Anticoagulation during pregnancy in patients with a prosthetic heart valve

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Abstract

Effective anticoagulation is mandatory for pregnant women with mechanical heart valves. Oral anticoagulants offer the best maternal protection against thrombosis, but their use might be associated with an appreciable risk of fetal malformations and pregnancy loss. By contrast, heparin derivatives are associated with a reduced risk of fetal damage, but an increased risk of valve thrombosis in the mother, even with appropriate dose adjustment and monitoring of therapeutic efficacy. Given the varying risks of available anticoagulation strategies, and the paucity of data to inform the optimal approach, no single accepted treatment option exists for pregnant women with mechanical prosthetic valves. Although low-molecular-weight heparin is considered more efficacious than unfractionated heparin, treatment failures, even at therapeutic levels of factor Xa inhibition, have been reported. The risk of warfarin-related embryopathy might be overstated, particularly at doses ≤5 mg daily. We advocate an individualized anticoagulation strategy that takes into account the patient's preferences, calls for the use of vitamin K antagonists throughout pregnancy (substituted with a heparin derivative only close to term) for those patients at the greatest risk of thromboembolism, and relies on close multidisciplinary collaboration between the cardiac and obstetric care teams.

Key Points

  • The management of pregnant women with prosthetic heart valves is a clinical challenge

  • No clear consensus exists on the optimal artificial valve and anticoagulation strategy for these women, owing to the paucity of data that can guide therapeutic decisions

  • Cardiac and obstetric care teams need to work collaboratively to help these patients make personalized decisions that consider the risks and benefits of various therapies

  • Consistent monitoring to maintain effective anticoagulation is crucial, regardless of the chosen treatment strategy

  • Warfarin throughout pregnancy might be appropriate for selected patients, particularly those at increased risk of thromboembolism and when the risk of adverse fetal outcomes is comparatively low

  • Heparin derivatives pose no direct risk to the fetus, but are limited by an appreciable risk of maternal thromboembolic complications, even in patients with seemingly therapeutic levels of anticoagulation

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Figure 1: Proposed algorithm for anticoagulation therapy during pregnancy in women with prosthetic heart valves.

References

  1. 1

    Di Saia, P. J. Pregnancy and delivery of a patient with a Starr-Edwards mitral valve prosthesis: report of a case. Obstet. Gynecol. 28, 469–472 (1966).

  2. 2

    Nassar, A. H. et al. Pregnancy outcome in women with prosthetic heart valves. Am. J. Obstet. Gynecol. 191, 1009–1013 (2004).

  3. 3

    Drenthen, W. et al. Predictors of pregnancy complications in women with congenital heart disease. Eur. Heart J. 31, 2124–2132 (2010).

  4. 4

    [No authors listed] Cardiovascular disease and use of oral and injectable progestogen-only contraceptives and combined injectable contraceptives. Results of an international, multicenter, case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Contraception 57, 315–324 (1998).

  5. 5

    Hung, L. & Rahimtoola, S. H. Prosthetic heart valves and pregnancy. Circulation 107, 1240–1246 (2003).

  6. 6

    Bonow, R. O. et al. 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J. Am. Coll. Cardiol. 52, e1–e142 (2008).

  7. 7

    Deruelle, P. & Coulon, C. The use of low-molecular-weight heparins in pregnancy—how safe are they? Curr. Opin. Obstet. Gynecol. 19, 573–577 (2007).

  8. 8

    de Boer, K., ten Cate, J. W., Sturk, A., Borm, J. J. & Treffers, P. E. Enhanced thrombin generation in normal and hypertensive pregnancy. Am. J. Obstet. Gynecol. 160, 95–100 (1989).

  9. 9

    Anderson, G. D. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin. Pharmacokinet. 44, 989–1008 (2005).

  10. 10

    Rahimtoola, S. H. Choice of prosthetic heart valve in adults: an update. J. Am. Coll. Cardiol. 55, 2413–2426 (2010).

  11. 11

    Yun, K. L. et al. Durability of the Hancock MO bioprosthesis compared with standard aortic valve bioprostheses. Ann. Thorac. Surg. 60 (Suppl. 2), S221–S228 (1995).

