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Иммуногистохимическое исследование плаценты у женщин с тромбофилией и невынашиванием
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Аннотация
В настоящей работе проведено иммуногистохимическое исследование маркеров ангиогенеза, антикоагулянтной защиты, клеточной гибели и пролиферации в плацентарной ткани у беременных с невынашиванием и тромбофилией. В исследование были включены 142 беременные. В основную группу вошли 56 беременных, которым с I триместра проводилась коррекция нарушений в системе гемостаза с применением препаратов Курантил® (дипиридамол) и Фраксипарин® (надропарин кальция). В группе сравнения (50 беременных) проводилась стандартная терапия, направленная на сохранение беременности, контрольную группу составили 36 беременных. Выявлена достоверно более низкая частота потери беременности в основной (3,57%) и контрольной (0%) группах в сопоставлении с группой сравнения (18%; р<0,05).
После проведения коррекции нарушений в системе свертывания крови площадь экспрессии аннексина V в синцитиотрофобласте и экспрессии сосудистого эндотелиального фактора в строме и эндотелии сосудов ворсин значительно превышала показатели в группе сравнения (28,80±2,76% и 22,06±1,93%, р<0,05; 17,38±4,87% и 1,08±0,46% соответственно, р<0,01).
Результаты иммуногистохимического исследования продемонстрировали положительное влияние проведенной терапии на процессы ангиогенеза, пролиферации и антикоагулянтной защиты в плацентарной ткани. Это позволяет патогенетически обосновать целесообразность применения дипиридамола и надропарина кальция у беременных с тромбофилией и невынашиванием.
Ключевые слова: маркеры ангиогенеза, невынашивание, тромбофилия, дипиридамол.
После проведения коррекции нарушений в системе свертывания крови площадь экспрессии аннексина V в синцитиотрофобласте и экспрессии сосудистого эндотелиального фактора в строме и эндотелии сосудов ворсин значительно превышала показатели в группе сравнения (28,80±2,76% и 22,06±1,93%, р<0,05; 17,38±4,87% и 1,08±0,46% соответственно, р<0,01).
Результаты иммуногистохимического исследования продемонстрировали положительное влияние проведенной терапии на процессы ангиогенеза, пролиферации и антикоагулянтной защиты в плацентарной ткани. Это позволяет патогенетически обосновать целесообразность применения дипиридамола и надропарина кальция у беременных с тромбофилией и невынашиванием.
Ключевые слова: маркеры ангиогенеза, невынашивание, тромбофилия, дипиридамол.
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The immunohistochemical study of angiogenesis, anticoagulative protection, cell death and proliferation in placental tissue in pregnant women with thrombophilia and pregnancy loss was carried out in the following research. The study included 142 pregnant women.
The study group included 56 pregnant women, who were, from the first trimester prescribed Curantyl® (dipyridamole) and Fraxiparine® (nadroparine) in order to correct the hemostatic disorders. As for the comparison group (consisting of 50 pregnant women), standard therapy aimed at the continuation of the pregnancy was carried out; the control group consisted of 36 pregnant women. A significantly lower incidence of pregnancy loss in the primary (3,57%) and the control group (0%) compared with the comparison group (18%; p<0,05) was revealed.
After correction of violations in blood coagulation system the annexin V expression area in syncytiotrophoblast and expression of vascular endothelial factor in the stroma and vascular endothelium of the villi were much higher than in the comparison group (28,80±2,76% and 22,06±1,93%, p<0,05; 17,38±4,87% and 1,08±0,46% respectively, p<0,01). These immunohistochemical studies have demonstrated the positive effects of the therapy on the angiogenesis process, proliferation and anticoagulant protection in placentic tissue. It enables us to justify the feasibility of dipyridamole and nadroparine in pregnant women with thrombophilia and pregnancy loss.
Key words: angiogenetic markers, miscarriage, thrombophilia, dipyridamole.
Полный текст
Список литературы
1. Аржанова О.Н., Шляхтенко Т.Н., Тышкевич О.В. Комплексная терапия плацентарной недостаточности у беременных с наличием в крови антифосфолипидных антител. Акушерство и гинекология. 2004; 6: 50–1.
