Journal of Thrombosis and Thrombolysis

, Volume 21, Issue 1, pp 57–65 | Cite as

Anticoagulants in Pregnancy



Venous thromboembolic (VTE) complications are a leading cause of maternal mortality in the developed world. To reduce the incidence of VTE in pregnancy, and improve outcomes, a wider understanding of the risk factors involved and a better identification of women at risk of thrombosis coupled with effective thromboprophylaxis and treatment of VTE are required. As coumarin is unsuitable for use in pregnancy because of problems with embryopathy and risk of fetal bleeding, anticoagulation therapy in pregnancy centres on the use of low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH). There is now extensive experience of the safety and efficacy of LMWH in pregnancy. LMWH's, such as enoxaparin and dalteparin, have clinical and practical advantages compared with UFH in terms of improved safety (significantly lower incidence of osteoporosis and heparin induced thrombocytopenia), and patient convenience with once daily dosing for the majority of women. Such therapy is not restricted only to prevention and treatment of VTE but is now being assessed in additional clinical situations such as the prevention of pregnancy complications.

Key Words

pregnancy thrombosis thrombophilia 


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  1. 1.
    CEMACH Why Mothers Die 2000–2002, London: RCOG, 2004. Scholar
  2. 2.
    Macklon NS, Greer IA. Venous thromboembolic disease in obstetrics and gynaecology: the Scottish experience. Scottish Medical Journal 1996;41:83–86.PubMedGoogle Scholar
  3. 3.
    Rutherford S, Montoro M, McGhee W, Strong T. Thromboembolic disease associated with pregnancy: an 11 year review (abstract). American Journal of Obstetrics & Gynecology 1991;164 Supplement: 286.Google Scholar
  4. 4.
    McColl M, Ellison J, Greer IA, et al. Prevalence of the post-thrombotic syndrome in young women with previous venous thromboembolism. British Journal of Haematology 2000;108:272–274.CrossRefPubMedGoogle Scholar
  5. 5.
    Robertson L, Wu O, Langhorne P, Twaddle S, Clark P, Lowe G, Walker ID, Brenkel I, Greaves M, Regan L, Greer IA. Thrombophilia and Pregnancy: a systematic review. British Journal of Haematology 2005;132:171–196.Google Scholar
  6. 6.
    Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003;361:901–908.CrossRefPubMedGoogle Scholar
  7. 7.
    McColl M, Ramsay JE, Tait RC, et al. Risk factors for pregnancy associated venous thromboembolism. Thrombosis Haemostasis 1997;78:1183–1188.Google Scholar
  8. 8.
    Kodama, H., Fukuda, J., Karube, et al. Status of the coagulation and fibrinolytic systems in ovarian hyperstimulation syndrome. Fertility Sterility 1996;3:417–424.Google Scholar
  9. 9.
    Arya R, Shehata H, et al. Internal jugular vein thrombosis after assisted conception therapy. British Journal of Haematology 2001;115:153–155.CrossRefPubMedGoogle Scholar
  10. 10.
    Clarke P, Brennand J, Conkie JA, McCall F, Greer IA, Walker ID. Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy. Thrombosis Haemostasis 1998;79:1166–1170.Google Scholar
  11. 11.
    Greer IA. Haemostasis and thrombosis in pregnancy. In: Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD (Eds). Haemostasis and Thrombosis. Churchill Livingstone: Edinburgh 1994:987–1015.Google Scholar
  12. 12.
    Macklon NS, Greer IA, Bowman AW. An ultrasound study of gestational and postural changes in the deep venous system of the leg in pregnancy. British Journal of Obstetrics & Gynaecology 1997;104:191–197.Google Scholar
  13. 13.
    Macklon NS, Greer IA. The deep leg venous system in the puerperium. An ultrasound study. British Journal of Obstetrics & Gynaecology 1997;104:198–200.Google Scholar
  14. 14.
    Lindhagen A, Bergqvist A, Bergqvist D, Hallbook T. Late venous function in the leg after deep venous thrombosis occurring in relation to pregnancy. British Journal of Obstetrics & Gynaecology 1996;93:348–352.Google Scholar
  15. 15.
