Skip to main content
SpringerLink
Log in

Role of Immunological Testing in Infertility

  • REVIEW
  • Published:
Current Obstetrics and Gynecology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Unexplained infertility, recurrent pregnancy loss, and recurrent implantation failure are challenging clinical scenarios, both for patients and providers. The role of immunologic testing for these conditions is an area of new and expanding research. This review presents the current, existing evidence on the role of immunological testing in infertility.

Recent Findings

A number of different immunological tests for infertility are available, including antiphospholipid antibodies, antithyroid antibodies, antinuclear antibodies, endometrial studies, uterine natural killer cells, systemic natural killer cells, Th1/Th2 cells, and Th17/regulatory T cells. There has been tremendous variation in the use of these tests for infertility and recurrent pregnancy loss, likely driven by a lack of consensus on their utility.

Summary

Our review concludes that there are significant limitations to immunological testing in this setting. Larger, prospective studies are needed prior to mass adoption of many immunologic tests.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Definitions of infertility and recurrent pregnancy loss. a committee opinion. Fertil Steril. 2020;113:533–5. https://doi.org/10.1016/j.fertnstert.2019.11.025.

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

  3. Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98: 1103–1111. https://doi.org/10.1016/j.fertnstert.2012.06.048.

    Article  Google Scholar 

  4. 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.

    Article  PubMed  Google Scholar 

  5. •• Gao R, Zeng R, Qing P, Meng C, Cheng K, Zhang S, et al. Antiphospholipid antibodies and pregnancy outcome of assisted reproductive treatment: a systematic review and meta-analysis. Am J Reprod Immunol. 2021;86:e13470. https://doi.org/10.1111/aji.13470. This is a large systematic review including 10 case-control studies and 13 cohort studies looking at the association between antiphospholipid antibodies and ART outcomes.

    Article  CAS  PubMed  Google Scholar 

  6. Willis R, Pierangeli SS. Pathophysiology of the antiphospholipid antibody syndrome. Auto Immun Highlights. 2011;2:35–52. https://doi.org/10.1007/s13317-011-0017-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Krivonos MI, Kh Khizroeva J, Zainulina MS, Eremeeva DR, Selkov SA, Chugunova A, et al. The role of lymphocytic cells in infertility and reproductive failures in women with antiphospholipid antibodies. J Matern Fetal Neonatal Med. 2022;35:871–7. https://doi.org/10.1080/14767058.2020.1732343.

    Article  CAS  PubMed  Google Scholar 

  8. • Del Porto F, Ferrero S, Cifani N, Sesti G, Proietta M. Antiphospholipid antibodies and idiopathic infertility. Lupus. 2022;31:347–53. https://doi.org/10.1177/09612033221076735. This was a retrospective observational study looking at reproductive outcomes of women with idiopathic infertility with persistently positive antiphospholipid antibodies.

    Article  CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  10. Hong YH, Kim SJ, Moon KY, Kim SK, Jee BC, Lee WD, et al. Impact of presence of antiphospholipid antibodies on in vitro fertilization outcome. Obstet Gynecol Sci. 2018;61:359–66. https://doi.org/10.5468/ogs.2018.61.3.359.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Simopoulou M, Sfakianoudis K, Maziotis E, Grigoriadis S, Giannelou P, Rapani A, et al. The impact of autoantibodies on IVF treatment and outcome: a systematic review. Int J Mol Sci. 2019;20:892. https://doi.org/10.3390/ijms20040892.

    Article  PubMed  PubMed Central  Google Scholar 

  12. • Wu L, Fang X, Lu F, Zhang Y, Wang Y, Kwak-Kim J. Anticardiolipin and/or anti-β2-glycoprotein-I antibodies are associated with adverse IVF outcomes. Front Immunol. 2022;13:986893. https://doi.org/10.3389/fimmu.2022.986893. This is a prospective study evaluating the effects of antiphospholipid antibodies on IVF outcomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chen X, Mo M-L, Huang C-Y, Diao L-H, Li G-G, Li Y-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.