  12. 12

    Jamieson, W. R. et al. Carpentier-Edwards standard porcine bioprosthesis: primary tissue failure (structural valve deterioration) by age groups. Ann. Thorac. Surg. 46, 155–162 (1988).

  13. 13

    North, R. A. et al. Long-term survival and valve-related complications in young women with cardiac valve replacements. Circulation 99, 2669–2676 (1999).

  14. 14

    Elkayam, U. & Bitar, F. Valvular heart disease and pregnancy: part II: prosthetic valves. J. Am. Coll. Cardiol. 46, 403–410 (2005).

  15. 15

    Jamieson, W. R. et al. Pregnancy and bioprostheses: influence on structural valve deterioration. Ann. Thorac. Surg. 60 (Suppl. 2), S282–S286 (1995).

  16. 16

    Badduke, B. R. et al. Pregnancy and childbearing in a population with biologic valvular prostheses. J. Thorac. Cardiovasc. Surg. 102, 179–186 (1991).

  17. 17

    Avila, W. S., Rossi, E. G., Grinberg, M. & Ramires, J. A. Influence of pregnancy after bioprosthetic valve replacement in young women: a prospective five-year study. J. Heart Valve Dis. 11, 864–869 (2002).

  18. 18

    O'Brien, M. F. et al. The homograft aortic valve: a 29-year, 99.3% follow up of 1,022 valve replacements. J. Heart Valve Dis. 10, 334–344 (2001).

  19. 19

    Denbow, C. E., Matadial, L., Sivapragasam, S. & Spencer, H. Pregnancy in patients after homograft cardiac valve replacement. Chest 83, 540–542 (1983).

  20. 20

    Sadler, L. et al. Pregnancy outcomes and cardiac complications in women with mechanical, bioprosthetic and homograft valves. BJOG 107, 245–253 (2000).

  21. 21

    Gopal, K. et al. Homograft aortic root replacement during pregnancy. Ann. Thorac. Surg. 74, 243–245 (2002).

  22. 22

    Ross, D. N. Replacement of aortic and mitral valves with a pulmonary autograft. Lancet 2, 956–958 (1967).

  23. 23

    Lentini, S. Ross principle and concept of a living valve. Lancet 376, 490–491 (2010).

  24. 24

    Martin, T. C., Idahosa, V., Ogunbiyi, A., Fevrier-Roberts, G. & Winter, A. Successful pregnancy and delivery after pulmonary autograft operation (Ross procedure) for rheumatic aortic valve insufficiency. West Indian Med. J. 52, 62–64 (2003).

  25. 25

    Dore, A. & Somerville, J. Pregnancy in patients with pulmonary autograft valve replacement. Eur. Heart J. 18, 1659–1662 (1997).

  26. 26

    Yap, S. C. et al. Outcome of pregnancy in women after pulmonary autograft valve replacement for congenital aortic valve disease. J. Heart Valve Dis. 16, 398–403 (2007).

  27. 27

    El-Hamamsy, I. et al. Long-term outcomes after autograft versus homograft aortic root replacement in adults with aortic valve disease: a randomised controlled trial. Lancet 376, 524–531 (2010).

  28. 28

    Klieverik, L. M. et al. The Ross operation: a trojan horse? Eur. Heart J. 28, 1993–2000 (2007).

  29. 29

    Takkenberg, J. J. et al. Report of the Dutch experience with the Ross procedure in 343 patients. Eur. J. Cardiothorac. Surg. 22, 70–77 (2002).

  30. 30

    Schmidtke, C., Stierle, U. & Sievers, H. H. Valve-sparing aortic root remodeling for pulmonary autograft aneurysm. J. Heart Valve Dis. 11, 504–505 (2002).

  31. 31

    McLintock, C. Anticoagulant therapy in pregnant women with mechanical prosthetic heart valves: no easy option. Thromb. Res. 127 (Suppl. 3), S56–S60 (2011).

  32. 32

    Ufer, M. Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. Clin. Pharmacokinet. 44, 1227–1246 (2005).

  33. 33

    Hirsh, J. et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 119 (Suppl. 1), 8S–21S (2001).

  34. 34

    Chan, W. S., Anand, S. & Ginsberg, J. S. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. Arch. Intern. Med. 160, 191–196 (2000).

