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Ассоциация уровня витамина D и полиморфизма гена VDR с исходами программ вспомогательных репродуктивных технологий
Ассоциация уровня витамина D и полиморфизма гена VDR с исходами программ вспомогательных репродуктивных технологий
Сыркашева А.Г., Киндышева С.В., Франкевич В.Е., Донников А.Е., Долгушина Н.В. Ассоциация уровня витамина D и полиморфизма гена VDR с исходами программ вспомогательных репродуктивных технологий. Гинекология. 2022;24(1):30–34. DOI: 10.26442/20795696.2022.1.201245
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Аннотация
Цель. Проанализировать исходы циклов вспомогательных репродуктивных технологий (ВРТ) у пациенток с разным уровнем витамина D.
Материалы и методы. В исследование включены 100 пациенток с бесплодием, обратившихся для проведения ВРТ. Уровень витамина D определяли методом масс-спектрометрии. Всем пациенткам проводили анализ аллельных вариантов гена VDR (FOKI-rs2228570, BsmI-rs1544410, TaqI-rs731236).
Результаты. Среди изученных пациенток 50% (n=50) имели достаточный уровень витамина D (группа 3), 36% (n=36) имели недостаточный уровень витамина D (группа 2), 14% (n=14) имели дефицит витамина D (группа 1). Уровень витамина D не связан с клинико-анамнестическими особенностями пациенток и с параметрами эмбриологического этапа цикла ВРТ. Частота наступления клинической беременности была минимальной в группе пациенток с дефицитом витамина D, однако различия не были значимыми. При этом наблюдали тенденцию к повышению частоты ранних репродуктивных потерь в группах пациенток с недостаточностью и дефицитом витамина D: 66,7% в группе 1, 26,3% в группе 2 и 13,6% в группе 3. В результате частота живорождения погранично значимо выше в группах пациенток с нормальным уровнем витамина D и с недостаточностью по сравнению с группой дефицита витамина D: 46,0 и 38,9% по сравнению с 7,1%; р=0,0821. При проведении многофакторного анализа на частоту наступления беременности влияли дефицит витамина D и генетические особенности гена VDR: наличие аллеля G (FOKI-rs2228570).
Заключение. Дефицит витамина D снижает эффективность циклов ВРТ.
Ключевые слова: вспомогательные репродуктивные технологии, беременность, качество ооцитов, качество эмбрионов, витамин D
Materials and methods. The study included 100 infertile patients who applied for ART. Vitamin D levels were determined by mass spectrometry. The VDR polymorphism was evaluated using real-time PCR.
Results. 50% of patients (n=50) had a sufficient level of vitamin D (group 3), 36% of patients (n=36) had an insufficient level of vitamin D (group 2), 14% of patients (n=14) had a deficiency of vitamin D (group 1). The level of vitamin D was not associated neither with baseline patients characteristics nor with embryological stage of the cycle.
The clinical pregnancy rate was lower in the group 1 (vitamin D deficiency), but the difference was not significant. There was a trend to an increase of miscarriage rate in the groups of patients with vitamin D insufficiency and deficiency: 66.7% in group 1, 26.3% in group 2, and 13.6% in group 3. The live birth rate was higher in the groups of patients with normal and insufficient levels of vitamin D compared with the group of vitamin D deficiency: 46.0 and 38.9% compared to 7.1%, p=0.0821. In multivariate analysis clinical pregnancy rate was influenced by vitamin D deficiency and the genetic characteristics of the VDR gene: the presence of the G allele (FOKI-rs2228570).
Conclusion. The vitamin D deficiency impairs the effectiveness of ART cycles.
Keywords: assisted reproductive technology, in vitro fertilization, pregnancy, oocyte quality, embryo quality, vitamin D
Материалы и методы. В исследование включены 100 пациенток с бесплодием, обратившихся для проведения ВРТ. Уровень витамина D определяли методом масс-спектрометрии. Всем пациенткам проводили анализ аллельных вариантов гена VDR (FOKI-rs2228570, BsmI-rs1544410, TaqI-rs731236).