    Article  CAS  PubMed  Google Scholar 

  14. ESHRE Guideline Group on RPL, Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018;2018:hoy004. https://doi.org/10.1093/hropen/hoy004.

    Article  Google Scholar 

  15. Bucci I, Giuliani C, Di Dalmazi G, Formoso G, Napolitano G. Thyroid autoimmunity in female infertility and assisted reproductive technology outcome. Front Endocrinol (Lausanne). 2022;13:768363. https://doi.org/10.3389/fendo.2022.768363.

    Article  PubMed  Google Scholar 

  16. Zhu Q, Xu Q-H, Xie T, Wang L-L, Liu H, Muyayalo KP, 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.

    Article  CAS  PubMed  Google Scholar 

  17. Bastos DCDS, Chiamolera MI, Silva RE, Souza MDCBD, Antunes RA, Souza MM, et al. Metabolomic analysis of follicular fluid from women with Hashimoto thyroiditis. Sci Rep. 2003;13:12497. https://doi.org/10.1038/s41598-023-39514-7. This study evaluated the metabolic profile of follicular fluid from patients undergoing IVF and antithyroid autoantibody levels in the context of Hashimoto thyroiditis.

    Article  CAS  Google Scholar 

  18. • Xie J, Gu A, He H, Zhao Q, Yu Y, Chen J, 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. This study utilized single-cell RNA sequencing to analyze the immune microenvironment in the endometrium of patients with autoimmune thyroid disease during the window of implantation.

    Article  PubMed  Google Scholar 

  19. •• Venables A, Wong W, Way M, Homer HA. Thyroid autoimmunity and IVF/ICSI outcomes in euthyroid women: a systematic review and meta-analysis. Reprod Biol Endocrinol. 2020;18:120. https://doi.org/10.1186/s12958-020-00671-3. This is a systematic review of 14 studies evaluating the relationship between thyroid autoimmunity and IVF/ICSI outcomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Toulis KA, Goulis DG, Venetis CA, Kolibianakis EM, Negro R, Tarlatzis BC, et al. Risk of spontaneous miscarriage in euthyroid women with thyroid autoimmunity undergoing IVF: a meta-analysis. Eur J Endocrinol. 2010;162:643–52. https://doi.org/10.1530/EJE-09-0850.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  22. • Zhang S, Yang M, Li T, Yang M, Wang W, Chen Y, 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;90:218–26. https://doi.org/10.1002/mrd.23677. This is a meta-analysis of seven studies examining whether the presence of anti-thyroid peroxidase antibody correlates with outcomes of assisted reproductive technology in a concentration dependent manner.

    Article  CAS  PubMed  Google Scholar 

  23. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum | Thyroid®. [cited 24 Aug 2023]. Available: https://www.liebertpub.com/doi/full/10.1089/thy.2016.0457.

  24. • Wu S, Zhang L, Liu X, Jiang Y, Teng Y. Antinuclear antibodies in follicular fluid may be a risk factor in vitro fertilization and embryo transfer. Am J Reprod Immunol. 2022;88:e13560. https://doi.org/10.1111/aji.13560. This is prospective study exploring the effect of anti-nuclear antibodies on the outcome of IVF-ET and the effect of anti-nuclear antibodies in follicular fluid on embryonic development.

    Article  CAS  PubMed  Google Scholar 

  25. Chighizola CB, Pregnolato F, Raschi E, Grossi C, Gentilini D, Borghi MO, et al. Antiphospholipid antibodies and infertility: a gene expression study in decidual stromal cells. Isr Med Assoc J. 2016;18:146–9.

    PubMed  Google Scholar 

  26. Molazadeh M, Karimzadeh H, Azizi MR. Prevalence and clinical significance of antinuclear antibodies in Iranian women with unexplained recurrent miscarriage. Iran J Reprod Med. 2014;12:221–6.