  35. 35

    Arnaout, M. S. et al. Is there a safe anticoagulation protocol for pregnant women with prosthetic valves? Clin. Exp. Obstet. Gynecol. 25, 101–104 (1998).

  36. 36

    Vitale, N. et al. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. J. Am. Coll. Cardiol. 33, 1637–1641 (1999).

  37. 37

    Meschengieser, S. S., Fondevila, C. G., Santarelli, M. T. & Lazzari, M. A. Anticoagulation in pregnant women with mechanical heart valve prostheses. Heart 82, 23–26 (1999).

  38. 38

    Lee, J. H. et al. Low molecular weight heparin treatment in pregnant women with a mechanical heart valve prosthesis. J. Korean Med. Sci. 22, 258–261 (2007).

  39. 39

    Howie, P. W. Anticoagulants in pregnancy. Clin. Obstet. Gynaecol. 13, 349–363 (1986).

  40. 40

    Rutherford, S. E. & Phelan, J. P. Thromboembolic disease in pregnancy. Clin. Perinatol. 13, 719–739 (1986).

  41. 41

    Villasanta, U. Therapy in antepartum thrombophlebitis. Obstet. Gynecol. 26, 534–541 (1965).

  42. 42

    Hall, J. G., Pauli, R. M. & Wilson, K. M. Maternal and fetal sequelae of anticoagulation during pregnancy. Am. J. Med. 68, 122–140 (1980).

  43. 43

    Stevenson, R. E., Burton, O. M., Ferlauto, G. J. & Taylor, H. A. Hazards of oral anticoagulants during pregnancy. JAMA 243, 1549–1551 (1980).

  44. 44

    Chong, M. K., Harvey, D. & de Swiet, M. Follow-up study of children whose mothers were treated with warfarin during pregnancy. Br. J. Obstet. Gynaecol. 91, 1070–1073 (1984).

  45. 45

    Whitfield, M. F. Chondrodysplasia punctata after warfarin in early pregnancy. Case report and summary of the literature. Arch. Dis. Child. 55, 139–142 (1980).

  46. 46

    Pauli, R. M., Lian, J. B., Mosher, D. F. & Suttie, J. W. Association of congenital deficiency of multiple vitamin K-dependent coagulation factors and the phenotype of the warfarin embryopathy: clues to the mechanism of teratogenicity of coumarin derivatives. Am. J. Hum. Genet. 41, 566–583 (1987).

  47. 47

    Menon, R. K., Gill, D. S., Thomas, M., Kernoff, P. B. & Dandona, P. Impaired carboxylation of osteocalcin in warfarin-treated patients. J. Clin. Endocrinol. Metab. 64, 59–61 (1987).

  48. 48

    Salazar, E., Izaguirre, R., Verdejo, J. & Mutchinick, O. Failure of adjusted doses of subcutaneous heparin to prevent thromboembolic phenomena in pregnant patients with mechanical cardiac valve prostheses. J. Am. Coll. Cardiol. 27, 1698–1703 (1996).

  49. 49

    Sbarouni, E. & Oakley, C. M. Outcome of pregnancy in women with valve prostheses. Br. Heart J. 71, 196–201 (1994).

  50. 50

    Ginsberg, J. S., Hirsh, J., Turner, D. C., Levine, M. N. & Burrows, R. Risks to the fetus of anticoagulant therapy during pregnancy. Thromb. Haemost. 61, 197–203 (1989).

  51. 51

    Ginsberg, J. S. & Hirsh, J. Anticoagulants during pregnancy. Ann. Rev. Med. 40, 79–86 (1989).

  52. 52

    Iturbe-Alessio, I. et al. Risks of anticoagulant therapy in pregnant women with artificial heart valves. N. Engl. J. Med. 315, 1390–1393 (1986).

  53. 53

    Wong, V., Cheng, C. H. & Chan, K. C. Fetal and neonatal outcome of exposure to anticoagulants during pregnancy. Am. J. Med. Genet. 45, 17–21 (1993).

  54. 54

    Sillesen, M., Hjortdal, V., Vejlstrup, N. & Sørensen, K. Pregnancy with prosthetic heart valves—30 years' nationwide experience in Denmark. Eur. J. Cardiothorac. Surg. 40, 448–454 (2011).

