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Ацетилсалициловая кислота как единственный медикаментозный метод профилактики преэклампсии
© ООО «КОНСИЛИУМ МЕДИКУМ», 2023 г.
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Kravtsova OM, Kuznetsov PA, Dzhokhadze LS, Dobrokhotova YuE, Zatevalov AM. Acetylsalicylic acid as the only pharmacological method for the prevention of preeclampsia: A retrospective study. Gynecology. 2023;25(2):239–244. DOI: 10.26442/20795696.2023.2.202231
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Цель. Оценить эффективность АСК и таких лекарственных препаратов, как НМГ, дипиридамол и препаратов крови крупного рогатого скота (Актовегин), у российской популяции беременных в группе высокого риска в качестве профилактики ПЭ.
Материалы и методы. В исследование включены 244 пациентки. Работа проводилась с архивными историями родов 103 пациенток с диагнозом «тяжелая ПЭ», родоразрешенных в 2019 г. в Перинатальном центре ГБУЗ «ГКБ №24», и также рассмотрена 141 беременная из Женской консультации №3 при ГБУЗ «ГКБ им. В.В. Вересаева», где по результатам расширенного комбинированного скрининга I триместра беременности риск ПЭ оценен как высокий. При этом 89 беременным АСК назначена в дозе 75 мг, 54 – в дозе 150 мг. Кроме того, 22 пациентки получали НМГ, 6 – дипиридамол, 3 – Актовегин. Для оценки эффективности приема АСК и других препаратов в качестве профилактики ПЭ в указанных выше группах риска подсчитаны абсолютные риски, отношение рисков и их статистическая значимость при приеме лекарственных средств в каждой из групп риска.
Результаты. Полученная обратная корреляция слабой силы (r=-0,31) между степенью тяжести ПЭ при родоразрешении и дозой АСК указывает на то, что увеличение дозы АСК сопровождается снижением степени тяжести ПЭ. Эффективность сочетаний различных препаратов для профилактики ПЭ исследовали с помощью анализа факторных соответствий. Двумерное шкалирование наиболее вероятных сочетаний показало, что в группе высокого риска, где в итоге ПЭ не развилась, большинство пациенток получали АСК. Дополнительное применение НМГ, дипиридамола и Актовегина не снижает риск развития ПЭ.
Заключение. АСК является единственным медикаментозным методом профилактики ПЭ в группах высокого риска. При этом с увеличением дозы АСК снижается степень тяжести ПЭ.
Ключевые слова: беременность, ацетилсалициловая кислота, преэклампсия
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Background. Preeclampsia (PE) complicates 2–8% of pregnancies worldwide, negatively impacting the pregnant woman and the fetus. Therefore, its prevention remains relevant. It is believed that the cause of PE, especially early PE, is a placentation disorder. It warrants studying drugs that can improve placenta development. The leadership in this matter is maintained by acetylsalicylic acid, which, according to the ASPRE study, reduced the incidence of PE at 34 weeks of pregnancy by 82%. The use of low molecular weight heparins (LMWH), dipyridamole, and antioxidants for PE prevention remains controversial and continues to be studied by foreign and Russian scientists.
Aim. To assess the efficacy of acetylsalicylic acid, LMWH, dipyridamole (Curantyl), and bovine blood derivates (Actovegin) in the Russian population of pregnant women at high risk for PE prevention.
Materials and methods. The study included 244 patients. We reviewed the archived case records of 103 patients diagnosed with severe PE, who delivered in 2019 at the State Clinical Hospital №24, and 141 pregnant women fr om the Maternity clinic №3 at the Veresaev Moscow State Clinical Hospital, wh ere the risk of PE was assessed as high, according to the results of extended combined screening of the first trimester of pregnancy. Eighty-nine pregnant women received acetylsalicylic acid at a dose of 75 mg and 54 at a dose of 150 mg. In addition, 22 patients received LMWH, 6 – dipyridamole, and 3 – Actovegin. The absolute risks, the risk ratio, and statistical significance when taking drugs in each risk group were calculated to assess the efficacy of acetylsalicylic acid and other drugs for PE prevention in the above risk groups.