2. Демидова Е.М. Привычный выкидыш (патогенез, акушерская тактика). Автореф. дис. … д-ра мед. наук. М., 1993.
3. Макацария А.Д., Бицадзе В.О. Тромбофилии и противотромботическая терапия в акушерской практике. М.: Триада-Х, 2003.
4. Репина М.А. и др. Наследственные нарушения системы гемостаза и беременность: методические рекомендации. Под ред. Э.К.Айламазяна. СПб.: Изд-во Н-Л, 2008.
5. Матвеева Т.Е., Бицадзе В.О., Баймурадова С.М. и др. Основные принципы ведения беременности у женщин с синдромом потери плода и тромбофилией в анамнезе. Акушерство и гинекология. 2003; 4: 26–30.
6. Сидельникова В.М., Кирющенков П.А., Ходжаева З.С. и др. Патогенетическое обоснование использования курантила в акушерстве. Акушерство и гинекология. 1999; 5: 52–4.
7. Савельева Г.М., Федорова М.В., Клименко П.А. и др. Плацентарная недостаточность. М.: Медицина, 1991.
8. Макацария А.Д. и др. Профилактика повторных осложнений беременности в условиях тромбофилии: руководство для врачей. М.: Триада-Х, 2008.
9. Радзинский В.Е., Оразмурадов А.А., Милованов А.П. Ранние сроки беременности. М.: МИА, 2005.
10. Сидельникова В.М. Невынашивание беременности – современный взгляд на проблему. Рос. вестн. акушера-гинеколога. 2007; 2: 62–4.
11. Сидельникова В.М., Милованов А.П., Кирющенков П.А. и др. Состояние фетоплацентарной системы при использовании курантила в комплексном лечении беременных с аутосенсибилизацией к хорионическому гонадотропину человека. Акушерство и гинекология. 2000; 6: 10–3.
12. Зайнулина М.С. и др. Тромбофилии в акушерской практике: учебно-методическое пособие. Под ред. Э.К.Айламазяна, Н.Н.Петрищева. СПб.: Изд-во Н-Л, 2005.
13. Dolitzky M, Inbal A, Segal Y et al. A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages. Fertil Steril 2006; 86 (2): 362–6.
14. Alonso A, Soto I, Urgellés MF et al. Acquired and inherited thrombophilia in women with unexplained fetal losses. Am J Obstet Gynecol 2002; 187 (5): 1337–42.
15. Johnny S et al. Activated protein C resistance and factor V Leiden mutation can be associated with first – as well as-second trimester recurrent pregnancy loss. Am J Reprod Immunol 2000; 43: 31–5.
16. Gris JC, Quéré I, Sanmarco M et al. Antiphospholipid and antiprotein syndromes in non-thrombotic, non-autoimmune women with unexplained recurrent primary early foetal loss. Thromb Haemost 2000; 84 (2): 228–36.
17. Grandone E et al. Antithrombotic prophylaxis during pregnancy in women with deficiency of natural anticoagulants. Blood Coagul Fibrinolysis 2008; 19 (3): 226–30.
18. Guan LX, Du XY, Wang JX et al. Association of genetic polymorphisms in plasminogen activator inhibitor-1 gene and 5, 10-methylenetetrahydrofolate reductase gene with recurrent early spontaneous abortion. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2005; 22 (3): 330–3.
19. Brenner B. Enoxaparin treatment improves the gestational outcome of pregnant women with thrombophilia and recurrent pregnancy loss: The LIVE-ENOX Study. Blood 2003; 102.
20. Brenner B, Kupferminc MJ. Inherited thrombophilia and poor pregnancy outcome. Best Pract Res Clin Obstet Gynaecol 2003; 17 (3): 427–39.
21. Deruelle P, Coulon C. The use of low-molecular-weight heparins in pregnancy – how safe are they? Curr Opin Obstet Gynecol 2007; 19 (6): 573–7.
22. Brenner B, Bar J, Ellis M et al. Effects of enoxaparin on late pregnancy complications and neonatal outcome in women with recurrent pregnancy loss and thrombophilia: results from the Live-Enox study. Fertil Steril 2005; 84 (3): 770–3.
