Молекулярные и иммунные предикторы эффективности программ вспомогательных репродуктивных технологий

Несмотря на значительный прогресс вспомогательных репродуктивных технологий (ВРТ), частота неудачных циклов экстракорпорального оплодотворения остается высокой, что обуславливает необходимость поиска дополнительных прогностических инструментов. В последние годы активно изучаются молекулярные и иммунные маркеры, способные отражать функциональное состояние ооцита, эмбриона и эндометрия, а также особенности системного воспалительного ответа пациентки. В представленном обзоре обобщены современные данные о диагностической и прогностической ценности биомаркеров фолликулярной жидкости, периферической крови и эндометрия. Рассмотрена роль показателей окислительного стресса (малоновый диальдегид, белковые продукты повышенной окисляемости), ферментативных антиоксидантов (глутатионпероксидаза и др.), микроРНК и других некодирующих РНК, а также иммунологических параметров, включая цитокины, компоненты системы комплемента и клеточные субпопуляции. Проанализированы данные о прогностической значимости внеклеточной ДНК как индикатора состояния фолликулярной микросреды. Показано, что дисбаланс редокс-системы и нарушения локальной иммунной регуляции могут ассоциироваться с ухудшением качества эмбрионов и снижением вероятности имплантации. В то же время высокая гетерогенность методик, малые выборки и отсутствие стандартизированных протоколов ограничивают клиническое применение большинства маркеров. Интеграция молекулярных показателей с клиническими данными и использование мультиомиксных подходов открывают перспективы персонализации программ ВРТ. Однако для внедрения данных технологий в рутинную практику необходимы крупные проспективные исследования с оценкой воспроизводимости и экономической целесообразности.

1. Корнеева И.Е., Назаренко Т.А., Перминова С.Г. и др. Медико-социальные факторы бесплодия в России. Акушерство и гинекология. 2023;(3):65–72. https://doi.org/10.18565/aig.2022.279.

2. Rezaeiyeh R.D., Mehrara A., Pour A.M.A. et al. Impact of various parameters as predictors of the success rate of in vitro fertilization. Int J Fertil Steril. 2022;16(2):76–84. https://doi.org/10.22074/IJFS.2021.531672.1134.

3. Анварова Ш.А., Шукуров Ф.И., Туламетова Ш.А. Инновационные методы решения проблемы женского бесплодия, ассоциированного с эндокринными нарушениями. Акушерство, Гинекология и Репродукция. 2024;18(5):706–19. https://doi.org/10.17749/2313-7347/ob.gyn.rep.2024.514.

4. Бурдули А.Г., Тетруашвили Н.К., Балмасова И.П. и др. Клинико-иммунологическая характеристика женщин с бесплодием и привычным выкидышем в анамнезе. Акушерство, Гинекология и Репродукция. 2025;19(6):836–48. https://doi.org/10.17749/2313-7347/ob.gyn.rep.2025.697.

5. Ибишев Х.С., Мамедов Э.А., Магомедов Г.А. Иммунологические аспекты мужского бесплодия: обзор литературы 2016-2020 годов. Вестник урологии. 2020;8(3):97–102. https://doi.org/10.21886/2308-6424-2020-8-3-97-102.

6. Тювина Н.А., Балабанова В.В., Николаевская А.О. Психосоматические механизмы идиопатического бесплодия: клинические наблюдения. Неврология, нейропсихиатрия, психосоматика. 2023;15(1):77–82. https://doi.org/10.14412/2074-2711-2023-1-77-82.

7. Никитин А.И. Экстракорпоральное оплодотворение как зеркало эволюции. Проблемы репродукции. 2022;28(2):81–5. https://doi.org/10.17116/repro20222802181.

8. Olszak-Wąsik K., Bednarska-Czerwińska A., Olejek A., Tukiendorf A. From "every day" hormonal to oxidative stress biomarkers in blood and follicular fluid, to embryo quality and pregnancy success? Oxid Med Cell Longev. 2019;2019:1092415. https://doi.org/10.1155/2019/1092415.

9. Gnoth C., Maxrath B., Skonieczny T. et al. Final ART success rates: a 10 years survey. Hum Reprod. 2011;26(8):2239–46. https://doi.org/10.1093/humrep/der178.

10. Брусиловский И.А., Лившиц И.В. Морфологическая оценка эмбрионов человека. «Коллеги, давайте договоримся!». Проблемы репродукции. 2018;24(2):63–8. https://doi.org/10.17116/repro201824263-68.

11. Адамян Л.В., Елагин В.В., Пивазян Л.Г., Исаева С.Г. Преимплантационное генетическое тестирование в гинекологии – быть или не быть? Проблемы репродукции. 2023;29(3):16–24. https://doi.org/10.17116/repro20232903116.