Результаты. Среди изученных пациенток 50% (n=50) имели достаточный уровень витамина D (группа 3), 36% (n=36) имели недостаточный уровень витамина D (группа 2), 14% (n=14) имели дефицит витамина D (группа 1). Уровень витамина D не связан с клинико-анамнестическими особенностями пациенток и с параметрами эмбриологического этапа цикла ВРТ. Частота наступления клинической беременности была минимальной в группе пациенток с дефицитом витамина D, однако различия не были значимыми. При этом наблюдали тенденцию к повышению частоты ранних репродуктивных потерь в группах пациенток с недостаточностью и дефицитом витамина D: 66,7% в группе 1, 26,3% в группе 2 и 13,6% в группе 3. В результате частота живорождения погранично значимо выше в группах пациенток с нормальным уровнем витамина D и с недостаточностью по сравнению с группой дефицита витамина D: 46,0 и 38,9% по сравнению с 7,1%; р=0,0821. При проведении многофакторного анализа на частоту наступления беременности влияли дефицит витамина D и генетические особенности гена VDR: наличие аллеля G (FOKI-rs2228570).
Заключение. Дефицит витамина D снижает эффективность циклов ВРТ.
Ключевые слова: вспомогательные репродуктивные технологии, беременность, качество ооцитов, качество эмбрионов, витамин D
________________________________________________
Materials and methods. The study included 100 infertile patients who applied for ART. Vitamin D levels were determined by mass spectrometry. The VDR polymorphism was evaluated using real-time PCR.
Results. 50% of patients (n=50) had a sufficient level of vitamin D (group 3), 36% of patients (n=36) had an insufficient level of vitamin D (group 2), 14% of patients (n=14) had a deficiency of vitamin D (group 1). The level of vitamin D was not associated neither with baseline patients characteristics nor with embryological stage of the cycle.
The clinical pregnancy rate was lower in the group 1 (vitamin D deficiency), but the difference was not significant. There was a trend to an increase of miscarriage rate in the groups of patients with vitamin D insufficiency and deficiency: 66.7% in group 1, 26.3% in group 2, and 13.6% in group 3. The live birth rate was higher in the groups of patients with normal and insufficient levels of vitamin D compared with the group of vitamin D deficiency: 46.0 and 38.9% compared to 7.1%, p=0.0821. In multivariate analysis clinical pregnancy rate was influenced by vitamin D deficiency and the genetic characteristics of the VDR gene: the presence of the G allele (FOKI-rs2228570).
Conclusion. The vitamin D deficiency impairs the effectiveness of ART cycles.
Keywords: assisted reproductive technology, in vitro fertilization, pregnancy, oocyte quality, embryo quality, vitamin D
Полный текст
Список литературы
1. Holick MF. The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention. Rev Endocr Metab Disord. 2017;18(2):153-65.
2. McMullan CJ, Borgi L, Curhan GC, et al. The effect of vitamin D on renin-angiotensin system activation and blood pressure: a randomized control trial. J Hypertens. 2017;35(4):822-9.
3. Ghorbani Z, Togha M, Rafiee P, et al. Vitamin D in migraine headache: a comprehensive review on literature. Neurol Sci. 2019;40(12):2459-77. DOI:10.1007/s10072-019-04021-z
4. Bizzaro G, Antico A, Fortunato A, Bizzaro N. Vitamin D and Autoimmune Diseases: Is Vitamin D Receptor (VDR) Polymorphism the Culprit? Isr Med Assoc J. 2017;19(7):438-43.
5. Zhao J, Liu S, Wang Y, et al. Vitamin D improves in-vitro fertilization outcomes in infertile women with polycystic ovary syndrome and insulin resistance. Minerva Med. 2019;110(3):199-208.
6. Voulgaris N, Papanastasiou L, Piaditis G, et al. Vitamin D and aspects of female fertility. Hormones (Athens). 2017;16(1):5-21. DOI:10.14310/horm.2002.1715
7. Banker M, Sorathiya D, Shah S. Vitamin D Deficiency Does Not Influence Reproductive Outcomes of IVF-ICSI: A Study of Oocyte Donors and Recipients. J Hum Reprod Sci. 2017;10(2):79-85.
8. Fatemi F, Mohammadzadeh A, Sadeghi MR, et al. Role of vitamin E and D(3) supplementation in Intra-Cytoplasmic Sperm Injection outcomes of women with polycystic ovarian syndrome: A double blinded randomized placebo-controlled trial. Clin Nutr ESPEN. 2017;18:23-30.
