al. Uterine natural killer cells in the context of implantation: immunohistochemical analysis of endometrial samples from women with habitual abortion and recurrent implantation failure. Physiol Res. 2022;71(6):99. https://doi.org/10.33549/physiolres.935012.

71. Ali S.B., Jeelall Y., Pennell C.E. et al. The role of immunological testing and intervention in reproductive medicine: A fertile collaboration? Am J Reprod Immunol. 2018;79(3). https://doi.org/10.1111/aji.12784.

72. Cavalcante M.B., da Silva P.H.A., Carvalho T.R. et al. Peripheral blood natural killer cell cytotoxicity in recurrent miscarriage: a systematic review and meta-analysis. J Reprod Immunol. 2023;158:103956. https://doi.org/10.1016/j.jri.2023.103956.

73. Sung N., Khan S.A., Yiu M.E. et al. Reproductive outcomes of women with recurrent pregnancy losses and repeated implantation failures are significantly improved with immunomodulatory treatment. J Reprod Immunol. 2021;148:103369. https://doi.org/10.1016/j.jri.2021.103369.

74. 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. https://doi.org/10.1111/j.1600-0897.2010.00852.x.

75. Akperbekova I.S., Ayupova F.M., Saidjalilova D.D. et al. The role and significance of the uterine natural killers in healthy pregnancy (literature review). [Rol' i znachenie matochnyh estestvennyh killerov v techenii zdorovoj beremennosti (obzor literatury)]. Problemy reprodukcii. 2020;26(6):15-25. (In Russ.).

76. Seshadri S., Sunkara S.K. Natural killer cells in female infertility and recurrent miscarriage: a systematic review and meta-analysis. Hum Reprod Update. 2014;20(3):429-38. https://doi.org/10.1093/humupd/dmt056.

77. Tang A.W., Alfirevic Z., Quenby S. Natural killer cells and pregnancy outcomes in women with recurrent miscarriage and infertility: a systematic review. Hum Reprod. 2011;26(8):1971-80. https://doi.org/10.1093/humrep/der164.

78. Mariee N., Tuckerman E., Ali A. et al. The observer and cycle-to-cycle variability in the measurement of uterine natural killer cells by immunohistochemistry. J Reprod Immunol. 2012;95(1-2):93-100. https://doi.org/10.1016/j.jri.2012.05.001.

79. Raghupathy R., Makhseed M.A., Azizieh F. et al. Maternal Th1-and Th2-type reactivity to placental antigens in normal human pregnancy and unexplained recurrent spontaneous abortions. Cell Immunol. 1999;196(2):122-30. https://doi.org/10.1006/cimm.1999.1532.

80. Kwak-Kim J.Y., Chung-Bang H.S., Ng S.C. et al. Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF. Hum Reprod. 2003;18(4):767-73. https://doi.org/10.1093/humrep/deg156.

81. Kuroda K., Horikawa T., Moriyama A. et al. Therapeutic efficacy of the optimization of thyroid function, thrombophilia, immunity and uterine milieu (OPTIMUM) treatment strategy on pregnancy outcomes after single euploid blastocyst transfer in advanced age women with recurrent reproductive failure. Reprod Med Biol. 2023;22(1):e12554. https://doi.org/10.1002/rmb2.12554.

82. Winger E.E., Reed J.L., Ashoush S. et al. Degree of TNF-a/IL-10 cytokine elevation correlates with IVF success rates in women undergoing treatment with Adalimumab (Humira) and IVIG. Am J Reprod Immunol. 2011;65(6):610-8. https://doi.org/10.1111/j.1600-0897.2010.00946.x.

83. Azizi R., Ahmadi M., Danaii S. et al. Cyclosporine A improves pregnancy outcomes in women with recurrent pregnancy loss and elevated Th1/Th2 ratio. J Cell Physiol. 2019;234(10):19039-47. https://doi.org/10.1002/jcp.28543.

84. Korn T., Bettelli E., Oukka M., Kuchroo V.K. IL-17 and Th17 cells. Annu Rev Immunol. 2009;27:485-517. https://doi.org/10.1146/annurev.immunol.021908.132710.

85. Vignali D.A., Collison L.W., Workman C.J. How regulatory T cells work. Nat Rev Immunol. 2008;8(7):523-32. https://doi.org/10.1038/nri2343.

86. Qian J., Zhang N., Lin J. et al. Distinct pattern of Th17/Treg cells in pregnant women with a history of unexplained recurrent spontaneous abortion. Biosci Trends. 2018;12(2):157-67. https://doi.org/10.5582/bst.2018.01012.

87. Ghaebi M., Abdolmohammadi-Vahid S., Ahmadi M. et al. T cell subsets in peripheral blood of women with recurrent implantation failure. J Reprod Immunol. 2019;131:21-9. https://doi.org/10.1016/j.jri.2018.11.002.

88. Huang Q., Wu H., Li M. et al. Prednisone improves pregnancy outcome in repeated implantation failure by enhance regulatory T cells bias. J Reprod Immunol. 2021;143:103245. https://doi.org/10.1016/j.jri.2020.103245.


What is already known about this subject?

► The immune system plays an important role in female reproductive function, from implantation to pregnancy maintenance. Changes in the immune system play a key role in the etiology and treatment of various infertility forms, including general infertility, idiopathic infertility (II), recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF).

► Reproductive immunological disorders are considered to be quite common among patients with II, RPL, and RIF. However, reproductive immunology is not a fully established and recognized discipline.

What are the new findings?

► Immunological tests can play an important role in infertility diagnostics and treatment. However, only testing for antiphospholipid antibodies (APA), thyroid-stimulating hormone (TSH) and anti-thyroperoxidase antibodies (TPOAb) has proven effectiveness.

► APA are significantly associated with poor-quality embryos, metaphase II eggs, blastocysts, as well as with lowered rate of implantation, clinical pregnancy and live birth. The presence of APA negatively affects assisted reproductive technologies (ART) results. Thus, it is necessary to carry out immunological testing for APA while choosing infertility therapy methods.

► A high level of anti-TPOAb antibodies negatively affects the outcome of pregnancy during ART, even in patients with euthyroidism.

How might it impact on clinical practice in the foreseeable future?

► Immunological testing can potentially be an effective tool in determining the cause of infertility and miscarriage by detecting immune system disorders. This allows to prescribe more targeted and effective treatment.

► Based on the results of immunological tests, it is possible to develop individual treatment plans, which will increase the odds of successful conception and gestation.

► Detection and correction of immune disorders before pregnancy will reduce a risk of miscarriage and other complications associated with immune system disorders.

Review

For citations:


Konkina A.V., Blikyan L.A., Aleynikova D.E., Abubakarov I.R., Dzhumanyazova A.S., Abramian A.V., Gafurova L.G., Lobko D.A., Pozoyan A.A., Thagapsova K.M., Golubeva M.S., Shvanova E.E., Ryzhov E.O. Immunological testing for female infertility: a modern view on the problem. Obstetrics, Gynecology and Reproduction. 2024;18(4):547-562. (In Russ.) https://doi.org/10.17749/2313-7347/ob.gyn.rep.2024.532

Views: 1446


ISSN 2313-7347 (Print)
ISSN 2500-3194 (Online)