Anticoagulation Therapy in Pregnant Patients

  • Steven A. Savella
  • Jessica A. Kvasic
  • Joe F. Lau


Pregnancy is an acquired hypercoagulable state. During pregnancy, there are increases in clotting factors and fibrinogen, coupled with decreases in fibrinolytic activity and endogenous anticoagulants such as protein S. The intricate balance that normally exists between endogenous anticoagulant and procoagulant factors may become disrupted, potentially leading to venous thromboembolism (VTE) affecting the mother or gestational complications involving the fetus. VTE has remained an important cause of mortality and morbidity in the pregnant patient, with pulmonary embolism (PE) as the leading cause of mortality. Moreover, in susceptible mothers with certain hypercoagulable conditions, the fetus may be subject to gestational complications that include preeclampsia, intrauterine growth restriction, and fetal loss.

The management of anticoagulation therapy during pregnancy can be challenging, particularly because anticoagulants such as the vitamin K antagonists like warfarin can cross the placenta and are associated with teratogenesis leading to congenital abnormalities, miscarriage, and fetal bleeding. Insufficient evidence currently exists on the use of direct oral anticoagulants (DOACs), so they are not recommended by current guidelines. Because negatively charged heparin molecules do not cross the placenta, low-molecular-weight heparins (LMWHs) are the preferred treatment for prophylaxis and treatment of VTE during pregnancy. In this chapter, the management of anticoagulation therapy for the pregnant patient will be reviewed.


Thromboembolism Anticoagulation Deep vein thrombosis Heparin Prophylaxis Pulmonary embolism Treatment Warfarin Thrombophilia Low-molecular-weight heparin 


  1. 1.
    McColl MD, Ramsay JE, Tait RC, et al. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost. 1997;78(4):1183–8.PubMedGoogle Scholar
  2. 2.
    Ray JG, Chan WS. Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the period of risk and leg of presentation. Obstet Gynecol Surv. 1999;54:254–71.Google Scholar
  3. 3.
    Romualdi E, Dentali F, Rancan E, Squizzato A, Steidl L, et al. Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta-analysis of the literature. J Thromb Haemost. 2013;11(4):788–9.CrossRefGoogle Scholar
  4. 4.
    Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med. 2005;143:697–706.CrossRefGoogle Scholar
  5. 5.
    Virkus RA, Lokkegaard EC, Bergholt T, Mogensen U, Langhoff-Roos J, Lidegaard O. Venous thromboembolism in pregnant and puerperal women in Denmark 1995-2005. A national cohort study. Thromb Haemost. 2011;106:304–9.CrossRefGoogle Scholar
  6. 6.
    Damodaram M, Kaladindi M, Luckit J, Yoong W. D-dimers are a screening test of venous thromboembolism in pregnancy: is it of any use? J Obstet Gynaecol. 2009;29:101–3.CrossRefGoogle Scholar
  7. 7.
    James A, Committee on Practice B-O. Practice bulletin no. 123: thromboembolism in pregnancy. Obstet Gynecol. 2011;118:718–29.CrossRefGoogle Scholar
  8. 8.
    Tan M, Huisman MV. The diagnostic management of acute venous thromboembolism during pregnancy: recent advancements and unresolved issues. Thromb Res. 2011;127(Suppl 3):S13–6.CrossRefGoogle Scholar
  9. 9.
    James AH. Prevention and treatment of venous thromboembolism in pregnancy. Clin Obstet Gynecol. 2012;55:774–87.CrossRefGoogle Scholar
  10. 10.
    James AH, Jamison MG, Brancazio LR, Myers ER. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol. 2006;194:1311–5.CrossRefGoogle Scholar
  11. 11.
    Sultan AA, West J, Tata LJ, Fleming KM, Nelson-Piercy C, Grainge MJ. Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study. Br J Haematol. 2012;156:366–73.CrossRefGoogle Scholar
  12. 12.
    Gerhardt A, Scharf RE, Greer IA, Zotz RB. Hereditary risk factors of thrombophilia and probability of venous thromboembolism during pregnancy and the puerperium. Blood. 2016;128(19):2343–9.CrossRefGoogle Scholar
  13. 13.