    PubMed  PubMed Central  Google Scholar 

  27. Ying Y, Zhong Y, Zhou C, Xu Y, Wang Q, Li J, et al. Antinuclear antibodies predicts a poor IVF-ET outcome: impaired egg and embryo development and reduced pregnancy rate. Immunol Invest. 2012;41:458–68. https://doi.org/10.3109/08820139.2012.660266.

    Article  CAS  PubMed  Google Scholar 

  28. • Li Y, Wang Y, Lan Y, Zhang J, Liang Y, Wang S. 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:e13289. https://doi.org/10.1111/aji.13289. This study looked at IVF-ET treatment outcomes in patients with and without antinuclear antibodies in follicular fluid.

    Article  CAS  PubMed  Google Scholar 

  29. •• Ticconi C, Inversetti A, Logruosso E, Ghio M, Casadei L, Selmi C, 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. This study is a systematic review analyzing correlations between serum antinuclear antibody and infertility in the context of IVF as well as idiopathic recurrent pregnancy losses.

    Article  CAS  PubMed  Google Scholar 

  30. Salahuddin SZ, Ablashi DV, Markham PD, Josephs SF, Sturzenegger S, Kaplan M, Halligan G, Biberfeld P, Wong-Staal F, Kramarsky B, et al. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science. 1986;234(4776):596–601. https://doi.org/10.1126/science.2876520. PMID: 2876520.

    Article  CAS  PubMed  Google Scholar 

  31. Leibovitch EC, Jacobson S. Evidence linking HHV-6 with multiple sclerosis: an update. Curr Opin Virol. 2014;9:127–33. https://doi.org/10.1016/j.coviro.2014.09.016. Epub 2014 Oct 17. PMID: 25462444; PMCID: PMC4269240.

    Article  CAS  PubMed  Google Scholar 

  32. Marci R, Gentili V, Bortolotti D, Lo Monte G, Caselli E, Bolzani S, Rotola A, Di Luca D, Rizzo R. 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.pone.0158304.PMID:27367597;PMCID:PMC4930213.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Caselli E, Zatelli MC, Rizzo R, Benedetti S, Martorelli D, Trasforini G, Cassai E, Degli Uberti EC, Di Luca D, Dolcetti R. Virologic and immunologic evidence supporting an association between HHV-6 and Hashimoto’s thyroiditis. PLoS Pathog. 2012;8(10):e1002951. https://doi.org/10.1371/journal.ppat.1002951. Epub 2012 Oct 4. PMID: 23055929; PMCID: PMC3464215.

  34. Grivel J-C, Santoro F, Chen S, et al. Pathogenic effects of human herpesvirus 6 in human lymphoid tissue ex vivo. J Virol. 2003;77(15):8280–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lusso P, Markham PD, Tschachler E, et al. In vitro cellular tropism of human B-lymphotropic virus (human herpesvirus-6). J Exp Med. 1988;167(5):1659–70.

    Article  CAS  PubMed  Google Scholar 

  36. Lusso P, De Maria A, Malnati M, et al. Induction of CD4 and susceptibility to HIV-1 infection in human CD8+ T lymphocytes by human herpesvirus 6. Nature. 1991;349(6309):533–5.

    Article  CAS  PubMed  Google Scholar 

  37. Lusso P, Gallo RC. Human herpesvirus 6. Bailliere’s Clin Haematol. 1995;8(1):201–23.

    Article  CAS  Google Scholar 

  38. Smith AP, Paolucci C, Di Lullo G, Burastero SE, Santoro F, Lusso P. Viral replication-independent blockade of dendritic cell maturation and interleukin-12 production by human herpesvirus 6. J Virol. 2005;79(5):2807–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kakimoto M, Hasegawa A, Fujita S, Yasukawa M. Phenotypic and functional alterations of dendritic cells induced by human herpesvirus 6 infection. J Virol. 2002;76(20):10338–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bortolotti D, Gentili V, Rotola A, Cultrera R, Marci R, Di Luca D, Rizzo R. 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. Epub 2019 Aug 17. PMID: 31338899.