    McColl MD, Ellison J, Reid F, et al. Prothrombin 20210GA, MTHFR C677T mutations in women with venous thromboembolism associated with pregnancy. British Journal of Obstetrics & Gynaecology 2000;107:567–569.Google Scholar
  16. 16.
    Bates SM, Ginsberg JS. Anticoagulants in pregnancy: fetal defects. In: Greer IA (Ed). Bailliere's Clinical Obstetrics and Gynaecology. Thromboembolic Disease in Obstetrics and Gynaecology. London: Bailliere Tindall. 1997:479–488.Google Scholar
  17. 17.
    Bates S, Greer IA, Ginsberg J, Hirsh J. Use of Antithrombotic agents during pregnancy. Chest 2004;126(3 Suppl):627S–644S.PubMedGoogle Scholar
  18. 18.
    Vitale N, De Feo M, De Santo LS, et al. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. Journal of American College of Cardiology 1999;33:1642–1645.Google Scholar
  19. 19.
    Howe AM, Webster WS. The warfarin embryopathy : a rat model showing maxillonasal hypoplasia and other skeletal disturbances Teratology 1992;46:379.CrossRefPubMedGoogle Scholar
  20. 20.
    Wesseling J, van Driel D, Heymans HAS, et al. Coumarins during pregnancy: long term effects on growth and development in school age children. Thromb Haemostas 2001;85:609–613.Google Scholar
  21. 21.
    Letsky E. Peripartum prophylaxis of thromboembolism. In: Greer IA (Ed), Bailliere's Clinical Obstetrics and Gynaecology – Thromboembolic Disease in Obstetrics and Gynaecology. London: Bailliere Tindall. 1997:523–543.Google Scholar
  22. 22.
    Flessa HC, Klapstrom AB, Glueck MJ, et al. Placental transport of heparin. American Journal of Obstetrics & Gynecology 1965;93:570–573.Google Scholar
  23. 23.
    Forestier F, Daffos F, Capella-Pavlovsky M. Low molecular weight heparin (PK 10169) does not cross the placenta during the second trimester of pregnancy: study by direct fetal blood sampling under ultrasound. Thrombosis Research 1984;34:557–560.CrossRefPubMedGoogle Scholar
  24. 24.
    Forestier F, Daffos F, Rainaut M, et al. Low molecular weight heparin (CY 216) does not cross the placenta during the third trimester of pregnancy. Thrombosis Haemostasis 1987;57:234.Google Scholar
  25. 25.
    Nelson-Piercy C. Hazards of heparin: allergy, heparin-induced thrombocytopenia and osteoporosis. In: Greer IA (Ed), Bailliere's Clinical Obstetrics and Gynaecology – Thromboembolic Disease in Obstetrics and Gynaecology. London: Bailliere Tindall. 1997:489–509.Google Scholar
  26. 26.
    Pettila V, Leinonen P, Markkola A, Hiilesmaa V, Kaaja R. Postpartum bone mineral density in women treated for thromboprophylaxis with unfractionated heparin or LMW heparin. Thrombosis Haemostasis 2002;87: 182–186.Google Scholar
  27. 27.
    Warkentin TE, Levine MN, Hirsh J, et al. Heparin induced thrombocytopenia in patients treated with low molecular weight heparin or unfractionated heparin. New England Journal of Medicine 1995;332:1330–133.CrossRefPubMedGoogle Scholar
  28. 28.
    Nelson-Piercy C, Letsky EA, de Swiet M. Low-molecular-weight heparin for obstetric thromboprophylaxis: experience of sixty-nine pregnancies in sixty-one women at high risk. American Journal of Obstetrics & Gynecology 1997;176:1062–1068.Google Scholar
  29. 29.
    Ellison J, Walker ID, Greer IA. Antifactor Xa profiles in pregnant women receiving antenatal thromboprophylaxis with enoxaparin for prevention and treatment of thromboembolism in pregnancy. British Journal of Obstetrics & Gynaecology 2000;107:1116–1121.Google Scholar
  30. 30.
    Lepercq J, Conard J, Borel-Derlon A. et al. Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies. British Journal of Obstetrics & Gynaecology 2001;108:1134–1140.Google Scholar
  31. 31.
    Hunt BJ, Doughty HA, Majumdar G, Copplestone A, et al. Thromboprophylaxis with low molecular weight heparin (Fragmin) in high risk pregnancies. Thrombosis & Haemostasis 1997;77:39–43.Google Scholar
  32. 32.
    Blomback M, Bremme K, Hellgren M, et al. Thromboprophylaxis with low molecular mass heparin, “Fragmin” (dalteparin), during pregnancy – longitudinal safety study. Blood Coagulation & Fibrinolysis 1998;9:1–9.Google Scholar
