Prophylaxis and management of venous thromboembolism during pregnancy and postpartum period

Introduction. Venous thromboembolism (VTE) is one of the lead causes for maternal mortality and morbidity during pregnancy in the majority of developed countries. The incidence rate of VTE per pregnancy-year increases during pregnancy and postpartum period about by 4-fold and at least 14-fold, respectively.

Aim: to analyze and summarize current view on risk factors of thrombotic events during gestation and to discuss recent guidelines for the management of venous thromboembolic complications during pregnancy and postpartum, by taking into account a balance between risks and benefits of using anticoagulants.

Materials and Methods. The literature search covering the last 10 years was carried out in the electronic scientific databases RSCI, PubMed/MEDLINE, and Embase. While formulating a search strategy for evidence-based information, the PICO method (P = Patient; I = Intervention; C = Comparison; O = Outcome) and the key terms “venous thromboembolism” and “pregnancy” were used.

Results. Risk factors were found to include a personal history of VTE, verified inherited or acquired thrombophilia, a family history of VTE and general medical conditions, such as immobilization, overweight, varicose veins, some hematological diseases and autoimmune disorders. VTE is considered being potentially preventable upon prophylactic administration of anticoagulants, but no high confidence randomized clinical trials comparing diverse strategies of thromboprophylaxis in pregnant women have been proposed so far. Because heparins do not cross the placenta, weight-adjusted therapeutic-dose low molecular weight heparins (LMWH) represent the anticoagulant treatment of choice for VTE during pregnancy. Once- and twice-daily dosing regimens are acceptable. However, no evidence suggesting benefits for measurement of factor Xa activities and consecutive LMWH dose adjustments to improve clinical outcomes are available. In case of uncomplicated pregnancy-related VTE, no routine administration of vitamin K antagonists, direct thrombin or factor Xa inhibitors, fondaparinux, or danaparoid is recommended. Lactating women may switch from applying LMWH to warfarin. Anticoagulation therapy should be continued for 6 weeks postpartum with total duration lasting at least for 3 months.

Conclusion. VTE is a challenging task in pregnant women expecting to apply a multi-faceted approach for its efficient solution by taking into account updated recommendations and personalized patient-oriented features.

1. Pregnancy Mortality Surveillance System. Center for Disease Control and Prevention, 2019. Available at: https://www.cdc.gov/reproductive health/ maternal-mortality/pregnancy-mortalitysurveillance-system.htm.

2. Creanga A.A., Syverson C., Seed K., Callaghan W.M. Pregnancy-related mortality in the United States, 2011–2013. Obstet Gynecol. 2017;130(2):366–73. https://doi.org/10.1097/AOG.0000000000002114.

3. Nichols K.M., Henkin S., Creager M.A. Venous thromboembolism associated with pregnancy: JACC Focus Seminar. J Am Coll Cardiol. 2020;76(18):2128–41. https://doi.org/10.1016/j.jacc.2020.06.090.

4. James A.H. Venous thromboembolism in pregnancy. Arterioscler Thromb Vasc Biol. 2009;29(3):326–31. https://doi.org/10.1161/ATVBAHA.109.184127.

5. Lussana F., Coppens M., Cattaneo M., Middeldorp S. Pregnancy-related venous thromboembolism: risk and the effect of thromboprophylaxis. Thromb Res. 2012;129(6):673–80. https://doi.org/10.1016/j.thromres.2012.01..017

6. Macklon N.S., Greer I.A., Bowman A.W. An ultrasound study of gestational and postural changes in the deep venous system of the leg in pregnancy. Br J Obstet Gynaecol. 1997;104(2):191–7. https://doi.org/10.1111/j.1471-0528.1997.tb11043.x.

7. Romanova I.S., Kozhanova I.N., Gavrilenko L.N., Sachek M.M. Safe use of anticoagulants in pregnancy (based on publications study purpose of doctors and recommendations under evidence-based medicine). [Bezopasnost' primeneniya antikoagulyantov v period beremennosti (real'naya praktika naznacheniya vrachej i rekomendacii v sootvetstvii s principami dokazatel'noj mediciny)]. Recept. 2013;(5):63–74. (In Russ.).

8. Schardt C., Adams M.B., Owens T. et al. Utilization of the PICO framework to improve searching PubMed for clinical questions. BMC Med Inform Decis Mak. 2007;7(1):16. https://doi.org/10.1186/1472-6947-7-16.

