Preimplantation genetic testing for embryo aneuploidy: opportunities, problems, and prospects

Savostina G.V., Perminova S.G., Ekimov A.N., Veyukova M.A.

Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of the Russian Federation, Moscow, Russia
Human embryo aneuploidies make a substantial contribution to the etiology of implantation failures and early reproductive losses in assisted reproductive technology (ART) programs. The currently available methods for the morphological assessment of embryo quality cannot rule out aneuploid embryo transfer into the uterine cavity. The most common method for assessing the ploidy of an embryo is preimplantation genetic testing for aneuploidy (PGT-A). The introduction of PGT-A into clinical practice could considerably reduce the likelihood of aneuploid embryo transfer into the uterine cavity and enhance the effectiveness of ART programs. However, the expediency of using PGT-A in various groups of patients at high risk for aneuploid embryo formation, as well as in married couples with a good prognosis requires discussion. The paper gives a detailed analysis of the literature data from the studies evaluating the effectiveness of using PGT-A for embryos in patients of older reproductive age, in those with recurrent implantation failures or recurrent miscarriage, as well as in couples in whom the male partner had severe spermatogenic failure. The paper discusses the expediency of routine use of PGT-A in married couples with a good prognosis, as well as when using donor oocytes. It presents the stages of PGT-A, advantages and disadvantages of various methods of PGT-A and material sampling methods for analysis, as well as the possible reasons for of false positive and false negative results of PGT-A.
Conclusion: PGT-A is a modern high-hrly informative method for assessing the chromosomal status of an embryo before its transfer in the ART programs. Currently, the most common method of PGT-A is high-throughput next-generation sequencing (NGS), whereas trophectoderm biopsy is a procedure to obtain material.

Keywords

preimplantation genetic testing
embryo aneuploidies
recurrent miscarriage
older reproductive age
recurrent ART failures