12. Бурдули А.Г., Кициловская Н.А., Сухова Ю.В. и др. Фолликулярная жидкость и исходы программ вспомогательных репродуктивных технологий (обзор литературы). Гинекология. 2020;21(6):36–40. https://doi.org/10.26442/20795696.2019.6.190663.

13. Краевая Е.Е., Силачев Д.Н., Безнощенко О.С. и др. Влияние внеклеточных везикул фолликулярной жидкости на коагуляционный гемостаз яичника. Проблемы репродукции. 2020;26(2):18–26. https://doi.org/10.17116/repro20202602118.

14. Das A., Roychoudhury S. Reactive oxygen species in the reproductive system: sources and physiological roles. Adv Exp Med Biol. 2022;1358:9–40. https://doi.org/10.1007/978-3-030-89340-8_2.

15. Шестакова М.А., Киселёва М.В., Проскурнина Е.В. Окислительный стресс в фолликуле и его влияние на исход экстракорпорального оплодотворения: состояние проблемы. Архив акушерства и гинекологии имени В.Ф. Снегирева. 2017;4(3):137–44. https://doi.org/10.18821/2313-8726-2017-4-3-137-144.

16. Al-Saleh I., Coskun S., Al-Rouqi R. et al. Oxidative stress and DNA damage status in couples undergoing in vitro fertilization treatment. Reprod Fertil. 2021;2(2):117–39. https://doi.org/10.1530/RAF-20-0062.

17. Chen Y., Yang J., Zhang L. The impact of follicular fluid oxidative stress levels on the outcomes of assisted reproductive therapy. Antioxidants (Basel). 2023;12(12):2117. https://doi.org/10.3390/antiox12122117.

18. Agarwal A., Aponte-Mellado A., Premkumar B.J. et al. The effects of oxidative stress on female reproduction: a review. Reprod Biol Endocrinol. 2012;10:49. https://doi.org/10.1186/1477-7827-10-49.

19. Afrough M., Nikbakht R., Hashemitabar M. et al. Association of follicular fluid antioxidants activity with aging and in vitro fertilization outcome: a cross-sectional study. Int J Fertil Steril. 2024;18(2):115–22. https://doi.org/10.22074/ijfs.2023.555601.1317.

20. Aebi H. Catalase in vitro. Methods Enzymol. 1984;105:121–6. https://doi.org/10.1016/s0076-6879(84)05016-3.

21. Debbarh H., Louanjli N., Aboulmaouahib S. et al. Antioxidant activities and lipid peroxidation status in human follicular fluid: age-dependent change. Zygote. 2021;29(6):490–4. https://doi.org/10.1017/S0967199421000241.

22. Liu Y., Yu Z., Zhao S. et al. Oxidative stress markers in the follicular fluid of patients with polycystic ovary syndrome correlate with a decrease in embryo quality. J Assist Reprod Genet. 2021;38(2):471–7. https://doi.org/10.1007/s10815-020-02014-y.

23. Prieto L., Quesada J.F., Cambero O. et al. Analysis of follicular fluid and serum markers of oxidative stress in women with infertility related to endometriosis. Fertil Steril. 2012;98(1):126–30. https://doi.org/10.1016/j.fertnstert.2012.03.052.

24. Choi Y.S., Cho .S, Seo S.K. et al. Alteration in the intrafollicular thiol-redox system in infertile women with endometriosis. Reproduction. 2015;149(2):155–62. https://doi.org/10.1530/REP-14-0438.

25. Nishihara T., Matsumoto K., Hosoi Y., Morimoto Y. Evaluation of antioxidant status and oxidative stress markers in follicular fluid for human in vitro fertilization outcome. Reprod Med Biol. 2018;17(4):481–6. https://doi.org/10.1002/rmb2.12229.

26. Mukheef M.A., Ali R.A., Alheidery H.H.A. Follicular fluid 8-Hydroxy-2-Deoxyguanosine (8-OHdG) as biomarker for oxidative stress in intracytoplasmic sperm injection. J Med Invest. 2022;69(1.2):112–6. https://doi.org/10.2152/jmi.69.112.

27. Song Y.L., Quan S., Tian J.W. et al. Relationship between protein oxidation levels in the follicular fluid and the outcome parameters of in vitro fertilization-embryo transplantation. Nan Fang Yi Ke Da Xue Xue Bao. 2009;29(1):160–3. (In Chinese).