  55. 55

    Barbour, L. A. Current concepts of anticoagulant therapy in pregnancy. Obstet. Gynecol. Clin. North Am. 24, 499–521 (1997).

  56. 56

    European Society of Gynecology et al. ESC guidelines on the management of cardiovascular diseases during pregnancy: The Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC). Eur. Heart J. 32, 3147–3197 (2011).

  57. 57

    Schaefer, C. et al. Vitamin K antagonists and pregnancy outcome. A multi-centre prospective study. Thromb. Haemost. 95, 949–957 (2006).

  58. 58

    Cotrufo, M. et al. Risk of warfarin during pregnancy with mechanical valve prostheses. Obstet. Gynecol. 99, 35–40 (2002).

  59. 59

    Soma-Pillay, P., Nene, Z., Mathivha, T. M. & Macdonald, A. P. The effect of warfarin dosage on maternal and fetal outcomes in pregnant women with prosthetic heart valves. Obstetric Medicine 4, 24–27 (2011).

  60. 60

    McLintock, C., McCowan, L. M. & North, R. A. Maternal complications and pregnancy outcome in women with mechanical prosthetic heart valves treated with enoxaparin. BJOG 116, 1585–1592 (2009).

  61. 61

    Mehndiratta, S., Suneja, A., Gupta, B. & Bhatt, S. Fetotoxicity of warfarin anticoagulation. Arch. Gynecol. Obstet. 282, 335–337 (2010).

  62. 62

    Hirsh, J., Dalen, J., Guyatt, G. & American College of Chest Physicians. The sixth (2000) ACCP guidelines for antithrombotic therapy for prevention and treatment of thrombosis. American College of Chest Physicians. Chest 119 (Suppl. 1), 1S–2S (2001).

  63. 63

    Quinn, J. et al. Use of high intensity adjusted dose low molecular weight heparin in women with mechanical heart valves during pregnancy: a single-center experience. Haematologica 94, 1608–1612 (2009).

  64. 64

    Greer, I. A. & Nelson-Piercy, C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 106, 401–407 (2005).

  65. 65

    Barbour, L. A., Oja, J. L. & Schultz, L. K. A prospective trial that demonstrates that dalteparin requirements increase in pregnancy to maintain therapeutic levels of anticoagulation. Am. J. Obstet. Gynecol. 191, 1024–1029 (2004).

  66. 66

    Sarig, G. & Brenner, B. Monitoring of low molecular weight heparin (LMWH) in pregnancy. Thromb. Res. 115 (Suppl. 1), 84–86 (2005).

  67. 67

    Guyatt, G. H. et al. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141 (Suppl. 2), 7S–47S (2012).

  68. 68

    Abildgaard, U. et al. Management of pregnant women with mechanical heart valve prosthesis: thromboprophylaxis with low molecular weight heparin. Thromb. Res. 124, 262–267 (2009).

  69. 69

    Oran, B., Lee-Parritz, A. & Ansell, J. Low molecular weight heparin for the prophylaxis of thromboembolism in women with prosthetic mechanical heart valves during pregnancy. Thromb. Haemost. 92, 747–751 (2004).

  70. 70

    Yinon, Y. et al. Use of low molecular weight heparin in pregnant women with mechanical heart valves. Am. J. Cardiol. 104, 1259–1263 (2009).

  71. 71

    Friedrich, E. & Hameed, A. B. Fluctuations in anti-factor Xa levels with therapeutic enoxaparin anticoagulation in pregnancy. J. Perinatol. 30, 253–257 (2010).

  72. 72

    Bates, S. M. et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 133 (Suppl. 6), 844S–886S (2008).

  73. 73

    Knol, H. M., Schultinge, L., Erwich, J. J. & Meijer, K. Fondaparinux as an alternative anticoagulant therapy during pregnancy. J. Thromb. Haemost. 8, 1876–1879 (2010).

  74. 74

    Chapman, M. L., Martinez-Borges, A. R. & Mertz, H. L. Lepirudin for treatment of acute thrombosis during pregnancy. Obstet. Gynecol. 112, 432–433 (2008).