References

  1. Российская Ассоциация Репродукции Человека. Отчет за 2018 год. Available at: http://www.rahr.ru/registr_otchet.php [Russian Association of Human Reprodaction. 2018 Report. (in Russian)]. http://www.rahr.ru/registr_otchet.php.
  2. Загайнова В.А., Коган И.Ю., Беспалова О.Н., Сельков С.А., Соколов Д.И. Роль периферических и эндометриальных NK-клеток при повторных репродуктивных потерях. Акушерство и гинекология. 2021; 7: 19-27. [Zagainova V.A., Kogan I.Yu., Bespalova O.N., Selkov S.A., Sokolov D.I. The role of peripheral and endometrial NK cells in repeated reproductive loss. Obstetrics and Gynecology. 2021; 7: 19-27. (in Russuan)]. https://dx.doi.org/10.18565/aig.2021.7.19-27.
  3. Кулакова Е.В., Калинина Е.А., Трофимов Д.Ю., Макарова Н.П., Хечумян Л.Р., Дударова А.Х. Вспомогательные репродуктивные технологии у супружеских пар с высоким риском генетических нарушений. Преимплантационный генетический скрининг. Акушерство и гинекология. 2017; 8: 21-7. [Kulakova E.V., Kalinina E.A., Trofimov D.Yu., Makarova N.P., Khechumyan L.R., Dudarova A.Kh. Assisted reproductive technologies in couples with a high risk of genetic disorders. Preimplantation genetic screening. Obstetrics and Gynecology. 2017; 8: 21-7. (in Russian)]. https://dx.doi.org/10.18565/aig.2017.8.21-7.
  4. Долгушина Н.В., Коротченко О.Е., Бейк Е.П., Абдурахманова Н.Ф., Ильина Е.О., Кулакова Е.В. Клинико-экономический анализ эффективности преимплантационного генетического скрининга у пациенток позднего репродуктивного возраста. Акушерство и гинекология. 2017; 11: 56-61. [Dolgushina N.V., Korotchenko O.E., Beik E.P., Abdurakhmanova N.F., Ilyina E.O., Kulakova E.V. Clinical and economic analysis of the effectiveness of pre-implantation genetic screening in patients of late reproductive age. Obstetrics and Gynecology. 2017; 11: 56-61 (in Russian)]. https://dx.doi.org/10.18565/aig.2017.11.56-61.
  5. Tyc K.M., McCoy R.C., Schindler K., Xing J. Mathematical modeling of human oocyte aneuploidy. Proc. Natl. Acad. Sci. USA. 2020; 117(19): 10455-64. https://dx.doi.org/10.1073/pnas.1912853117.
  6. Смирнова А.А., Зыряева Н.А., Аншина М.Б. Возрастные изменения и риск хромосомных аномалий в ооцитах человека (обзор литературы). Проблемы репродукции. 2019; 25(2): 16-26. [Smirnova A.A., Zyryaeva N.A., Anshina M.B. Age-related changes and the risk of chromosomal abnormalities in human oocytes (literature review). Problems of Reproduction. 2019; 25(2): 16-26. (in Russian)]. https://dx.doi.org/10.17116/repro20192502116.
  7. Capalbo A., Hoffmann E.R., Cimadomo D., Ubaldi F.M., Rienzi L. Human female meiosis revised: new insights into the mechanisms of chromosome segregation and aneuploidies from advanced genomics and time-lapse imaging. Hum. Reprod. Update. 2017; 23(6): 706-22. https://dx.doi.org/10.1093/humupd/dmx026.
  8. Королькова А.И., Мишиева Н.Г., Бурменская О.В. Современные методы селекции эмбрионов при проведении программ вспомогательных репродуктивных технологий. Акушерство и гинекология. 2018; 2: 13-8. [Korolkova A.I., Mishieva N.G., Burmenskaya O.V. Modern methods of embryo selection in assisted reproductive technology programs. Obstetrics and Gynecology. 2018; 2: 13-8. (in Russian)]. https://dx.doi.org/10.18565/aig.2018.2.13-18.
  9. Minasi M.G., Fiorentino F., Ruberti A., Biricik A., Cursio E., Cotroneo E. et al. Genetic diseases and aneuploidies can be detected with a single blastocyst biopsy: a successful clinical approach. Hum. Reprod. 2017; 32(8): 1770-7. https://dx.doi.org/10.1093/humrep/dex215.
  10. Keltz M.D., Vega M., Sirota I., Lederman M., Moshier E.L., Gonzales E., Stein D. Preimplantation genetic screening (PGS) with Comparative genomic hybridization (CGH) following day 3 single cell blastomere biopsy markedly improves IVF outcomes while lowering multiple pregnancies and miscarriages. J. Assist. Reprod. Genet. 2013; 30(10): 1333-9. https://dx.doi.org/10.1007/s10815-013-0070-6.
  11. Dahdouh E.M., Balayla J., Audibert F.; Genetics Committee, Wilson R.D., Audibert F., Brock J.A., Campagnolo C., Carroll J., Chong K. et al. Technical Update: Preimplantation genetic diagnosis and screening. J. Obstet. Gynaecol. Can. 2015; 37(5): 451-63. https://dx.doi.org/10.1016/s1701-2163(15)30261-9.
  12. Keltz M.D., Vega M., Sirota I., Lederman M., Moshier E.L., Gonzales E., Stein D. Preimplantation genetic screening (PGS) with Comparative genomic hybridization (CGH) following day 3 single cell blastomere biopsy markedly improves IVF outcomes while lowering multiple pregnancies and miscarriages. J. Assist. Reprod. Genet. 2013; 30(10): 1333-9. https://dx.doi.org/10.1007/s10815-013-0070-6.