    Article  CAS  PubMed  Google Scholar 

  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. PMID: 1359342.

    Article  CAS  PubMed  Google Scholar 

  42. Drago F, Broccolo F, Zaccaria E, Malnati M, Cocuzza C, Lusso P, Rebora A. 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. PMID: 18489054.

    Article  PubMed  Google Scholar 

  43. Drago F, Broccolo F, Javor S, Drago F, Rebora A, Parodi A. 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. PMID: 24947696.

    Article  PubMed  Google Scholar 

  44. Revest M, Minjolle S, Veyer D, Lagathu G, Michelet C, Colimon R. Detection of HHV-6 in over a thousand samples: new types of infection revealed by an analysis of positive results. J Clin Virol. 2011;51(1):20–4. https://doi.org/10.1016/j.jcv.2011.02.001. Epub 2011 Mar 3 PMID: 21376662.

    Article  PubMed  Google Scholar 

  45. • Miura H, Kawamura Y, Ohye T, Hattori F, Kozawa K, Ihira M, Yatsuya H, Nishizawa H, Kurahashi H, Yoshikawa T. Inherited Chromosomally integrated human herpesvirus 6 is a risk factor for spontaneous abortion. J Infect Dis. 2021;223(10):1717–23. https://doi.org/10.1093/infdis/jiaa606. A study investigating the association between inherited chromosomally integrated HHV-6 status in mothers and fathers and spontaneous abortion.

    Article  CAS  PubMed  Google Scholar 

  46. Coulam CB, Bilal M, Salazar Garcia MD, Katukurundage D, Elazzamy H, Fernandez EF, Kwak-Kim J, Beaman K, Dambaeva SV. 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. Epub 2018 Apr 17. PMID: 29667291.

    Article  CAS  PubMed  Google Scholar 

  47. Almquist LD, Likes CE, Stone B, Brown KR, Savaris R, Forstein DA, Miller PB, Lessey BA. 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. Epub 2017 Nov 7. PMID: 29126613; PMCID: PMC5726554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Evans-Hoeker E, Lessey BA, Jeong JW, Savaris RF, Palomino WA, Yuan L, Schammel DP, Young SL. Endometrial BCL6 overexpression in eutopic endometrium of women with endometriosis. Reprod Sci. 2016;23(9):1234-41. https://doi.org/10.1177/1933719116649711. Epub 2016 May 24. PMID: 27222232; PMCID: PMC5933165.

  49. Arguni E, Arima M, Tsuruoka N, Sakamoto A, Hatano M, Tokuhisa T. JunD/AP-1 and STAT3 are the major enhancer molecules for high Bcl6 expression in germinal center B cells. Int Immunol. 2006;18(7):1079–89.

    Article  CAS  PubMed  Google Scholar 

  50. Kim BG, Yoo JY, Kim TH, et al. Aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling in endometriosis. Hum Reprod. 2015;30(5):1069–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Li X, Large MJ, Creighton CJ, et al. COUP-TFII regulates human endometrial stromal genes involved in inflammation. Mol Endocrinol. 2013;27(12):2041–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lin SC, Li YH, Wu MH, et al. Suppression of COUP-TFII by proinflammatory cytokines contributes to the pathogenesis of endometriosis. J Clin Endocrinol Metab. 2014;99(3):E427–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nezhat C, Rambhatla A, Miranda-Silva C, Asiaii A, Nguyen K, Eyvazzadeh A, Tazuke S, Agarwal S, Jun S, Nezhat A, Roman RA. 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.2020.00064. PMID: 33414614; PMCID: PMC7757768.