9. Rhodes JM, Subramanian S, Laird E, et al. Perspective: Vitamin D deficiency and COVID-19 severity – plausibly linked by latitude, ethnicity, impacts on cytokines, ACE2 and thrombosis. J Intern Med. 2021;289(1):97-115. DOI:10.1111/joim.13149
10. Owens DJ, Allison R, Close GL. Vitamin D and the Athlete: Current Perspectives and New Challenges. Sports Med. 2018;48(Suppl. 1):3-16.
11. Дедов И., Мельниченко Г., Рожинская Л., и др. Клинические рекомендации «Дефицит витамина D: диагностика, лечение и профилактика». Российская ассоциация эндокринологов, ФГБУ «Эндокринолонический научный центр» Минздрава России. М. 2014; с. 1-77 [Dedov I, Mel'nichenko G, Rozhinskaia L, et al. Klinicheskie rekomendatsii “Defitsit vitamina D: diagnostika, lechenie i profilaktika”. Rossiiskaia assotsiatsiia endokrinologov, FGBU “Endokrinolonicheskii nauchnyi tsentr” Minzdrava Rossii. Moscow. 2014; p. 1-77 (in Russian)].
12. Walz NL, Hinchliffe PM, Soares MJ, et al. Serum Vitamin D status is associated with increased blastocyst development rate in women undergoing IVF. Reprod Biomed Online. 2020;41(6):1101-11.
13. Cozzolino M, Busnelli A, Pellegrini L,et al. How vitamin D level influences in vitro fertilization outcomes: results of a systematic review and meta-analysis. Fertil Steril. 2020;114(5):1014-25.
14. Neville G, Martyn F, Kilbane M, et al. Vitamin D status and fertility outcomes during winter among couples undergoing in vitro fertilization/intracytoplasmic sperm injection. Int J Gynaecol Obstet. 2016;135(2):172-6. DOI:10.1016/j.ijgo.2016.04.018
15. Paffoni A, Ferrari S, Mangiarini A, et al. Concordance of vitamin D peripheral levels in infertile couples’ partners. Gynecol Endocrinol. 2017;33(8):649-52.
16. Paffoni A, Somigliana E, Sarais V, et al. Effect of vitamin D supplementation on assisted reproduction technology (ART) outcomes and underlying biological mechanisms: protocol of a randomized clinical controlled trial. The “supplementation of vitamin D and reproductive outcome” (SUNDRO) study. BMC Pregnancy Childbirth. 2019;19(1):395.
17. Boroňová I, Bernasovská J, Mačeková S, et al. Association between vitamin D receptor gene polymorphisms (Fok I, Cdx-2) and bone mineral density in Slovak postmenopausal women. Anthropol Anz. 2020;77(3):195-203.
18. Biswas S, Kanwal B, Jeet C, Seminara RS. Fok-I, Bsm-I, and Taq-I Variants of Vitamin D Receptor Polymorphism in the Development of Autism Spectrum Disorder: A Literature Review. Cureus. 2018;10(8):e3228.
2. McMullan CJ, Borgi L, Curhan GC, et al. The effect of vitamin D on renin-angiotensin system activation and blood pressure: a randomized control trial. J Hypertens. 2017;35(4):822-9.
3. Ghorbani Z, Togha M, Rafiee P, et al. Vitamin D in migraine headache: a comprehensive review on literature. Neurol Sci. 2019;40(12):2459-77. DOI:10.1007/s10072-019-04021-z
4. Bizzaro G, Antico A, Fortunato A, Bizzaro N. Vitamin D and Autoimmune Diseases: Is Vitamin D Receptor (VDR) Polymorphism the Culprit? Isr Med Assoc J. 2017;19(7):438-43.
5. Zhao J, Liu S, Wang Y, et al. Vitamin D improves in-vitro fertilization outcomes in infertile women with polycystic ovary syndrome and insulin resistance. Minerva Med. 2019;110(3):199-208.
6. Voulgaris N, Papanastasiou L, Piaditis G, et al. Vitamin D and aspects of female fertility. Hormones (Athens). 2017;16(1):5-21. DOI:10.14310/horm.2002.1715
7. Banker M, Sorathiya D, Shah S. Vitamin D Deficiency Does Not Influence Reproductive Outcomes of IVF-ICSI: A Study of Oocyte Donors and Recipients. J Hum Reprod Sci. 2017;10(2):79-85.