  75. 75

    Magnani, H. N. An analysis of clinical outcomes of 91 pregnancies in 83 women treated with danaparoid (Orgaran). Thromb. Res. 125, 297–302 (2010).

  76. 76

    de Valk, H. W. et al. Comparing subcutaneous danaparoid with intravenous unfractionated heparin for the treatment of venous thromboembolism. A randomized controlled trial. Ann. Intern. Med. 123, 1–9 (1995).

  77. 77

    Krauel, K. et al. Heparin-induced thrombocytopenia—therapeutic concentrations of danaparoid, unlike fondaparinux and direct thrombin inhibitors, inhibit formation of platelet factor 4-heparin complexes. J. Thromb. Haemost. 6, 2160–2167 (2008).

  78. 78

    Ofosu, F. A. Anticoagulant mechanisms of Orgaran (Org 10172) and its fraction with high affinity to antithrombin III (Org 10849). Haemostasis 22, 66–72 (1992).

  79. 79

    Dendrinos, S., Sakkas, E. & Makrakis, E. Low-molecular-weight heparin versus intravenous immunoglobulin for recurrent abortion associated with antiphospholipid antibody syndrome. Int. J. Gynaecol. Obstet. 104, 223–225 (2009).

  80. 80

    Heilmann, L. et al. Pregnancy outcome in women with antiphospholipid antibodies: report on a retrospective study. Semin. Thromb. Hemost. 34, 794–802 (2008).

  81. 81

    Goldenberg, R. L., Culhane, J. F., Iams, J. D. & Romero, R. Epidemiology and causes of preterm birth. Lancet 371, 75–84 (2008).

  82. 82

    Bauer, K. A., Eriksson, B. I., Lassen, M. R., Turpie, A. G. & Steering Committee of the Pentasaccharide in Major Knee Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N. Engl. J. Med. 345, 1305–1310 (2001).

  83. 83

    Wijesiriwardana, A., Lees, D. A. & Lush, C. Fondaparinux as anticoagulant in a pregnant woman with heparin allergy. Blood Coagul. Fibrinolysis 17, 147–149 (2006).

  84. 84

    Gerhardt, A., Zotz, R. B., Stockschlaeder, M. & Scharf, R. E. Fondaparinux is an effective alternative anticoagulant in pregnant women with high risk of venous thromboembolism and intolerance to low-molecular-weight heparins and heparinoids. Thromb. Haemost. 97, 496–497 (2007).

  85. 85

    Di Nisio, M., Middeldorp, S. & Buller, H. R. Direct thrombin inhibitors. N. Engl. J. Med. 353, 1028–1040 (2005).

  86. 86

    Haas, S. New oral Xa and IIa inhibitors: updates on clinical trial results. J. Thromb. Thrombolysis 25, 52–60 (2008).

  87. 87

    Tran, A. & Cheng-Lai, A. Dabigatran etexilate: the first oral anticoagulant available in the United States since warfarin. Cardiol. Rev. 19, 154–161 (2011).

  88. 88

    Horlocker, T. T. et al. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine evidence-based guidelines (3rd edition). Reg. Anesth. Pain Med. 35, 64–101 (2010).

  89. 89

    Leon, M. B. et al. Transcatheter aortic–valve implantation for aortic stenosis in patients who cannot undergo surgery. N. Engl. J. Med. 363, 1597–1607 (2010).

  90. 90

    Kawamata, K. et al. Risks and pregnancy outcome in women with prosthetic mechanical heart valve replacement. Circ. J. 71, 211–213 (2007).

  91. 91

    Izaguirre, R. et al. Anti-Xa activity with low-molecular-weight heparin, enoxaparin, during pregnancy in women with mechanical heart valves. Proc. West. Pharmacol. Soc. 45, 127–128 (2002).

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J. M. Castellano, R. Narayan, and P. Vaishnava researched the data for the article. All the authors provided substantial contributions to discussions of its content, wrote the article, and reviewed and/or edited the manuscript before submission.

Correspondence to Jose M. Castellano.

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Castellano, J., Narayan, R., Vaishnava, P. et al. Anticoagulation during pregnancy in patients with a prosthetic heart valve. Nat Rev Cardiol 9, 415–424 (2012) doi:10.1038/nrcardio.2012.69

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