  54. • Louwen F, Kreis NN, Ritter A, Friemel A, Solbach C, Yuan J. 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. A narrative review of the role of BCL-6 in placental development and the pathogenesis of pre-eclampsia and endometriosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Likes CE, Cooper LJ, Efird J, Forstein DA, Miller PB, Savaris R, Lessey BA. 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. Epub 2019 Jan 4. PMID: 30610661; PMCID: PMC6439015.

    Article  PubMed  PubMed Central  Google Scholar 

  56. •• Dambaeva S, Bilal M, Schneiderman S, Germain A, Fernandez E, Kwak-Kim J, Beaman K, Coulam C. 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.2020.12.004.PMID:34223279;PMCID:PMC8244268. A retrospective cohort study comparing endometrial decidualization scores in women with recurrent pregnancy loss or unexplained infertility compared to fertile individuals.

    Article  PubMed  PubMed Central  Google Scholar 

  57. von Wolff M, Ursel S, Hahn U, Steldinger R, Strowitzki T. 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.

    Article  Google Scholar 

  58. Salker MS, Christian M, Steel JH, Nautiyal J, Lavery S, Trew G, et al. Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure. Nat Med. 2011;17(11):1509–13.

    Article  CAS  PubMed  Google Scholar 

  59. Brighton PJ, Maruyama Y, Fishwick K, Vrljicak P, Tewary S, Fujihara R, et al. Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium. Elife. 2017;6:e31274.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Ruan YC, Guo JH, Liu X, Zhang R, Tsang LL, Dong JD, 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.

    Article  CAS  PubMed  Google Scholar 

  61. •• Lédée N, Petitbarat M, Prat-Ellenberg L, Dray G, Cassuto GN, Chevrier L, Kazhalawi A, Vezmar K, Chaouat G. 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. A prospective, multicenter cohort study evaluating the endometrial immune profile to create personalized treatment plans for patients with infertility.

    Article  CAS  PubMed  Google Scholar 

  62. Lédée N, Petitbarat M, Prat-Ellenberg L, Dray G, Cassuto GN, Chevrier L, Kazhalawi A, Vezmar K, Chaouat G. 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.PMID:32582163;PMCID:PMC7287127.

    Article  Google Scholar 

  63. Lédée N, Prat-Ellenberg L, Chevrier L, Balet R, Simon C, Lenoble C, Irani EE, Bouret D, Cassuto G, Vitoux D, Vezmar K, Bensussan A, Chaouat G, Petitbarat M. 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. Epub 2016 Nov 24 PMID: 27915039.

    Article  PubMed  Google Scholar 

  64. Gellersen B, et al. Decidualization of the human endometrium: mechanisms, functions, and clinical perspectives. Semin Reprod Med. 2007;25:445–53.

    Article  CAS  PubMed  Google Scholar 

  65. Seshadri S, Sunkara SK. Natural killer cells in female infertility and recurrent miscarriage: a systematic review and meta-analysis. Hum Reprod Update. 2014;20:429–38.

    Article  PubMed  Google Scholar 

  66. Tang AW, 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. Epub 2011 May 25 PMID: 21613313.

    Article  CAS  PubMed  Google Scholar 

  67. Mariee N, Tuckerman E, Ali A, Li W, Laird S, Li TC. The observer and cycleto-cycle variability in the measurement of uterine natural killer cells by immunohistochemistry. J Reprod Immunol. 2012;95:93–100.

    Article  CAS  PubMed  Google Scholar 

  68. Moffett-King A. Natural killer cells and pregnancy. Nat Rev Immunol. 2002;2(9):656–63.

    CAS  PubMed  Google Scholar 

  69. Kwak-Kim J, Gilman-Sachs A. Clinical implication of natural killer cells and reproduction. Am J Reprod Immunol. 2008;59(5):388–400.