8. Fatemi F, Mohammadzadeh A, Sadeghi MR, et al. Role of vitamin E and D(3) supplementation in Intra-Cytoplasmic Sperm Injection outcomes of women with polycystic ovarian syndrome: A double blinded randomized placebo-controlled trial. Clin Nutr ESPEN. 2017;18:23-30.
9. Rhodes JM, Subramanian S, Laird E, et al. Perspective: Vitamin D deficiency and COVID-19 severity – plausibly linked by latitude, ethnicity, impacts on cytokines, ACE2 and thrombosis. J Intern Med. 2021;289(1):97-115. DOI:10.1111/joim.13149
10. Owens DJ, Allison R, Close GL. Vitamin D and the Athlete: Current Perspectives and New Challenges. Sports Med. 2018;48(Suppl. 1):3-16.
11. Dedov I, Mel'nichenko G, Rozhinskaia L, et al. Klinicheskie rekomendatsii “Defitsit vitamina D: diagnostika, lechenie i profilaktika”. Rossiiskaia assotsiatsiia endokrinologov, FGBU “Endokrinolonicheskii nauchnyi tsentr” Minzdrava Rossii. Moscow. 2014; p. 1-77 (in Russian).
12. Walz NL, Hinchliffe PM, Soares MJ, et al. Serum Vitamin D status is associated with increased blastocyst development rate in women undergoing IVF. Reprod Biomed Online. 2020;41(6):1101-11.
13. Cozzolino M, Busnelli A, Pellegrini L,et al. How vitamin D level influences in vitro fertilization outcomes: results of a systematic review and meta-analysis. Fertil Steril. 2020;114(5):1014-25.
14. Neville G, Martyn F, Kilbane M, et al. Vitamin D status and fertility outcomes during winter among couples undergoing in vitro fertilization/intracytoplasmic sperm injection. Int J Gynaecol Obstet. 2016;135(2):172-6. DOI:10.1016/j.ijgo.2016.04.018
15. Paffoni A, Ferrari S, Mangiarini A, et al. Concordance of vitamin D peripheral levels in infertile couples’ partners. Gynecol Endocrinol. 2017;33(8):649-52.
16. Paffoni A, Somigliana E, Sarais V, et al. Effect of vitamin D supplementation on assisted reproduction technology (ART) outcomes and underlying biological mechanisms: protocol of a randomized clinical controlled trial. The “supplementation of vitamin D and reproductive outcome” (SUNDRO) study. BMC Pregnancy Childbirth. 2019;19(1):395.
17. Boroňová I, Bernasovská J, Mačeková S, et al. Association between vitamin D receptor gene polymorphisms (Fok I, Cdx-2) and bone mineral density in Slovak postmenopausal women. Anthropol Anz. 2020;77(3):195-203.
18. Biswas S, Kanwal B, Jeet C, Seminara RS. Fok-I, Bsm-I, and Taq-I Variants of Vitamin D Receptor Polymorphism in the Development of Autism Spectrum Disorder: A Literature Review. Cureus. 2018;10(8):e3228.
2. McMullan CJ, Borgi L, Curhan GC, et al. The effect of vitamin D on renin-angiotensin system activation and blood pressure: a randomized control trial. J Hypertens. 2017;35(4):822-9.
3. Ghorbani Z, Togha M, Rafiee P, et al. Vitamin D in migraine headache: a comprehensive review on literature. Neurol Sci. 2019;40(12):2459-77. DOI:10.1007/s10072-019-04021-z
4. Bizzaro G, Antico A, Fortunato A, Bizzaro N. Vitamin D and Autoimmune Diseases: Is Vitamin D Receptor (VDR) Polymorphism the Culprit? Isr Med Assoc J. 2017;19(7):438-43.
5. Zhao J, Liu S, Wang Y, et al. Vitamin D improves in-vitro fertilization outcomes in infertile women with polycystic ovary syndrome and insulin resistance. Minerva Med. 2019;110(3):199-208.
6. Voulgaris N, Papanastasiou L, Piaditis G, et al. Vitamin D and aspects of female fertility. Hormones (Athens). 2017;16(1):5-21. DOI:10.14310/horm.2002.1715
7. Banker M, Sorathiya D, Shah S. Vitamin D Deficiency Does Not Influence Reproductive Outcomes of IVF-ICSI: A Study of Oocyte Donors and Recipients. J Hum Reprod Sci. 2017;10(2):79-85.