  13. Rodrigo L., Mateu E., Mercader A., Cobo A.C., Peinado V., Milán M. et al. New tools for embryo selection: comprehensive chromosome screening by array comparative genomic hybridization. Biomed. Res. Int. 2014; 2014: 517125. https://dx.doi.org/10.1155/2014/517125.
  14. Coonen E., Rubio C., Christopikou D., Dimitriadou E., Gontar J., Goossens V. et al.; ESHRE PGT-SR/PGT-A Working Group. ESHRE PGT Consortium good practice recommendations for the detection of structural and numerical chromosomal aberrations. Hum. Reprod. Open. 2020; 2020(3): hoaa017. https://dx.doi.org/10.1093/hropen/hoaa017.
  15. Munné S., Cohen J. Advanced maternal age patients benefit from preimplantation genetic diagnosis of aneuploidy. Fertil. Steril. 2017; 107(5): 1145-6. https://dx.doi.org/10.1016/j.fertnstert.2017.03.015.
  16. Werner M.D., Scott R.T. Jr, Treff N.R. 24-chromosome PCR for aneuploidy screening. Curr. Opin. Obstet. Gynecol. 2015; 27(3): 201-5. https://dx.doi.org/10.1097/GCO.0000000000000167.
  17. Малышева О.В., Бичевая Н.К., Гзгзян А.М. Технологические платформы преимплантационного генетического тестирования на анеуплоидии: сравнительная эффективность диагностики хромосомной патологии. Акушерство и гинекология. 2020; 4: 65-71. [Malysheva O.V., Bichevaya N.K., Gzgzyan A.M. Technological platforms for preimplantation genetic testing for aneuploidy: comparative effectiveness of diagnosing chromosomal abnormalities. Obstetrics and Gynecology. 2020; 4: 65-71. (in Russian)]. https://dx.doi.org/10.18565/aig.2020.4.65-71.
  18. Глинкина Ж.И., Курцер М.А., Младова Е.С., Овчинникова М.М., Высоцкий А.Ю., Троценко И.Д. Скрининг анеуплоидий у преимплантационных эмбрионов с использованием высокопроизводительного секвенирования. Доктор.Ру. 2016; 7: 39-44. [Glinkina Zh.I., Kurtser M.A., Mladova E.S., Ovchinnikova M.M., Vysotsky A.Yu., Trotsenko I.D. Using next-generation sequencing technology for aneuploidy screening in preimplantation embryos. Doctor.ru. 2016; 7: 39-44 (in Russian)].
  19. Munné S., Spinella F., Grifo J., Zhang J., Beltran M.P., Fragouli E., Fiorentino F. Clinical outcomes after the transfer of blastocysts characterized as mosaic by high resolution Next Generation Sequencing- further insights. Eur. J. Med. Genet. 2020; 63(2): 103741. https://dx.doi.org/10.1016/j.ejmg.2019.103741.
  20. Aleksandrova N.V., Shubina E.S., Ekimov A.N., Kodyleva T.A., Mukosey I.S., Makarova N.P., Kulakova E.V., Levkov L.A., Barkov I.Y., Trofimov D.Y., Sukhikh G.T. Comparative results of preimplantation genetic screening by array comparative genomic hybridization and new-generation sequencing. Mol. Biol. (Mosk.). 2017; 51(2): 308-13. https://dx.doi.org/10.7868/S0026898417010025.
  21. Friedenthal J., Maxwell S.M., Munné S., Kramer Y., McCulloh D.H., McCaffrey C., Grifo J.A. Next generation sequencing for preimplantation genetic screening improves pregnancy outcomes compared with array comparative genomic hybridization in single thawed euploid embryo transfer cycles. Fertil. Steril. 2018; 109(4): 627-32. https://dx.doi.org/10.1016/j.fertnstert.2017.12.017.
  22. Munné S., Kaplan B., Frattarelli J.L., Child T., Nakhuda G., Shamma F.N. et al.; STAR Study Group. Preimplantation genetic testing for aneuploidy versus morphology as selection criteria for single frozen-thawed embryo transfer in good-prognosis patients: a multicenter randomized clinical trial. Fertil. Steril. 2019; 112(6): 1071-9.e7. https://dx.doi.org/10.1016/j.fertnstert.2019.07.1346.
  23. Лебедев И.Н. Преимплантационное генетическое тестирование анеуплоидий: современное состояние, тренды и перспективы развития. Медицинская генетика. 2019; 18(3): 3-12. https://dx.doi.org/10.25557/2073-7998.2019.03. 3-12. [Lebedev I.N. Preimplantation genetic testing for aneuploidy: state of the art, trends and perspectives. Medical Genetics. 2019; 18(3): 3-12. (in Russian)]. https://dx.doi.org/10.25557/2073-7998.2019.03. 3-12.
  24. Neumann K., Sermon K., Bossuyt P., Goossens V., Geraedts J., Traeger-Synodinos J. et al. An economic analysis of preimplantation genetic testing for aneuploidy by polar body biopsy in advanced maternal age. BJOG. 2020; 127(6): 710-8. https://dx.doi.org/10.1111/1471-0528.16089.