23. Quenby S, Mountfield S, Cartwright JE et al. Effects of low molecular-weight and unfractionated heparin on trophoblast function. Obstet Gynecol 2004; 104: 354–61.
24. Santoro R, Iannaccaro P, Prejanò S et al. Efficacy and safety of the long-term administration of low-molecular-weight heparins in pregnancy. Blood Coagul Fibrinolysis 2009; 20 (4): 240–3.
25. Marzusch K, Ruck P, Horny HP et al. Expression of the p53 tumour suppressor gene in human placenta: an immunohistochemical study. Placenta 1995; 16 (1): 101–4.
26. Bulmer JN, Morrison L, Johnson PM. Expression of the proliferation markers Ki67 and transferring receptor by human trophoblast populations. J Reprod Immunol 1988; 14 (3): 291–302.
27. Edstrom CS, Calhoun DA, Christensen RD. Expression of tissue factor pathway inhibitor in human fetal and placental tissues. Early Hum Dev 2000; 59 (2): 77–84.
28. Rai R et al. Factor V Leiden and acquired activated protein C resistance among 1000 women with recurrent miscarriage. Hum Reprod 2001; 16 (5): 961–5.
29. Grandone E, Margaglione M, Colaizzo D et al. Factor V Leiden is associated with repeated and recurrent unexplained fetal losses. Thromb Haemost 1997; 77 (5): 822–4.
30. Greer IA. Antithrombotic Therapy for Recurrent Miscarriage? N Engl J Med 2010; 362: 1630–1.
31. F Hills A et al. Heparin prevents programmed cell death in human throphoblast. Mol Hum Reprod 2006; 12 (4): 237–43.
32. Haidacher S et al. Immunohistochemical evidence of p53 protein in human placenta and choriocarcinoma cell lines. Hum Reprod 1995; 10 (4): 983–8.
33. Kupferminc MJ et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340 (1): 9–13.
34. Di Simone N et al. Low molecular weight heparin actions on human endometrial angiogenesis. Thromb Research 2011; 127 (Suppl. 3): 125.
35. Badawy AM et al. Low-molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology. J Obstet Gynaecol 2008; 28 (3): 280–4.
36. Sambrook J et al. Molecular cloning: A Laboratory Manual. Cold Spring Harbor Laboratory Press 1989; p. 1659.
37. Martinelli I et al. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med 2000; 343 (14): 1015–8.
38. Nelson SM, Greer IA. The potential role of heparin in assisted conception. Hum Reprod Update 2008; 14 (6): 623–45.
39. Pabinger I. Thrombophilia and its impact on pregnancy. Thromb Res 2009; 123 (Suppl. 3): 16–21.
40. Sebire NJ et al. Placental massive perivillous fibrin deposition associated with antiphospholipid antibody syndrome. Br J Obstet Gynaecol 2002; 109 (5): 570–3.
41. Sebire NJ et al. Placental pathology, antiphospholipid antibodies, and pregnancy outcome in recurrent miscarriage patients. Obstet Gynecol 2003; 101: 258–63.
42. Dossenbach-Glaninger A et al. Plasminogen Activator Inhibitor 1 4G/5G Polymorphism and Coagulation Factor XIII Val34Leu Polymorphism: Impaired Fibrinolysis and Early Pregnancy Loss. Clinical Chemistry 2003; 49 (7): 1081–6.
43. Isermann B et al. Platelet activation impairs placental function. Thromb Res 2009; 123 (Suppl. 2): 85–7.
44. Sato Y et al. Platelet-derived soluble factors induce human extravillous trophoblast migration and differentiation: platelets are a possible regulator of trophoblast infiltration into maternal spiral arteries. Blood 2005; 106 (2): 428–35.
45. Aarabi M et al. Polymorphisms of plasminogen activator inhibitor-1, angiotensin converting enzyme and coagulation factor XIII genes in patients with recurrent spontaneous abortion. J Matern Fetal Neonatal Med 2010; 24 (3): 545–8.