28. Kokot I., Piwowar A., Jędryka M., Kratz E.M. Is there a balance in oxidative-antioxidant status in blood serum of patients with advanced endometriosis? Antioxidants (Basel). 2021;10(7):1097. https://doi.org/10.3390/antiox10071097.

29. Кузнецов К.О., Шарипова Э.Ф., Низаева А.С. и др. Роль микроРНК в норме и при патологии эндометрия. Российский вестник акушера-гинеколога. 2023;23(4):27–34. https://doi.org/10.17116/rosakush20232304127

30. Feng R., Sang Q., Zhu Y. et al. MiRNA-320 in the human follicular fluid is associated with embryo quality in vivo and affects mouse embryonic development in vitro. Sci Rep. 2015;5:8689. https://doi.org/10.1038/srep08689.

31. Martinez R.M., Liang L., Racowsky C. et al. Extracellular microRNAs profile in human follicular fluid and IVF outcomes. Sci Rep. 2018;8(1):17036. https://doi.org/10.1038/s41598-018-35379-3.

32. Scalici E., Traver S., Mullet T. et al. Circulating microRNAs in follicular fluid, powerful tools to explore in vitro fertilization process. Sci Rep. 2016;6:24976. https://doi.org/10.1038/srep24976.

33. Machtinger R., Rodosthenous R.S., Adir M. et al. Extracellular microRNAs in follicular fluid and their potential association with oocyte fertilization and embryo quality: an exploratory study. J Assist Reprod Genet. 2017;34(4):525–33. https://doi.org/10.1007/s10815-017-0876-8.

34. Fu J., Qu R.G., Zhang Y.J. et al. Screening of miRNAs in human follicular fluid reveals an inverse relationship between microRNA-663b expression and blastocyst formation. Reprod Biomed Online. 2018;37(1):25–32. https://doi.org/10.1016/j.rbmo.2018.03.021.

35. Khan H.L., Bhatti S., Abbas S. et al. Extracellular microRNAs: key players to explore the outcomes of in vitro fertilization. Reprod Biol Endocrinol. 2021;19(1):72. https://doi.org/10.1186/s12958-021-00754-9.

36. Zhang Q., Su J., Kong W. et al. Roles of miR-10a-5p and miR-103a-3p, regulators of BDNF expression in follicular fluid, in the outcomes of IVF-ET. Front Endocrinol (Lausanne). 2021;12:637384. https://doi.org/10.3389/fendo.2021.637384.

37. Muraoka A., Yokoi A., Yoshida K. et al. Small extracellular vesicles in follicular fluids for predicting reproductive outcomes in assisted reproductive technology. Commun Med (Lond). 2024;4(1):33. https://doi.org/10.1038/s43856-024-00460-8.

38. Esfandyari S., Elkafas H., Chugh R.M. et al. Exosomes as biomarkers for female reproductive diseases diagnosis and therapy. Int J Mol Sci. 2021;22(4):2165. https://doi.org/10.3390/ijms22042165.

39. Li J., Cao Y., Xu X. et al. Increased new lncRNA-mRNA gene pair levels in human cumulus cells correlate with oocyte maturation and embryo development. Reprod Sci. 2015;22(8):1008–14. https://doi.org/10.1177/1933719115570911.

40. Xiong Y., Liu T., Wang S. et al. Cyclophosphamide promotes the proliferation inhibition of mouse ovarian granulosa cells and premature ovarian failure by activating the lncRNA-Meg3-p53-p66Shc pathway. Gene. 2017;596:1–8. https://doi.org/10.1016/j.gene.2016.10.011.

41. Jiao J., Shi B., Wang T. et al. Characterization of long non-coding RNA and messenger RNA profiles in follicular fluid from mature and immature ovarian follicles of healthy women and women with polycystic ovary syndrome. Hum Reprod. 2018;33(9):1735–48. https://doi.org/10.1093/humrep/dey255.

42. Zhang L., Zou J., Wang Z. Li L. A subpathway and target gene cluster-based approach uncovers lncRNAs associated with human primordial follicle activation. Int J Mol Sci. 2023;24(13):10525. https://doi.org/10.3390/ijms241310525.

43. Ernst E.H., Nielsen J., Ipsen M.B. et al. Transcriptome analysis of long non-coding RNAs and genes encoding paraspeckle proteins during human ovarian follicle development. Front Cell Dev Biol. 2018;6:78. https://doi.org/10.3389/fcell.2018.00078.

44. Czamanski-Cohen J., Sarid O., Cwikel J. et al. Increased plasma cell-free DNA is associated with low pregnancy rates among women undergoing IVF-embryo transfer. Reprod Biomed Online. 2013;26(1):36–41. https://doi.org/10.1016/j.rbmo.2012.09.018.