    Yarrington CD, Valente AM, Economy KE. Cardiovascular management in pregnancy: antithrombotic agents and antiplatelet agents. Circulation. 2015;132:1354–64.CrossRefGoogle Scholar
  14. 14.
    Long AA, Ginsberg JS, Brill-Edwards P, et al. The relationship of antiphospholipid antibodies to thromboembolic disease in systemic lupus erythematosus: a cross-sectional study. Thromb Haemost. 1991;66:520–4.PubMedGoogle Scholar
  15. 15.
    Den Heijer M, Rosendaal FR, Blom HJ, et al. Hyperhomocysteinemia as a risk for deep-vein thrombosis. N Engl J Med. 1995;334:759–62.CrossRefGoogle Scholar
  16. 16.
    Robertson L, Wu O, Langhorne P, et al. Thrombosis risk and economic assessment of thrombophilia screening (treats) study. Thrombophilia in pregnancy; a systematic review. Br J Haematol. 2005;132:171–96.CrossRefGoogle Scholar
  17. 17.
    Gordon M. Maternal physiology in pregnancy. In: Gabbe S, Niebyl J, Simpson J, editors. Normal and problem pregnancies. 4th ed. New York: Churchill Livingstone; 2002. p. 63–92.Google Scholar
  18. 18.
    Bremme KA. Haemostatic changes in pregnancy. Best Pract Res Clin Haematol. 2003;16:153–68.CrossRefGoogle Scholar
  19. 19.
    Hellgren M. Hemostasis during normal pregnancy and puerperium. Semin Thromb Hemost. 2003;29:125–30.CrossRefGoogle Scholar
  20. 20.
    James AH. Pregnancy-associated thrombosis. Hematology Am Soc Hematol Educ Program. 2009;2009:277–85.Google Scholar
  21. 21.
    Lindqvist P, Dahlback B, Marsal K. Thrombotic risk during pregnancy: a population study. Obstet Gynecol. 1999;94:595–9.PubMedGoogle Scholar
  22. 22.
    Jacobsen AF, Skjeldestad FE, Sandset PM. Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium--a register-based case-control study. Am J Obstet Gynecol. 2008;198:233.e1–7.CrossRefGoogle Scholar
  23. 23.
    Pabinger I, Grafenhofer H, Kyrle PA, et al. Temporary increase in the risk for recurrence during pregnancy in women with a history of venous thromboembolism. Blood. 2002;100:1060–2.CrossRefGoogle Scholar
  24. 24.
    Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos A-M, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e691S–736S.CrossRefGoogle Scholar
  25. 25.
    James AH, Brancazio LR, Ortel TL. Thrombosis, thrombophilia, and thromboprophylaxis in pregnancy. Clin Adv Hematol Oncol. 2005;3:187–97.PubMedGoogle Scholar
  26. 26.
    Tormene D, Grandone E, De Stefano V, et al. Obstetric complications and pregnancy-related venous thromboembolism: the effect of low-molecular-weight heparin on their prevention in carriers of factor V Leiden or prothrombin G20210A mutation. Thromb Haemost. 2012;107:477–84.CrossRefGoogle Scholar
  27. 27.
    Folkeringa N, Brouwer JL, Korteweg FJ, et al. Reduction of high fetal loss rate by anticoagulant treatment during pregnancy in antithrombin, protein C or protein S deficient women. Br J Haematol. 2007;136:656–61.CrossRefGoogle Scholar
  28. 28.
    Gris JC, Mercier E, Quere I, Lavigne-Lissalde G, Cochery-Nouvellon E, Hoffet M, et al. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder. Blood. 2004;103:3695–9.CrossRefGoogle Scholar
  29. 29.
    Johnston JA, Brill-Edwards P, Ginsberg JS, Pauker SG, Eckman MH. Cost-effectiveness of prophylactic low molecular weight heparin in pregnant women with a prior history of venous thromboembolism. Am J Med. 2005;118:503–14.CrossRefGoogle Scholar
  30. 30.