46. Rai R et al. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997; 314 (7076): 728–36.
47. Bdolah Y et al. Recent advances in understanding preeclampsia. Croat Med J 2005; 46 (5): 728–36.
48. Toth B et al. Recurrent miscarriage: current concepts in diagnosis and treatment. J Reprod Immunol 2010; 85 (1): 23–32.
49. Folkeringa N et al. Reduction of high fetal loss rate by anticoagulant treatment during pregnancy in antithrombin, protein C or protein S deficient women. Haematol 2007; 136 (4): 656–61.
50. Gris JC et al. Respective evaluation of the prevalence of haemostasis abnormalities in unexplained primary early recurrent miscarriages. The Nimes Obstetricians and Haematologists (NOHA) Study. Thromb Haemost 1997; 77 (6): 1096–103.
51. Sood R. Thrombophilia and fetal loss: Lessons from gene targeting in mice. Thromb Res 2009; 123 (Suppl. 2): 79–84.
52. Deligiannidis A et al. Thrombophilia and antithrombotic therapy in women with recurrent spontaneous abortions. J Reprod Med 2007; 52 (6): 499–502.
53. J Park S et al. Vascular endothelial growth factor, fms-like tyrosine kinase-1 (Flt-1) and soluble Flt-1 gene expressions in Korean pre-eclamptic placentas. J Obstet Gynaecol Res 2010; 36 (4): 726–32.
54. Zhou Q et al. VEGF deficit is involved in endothelium dysfunction in preeclampsia. J Huazhong Univ Sci Technol (Med Sci) 2010; 30 (3): 370–4.
55. Widdows K. Gestational related morphological abnormalities in placental villous trophoblast turnover in compromised pregnancies. Brunel University, Uxbridge 2004.
2. Демидова Е.М. Привычный выкидыш (патогенез, акушерская тактика). Автореф. дис. … д-ра мед. наук. М., 1993.
3. Макацария А.Д., Бицадзе В.О. Тромбофилии и противотромботическая терапия в акушерской практике. М.: Триада-Х, 2003.
4. Репина М.А. и др. Наследственные нарушения системы гемостаза и беременность: методические рекомендации. Под ред. Э.К.Айламазяна. СПб.: Изд-во Н-Л, 2008.
5. Матвеева Т.Е., Бицадзе В.О., Баймурадова С.М. и др. Основные принципы ведения беременности у женщин с синдромом потери плода и тромбофилией в анамнезе. Акушерство и гинекология. 2003; 4: 26–30.
6. Сидельникова В.М., Кирющенков П.А., Ходжаева З.С. и др. Патогенетическое обоснование использования курантила в акушерстве. Акушерство и гинекология. 1999; 5: 52–4.
7. Савельева Г.М., Федорова М.В., Клименко П.А. и др. Плацентарная недостаточность. М.: Медицина, 1991.
8. Макацария А.Д. и др. Профилактика повторных осложнений беременности в условиях тромбофилии: руководство для врачей. М.: Триада-Х, 2008.
9. Радзинский В.Е., Оразмурадов А.А., Милованов А.П. Ранние сроки беременности. М.: МИА, 2005.
10. Сидельникова В.М. Невынашивание беременности – современный взгляд на проблему. Рос. вестн. акушера-гинеколога. 2007; 2: 62–4.
11. Сидельникова В.М., Милованов А.П., Кирющенков П.А. и др. Состояние фетоплацентарной системы при использовании курантила в комплексном лечении беременных с аутосенсибилизацией к хорионическому гонадотропину человека. Акушерство и гинекология. 2000; 6: 10–3.
12. Зайнулина М.С. и др. Тромбофилии в акушерской практике: учебно-методическое пособие. Под ред. Э.К.Айламазяна, Н.Н.Петрищева. СПб.: Изд-во Н-Л, 2005.
13. Dolitzky M, Inbal A, Segal Y et al. A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages. Fertil Steril 2006; 86 (2): 362–6.
14. Alonso A, Soto I, Urgellés MF et al. Acquired and inherited thrombophilia in women with unexplained fetal losses. Am J Obstet Gynecol 2002; 187 (5): 1337–42.
15. Johnny S et al. Activated protein C resistance and factor V Leiden mutation can be associated with first – as well as-second trimester recurrent pregnancy loss. Am J Reprod Immunol 2000; 43: 31–5.