9. Kourlaba G., Relakis J., Kontodimas S. et al. A systematic review and metaanalysis of the epidemiology and burden of venous thromboembolism among pregnant women. Int J Gynaecol Obstet. 2016;132(1):4–10. https://doi.org/10.1016/j.ijgo.2015.06.054.

10. Dulaeva E.V., Sibryaeva V.A., Novikova S.V. et al. Successful spontaneous delivery of a patient with floating thrombosis during pregnancy. [Uspeshnoe samoproizvol'noe rodorazreshenie pacientki s flotiruyushchim trombozom vo vremya beremennosti]. Rossijskij vestnik akusheraginekologa. 2020;20(6):86–9. (In Russ.). https://doi.org/10.17116/rosakush20202006186.

11. Konstantinides S.V., Meyer G., Becattini C. et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020;41(4):543–603. https://doi.org/10.1093/eurheartj/ehz405.

12. Virkus R.A., Lokkegaard E.C., Bergholt T. et al. Venous thromboembolism in pregnant and puerperal women in Denmark 1995–2005. A national cohort study. Thromb Haemost. 2011;106(2):304–9. https://doi.org/10.1160/TH10-12-0823.

13. Middeldorp S., Ganzevoort W. How I treat venous thromboembolism in pregnancy. Blood. 2020;136(19):2133–42. https://doi.org/10.1182/blood.2019000963.

14. Petersen J.F., Bergholt T., Nielsen A.K. et al. Combined hormonal contraception and risk of venous thromboembolism within the first year following pregnancy. Danish nationwide historical cohort 1995–2009. Thromb Haemost. 2014;112(1):73–8. https://doi.org/10.1160/TH13-09-0797.

15. Liu N., Vigod S.N., Farrugia M.M. et al. Venous thromboembolism after induced abortion: a population-based, propensity-score matched cohort study in Canada. Lancet Haematol. 2018;5(7):e279–e288. https://doi.org/10.1016/S2352-3026(18)30069-3.

16. Chan W.S., Spencer F.A., Ginsbergm J.S. Anatomic distribution of deep vein thrombosis in pregnancy. CMAJ. 2010;182(7):657–60. https://doi.org/10.1503/cmaj.091692.

17. Sultan A.A., West J., Tata L.J. et al. Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study. Br J Haematol. 2012;156(3):366–73. https://doi.org/10.1111/j.1365-2141.2011.08956.x.

18. Rodger M. Pregnancy and venous thromboembolism: ’TIPPS’ for risk stratification. Hematology Am Soc Hematol Educ Program. 2014;2014(1):387–92. https://doi.org/10.1182/asheducation-2014.1.387.

19. Villani M., Dentali F., Colaizzo D. et al. Pregnancy-related venous thrombosis: comparison between spontaneous and ART conception in an Italian cohort. BMJ Open. 2015;5(10):e008213. https://doi.org/10.1136/bmjopen-2015-008213.

20. O'Shaughnessy F., O'Reilly D., Ní Áinle F. Current opinion and emerging trends on the treatment, diagnosis and prevention of pregnancy-associated venous thromboembolic disease: a review. Transl Res. 2020;225:20–32. https://doi.org/10.1016/j.trsl.2020.06.004.

21. Parunov L.A., Soshitova N.P., Ovanesov M.V. et al. Epidemiology of venous thromboembolism (VTE) associated with pregnancy. Birth Defects Res C Embryo Today. 2015;105(3):167–84. https://doi.org/10.1002/bdrc.21105.

22. Di Prima F.A., Valenti O., Hyseni E. et al. Antiphospholipid Syndrome during pregnancy: the state of the art. J Prenat Med. 2011;5(2):41–53.

23. ACOG Practice Bulletin No. 196: Thromboembolism in pregnancy. American College of Obstetricians and Gynecologists' Committee on Practice Bulletins – Obstetrics. Obstet Gynecol. 2018;132(1):e1–e17. https://doi.org/10.1097/AOG.0000000000002706.

24. Bates S.M., Middeldorp S., Rodger M. et al. Guidance for the treatment and prevention of obstetric-associated venous thromboembolism. J Thromb Thrombolysis. 2016;41(1):92–128. https://doi.org/10.1007/s11239-015-1309-0.