Results. The resulting weak inverse correlation (r=-0.31) between the PE severity at delivery and the dose of acetylsalicylic acid indicates that an increase in the acetylsalicylic acid dose was associated with a decrease in the PE severity. The effectiveness of combinations of various drugs for PE prevention was assessed by analyzing factor correspondences. Two-dimensional scaling of the most likely combinations showed that most patients received acetylsalicylic acid in the high-risk group with no PE. Additional use of LMWH, Curantyl, and Actovegin did not reduce the risk of PE.
Conclusion. Acetylsalicylic acid is the only pharmaceutical method for preventing PE in high-risk groups. Higher doses of acetylsalicylic acid are associated with lower PE severity.
Keywords: pregnancy, acetylsalicylic acid, preeclampsia
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3. Smith SD, Dunk CE, Aplin JD. Evidence for immune cell involvement in decidual spiral arteriole remodeling in early human pregnancy. Am J Pathol. 2009;174(5):1959-7. DOI:10.2353/ajpath.2009.080995
4. Brosens I, Pijnenborg R, Vercruysse L, Romero R. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am J Obstet Gynecol. 2011;204(3):193-201. DOI:10.1016/j.ajog.2010.08.009
5. Falco ML, Sivanathan J, Laoreti A, et al. Placental histopathology associated with pre-eclampsia: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2017;50(3):295-301. DOI:10.1002/uog.17494
6. Tan MY, Syngelaki A, Poon LC, et al. Screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks' gestation. Ultrasound Obstet Gynecol. 2018;52(2):186-95. DOI:10.1002/uog.19112
7. Burton GJ, Redman CW, Roberts J M, et al. Pre-eclampsia: pathophysiology and clinical implications. BMJ. 2019;366:l2381. DOI:10.1136/bmj.l2381
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10. Dipietro L, Evenson KR, Bloodgood B, et al. Benefits of Physical Activity during Pregnancy and Postpartum. Med Sci Sports Exerc. 2019;51(6):1292-302. DOI:10.1249/mss.0000000000001941
11. Marchi J, Berg M, Dencker A, et al. Risks associated with obesity in pregnancy, for the mother and baby: a systematic review of reviews. Obes Rev. 2019;16(8):621-38. DOI:10.1111/obr.12288
12. Rolnik DL, Wright D, Poon LC, et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med. 2017;377(7):613-22. DOI:10.1056/NEJMoa1704559
13. Raikwar NS, Santillan MK, Santillan DA, et al. Aspirin inhibits expression of sFLT1 from human cytotrophoblasts induced by hypoxia, via cyclo-oxygenase 1. Placenta. 2015;36(4):446-53. DOI:10.1016/j.placenta.2015.01.004
14. Relman AS. Aspirin for the primary prevention of myocardial infarction. N Engl J Med. 1988;318:245-6. DOI:10.1056/NEJM198801283180410
15. Hofmeyr GJ, Belizán JM, von Dadelszen P. Calcium and Preeclampsia (CAP) Study Group. Low-dose calcium supplementation for preventing pre-eclampsia: a systematic review and commentary. BJOG. 2014;121(08):951-7. DOI:10.1111/1471-0528.12613
16. ACOG. Practice Bulletin No. 203: chronic hypertension in pregnancy. Obstet Gynecol. 2019;133(1):e26-50. DOI:10.1097/AOG.0000000000003020
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19. Kingdom JCP, Drewlo S. Is heparin a placental anticoagulant in high-risk pregnancies? Blood. 2011;118(18):4780-8. DOI:10.1182/blood-2011-07-319749
20. Grandone E, Brancaccio V, Colaizzo D, et al. Preventing adverse obstetric outcomes in women with genetic thrombophilia. Fertil Steril. 2002;78(2):371-5.
DOI:10.1016/s0015-0282(02)03222-3
21. Llurba E, Bella M, Burgos J, et al. Early prophylactic enoxaparin for the prevention of preeclampsia and intrauterine growth restriction: a randomized trial. Fetal Diagn Ther. 2020;47(11):824-33. DOI:10.1159/000509662
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24. Uzan S, Beaufils M, Bazin B, et al. Idiopathic recurrent fetal growth retardation and aspirin-dipyridamole therapy. Am J Obstet Gynecol. 1989;160(3):763.