16. Gris JC, Quéré I, Sanmarco M et al. Antiphospholipid and antiprotein syndromes in non-thrombotic, non-autoimmune women with unexplained recurrent primary early foetal loss. Thromb Haemost 2000; 84 (2): 228–36.
17. Grandone E et al. Antithrombotic prophylaxis during pregnancy in women with deficiency of natural anticoagulants. Blood Coagul Fibrinolysis 2008; 19 (3): 226–30.
18. Guan LX, Du XY, Wang JX et al. Association of genetic polymorphisms in plasminogen activator inhibitor-1 gene and 5, 10-methylenetetrahydrofolate reductase gene with recurrent early spontaneous abortion. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2005; 22 (3): 330–3.
19. Brenner B. Enoxaparin treatment improves the gestational outcome of pregnant women with thrombophilia and recurrent pregnancy loss: The LIVE-ENOX Study. Blood 2003; 102.
20. Brenner B, Kupferminc MJ. Inherited thrombophilia and poor pregnancy outcome. Best Pract Res Clin Obstet Gynaecol 2003; 17 (3): 427–39.
21. Deruelle P, Coulon C. The use of low-molecular-weight heparins in pregnancy – how safe are they? Curr Opin Obstet Gynecol 2007; 19 (6): 573–7.
22. Brenner B, Bar J, Ellis M et al. Effects of enoxaparin on late pregnancy complications and neonatal outcome in women with recurrent pregnancy loss and thrombophilia: results from the Live-Enox study. Fertil Steril 2005; 84 (3): 770–3.
23. Quenby S, Mountfield S, Cartwright JE et al. Effects of low molecular-weight and unfractionated heparin on trophoblast function. Obstet Gynecol 2004; 104: 354–61.
24. Santoro R, Iannaccaro P, Prejanò S et al. Efficacy and safety of the long-term administration of low-molecular-weight heparins in pregnancy. Blood Coagul Fibrinolysis 2009; 20 (4): 240–3.
25. Marzusch K, Ruck P, Horny HP et al. Expression of the p53 tumour suppressor gene in human placenta: an immunohistochemical study. Placenta 1995; 16 (1): 101–4.
26. Bulmer JN, Morrison L, Johnson PM. Expression of the proliferation markers Ki67 and transferring receptor by human trophoblast populations. J Reprod Immunol 1988; 14 (3): 291–302.
27. Edstrom CS, Calhoun DA, Christensen RD. Expression of tissue factor pathway inhibitor in human fetal and placental tissues. Early Hum Dev 2000; 59 (2): 77–84.
28. Rai R et al. Factor V Leiden and acquired activated protein C resistance among 1000 women with recurrent miscarriage. Hum Reprod 2001; 16 (5): 961–5.
29. Grandone E, Margaglione M, Colaizzo D et al. Factor V Leiden is associated with repeated and recurrent unexplained fetal losses. Thromb Haemost 1997; 77 (5): 822–4.
30. Greer IA. Antithrombotic Therapy for Recurrent Miscarriage? N Engl J Med 2010; 362: 1630–1.
31. F Hills A et al. Heparin prevents programmed cell death in human throphoblast. Mol Hum Reprod 2006; 12 (4): 237–43.
32. Haidacher S et al. Immunohistochemical evidence of p53 protein in human placenta and choriocarcinoma cell lines. Hum Reprod 1995; 10 (4): 983–8.
33. Kupferminc MJ et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340 (1): 9–13.
34. Di Simone N et al. Low molecular weight heparin actions on human endometrial angiogenesis. Thromb Research 2011; 127 (Suppl. 3): 125.
35. Badawy AM et al. Low-molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology. J Obstet Gynaecol 2008; 28 (3): 280–4.
36. Sambrook J et al. Molecular cloning: A Laboratory Manual. Cold Spring Harbor Laboratory Press 1989; p. 1659.
37. Martinelli I et al. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med 2000; 343 (14): 1015–8.
38. Nelson SM, Greer IA. The potential role of heparin in assisted conception. Hum Reprod Update 2008; 14 (6): 623–45.
39. Pabinger I. Thrombophilia and its impact on pregnancy. Thromb Res 2009; 123 (Suppl. 3): 16–21.
40. Sebire NJ et al. Placental massive perivillous fibrin deposition associated with antiphospholipid antibody syndrome. Br J Obstet Gynaecol 2002; 109 (5): 570–3.