25. Gusina A.A., Gusina N.B. Hereditary thrombophilia and venous thromboembolism in obstetrics. [Nasledstvennye trombofilii i venoznye tromboembolicheskie oslozhneniya v akusherstve]. Reproduktivnoe zdorov'e. Vostochnaya Evropa. 2016;6(3):380–92. (In Russ.).

26. Gerhardt A., Scharf R.E., Greer I.A., Zotz R.B. Hereditary risk factors for thrombophilia and probability of venous thromboembolism during pregnancy and the puerperium. Blood. 2016;128(19):2343–9. https://doi.org/10.1182/blood-2016-03-703728.

27. Branch D.W., Holmgren C., Goldberg J.D. Committee on Practice BulletinsObstetrics Practice Bulletin no 132: antiphospholipid antibody syndrome. Obstet Gynecol. 2012;120(6):1514–21. https://doi.org/10.1097/01.AOG.0000423816.39542.0f.

28. Trofimov E.A., Trofimova A.S. Antiphospholipid syndrome: course features in pregnant women and treatment options. [Antifosfolipidnyj sindrom: osobennosti techeniya u beremennyh i varianty terapii]. RMZh. 2016;(15):1032–6. (In Russ.).

29. Sennström M., Rova K., Hellgren M. et al. Thromboembolism and in vitro fertilization – a systematic review. Acta Obstet Gynecol Scand. 2017;96(9):1045–52. https://doi.org/10.1111/aogs.13147.

30. Rova K., Passmark H., Lindqvist P.G. Venous thromboembolism in relation to in vitro fertilization: an approach to determining the incidence and increase in risk in successful cycles. Fertil Steril. 2012;97(1):95–100. https://doi.org/10.1016/j.fertnstert.2011.10.038.

31. Rodger M.A., Hague W.M., Kingdom J. et al. Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open-label randomised trial. Lancet. 2014;384(9955):1673–83. https://doi.org/10.1016/S0140-6736(14)60793-5.

32. Rodger M.A., Gris J.C., de Vries J.I.P. et al. Low-molecular-weight heparin and recurrent placenta mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials. Lancet. 2016;388(10060):2629–41. https://doi.org/10.1016/S0140-6736(16)31139-4.

33. Linnemann B., Seelbach-Goebel B., Heimerl S., Hart C. How do we treat pregnancy-related venous thromboembolism? Hamostaseologie. 2020;40(1):54–63. https://doi.org/10.1055/s-0039-1700501.

34. Bates S.M., Rajasekhar A., Middeldorp S. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv. 2018;2(22):3317–59. https://doi.org/10.1182/bloodadvances.2018024802.

35. Bapat P., Pinto L.S., Lubetsky A. et al. Examining the transplacental passage of apixaban using the dually perfused human placenta. J Thromb Haemost. 2016;14(7):1436–41. https://doi.org/10.1111/jth.13353.

36. Yarrington C.D., Valente A.M., Economy K.E. Cardiovascular management in pregnancy: antithrombotic agents and antiplatelet agents. Circulation. 20156;132(14):1354–64. https://doi.org/10.1161/CIRCULATIONAHA.

37. Sessa M., Mascolo A., Callreus T. et al. Direct-acting oral anticoagulants (DOACs) in pregnancy: new insight from VigiBase®. Sci Rep. 2019;9(1):7236. https://doi.org/10.1038/s41598-019-43715-4.

38. Cohen H., Arachchillage D.R., Middeldorp S. et al. Management of direct oral anticoagulants in women of childbearing potential: guidance from the SSC of the ISTH: reply. J Thromb Haemost. 2017;15(1):195–7. https://doi.org/10.1111/jth.13535.

39. Galambosi P., Hiilesmaa V., Ulander V.M. et al. Prolonged low-molecularweight heparin use during pregnancy and subsequent bone mineral density. Thromb Res. 2016;143:122–6. https://doi.org/10.1016/j.thromres.2016.05.016.

40. Stephenson M.L., Serra A.E., Neeper J.M. et al. A randomized controlled trial of differing doses of postcesarean enoxaparin thromboprophylaxis in obese women. J Perinatol. 2016;36(2):95–9. https://doi.org/10.1038/jp.2015.130.

41. Knol H.M., Schultinge L., Veeger N.J. et al. The risk of postpartum hemorrhage in women using high dose of low-molecular-weight heparins during pregnancy. Thromb Res. 2012;130(3):334–8. https://doi.org/10.1016/j.thromres.2012.03.007.