    Okoroh EM, Azonobi IC, Grosse SD, Grant AM, Atrash HK, James AH. Prevention of venous thromboembolism in pregnancy: a review of guidelines, 2000-2011. J Women’s Health. 2012;21:611–5.CrossRefGoogle Scholar
  31. 31.
    Brill-Edwards P, Ginsberg JS, Gent M, et al. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. N Engl J Med. 2000;343:1439–44.CrossRefGoogle Scholar
  32. 32.
    Bates SM, Ginsberg JS. How we manage venous thromboembolism during pregnancy. Blood. 2002;100:3470–8.CrossRefGoogle Scholar
  33. 33.
    Chan WS, Spencer FA, Ginsberg JS. Anatomic distribution of deep vein thrombosis in pregnancy. CMAJ. 2010;182:657–60.CrossRefGoogle Scholar
  34. 34.
    Chan WS, Lee A, Spencer FA, et al. Predicting deep venous thrombosis in pregnancy: out in “LEFt” field? Ann Intern Med. 2009;151:85–92.CrossRefGoogle Scholar
  35. 35.
    Dargaud Y, Rugeri L, Vergnes MC, et al. A risk score for the management of pregnant women with increased risk of venous thromboembolism: a multicentre prospective study. Br J Haematol. 2009;145:825–35.CrossRefGoogle Scholar
  36. 36.
    Chan WS, Chunilal S, Lee A, Crowther M, Rodger M, Ginsberg JS. A red blood cell agglutination D-dimer test to exclude deep venous thrombosis in pregnancy. Ann Intern Med. 2007;147:165–70.CrossRefGoogle Scholar
  37. 37.
    Hirai K, Sugimura M, Ohashi R, et al. A rapid activated protein C sensitivity test as a diagnostic marker for a suspected venous thromboembolism in pregnancy and puerperium. Gynecol Obstet Investig. 2011;72:55–62.CrossRefGoogle Scholar
  38. 38.
    Kearon C, Julian JA, Newman TE, Ginsberg JS. Noninvasive diagnosis of deep venous thrombosis. McMaster diagnostic imaging practice guidelines initiative. Ann Intern Med. 1998;128:663–77.CrossRefGoogle Scholar
  39. 39.
    Nijkeuter M, Ginsberg JS, Huisman MV. Diagnosis of deep vein thrombosis and pulmonary embolism in pregnancy: a systematic review. J Thromb Haemost. 2006;4:496–500.CrossRefGoogle Scholar
  40. 40.
    Groves AM, Yates SJ, Win T, Kayani I, Gallagher FA, et al. CT pulmonary angiography versus ventilation-perfusion scintigraphy in pregnancy: implications from a UK survey of doctors’ knowledge of radiation exposure. Radiology. 2006;240:765–70.CrossRefGoogle Scholar
  41. 41.
    Hunsaker AR, MT L, Goldhaber SZ, Rybicki FJ. Imaging in acute pulmonary embolism with special clinical scenarios. Circ Cardiovasc Imaging. 2010;3:491–500.CrossRefGoogle Scholar
  42. 42.
    Litmanovich D, Boiselle PM, Bankier AA, Kataoka ML, Pianykh O, Raptopoulos V. Dose reduction in computed tomographic angiography of pregnant patients with suspected acute pulmonary embolism. J Comput Assist Tomogr. 2009;33(6):961.CrossRefGoogle Scholar
  43. 43.
    Ridge CA, McDermott S, Freyne BJ, Brennan DJ, Collins CD, Skehan SJ. Pulmonary embolism in pregnancy: comparison of pulmonary CT angiography and lung scintigraphy. Am J Roentgenol. 2009;193:1223–7.CrossRefGoogle Scholar
  44. 44.
    Cahill AG, Stout MJ, Macones GA, Bhalla S. Diagnosing pulmonary embolism in pregnancy using computed tomographic angiography or ventilation-perfusion. Obstet Gynecol. 2009;114:124–9.CrossRefGoogle Scholar
  45. 45.