  25. Scott R.T. Jr, Upham K.M., Forman E.J., Hong K.H., Scott K.L., Taylor D. et al. Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases in vitro fertilization implantation and delivery rates: a randomized controlled trial. Fertil. Steril. 2013; 100(3): 697-703. https://dx.doi.org/10.1016/j.fertnstert.2013.04.035.
  26. Schmutzler A.G. Theory and practice of preimplantation genetic screening (PGS). Eur. J. Med. Genet. 2019; 62(8): 103670. https://dx.doi.org/10.1016/j.ejmg.2019.103670.
  27. Адамян Л.В., ред. Женское бесплодие (современные подходы к диагностике и лечению). Клинические рекомендации (протокол лечения). М.: Министерство здравоохранения Российской Федерации; 2019. [Adamyan L.V., ed. Female infertility (modern approaches to diagnosis and treatment). Clinical guidelines (Treatment protocol). Moscow: Ministry of Health of the Russian Federation; 2019. (in Russian)].
  28. Ubaldi F.M., Cimadomo D., Capalbo A., Vaiarelli A., Buffo L., Trabucco E. et al. Preimplantation genetic diagnosis for aneuploidy testing in women older than 44 years: a multicenter experience. Fertil. Steril. 2017; 107(5): 1173-80. https://dx.doi.org/10.1016/j.fertnstert.2017.03.007.
  29. Rubio C., Bellver J., Rodrigo L., Castillón G., Guillén A., Vidal C. et al. In vitro fertilization with preimplantation genetic diagnosis for aneuploidies in advanced maternal age: a randomized, controlled study. Fertil. Steril. 2017; 107(5):1122-9. https://dx.doi.org/10.1016/j.fertnstert.2017.03.011.
  30. Бейк Е.П., Коротченко О.Е., Гвоздева А.Д., Сыркашева А.Г., Долгушина Н.В. Роль преимплантационного генетического скрининга в повышении эффективности программ вспомогательных репродуктивных технологий у пациенток позднего репродуктивного возраста. Акушерство и гинекология. 2018; 4: 78-84. [Beik E.P., Korotchenko O.E., Gvozdeva A.D., Syrkasheva A.G., Dolgushina N.V. Role of preimplantation genetic screening in enhancing the effetiveness of assisted reproductive technology programs in late reproductive-aged patients. Obstetrics and Gynecology. 2018; 4: 78-84 (in Russian)]. https://dx.doi.org/10.18565/aig.2018.4.78-84.
  31. Reig A., Franasiak J., Scott R.T. Jr, Seli E. The impact of age beyond ploidy: outcome data from 8175 euploid single embryo transfers. J. Assist. Reprod. Genet. 2020; 37(3): 595-602. https://dx.doi.org/10.1007/s10815-020-01739-0.
  32. Murphy L.A., Seidler E.A., Vaughan D.A., Resetkova N., Penzias A.S., Toth T.L. et al. To test or not to test? A framework for counselling patients on preimplantation genetic testing for aneuploidy (PGT-A). Hum. Reprod. 2019; 34(2): 268-75. https://dx.doi.org/10.1093/humrep/dey346.
  33. Hong Li Y., Marren A. Recurrent pregnancy loss: A summary of international evidence-based guidelines and practice. Aust. J. Gen. Pract. 2018; 47(7): 432-6. https://dx.doi.org/10.31128/AJGP-01-18-4459.
  34. El Hachem H., Crepaux V., May-Panloup P., Descamps P., Legendre G., Bouet P.E. Recurrent pregnancy loss: current perspectives. Int. J. Womens Health. 2017; 9: 331-45. https://dx.doi.org/10.2147/IJWH.S100817.
  35. Тетруашвили Н.К. Привычный выкидыш. Акушерство и гинекология: новости, мнения, обучение. 2017; 4: 70-87. [Tetruashvili N.K. Reccurent miscarriage. Obstetrics and Gynecology: News. Opinions. Training. 2017; 4: 70-87. (in Russian)]. https://dx.doi.org/10.24411/2303-9698-2017-00010.
  36. Popescu F., Jaslow C.R., Kutteh W.H. Recurrent pregnancy loss evaluation combined with 24-chromosome microarray of miscarriage tissue provides a probable or definite cause of pregnancy loss in over 90% of patients. Hum. Reprod. 2018; 33(4): 579-87. https://dx.doi.org/10.1093/humrep/dey021.
  37. Sato T., Sugiura-Ogasawara M., Ozawa F., Yamamoto T., Kato T., Kurahashi H. et al. Preimplantation genetic testing for aneuploidy: a comparison of live birth rates in patients with recurrent pregnancy loss due to embryonic aneuploidy or recurrent implantation failure. Hum. Reprod. 2019; 34(12): 2340-8. https://dx.doi.org/10.1093/humrep/dez229. Erratum in: Hum. Reprod. 2020; 35(1): 255.
  38. ESHRE Reproductive Endocrinology Guideline Group. Ovarian stimulation gor IVF/ICSI. Guideline of the European Society of Human Reproduction and Embryology. October, 2019.
  39. Лычагин А.С., Малинина О.Ю. Невынашивание беременности: вклад мужского фактора и возможности его преодоления. Проблемы репродукции. 2017; 23(5): 106-14. [Lychagin A.S., Malinina O.Yu. Miscarriage: the contribution of the male factor and the possibility of overcoming it. Problems of Reproduction. 2017; 23(5): 106-14. (in Russian)]. https://dx.doi.org/10.17116/repro2017235106-114.