42. Roshani S., Cohn D.M., Stehouwer A.C. et al. Incidence of postpartum haemorrhage in women receiving therapeutic doses of low-molecular weight heparin: results of a retrospective cohort study. BMJ Open. 2011;1(2):e000257. https://doi.org/10.1136/bmjopen-2011-000257.

43. Rodger M.A., Phillips P., Kahn S.R. et al. Low molecular weight heparin to prevent postpartum venous thromboembolism: a pilot study to assess the feasibility of a randomized, open-label trial. Thromb Res. 2016;142:17–20. https://doi.org/10.1016/j.thromres.2016.04.004.

44. Lamont M.C., McDermott C., Thomson A.J., Greer I.A. United Kingdom recommendations for obstetric venous thromboembolism prophylaxis: Evidence and rationale. Semin Perinatol. 2019;43(4):222–8. https://doi.org/10.1053/j.semperi.2019.03.008.

45. Leffert L.R., Dubois H.M., Butwick A.J. et al. Neuraxial anesthesia in obstetric patients receiving thromboprophylaxis with unfractionated or low molecular-weight heparin: a systematic review of spinal epidural hematoma. Anesth Analg. 2017;125(1):223–31. https://doi.org/10.1213/ANE.0000000000002173.

46. Bates S.M., Greer I.A., Middeldorp S et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th еd: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e691S–e736S. https://doi.org/10.1378/chest.11-2300.

47. Bleker S.M., Buchmüller A., Chauleur C. et al. Low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy: Rationale and design of the Highlow study, a randomised trial of two doses. Thromb Res. 2016;144:62–8. https://doi.org/10.1016/j.thromres.2016.06.001.

48. Chan W.S., Kent N.E., Rey E. et al. Venous thromboembolism and antithrombotic therapy in pregnancy. J Obstet Gynaecol Can. 2014;36(6):527–53. https://doi.org/10.1016/s1701-2163(15)30569-7.

49. Kamel H., Navi B.B., Sriram N. et al. Risk of a thrombotic event after the 6-week postpartum period. N Engl J Med. 2014;370(14):1307–15. https://doi.org/10.1056/NEJMoa1311485.

50. Nordic Federation of Societies of Obstetrics and Gynecology. Clinical Guideline of Thromboprophylaxis in IVF. 2015. Available at: https://nfog.org/about-us/guidelines/.

51. Sultan A.A., West J., Grainge M.J. et al. Development and validation of risk prediction model for venous thromboembolism in postpartum women: multinational cohort study. BMJ. 2016;355:i6253. https://doi.org/10.1136/bmj.i6253.

52. Dargaud Y., Rugeri L., Fleury C. et al. Personalized thromboprophylaxis using a risk score for the management of pregnancies with high risk of thrombosis: a prospective clinical study. J Thromb Haemost. 2017;15(5):897–906. https://doi.org/10.1111/jth.13660.

53. D'Alton M.E., Friedman A.M., Smiley R.M. et al. National partnership for maternal safety: consensus bundle on venous thromboembolism. J Obstet Gynecol Neonatal Nurs. 2016;45(5):706–17. https://doi.org/10.1016/j.jogn.2016.07.001.

54. Polyantsev A.A., Frolov D.V., Andreeva M.D. et al. Analysis of clinical cases of venous thromboembolic complications during pregnancy, childbirth and early postpartum period. [Analiz klinicheskih sluchaev venoznyh tromboembolicheskih oslozhnenij vo vremya beremennosti, rodov i rannego poslerodovogo perioda]. Vestnik VolgGMU. 2020;(3):170–4. (In Russ.). https://doi.org/10.19163/1994-9480-2020-3(75)-170-174.

55. Guyatt G.H., Akl E.A., Crowther M. et al. Executive summary: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):7S–47S. https://doi.org/10.1378/chest.1412S3.

56. Bain E., Wilson A., Tooher R. et al. Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period. Cochrane Database Syst Rev. 2014;(2):CD001689. https://doi.org/10.1002/14651858.CD001689.pub3.

57. Dentali F., Grandone E., Rezoagli E., Ageno W. Efficacy of low molecular weight heparin in patients undergoing in vitro fertilization or intracytoplasmic sperm injection. J Thromb Haemost. 2011;9(12):2503–6. https://doi.org/10.1111/j.1538-7836.2011.04535.x.