45. Casteleiro Alves M.M., Oliani L., Almeida M. et al. Cell-free DNA as a new biomarker of IVF success, independent of any infertility factor, including endometriosis. Diagnostics (Basel). 2023;13(2):208. https://doi.org/10.3390/diagnostics13020208.

46. Destouni A., Vrettou C., Antonatos D. et al. Cell-free DNA levels in acute myocardial infarction patients during hospitalization. Acta Cardiol. 2009;64(1):51–7. https://doi.org/10.2143/AC.64.1.2034362.

47. Kamat A.A., Baldwin M., Urbauer D. et al. Plasma cell-free DNA in ovarian cancer: an independent prognostic biomarker. Cancer. 2010;116(8):1918–25. https://doi.org/10.1002/cncr.24997.

48. Lenz M., Maiberger T., Armbrust L. et al. cfDNA and DNases: new biomarkers of sepsis in preterm neonates – a pilot study. Cells. 2022;11(2):192. https://doi.org/10.3390/cells11020192.

49. Hahn S., Rusterholz C., Hösli I., Lapaire O. Cell-free nucleic acids as potential markers for preeclampsia. Placenta. 2011;32(l):S17–20. https://doi.org/10.1016/j.placenta.2010.06.018.

50. Traver S., Scalici E., Mullet T. et al. Cell-free DNA in yuman follicular microenvironment: new prognostic biomarker to predict in vitro fertilization outcomes. PLoS One. 2015;10(8):e0136172. https://doi.org/10.1371/journal.pone.0136172.

51. Hart E.A., Patton W.C., Jacobson J.D. et al. Luteal phase serum cell-free DNA as a marker of failed pregnancy after assisted reproductive technology. J Assist Reprod Genet. 2005;22(5):213–7. https://doi.org/10.1007/s10815-005-4924-4.

52. Ozgu-Erdinc A.S., Coskun B., Yorganci A. et al. The role of inflammatory hematological markers in predicting IVF success. JBRA Assist Reprod. 2021;25(1):71–5. https://doi.org/10.5935/1518-0557.20200050.

53. Çakıroğlu Y., Vural F., Vural B. The inflammatory markers in polycystic ovary syndrome: association with obesity and IVF outcomes. J Endocrinol Invest. 2016;39(8):899–907. https://doi.org/10.1007/s40618-016-0446-4.

54. Balta S., Celik T., Mikhailidis D.P. et al. The relation between atherosclerosis and the neutrophil-lymphocyte ratio. Clin Appl Thromb Hemost. 2016;22(5):405–11. https://doi.org/10.1177/1076029615569568.

55. Tola E.N. The association between in vitro fertilization outcome and the inflammatory markers of complete blood count among nonobese unexplained infertile couples. Taiwan J Obstet Gynecol. 2018;57(2):289–94. https://doi.org/10.1016/j.tjog.2018.02.019.

56. Hantoushzadeh S., Poorabdoli M., Parsaei M. et al. Predicting the outcomes of in vitro fertilization using baseline maternal serum inflammatory markers: a retrospective cohort study. Am J Reprod Immunol. 2024;92(1):e13900. https://doi.org/10.1111/aji.13900.

57. Wu L., Liu D., Fang X. et al. Increased serum IL-12 levels are associated with adverse IVF outcomes. J Reprod Immunol. 2023;159:103990. https://doi.org/10.1016/j.jri.2023.103990.

58. Ramanjaneya M., Diboun I., Rizwana N. et al. Elevated adipsin and reduced C5a levels in the maternal serum and follicular fluid during implantation are associated with successful pregnancy in obese women. Front Endocrinol (Lausanne). 2022;13:918320. https://doi.org/10.3389/fendo.2022.918320.

59. Hu C., Zhen Y., Pang B. et al. Myeloid-derived suppressor cells are regulated by estradiol and are a predictive marker for IVF outcome. Front Endocrinol (Lausanne). 2019;10:521. https://doi.org/10.3389/fendo.2019.00521.

60. Cai J.Y., Tang Y..Y, Deng X.H. et al. Recurrent implantation failure may be identified by a combination of diagnostic biomarkers: an analysis of peripheral blood lymphocyte subsets. Front Endocrinol (Lausanne). 2022;13:865807. https://doi.org/10.3389/fendo.2022.865807.

61. 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.2020.00064.

62. Ganeva R., Parvanov D., Vidolova N. et al. Endometrial immune cell ratios and implantation success in patients with recurrent implantation failure. J Reprod Immunol. 2023;156:103816. https://doi.org/10.1016/j.jri.2023.103816.