    Turrentine MA, Braems G, Ramirez MM. Use of thrombolytics for the treatment of thromboembolic disease during pregnancy. Obstet Gynecol Surv. 1995;50:534–41.CrossRefGoogle Scholar
  46. 46.
    Pillny M, Sandmann W, Luther B, et al. Deep venous thrombosis during pregnancy and after delivery: indications for and results of thrombectomy. J Vasc Surg. 2003;37:528–32.CrossRefGoogle Scholar
  47. 47.
    Taniguchi S, Fukuda I, Minakawa M, Watanabe K, Daitoku K, Suzuki Y. Emergency pulmonary embolectomy during the second trimester of pregnancy: report of a case. Surg Today. 2008;38:59–61.CrossRefGoogle Scholar
  48. 48.
    Baker WH, Mahler DK, Foldes MS, et al. Pneumatic compression devices for prophylaxis of deep venous thrombosis (DVT). Am Surg. 1986;52:371–3.PubMedGoogle Scholar
  49. 49.
    Ratiu A, Motoc A, Pascut D, Crisan DC, Anca T, Pascut M. Compression and walking compared with bed rest in the treatment of proximal deep venous thrombosis during pregnancy. Rev Med Chir Soc Med Nat Iasi. 2009;113:795–8.PubMedGoogle Scholar
  50. 50.
    Arya R. How I manage venous thromboembolism in pregnancy. Br J Haemotol. 2011;153:698–708.CrossRefGoogle Scholar
  51. 51.
    Walfisch A, Koren G. The “warfarin window” in pregnancy: the importance of half-life. J Obstet Gynaecol Can. 2010;32:988–9.CrossRefGoogle Scholar
  52. 52.
    Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med. 1980;68(1):122–40.CrossRefGoogle Scholar
  53. 53.
    Hassouna A, Allam H. Anticoagulation of pregnant women with mechanical heart valve prosthesis: a systematic review of the literature (2000-2009). J Coagul Disord. 2010;2(1):81–8.Google Scholar
  54. 54.
    Blickstein D, Blickstein I. The risk of fetal loss associated with warfarin anticoagulation. Int J Gynaecol Obstet. 2002;78:221–5.CrossRefGoogle Scholar
  55. 55.
    Vitale N, De Eeo M, De Santo LS, et al. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. J Am Coll Cardiol. 1999;33:1637–41.CrossRefGoogle Scholar
  56. 56.
    Cotrufo M, De Feo M, De Santo LS, et al. Risk of warfarin during pregnancy with mechanical valve prostheses. Obstet Gynecol. 2002;99:35–40.PubMedGoogle Scholar
  57. 57.
    Massonnet-Castel S, Pelissier E, Bara L, et al. Partial reversal of low molecular-weight heparin (PK 101699) anti-Xa activity by protamine sulfate: in vitro and in vivo study during cardiac surgery with extracorporeal circulation. Haemostasis. 1986;16:139–46.PubMedGoogle Scholar
  58. 58.
    Xu Z, Fan J, Luo X, et al. Anticoagulation regimens during pregnancy in patients with mechanical heart valves: a systematic review and meta-analysis. Can J Cardiol. 2016;32(10):1248.e1–9.CrossRefGoogle Scholar
  59. 59.
    Alshawabkeh L, Economy KE, Valente AM. Anticoagulation during pregnancy: evolving strategies with a focus on mechanical valves. J Am Coll Cardiol. 2016;68:1804–13.CrossRefGoogle Scholar
  60. 60.
    Chunilal SD, Bates SM. Venous thromboembolism in pregnancy: diagnosis, management and prevention. Thromb Haemost. 2009;101:428–43.PubMedGoogle Scholar
  61. 61.
    Stone SE, Morris TA. Pulmonary embolism during and after pregnancy. Crit Care Med. 2005;33(Suppl. 10):S294–300.CrossRefGoogle Scholar
  62. 62.
    Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood. 2005;106(2):401–7.CrossRefGoogle Scholar
  63. 63.
    Romualdi E, Dentali F, Rancan E, Squizzato A, Steidl L, et al. Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta-analysis of the literature. J Thromb Haemost. 2013;11(2):270–81.CrossRefGoogle Scholar
  64. 64.
    Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med. 1995;332(20):1330–5.CrossRefGoogle Scholar
  65. 65.
    Linkins L-A, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence- Based Clinical Practice Guidelines. Chest. 2012;141:e495S–530S.CrossRefGoogle Scholar
  66. 66.
    Mehta R, Golichowski A. Treatment of heparin induced thrombocytopenia and thrombosis during the first trimester of pregnancy. J Thromb Haemost. 2004;2:1665–6.CrossRefGoogle Scholar
  67. 67.
    Young SK, Al-Mondhiry HA, Vaida SJ, Ambrose A, Botti JJ. Successful use of argatroban during the third trimester of pregnancy: case report and review of the literature. Pharmacotherapy. 2008;28:1531–6.CrossRefGoogle Scholar
  68. 68.
    Tanimura K, Ebina Y, Sonoyama A, Morita H, Miyata S, Yamada H. Argatroban therapy for heparin-induced thrombocytopenia during pregnancy in a woman with hereditary antithrombin deficiency. J Obstet Gynaecol Res. 2012;38:749–52.CrossRefGoogle Scholar
  69. 69.
    Jacobsen AF, Sandset PM. Venous thromboembolism associated with pregnancy and hormonal therapy. Best Pract Res Clin Haematol. 2012;25:319–32.CrossRefGoogle Scholar
  70. 70.
    Kawamata K, Chiba Y, Tanaka R, Higashi M, Nishigami K. Experience of temporary inferior vena cava filters inserted in the perinatal period to prevent pulmonary embolism in pregnant women with deep vein thrombosis. J Vasc Surg. 2005;41:652–6.CrossRefGoogle Scholar
  71. 71.
    Decousus H, Quéré I, Presles E, et al. POST (prospective observational superficial thrombophlebitis). Superficial venous thrombosis and venous thromboembolism: a large, prospective epidemiologic study. Ann Intern Med. 2010;152(4):218–24.CrossRefGoogle Scholar
  72. 72.
    Decousus H, Prandoni P, Mismetti P, CALISTO Study Group CALISTO Study Group, et al. Fondaparinux for the treatment of superficial-vein thrombosis in the legs. N Engl J Med. 2010;363(13):1222–32.CrossRefGoogle Scholar
  73. 73.
    Basude S, Hein C, Curtis S, Clark A, Trinder J. Low-molecular-weight heparin or warfarin for anticoagulation in pregnant women with mechanical heart valves: what are the risks? A retrospective observational study. BJOG. 2012;119:1008–13.CrossRefGoogle Scholar
  74. 74.
    Pauli RM, Haun J. Intrauterine effects of coumadin derivatives. Dev Brain Dysfunct. 1993;6:229–47.Google Scholar
  75. 75.
    Steinberg ZL, Dominguez-Islas CP, Otto CM, Stout KK, Krieger EV. Maternal and fetal outcomes of anticoagulation in pregnant women with mechanical heart valves. J Am Coll Cardiol. 2017;69:2681–91.CrossRefGoogle Scholar
  76. 76.
    Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, Guyton RA, ACC/AHA Task Force Members, et al. 2014 AHA/ACC guideline 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. Circulation. 2014;129:e521–643.CrossRefGoogle Scholar
  77. 77.
    van Hagen IM, Roos-Hesselink JW, Ruys TPE, Merz WM, Goland S, et al. Pregnancy in women with a mechanical heart valve: data of the European Society of Cardiology Registry Of Pregnancy And Cardiac disease (ROPAC). Circulation. 2015;132:132–42.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Steven A. Savella
    • 1
  • Jessica A. Kvasic
    • 2
  • Joe F. Lau
    • 3
  1. 1.Department of CardiologyZucker School of Medicine at Hofstra/Northwell, Northwell HealthManhassetUSA
  2. 2.Department of MedicineZucker School of Medicine at Hofstra/Northwell, Northwell HealthManhassetUSA
  3. 3.Department of CardiologyZucker School of Medicine at Hofstra/NorthwellNorthwell Health, ManhassetUSA

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