DOI:10.1016/s0002-9378(89)80079-1
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26. Tenório MB, Ferreira RC, Moura FA, et al. Oral antioxidant therapy for prevention and treatment of preeclampsia: Meta-analysis of randomized controlled trials. Nutr Metab Cardiovasc Dis. 2018;28(9):865-76. DOI:10.1016/j.numecd.2018.06.002
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1. ACOG. Gestational Hypertension and Preeclampsia. Obstet Gynecol. 2020;135(6):1492-5. DOI:10.1097/aog.0000000000003892
2. Poon LC, Shennan A, Hyett, et al. The International Federation of Gynecology and Obstetrics (FIGO) initiative on pre-eclampsia: A pragmatic guide for first-trimester screening and prevention. Int J Gynecol Obstet. 2019;145(S1):1-33. DOI:10.1002/ijgo.12802
3. Smith SD, Dunk CE, Aplin JD. Evidence for immune cell involvement in decidual spiral arteriole remodeling in early human pregnancy. Am J Pathol. 2009;174(5):1959-7. DOI:10.2353/ajpath.2009.080995
4. Brosens I, Pijnenborg R, Vercruysse L, Romero R. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am J Obstet Gynecol. 2011;204(3):193-201. DOI:10.1016/j.ajog.2010.08.009
5. Falco ML, Sivanathan J, Laoreti A, et al. Placental histopathology associated with pre-eclampsia: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2017;50(3):295-301. DOI:10.1002/uog.17494
6. Tan MY, Syngelaki A, Poon LC, et al. Screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks' gestation. Ultrasound Obstet Gynecol. 2018;52(2):186-95. DOI:10.1002/uog.19112
7. Burton GJ, Redman CW, Roberts J M, et al. Pre-eclampsia: pathophysiology and clinical implications. BMJ. 2019;366:l2381. DOI:10.1136/bmj.l2381
8. Kuznetsov PA, Dzhokhadze LS, Shamugiya VV, et al. Acetylsalicylic acid to prevent preeclampsia and its complications. State-of-the-art of risk groups. Russian Journal of Woman and Child Health. 2022;5(1):28-34 (in Russian). DOI:10.32364/2618-8430-2022-5-1-28-34
9. Morales-Prieto DM, Fuentes-Zacarías P, Murrieta-Coxca JM, et al. Smoking for two- effects of tobacco consumption on placenta. Mol Aspects Med. 2022;87:101023. DOI:10.1016/j.mam.2021.101023
10. Dipietro L, Evenson KR, Bloodgood B, et al. Benefits of Physical Activity during Pregnancy and Postpartum. Med Sci Sports Exerc. 2019;51(6):1292-302. DOI:10.1249/mss.0000000000001941
11. Marchi J, Berg M, Dencker A, et al. Risks associated with obesity in pregnancy, for the mother and baby: a systematic review of reviews. Obes Rev. 2019;16(8):621-38. DOI:10.1111/obr.12288
12. Rolnik DL, Wright D, Poon LC, et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med. 2017;377(7):613-22. DOI:10.1056/NEJMoa1704559
13. Raikwar NS, Santillan MK, Santillan DA, et al. Aspirin inhibits expression of sFLT1 from human cytotrophoblasts induced by hypoxia, via cyclo-oxygenase 1. Placenta. 2015;36(4):446-53. DOI:10.1016/j.placenta.2015.01.004
14. Relman AS. Aspirin for the primary prevention of myocardial infarction. N Engl J Med. 1988;318:245-6. DOI:10.1056/NEJM198801283180410
15. Hofmeyr GJ, Belizán JM, von Dadelszen P. Calcium and Preeclampsia (CAP) Study Group. Low-dose calcium supplementation for preventing pre-eclampsia: a systematic review and commentary. BJOG. 2014;121(08):951-7. DOI:10.1111/1471-0528.12613
16. ACOG. Practice Bulletin No. 203: chronic hypertension in pregnancy. Obstet Gynecol. 2019;133(1):e26-50. DOI:10.1097/AOG.0000000000003020
17. ROAG, AAR, AAAR. Klinicheskiie rekomendatsii. Preeklampsiia. Eklampsiia. Oteki, proteinuriia i gipertenzivnyie rasstroistva vo vremia beremennosti, v rodakh i poslerodovom periode. Moscow, 2021 (in Russian).