41. Sebire NJ et al. Placental pathology, antiphospholipid antibodies, and pregnancy outcome in recurrent miscarriage patients. Obstet Gynecol 2003; 101: 258–63.
42. Dossenbach-Glaninger A et al. Plasminogen Activator Inhibitor 1 4G/5G Polymorphism and Coagulation Factor XIII Val34Leu Polymorphism: Impaired Fibrinolysis and Early Pregnancy Loss. Clinical Chemistry 2003; 49 (7): 1081–6.
43. Isermann B et al. Platelet activation impairs placental function. Thromb Res 2009; 123 (Suppl. 2): 85–7.
44. Sato Y et al. Platelet-derived soluble factors induce human extravillous trophoblast migration and differentiation: platelets are a possible regulator of trophoblast infiltration into maternal spiral arteries. Blood 2005; 106 (2): 428–35.
45. Aarabi M et al. Polymorphisms of plasminogen activator inhibitor-1, angiotensin converting enzyme and coagulation factor XIII genes in patients with recurrent spontaneous abortion. J Matern Fetal Neonatal Med 2010; 24 (3): 545–8.
46. Rai R et al. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997; 314 (7076): 728–36.
47. Bdolah Y et al. Recent advances in understanding preeclampsia. Croat Med J 2005; 46 (5): 728–36.
48. Toth B et al. Recurrent miscarriage: current concepts in diagnosis and treatment. J Reprod Immunol 2010; 85 (1): 23–32.
49. Folkeringa N et al. Reduction of high fetal loss rate by anticoagulant treatment during pregnancy in antithrombin, protein C or protein S deficient women. Haematol 2007; 136 (4): 656–61.
50. Gris JC et al. Respective evaluation of the prevalence of haemostasis abnormalities in unexplained primary early recurrent miscarriages. The Nimes Obstetricians and Haematologists (NOHA) Study. Thromb Haemost 1997; 77 (6): 1096–103.
51. Sood R. Thrombophilia and fetal loss: Lessons from gene targeting in mice. Thromb Res 2009; 123 (Suppl. 2): 79–84.
52. Deligiannidis A et al. Thrombophilia and antithrombotic therapy in women with recurrent spontaneous abortions. J Reprod Med 2007; 52 (6): 499–502.
53. J Park S et al. Vascular endothelial growth factor, fms-like tyrosine kinase-1 (Flt-1) and soluble Flt-1 gene expressions in Korean pre-eclamptic placentas. J Obstet Gynaecol Res 2010; 36 (4): 726–32.
54. Zhou Q et al. VEGF deficit is involved in endothelium dysfunction in preeclampsia. J Huazhong Univ Sci Technol (Med Sci) 2010; 30 (3): 370–4.
55. Widdows K. Gestational related morphological abnormalities in placental villous trophoblast turnover in compromised pregnancies. Brunel University, Uxbridge 2004.
________________________________________________
1. Аржанова О.Н., Шляхтенко Т.Н., Тышкевич О.В. Комплексная терапия плацентарной недостаточности у беременных с наличием в крови антифосфолипидных антител. Акушерство и гинекология. 2004; 6: 50–1.
2. Демидова Е.М. Привычный выкидыш (патогенез, акушерская тактика). Автореф. дис. … д-ра мед. наук. М., 1993.
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Авторы
Е.А.Корнюшина, М.С.Зайнулина, И.Н.Костючек, М.А.Клещев
ФГБУ Научно-исследовательский институт акушерства и гинекологии им. Д.О.Отта
Северо-Западного отделения РАМН, Санкт-Петербург
ФГБУ Научно-исследовательский институт акушерства и гинекологии им. Д.О.Отта
Северо-Западного отделения РАМН, Санкт-Петербург
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E.A.Kornyushina, M.S.Zaynulina, I.N.Kostyuchek, M.A.Kleschev
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