    CAS  PubMed  Google Scholar 

  70. Hiby SE, Walker JJ, O’shaughnessy KM, Redman CW, Carrington M, Trowsdale J, Moffett A. Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J Exp Med. 2004;200(8):957–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. • Shojaei Z, Jafarpour R, Mehdizadeh S, Bayatipoor H, Pashangzadeh S, Motallebnezhad M. Functional prominence of natural killer cells and natural killer T cells in pregnancy and infertility: a comprehensive review and update. Pathol Res Pract. 2022;8:154062. This recent review article describes how NK cells play a complex role in implantation, placentation, and fetal tolerance, though there is conflicting evidence regarding the role of NK cells in infertility.

    Article  Google Scholar 

  72. • Azargoon A, Mirrasouli Y, Barough MS, Barati M, Kokhaei P. 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. Infertility patients had a significantly higher percentage of CD56+NK cells in comparison with the healthy control group (p=0.007). RPL patients had a significantly higher percentage of CD69+lymphocytes than in the infertility group (p=0.004).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. • Glover LE, Crosby D, Thiruchelvam U, Harmon C, Chorcora CN, Wingfield MB, O’Farrelly C. Uterine natural killer cell progenitor populations predict successful implantation in women with endometriosis-associated infertility. Am J Reprod Immunol. 2018;79(3):e12817. Patients with successful implantation had larger populations of endometrial CD34+hematopoietic stem cells (3.97% vs 0.69%; p < .0004) and increased coexpression of NK cell marker CD56 (81.1% vs 60.9%; p < .034) compared with patients with failed implantation.

    Article  Google Scholar 

  74. Lapides L, Klein M, Belušáková V, Csöbönyeiová M, Varga I, Babal P. 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 Suppl 1):S99.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. • Ali SB, Jeelall Y, Pennell CE, Hart R, McLean-Tooke A, Lucas M. The role of immunological testing and intervention in reproductive medicine: a fertile collaboration? Am J Reprod Immunol. 2018;79(3):e12784. There is no current consensus on testing for NK cell levels and subsets for infertility patients. Small studies exist that suggest that identification and treatment of NK cell abnormalities can improve reproductive outcomes.

    Article  Google Scholar 

  76. • Cavalcante MB, da Silva PH, Carvalho TR, Sampaio OG, Câmara FE, Cavalcante CT, Barini R, Kwak-Kim J. Peripheral blood natural killer cell cytotoxicity in recurrent miscarriage: a systemic review and meta-analysis. J Reprod Immunol. 2023;18:103956. High peripheral blood NK cell cytotoxicity assays have been significantly associated with RPL and can also help select patients who would benefit from immunotherapy.

    Article  Google Scholar 

  77. • Sung N, Khan SA, Yiu ME, Jubiz G, Salazar MD, Skariah A, Dambaeva S, Kwak-Kim J. Reproductive outcomes of women with recurrent pregnancy losses and repeated implantation failures are significantly improved with immunomodulatory treatment. J Reprod Immunol. 2021;1(148):103369. IVF pregnancy rates (48.2 % vs. 33.0 %, p < 0.001) and live birth per embryo transfer cycle (1.8 % vs. 39.6 %, p < 0.001) were higher for patients treated with immunomodulatory treatment. These patients were also found to have changes in their NK cell levels after undergoing treatment, suggesting a possible mechanistic role of abnormal NK levels and pregnancy failure.

    Article  Google Scholar 

  78. 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.

    CAS  PubMed  Google Scholar 

  79. Raghupathy R, Makhseed MA, Azizieh F, Hassan N, Al-Azemi M, Al-Shamali E. 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.

    CAS  PubMed  Google Scholar 

  80. Kwak-Kim JY, Chung-Bang HS, Ng SC, Ntrivalas EI, Mangubat CP, Beaman KD, Beer AE, Gilman-Sachs A. 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.