63. Sudoma I., Goncharova Y., Dons'koy B., Mykytenko D. Immune phenotype of the endometrium in patients with recurrent implantation failures after the transfer of genetically tested embryos in assisted reproductive technology programs. J Reprod Immunol. 2023;157:103943. https://doi.org/10.1016/j.jri.2023.103943.

64. Jia Y., Huang Y., Ai Z.H. et al. Exploring the effectiveness of endometrial receptivity array and immune profiling in patients with multiple implantation failure: a retrospective cohort study based on propensity score matching. J Reprod Immunol. 2024;163:104218. https://doi.org/10.1016/j.jri.2024.104218.

65. Garratt J., Mohammadi B., Al-Hashimi B. et al. Endometrial immune assessment in patients with a history of previous euploid blastocyst failure. Front Immunol. 2025;16:1547159. https://doi.org/10.3389/fimmu.2025.1547159.

66. Lédée N., Petitbarat M., Dray G. et al. Endometrial immune profiling and precision therapy increase live birth rate after embryo transfer: a randomised controlled trial. Front Immunol. 2025;16:1523871. https://doi.org/10.3389/fimmu.2025.1523871.

67. Saadat Varnosfaderani A., Kalantari S., Ramezanali F. et al. Increased gene expression of LITAF, TNF-α and BCL6 in endometrial tissues of women with endometriosis: a case-control study. Cell J. 2024;26(4):243–9. https://doi.org/10.22074/cellj.2024.2022348.1503.

68. Dan A. Outcomes in women with IVF failure who tested positive for BCL6 using ReceptivaDx™ testing: effect of treatment on subsequent embryo transfer. Fertil Steril. 2020;113:e13. https://doi.org/10.1016/j.fertnstert.2020.02.034.

69. 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.

70. 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.

71. Ekemen S., Comunoglu C., Kayhan C.K. et al. Endometrial staining of CD56 (uterine natural killer), BCL-6, and CD138 (plasma cells) improve diagnosis and clinical pregnancy outcomes in unexplained infertility and recurrent IVF failures: standardization of diagnosis with digital pathology. Diagnostics (Basel). 2023;13(9):1557. https://doi.org/10.3390/diagnostics13091557.

72. Kofod L., Lindhard A., Bzorek M. et al. Endometrial immune markers are potential predictors of normal fertility and pregnancy after in vitro fertilization. Am J Reprod Immunol. 2017;78(3). https://doi.org/10.1111/aji.12684.

73. Zhao Y., Man G.C.W., Wang J. et al. The identification of endometrial immune cell densities and clustering analysis in the mid-luteal phase as predictor for pregnancy outcomes after IVF-ET treatment. J Reprod Immunol. 2021;148:103431. https://doi.org/10.1016/j.jri.2021.103431.

74. Diao L., Cai S., Huang C. et al. New endometrial immune cell-based score (EI-score) for the prediction of implantation success for patients undergoing IVF/ICSI. Placenta. 2020;99:180–8. https://doi.org/10.1016/j.placenta.2020.07.025.

75. Жирнов И.А., Назмиева К.А., Хабибуллина А.И. и др. Влияние факторов окружающей среды на репродуктивное здоровье женщины. Акушерство, Гинекология и Репродукция. 2024;18(6):858–73. https://doi.org/10.17749/2313-7347/ob.gyn.rep.2024.564

76. Harville E.W., Kruse A.N., Zhao Q. The impact of early-life exposures on women's reproductive health in adulthood. Curr Epidemiol Rep. 2021;8(4):175–89. https://doi.org/10.1007/s40471-021-00279-0.

77. Siristatidis C., Stavros S., Drakeley A. et al. Omics and artificial intelligence to improve in vitro fertilization (IVF) success: a proposed protocol. Diagnostics (Basel). 2021;11(5):743. https://doi.org/10.3390/diagnostics11050743.

78. Sadegh-Zadeh S.A., Khanjani S., Javanmardi S. et al. Catalyzing IVF outcome prediction: exploring advanced machine learning paradigms for enhanced success rate prognostication. Front Artif Intell. 2024;7:1392611. https://doi.org/10.3389/frai.2024.1392611.

79. AlSaad R., Abd-Alrazaq A., Choucair F. et al. Harnessing Artificial intelligence to predict ovarian stimulation outcomes in in vitro fertilization: scoping review. J Med Internet Res. 2024;26:e53396. https://doi.org/10.2196/53396.

80. Hanassab S., Abbara A., Yeung A.C. et al. The prospect of artificial intelligence to personalize assisted reproductive technology. NPJ Digit Med. 2024;7(1):55. https://doi.org/10.1038/s41746-024-01006-x.