8. Fatemi F, Mohammadzadeh A, Sadeghi MR, et al. Role of vitamin E and D(3) supplementation in Intra-Cytoplasmic Sperm Injection outcomes of women with polycystic ovarian syndrome: A double blinded randomized placebo-controlled trial. Clin Nutr ESPEN. 2017;18:23-30.
9. Rhodes JM, Subramanian S, Laird E, et al. Perspective: Vitamin D deficiency and COVID-19 severity – plausibly linked by latitude, ethnicity, impacts on cytokines, ACE2 and thrombosis. J Intern Med. 2021;289(1):97-115. DOI:10.1111/joim.13149
10. Owens DJ, Allison R, Close GL. Vitamin D and the Athlete: Current Perspectives and New Challenges. Sports Med. 2018;48(Suppl. 1):3-16.
11. Дедов И., Мельниченко Г., Рожинская Л., и др. Клинические рекомендации «Дефицит витамина D: диагностика, лечение и профилактика». Российская ассоциация эндокринологов, ФГБУ «Эндокринолонический научный центр» Минздрава России. М. 2014; с. 1-77 [Dedov I, Mel'nichenko G, Rozhinskaia L, et al. Klinicheskie rekomendatsii “Defitsit vitamina D: diagnostika, lechenie i profilaktika”. Rossiiskaia assotsiatsiia endokrinologov, FGBU “Endokrinolonicheskii nauchnyi tsentr” Minzdrava Rossii. Moscow. 2014; p. 1-77 (in Russian)].
12. Walz NL, Hinchliffe PM, Soares MJ, et al. Serum Vitamin D status is associated with increased blastocyst development rate in women undergoing IVF. Reprod Biomed Online. 2020;41(6):1101-11.
13. Cozzolino M, Busnelli A, Pellegrini L,et al. How vitamin D level influences in vitro fertilization outcomes: results of a systematic review and meta-analysis. Fertil Steril. 2020;114(5):1014-25.
14. Neville G, Martyn F, Kilbane M, et al. Vitamin D status and fertility outcomes during winter among couples undergoing in vitro fertilization/intracytoplasmic sperm injection. Int J Gynaecol Obstet. 2016;135(2):172-6. DOI:10.1016/j.ijgo.2016.04.018
15. Paffoni A, Ferrari S, Mangiarini A, et al. Concordance of vitamin D peripheral levels in infertile couples’ partners. Gynecol Endocrinol. 2017;33(8):649-52.
16. Paffoni A, Somigliana E, Sarais V, et al. Effect of vitamin D supplementation on assisted reproduction technology (ART) outcomes and underlying biological mechanisms: protocol of a randomized clinical controlled trial. The “supplementation of vitamin D and reproductive outcome” (SUNDRO) study. BMC Pregnancy Childbirth. 2019;19(1):395.
17. Boroňová I, Bernasovská J, Mačeková S, et al. Association between vitamin D receptor gene polymorphisms (Fok I, Cdx-2) and bone mineral density in Slovak postmenopausal women. Anthropol Anz. 2020;77(3):195-203.
18. Biswas S, Kanwal B, Jeet C, Seminara RS. Fok-I, Bsm-I, and Taq-I Variants of Vitamin D Receptor Polymorphism in the Development of Autism Spectrum Disorder: A Literature Review. Cureus. 2018;10(8):e3228.
________________________________________________
2. McMullan CJ, Borgi L, Curhan GC, et al. The effect of vitamin D on renin-angiotensin system activation and blood pressure: a randomized control trial. J Hypertens. 2017;35(4):822-9.
3. Ghorbani Z, Togha M, Rafiee P, et al. Vitamin D in migraine headache: a comprehensive review on literature. Neurol Sci. 2019;40(12):2459-77. DOI:10.1007/s10072-019-04021-z
4. Bizzaro G, Antico A, Fortunato A, Bizzaro N. Vitamin D and Autoimmune Diseases: Is Vitamin D Receptor (VDR) Polymorphism the Culprit? Isr Med Assoc J. 2017;19(7):438-43.
5. Zhao J, Liu S, Wang Y, et al. Vitamin D improves in-vitro fertilization outcomes in infertile women with polycystic ovary syndrome and insulin resistance. Minerva Med. 2019;110(3):199-208.