    Article  CAS  PubMed  Google Scholar 

  81. • Kuroda K, Nakagawa K, Horikawa T, Moriyama A, Ojiro Y, Takamizawa S, Ochiai A, Matsumura Y, Ikemoto Y, Yamaguchi K, Sugiyama R. Increasing number of implantation failures and pregnancy losses associated with elevated Th1/Th2 cell ratio. Am J Reprod Immunol. 2021;86(3):e13429. The Th1/Th2 cell ratios in RIF and RPL patients were found to be significantly higher than the ratios in fertile women. These higher ratios were associated with ≥4 implantation failure cycles and ≥2 pregnancy losses, but not to general infertility overall.

    Article  CAS  PubMed  Google Scholar 

  82. Winger EE, Reed JL, Ashoush S, El-Toukhy T, Ahuja S, Taranissi M. 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;65:610–8.

    Article  CAS  PubMed  Google Scholar 

  83. • Azizi R, Ahmadi M, Danaii S, Abdollahi-Fard S, Mosapour P, Eghbal-Fard S, Dolati S, Kamrani A, Rahnama B, Mehdizadeh A, Jadidi-Niaragh F. Cyclosporine A improves pregnancy outcomes in women with recurrent pregnancy loss and elevated Th1/Th2 ratio. J Cell Physiol. 2019;234(10):19039–47. Th1 frequency (p=0.0004), Th1/Th2 ratio (p<0.0001), T‐bet mRNA expression (p<0.0001), IFN‐γ (p=0.0007), and tumor necrosis factor α (p=0.0002) secretion level were statistically lower in RPL patients treated with cyclosporine. 81.5% of RPL patients treated with cyclosporine had successful childbirth, compared to 42.1% of RPL patients in the control group (p=0.0001).

    Article  CAS  PubMed  Google Scholar 

  84. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu Rev Immunol. 2009;23(27):485–517.

    Google Scholar 

  85. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008;8(7):523–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Qian J, Zhang N, Lin J, Wang C, Pan X, Chen L, Li D, Wang L. Distinct pattern of Th17/Treg cells in pregnant women with a history of unexplained recurrent spontaneous abortion. Biosci Trends. 2018;12(2):157–67.

    CAS  PubMed  Google Scholar 

  87. Ghaebi M, Abdolmohammadi-Vahid S, Ahmadi M, Eghbal-Fard S, Dolati S, Nouri M, Talebi M, Hamdi K, Marofi F, Aghebati-Maleki L, Jadidi-Niaragh F. T cell subsets in peripheral blood of women with recurrent implantation failure. J Reprod Immunol. 2019;1(131):21–9.

    Google Scholar 

  88. Huang Q, Wu H, Li M, Yang Y, Fu X. Prednisone improves pregnancy outcome in repeated implantation failure by enhance regulatory T cells bias. J Reprod Immunol. 2021;1(143):103245.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Center for Infertility and Reproductive Surgery, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA, 02115, USA

    Mary Kathryn Abel, Mackenzie N. Naert & Antonio R. Gargiulo

  2. Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA

    Abigail M. Kempf

Authors
  1. Mary Kathryn Abel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mackenzie N. Naert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abigail M. Kempf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Antonio R. Gargiulo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.K.A., M.N.N., and A.M.K. wrote the main manuscript text. All authors reviewed the manuscript.

Corresponding author

Correspondence to Mary Kathryn Abel.

Ethics declarations

Conflict of Interest

Dr. Gargiulo is the Chair of the Medical Advisory Board of Pregmune, Inc, a company using artificial intelligence algorithms to provide prognostic assessment and therapeutic recommendations for patients with immunologic reproductive failure. The remaining authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abel, M.K., Naert, M.N., Kempf, A.M. et al. Role of Immunological Testing in Infertility. Curr Obstet Gynecol Rep (2024). https://doi.org/10.1007/s13669-024-00381-2

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s13669-024-00381-2

Keywords

Search

Navigation