  40. Cozzolino M., Diaz-Gimeno P., Pellicer A., Garrido N. Evaluation of the endometrial receptivity assay and the preimplantation genetic test for aneuploidy in overcoming recurrent implantation failure. J. Assist. Reprod. Genet. 2020; 37(12): 2989-97. https://dx.doi.org/10.1007/s10815-020-01948-7.
  41. Colaco S., Sakkas D. Paternal factors contributing to embryo quality. J. Assist. Reprod. Genet. 2018; 35(11):1953-68. https://dx.doi.org/10.1007/s10815-018-1304-4.
  42. Petousis S., Prapas Y., Papatheodorou A., Margioula-Siarkou C., Papatzikas G., Panagiotidis Y. et al. Fluorescence in situ hybridisation sperm examination is significantly impaired in all categories of male infertility. Andrologia. 2018; 50(2). https://dx.doi.org/10.1111/and.12847.
  43. Coates A., Hesla J.S., Hurliman A., Coate B., Holmes E., Matthews R. et al. Use of suboptimal sperm increases the risk of aneuploidy of the sex chromosomes in preimplantation blastocyst embryos. Fertil. Steril. 2015; 104(4): 866-72. https://dx.doi.org/10.1016/j.fertnstert.2015.06.033.
  44. Киселева Ю.Ю., Кодылева Т.А., Кириллова А.О. Использование скрининговых тестов на выявление наиболее распространенных мутаций перед программой вспомогательных репродуктивных технологий. Проблемы репродукции. 2017; 23(2): 47-9. [Kiseleva Yu.Yu., Kodyleva T.A., Kirillova A.O. The use of screening tests for the detection of the most common mutations by an advanced program of special reproductive technologies. Problems of reproduction. 2017; 23(2): 47-9. (in Russian)]. https://dx.doi.org/10.17116/repro201723247-49.
  45. Tarozzi N., Nadalini M., Lagalla C., Coticchio G., Zacà C., Borini A. Male factor infertility impacts the rate of mosaic blastocysts in cycles of preimplantation genetic testing for aneuploidy. J. Assist. Reprod. Genet. 2019; 36(10): 2047-55. https://dx.doi.org/10.1007/s10815-019-01584-w.
  46. Gat I., Li N., Yasovich N., Antes R., Kuznyetsov V., Zohni K. et al. Sperm DNA fragmentation index does not correlate with blastocyst euploidy rate in egg donor cycles. Gynecol. Endocrinol. 2018; 34(3): 212-6. https://dx.doi.org/10.1080/09513590.2017.1379500.
  47. Ozgur K., Berkkanoglu M., Bulut H., Yoruk G.D.A., Candurmaz N.N., Coetzee K. Single best euploid versus single best unknown-ploidy blastocyst frozen embryo transfers: a randomized controlled trial. J. Assist. Reprod. Genet. 2019; 36(4): 629-36. https://dx.doi.org/10.1007/s10815-018-01399-1.
  48. Doyle N., Gainty M., Eubanks A., Doyle J., Hayes H., Tucker M. et al. Donor oocyte recipients do not benefit from preimplantation genetic testing for aneuploidy to improve pregnancy outcomes. Hum. Reprod. 2020; 35(11):2548-55. https://dx.doi.org/10.1093/humrep/deaa219.
  49. Masbou A.K., Friedenthal J.B., McCulloh D.H., McCaffrey C., Fino M.E., Grifo J.A., Licciardi F. A comparison of pregnancy outcomes in patients undergoing donor egg single embryo transfers with and without preimplantation genetic testing. Reprod. Sci. 2019; 26(12): 1661-5. https://dx.doi.org/10.1177/1933719118820474.
  50. Franasiak J.M., Forman E.J., Hong K.H., Werner M.D., Upham K.M., Treff N.R., Scott R.T. Jr. The nature of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening. Fertil. Steril. 2014; 101(3): 656-63.e1. https://dx.doi.org/10.1016/j.fertnstert.2013.11.004.
  51. Yang Z., Liu J., Collins G.S., Salem S.A., Liu X., Lyle S.S. et al. Selection of single blastocysts for fresh transfer via standard morphology assessment alone and with array CGH for good prognosis IVF patients: results from a randomized pilot study. Mol. Cytogenet. 2012; 5(1): 24. https://dx.doi.org/10.1186/1755-8166-5-24.
  52. Gleicher N., Patrizio P., Brivanlou A. Preimplantation genetic testing for aneuploidy – a castle built on sand. Trends Mol. Med. 2021; 27(8): 731-42. https://dx.doi.org/10.1016/j.molmed.2020.11.009.
  53. Li P., Xu Y., Wei Y., Yang Y. Self-correction for human parsing. IEEE Trans. Pattern Anal. Mach. Intell. 2020; Dec 24: PP. https://dx.doi.org/10.1109/TPAMI.2020.3048039.
  54. Gleicher N., Metzger J., Croft G., Kushnir V.A., Albertini D.F., Barad D.H. A single trophectoderm biopsy at blastocyst stage is mathematically unable to determine embryo ploidy accurately enough for clinical use. Reprod. Biol. Endocrinol. 2017; 15(1): 33. https://dx.doi.org/10.1186/s12958-017-0251-8.