6. Voulgaris N, Papanastasiou L, Piaditis G, et al. Vitamin D and aspects of female fertility. Hormones (Athens). 2017;16(1):5-21. DOI:10.14310/horm.2002.1715
7. Banker M, Sorathiya D, Shah S. Vitamin D Deficiency Does Not Influence Reproductive Outcomes of IVF-ICSI: A Study of Oocyte Donors and Recipients. J Hum Reprod Sci. 2017;10(2):79-85.
8. Fatemi F, Mohammadzadeh A, Sadeghi MR, et al. Role of vitamin E and D(3) supplementation in Intra-Cytoplasmic Sperm Injection outcomes of women with polycystic ovarian syndrome: A double blinded randomized placebo-controlled trial. Clin Nutr ESPEN. 2017;18:23-30.
9. Rhodes JM, Subramanian S, Laird E, et al. Perspective: Vitamin D deficiency and COVID-19 severity – plausibly linked by latitude, ethnicity, impacts on cytokines, ACE2 and thrombosis. J Intern Med. 2021;289(1):97-115. DOI:10.1111/joim.13149
10. Owens DJ, Allison R, Close GL. Vitamin D and the Athlete: Current Perspectives and New Challenges. Sports Med. 2018;48(Suppl. 1):3-16.
11. Dedov I, Mel'nichenko G, Rozhinskaia L, et al. Klinicheskie rekomendatsii “Defitsit vitamina D: diagnostika, lechenie i profilaktika”. Rossiiskaia assotsiatsiia endokrinologov, FGBU “Endokrinolonicheskii nauchnyi tsentr” Minzdrava Rossii. Moscow. 2014; p. 1-77 (in Russian).
12. Walz NL, Hinchliffe PM, Soares MJ, et al. Serum Vitamin D status is associated with increased blastocyst development rate in women undergoing IVF. Reprod Biomed Online. 2020;41(6):1101-11.
13. Cozzolino M, Busnelli A, Pellegrini L,et al. How vitamin D level influences in vitro fertilization outcomes: results of a systematic review and meta-analysis. Fertil Steril. 2020;114(5):1014-25.
14. Neville G, Martyn F, Kilbane M, et al. Vitamin D status and fertility outcomes during winter among couples undergoing in vitro fertilization/intracytoplasmic sperm injection. Int J Gynaecol Obstet. 2016;135(2):172-6. DOI:10.1016/j.ijgo.2016.04.018
15. Paffoni A, Ferrari S, Mangiarini A, et al. Concordance of vitamin D peripheral levels in infertile couples’ partners. Gynecol Endocrinol. 2017;33(8):649-52.
16. Paffoni A, Somigliana E, Sarais V, et al. Effect of vitamin D supplementation on assisted reproduction technology (ART) outcomes and underlying biological mechanisms: protocol of a randomized clinical controlled trial. The “supplementation of vitamin D and reproductive outcome” (SUNDRO) study. BMC Pregnancy Childbirth. 2019;19(1):395.
17. Boroňová I, Bernasovská J, Mačeková S, et al. Association between vitamin D receptor gene polymorphisms (Fok I, Cdx-2) and bone mineral density in Slovak postmenopausal women. Anthropol Anz. 2020;77(3):195-203.
18. Biswas S, Kanwal B, Jeet C, Seminara RS. Fok-I, Bsm-I, and Taq-I Variants of Vitamin D Receptor Polymorphism in the Development of Autism Spectrum Disorder: A Literature Review. Cureus. 2018;10(8):e3228.
Авторы
А.Г. Сыркашева*, С.В. Киндышева, В.Е. Франкевич, А.Е. Донников, Н.В. Долгушина
ФГБУ «Национальный медицинский исследовательский центр акушерства, гинекологии и перинатологии им. акад. В.И. Кулакова» Минздрава России, Москва, Россия
*a_syrkasheva@oparina4.ru
Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia
*a_syrkasheva@oparina4.ru
ФГБУ «Национальный медицинский исследовательский центр акушерства, гинекологии и перинатологии им. акад. В.И. Кулакова» Минздрава России, Москва, Россия
*a_syrkasheva@oparina4.ru
________________________________________________
Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia
*a_syrkasheva@oparina4.ru
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