58. Dentali F., Ageno W., Rezoagli E. et al. Low-dose aspirin for in vitro fertilization or intracytoplasmic sperm injection: a systematic review and a meta-analysis of the literature. J Thromb Haemost. 2012;10(10):2075–85. https://doi.org/10.1111/j.1538-7836.2012.04886.x.

59. Siristatidis C.S., Basios G., Pergialiotis V., Vogiatzi P. Aspirin for in vitro fertilisation. Cochrane Database Syst Rev. 2016;11(11):CD004832. https://doi.org/10.1002/14651858.CD004832.pub4.

60. Akhtar M.A., Sur S., Raine-Fenning N. et al. Heparin for assisted reproduction: summary of a Cochrane review. Fertil Steril. 2015;103(1):33– 4. https://doi.org/10.1016/j.fertnstert.2014.09.005.

61. Lindqvist P.G., Bremme K., Hellgren M. Working Group on Hemostatic Disorders, Swedish Society of Obstetrics and Gynecology. Efficacy of obstetric thromboprophylaxis and long-term risk of recurrence of venous thromboembolism. Acta Obstet Gynecol Scand. 2011;90(6):648–53. https://doi.org/10.1111/j.1600-0412.2011.01098.x.

62. Ricci G., Bogatti P., Fischer-Tamaro L. et al. Factor V Leiden and prothrombin gene G20210A mutation and in vitro fertilization: prospective cohort study. Hum Reprod. 2011;26(11):3068–77. https://doi.org/10.1093/humrep/der261.

63. Sushkov S.A., Divakova T.S., Nebylitsin Yu.S. et al. Clinical management of deep vein thrombosis of the inferior vena cava system in pregnant women. [Taktika vedeniya tromboza glubokih ven sistemy nizhnej poloj veny u beremennyh]. Rossijskij mediko-biologicheskij vestnik imeni akademika I.P. Pavlova. 2016;24(3):92–102. (In Russ.).

64. McLintock C., Brighton T., Chunilal S. et al. Recommendations for the diagnosis and treatment of deep venous thrombosis and pulmonary embolism in pregnancy and the postpartum period. Aust N Z J Obstet Gynaecol. 2012;52(1):14–22. https://doi.org/10.1111/j.1479-828X.2011.01361.x.

65. Erkens P.M., Prins M.H. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev. 20108;(9):CD001100. https://doi.org/10.1002/14651858.CD001100.pub3.

66. De Carolis S., di Pasquo E., Rossi E. et al. Fondaparinux in pregnancy: Could it be a safe option? A review of the literature. Thromb Res. 2015;135(6):1049–51. https://doi.org/10.1016/j.thromres.2015.04.001.

67. Bhutia S., Wong P.F. Once versus twice daily low molecular weight heparin for the initial treatment of venous thromboembolism. Cochrane Database Syst Rev. 2013;(7):CD003074. https://doi.org/10.1002/14651858.CD003074.pub3.

68. McDonnell B.P., Glennon K., McTiernan A. et al. Adjustment of therapeutic LMWH to achieve specific target anti-fxa activity does not affect outcomes in pregnant patients with venous thromboembolism. J Thromb Thrombolysis. 2017;43(1):105–11. https://doi.org/10.1007/s11239-016-1409-5.

69. Boban A., Paulus S., Lambert C., Hermans C. The value and impact of anti-Xa activity monitoring for prophylactic dose adjustment of lowmolecular-weight heparin during pregnancy: a retrospective study. Blood Coagul Fibrinolysis. 2017;28(3):199–204. https://doi.org/10.1097/MBC.0000000000000573.

70. Devis P., Knuttinen M.G. Deep venous thrombosis in pregnancy: incidence, pathogenesis and endovascular management. Cardiovasc Diagn Ther. 2017;7(Suppl 3):S309–S319. https://doi.org/10.21037/cdt.2017.10.08.

71. Nelson-Piercy C., Powrie R., Borg J.Y. et al. Tinzaparin use in pregnancy: an international, retrospective study of the safety and efficacy profile. Eur J Obstet Gynecol Reprod Biol. 2011;159(2):293–9. https://doi.org/10.1016/j.ejogrb.2011.08.005.

72. Wiesen M.H., Blaich C., Muller C. et al. The direct factor Xa inhibitor rivaroxaban passes into human breast milk. Chest. 2016;150(1):e1–4. https://doi.org/10.1016/j.chest.2016.01.021.