Received 31.05.2021

Accepted 02.09.2021

About the Authors

Guzel V. Savostina, graduate student, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology,
Ministry of Health of the Russian Federation, +7(925)633-35-16, savostina2324@gmail.com, 117997, Russia, Moscow, Ac. Oparin str., 4.
Svetlana G. Perminova, MD, PhD, Leading Researcher of Reproductology Department, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of the Russian Federation, perisvet@list.ru, 117997, Russia, Moscow, Ac. Oparin str., 4.
Alexey N. Ekimov, doctor-laboratory geneticist, Head of the Group of preimplantation genetic screening of the Laboratory of Molecular Genetic Methods,
Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of the Russian Federation,
a_ekimov@oparina4.ru, 117997, Russia, Moscow, Ac. Oparin str., 4.
Maria A. Veyukova, MD, PhD, Leading Embriologist of Reproductology Department, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of the Russian Federation, veymary@gmail.com 117997, Russia, Moscow, Ac. Oparin str., 4.

Authors’ contributions: Savostina G.V. – literature search and analysis; processing of the source material, writing the text of the manuscript; Perminova S.G., Ekimov A.N., Veyukova M.A. – editing the manuscript and its final approval.
Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding: The paper has been prepared without sponsorship.
For citation: Savostina G.V., Perminova S.G., Ekimov A.N., Veyukova M.A. Preimplantation genetic testing for embryo aneuploidy: opportunities, problems, and prospects.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2021; 11: 42-49 (in Russian)
https://dx.doi.org/10.18565/aig.2021.11.42-49

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