18. Cruz-Lemini M, Vázquez JC, Ullmo J, et al. Low-molecular-weight heparin for prevention of preeclampsia and other placenta-mediated complications: a systematic review and meta-analysis. Am J Obstet Gynecol. 2022;226(2S):S1126-44.e17. DOI:10.1016/j.ajog.2020.11.006
19. Kingdom JCP, Drewlo S. Is heparin a placental anticoagulant in high-risk pregnancies? Blood. 2011;118(18):4780-8. DOI:10.1182/blood-2011-07-319749
20. Grandone E, Brancaccio V, Colaizzo D, et al. Preventing adverse obstetric outcomes in women with genetic thrombophilia. Fertil Steril. 2002;78(2):371-5.
DOI:10.1016/s0015-0282(02)03222-3
21. Llurba E, Bella M, Burgos J, et al. Early prophylactic enoxaparin for the prevention of preeclampsia and intrauterine growth restriction: a randomized trial. Fetal Diagn Ther. 2020;47(11):824-33. DOI:10.1159/000509662
22. Groom KM, McCowan LM, Mackay LK, et al. Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a history: a randomized trial. Am J Obstet Gynecol. 2017;216(3):296.e1-14. DOI:10.1016/j.ajog.2017.01.014
23. Cruz-Lemini M, Vázquez JC, Ullmo J, et al. Low-molecular-weight heparin for prevention of preeclampsia and other placenta-mediated complications: a systematic review and meta-analysis. Am J Obstet Gynecol. 2022;226(2S):S1126-44.e17. DOI:10.1016/j.ajog.2020.11.006
24. Uzan S, Beaufils M, Bazin B, et al. Idiopathic recurrent fetal growth retardation and aspirin-dipyridamole therapy. Am J Obstet Gynecol. 1989;160(3):763.
DOI:10.1016/s0002-9378(89)80079-1
25. Askie LM, Duley L, Henderson-Smart DJ, et al. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007;369(9575):1791-8. DOI:10.1016/s0140-6736(07)60712-0
26. Tenório MB, Ferreira RC, Moura FA, et al. Oral antioxidant therapy for prevention and treatment of preeclampsia: Meta-analysis of randomized controlled trials. Nutr Metab Cardiovasc Dis. 2018;28(9):865-76. DOI:10.1016/j.numecd.2018.06.002
27. Urbach VIu. Statisticheskii analiz v biologicheskikh i meditsinskikh issledovaniiakh Moscow: Meditsina, 1975 (in Russian).
1 ФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России, Москва, Россия;
2 ГБУЗ «Государственная клиническая больница №67 им. Л.А. Ворохобова» Департамента здравоохранения г. Москвы, Москва, Россия;
3 ГБУЗ «Московский многопрофильный клинический центр “Коммунарка”» Департамента здравоохранения г. Москвы, Москва, Россия;
4 ФБУН «Московский научно-исследовательский институт эпидемиологии и микробиологии им. Г.Н. Габричевского» Роспотребнадзора, Москва, Россия
*seliverstova.o.m@gmail.com
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Olga M. Kravtsova*1,2, Pavel A. Kuznetsov1, Lela S. Dzhokhadze1,3, Yulia E. Dobrokhotova1, Aleksandr M. Zatevalov4
1 Pirogov Russian National Research Medical University, Moscow, Russia;
2 Vorokhobov City Clinical Hospital №67, Moscow, Russia;
3 Moscow Multidisciplinary Clinical Center "Kommunarka", Moscow, Russia;
4 Gabrichevsky Moscow Research Institute of Epidemiology and Microbiology, Moscow, Russia
*seliverstova.o.m@gmail.com