73. Burnett A.E., Mahan C.E., Vazquez S.R. et al. Guidance for the practical management of the direct oral anticoagulants (doacs) in VTE treatment. J Thromb Thrombolysis. 2016;41(1):206–32. https://doi.org/10.1007/s11239-015-1310-7.

74. Scheres L.J.J., Bistervels I.M., Middeldorp S. Everything the clinician needs to know about evidence-based anticoagulation in pregnancy. Blood Rev. 2019;33:82–97. https://doi.org/10.1016/j.blre.2018.08.001.

75. Othman M., Ortiz A.S., Cerdá M. et al. Thrombosis and hemostasis health in pregnancy: Registries from the International Society on Thrombosis and Haemostasis. Res Pract Thromb Haemost. 2019;3(4):607–14. https://doi.org/10.1002/rth2.12243.

76. Shaw P., Duncan A., Vouyouka A., Ozsvath K. Radiation exposure and pregnancy. J Vasc Surg. 2011;53(1 Suppl):28S–34S. https://doi.org/10.1016/j.jvs.2010.05.140.

77. Harris S.A., Velineni R., Davies A.H. Inferior vena cava filters in pregnancy: a systematic review. J Vasc Interv Radiol. 2016;27(3):354–60.e8. https://doi.org/10.1016/j.jvir.2015.11.024.

78. Duffett L., Carrier M. Inferior vena cava filters. J Thromb Haemost. 2017;15(1):3–12. https://doi.org/10.1111/jth.13564.

79. Jaff M.R., McMurtry M.S., Archer S.L. et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011;123(16):1788–830. https://doi.org/10.1161/CIR.0b013e318214914f.

80. Bloom A.I., Farkas A., Kalish Y. et al. Pharmacomechanical catheterdirected thrombolysis for pregnancy-related iliofemoral deep vein thrombosis. J Vasc Interv Radiol. 2015;26(7):992–1000. https://doi.org/10.1016/j.jvir.2015.03.001.

81. Herrera S., Comerota A.J., Thakur S. et al. Managing iliofemoral deep venous thrombosis of pregnancy with a strategy of thrombus removal is safe and avoids post-thrombotic morbidity. J Vasc Surg. 2014;59(2):456– 64. https://doi.org/10.1016/j.jvs.2013.07.108.

82. Piazza G., Hohlfelder B., Jaff M.R. et al. A prospective, single-arm, multicenter trial of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis for acute massive and submassive pulmonary embolism: the SEATTLE II Study. JACC Cardiovasc Interv. 2015;8(10):1382–92. https://doi.org/10.1016/j.jcin.2015.04.020.

83. Kucher N., Boekstegers P., Müller O.J. et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediaterisk pulmonary embolism. Circulation. 2014;129(4):479–86. https://doi.org/10.1161/CIRCULATIONAHA.113.005544.

84. Schissler A.J., Gylnn R.J., Sobieszczyk P.S., Waxman A.B. Ultrasoundassisted catheter-directed thrombolysis compared with anticoagulation alone for treatment of intermediate-risk pulmonary embolism. Pulm Circ. 2018;8(4):2045894018800265. https://doi.org/10.1177/2045894018800265.

85. Pick J., Berlin D., Horowitz J. et al. Massive pulmonary embolism in pregnancy treated with catheter-directed tissue plasminogen activator. A A Case Rep. 2015;4(7):91–4. https://doi.org/10.1213/XAA.0000000000000128.

86. Marti C., John G., Konstantinides S. et al. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and metaanalysis. Eur Heart J. 2015;36(10):605–14. https://doi.org/10.1093/eurheartj/ehu218.

87. Martillotti G., Boehlen F., Robert-Ebadi H. et al. Treatment options for severe pulmonary embolism during pregnancy and the postpartum period: a systematic review. J Thromb Haemost. 2017;15(10):1942–50. https://doi.org/10.1111/jth.13802.

88. Sharma N.S., Wille K.M., Bellot S.C., Diaz-Guzman E. Modern use of extracorporeal life support in pregnancy and postpartum. ASAIO J. 2015;61(1):110–4. https://doi.org/10.1097/MAT.0000000000000154.

89. Bataillard A., Hebrard A., Gaide-Chevronnay L. et al. Extracorporeal life support for massive pulmonary embolism during pregnancy. Perfusion. 2016;31(2):169–71. https://doi.org/10.1177/0267659115586578.