  33. 33.
    Sanson BJ, Lensing AWA, Prins MH, et al. Safety of low-molecular-weight heparin in pregnancy: A systematic review. Thrombosis Haemostasis 1999;81:668–672.Google Scholar
  34. 34.
    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 (In Press).Google Scholar
  35. 35.
    Smith MP, Norris LA, Steer PJ, Savidge GF, Bonnar J. Tinzaparin sodium for thrombosis treatment and prevention during pregnancy. Am J Obstet Gynecol. 2004 Feb;190(2):495–501.Google Scholar
  36. 36.
    Norris LA, Bonnar J, Smith MP, Steer PJ, Savidge G. Low molecular weight heparin (tinzaparin) therapy for moderate risk thromboprophylaxis during pregnancy. A pharmacokinetic study. Thromb Haemost. 2004 Oct;92(4): 791–796.Google Scholar
  37. 37.
    Byrd LM, Johnston TA, Shiach C, Hay CRM. Osteoporotic fracture and low molecular weight heparin. J Obstet Gynaecol 2004;24 (Suppl 1):S11.Google Scholar
  38. 38.
    Samama MM, Gerotziafas GT. Comparative pharmacokinetics of LMWHs. Semin Thromb Hemost. 2000;26 (Suppl 1):31–38.PubMedGoogle Scholar
  39. 39.
    Ellison, J, Thomson, AJ, Conkie, JA, McCall, F, Walker, ID & Greer, IA. Thromboprophylaxis following caesarean section: a comparison of the antithrombotic properties of three low molecular weight heparins – dalteparin, enoxaparin and tinzaparin. Thrombosis & Haemostasis, 2001;86:1374–1378.Google Scholar
  40. 40.
    Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004 Sep;126(3 Suppl): 311S–337S.Google Scholar
  41. 41.
    Pabinger I, Grafenhofer H, Kyrle PA, Quehenberger P, Mannhalter C, Lechner K, Kaider A. Temporary increase in the risk for recurrence during pregnancy in women with a history of venous thromboembolism. Blood 2002;100(3):1060–1062CrossRefPubMedGoogle Scholar
  42. 42.
    Brill-Edwards P, Ginsberg JS for the Recurrence Of Clot In This Pregnancy (ROCIT) Study Group. Safety of withholding antepartum heparin in women with a previous episode of venous thromboembolism. New England Journal of Medicine 2000;343:1439–1444.Google Scholar
  43. 43.
    Pabinger I, Grafenhofer H, Kaider A, Kyrle PA, Quehenberger P, Mannhalter C, Lechner K. Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis. J Thromb Haemost. 2005;3(5):949–954.CrossRefPubMedGoogle Scholar
  44. 44.
    CLASP Collaborative Group. CLASP: A randomised trial of low dose aspirin for the prevention and treatment of pre-eclampsia among 9,364 pregnant women. Lancet 1994;343:619–629.Google Scholar
  45. 45.
    Imperiale TF, Petrulis AS. A meta-analysis of low-dose aspirin for prevention of pregnancy-induced hypertensive disease. Journal of American Medical Association 1991;266:260–264.CrossRefGoogle Scholar
  46. 46.
    Scottish Intercollegiate Guidelines Network. Prophylaxis of venous thromboembolism. A national clinical guideline 2002; Edinburgh ISBN 1 899893 03 2 (
  47. 47.
    Greer IA. Epidemiology, risk factors and prophylaxis of venous thrombo-embolism in obstetrics and gynaecology. In: Greer IA (Ed), Bailliere's Clinical Obstetrics and Gynaecology -Thromboembolic Disease in Obstetrics and Gynaecology. London: Bailliere Tindall. 1997:403–430.Google Scholar
  48. 48.
    Greer, IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet 1999;353:1258–1265.CrossRefPubMedGoogle Scholar
  49. 49.
    Nelson Piercy C. Clinical Green Top[Guideline. Thromboprophylaxis during Pregnancy, Labour and after Vaginal Delivery (37) – RCOG London January 2004 (
  50. 50.
    Thomson AJ, Greer IA. Thromboembolic Disease in Pregnancy and the Puerperium: Acute Management. Royal College of Obstetricians and Gyn-aecologists, RCOG Press, London. Guideline No 28, 2001 (
  51. 51.
    Rodie VA, Thomson AJ, Stewart FM, Quinn AJ, Walker ID, Greer IA. Low molecular weight heparin for the treatment of venous thromboembolism in pregnancy – a case series. British Journal Obstetrics & Gynaecology. 2002;109(9):1020–1024.Google Scholar
  52. 52.
    Thomson AJ, Walker ID, Greer IA. Low molecular weight heparin for the immediate management of thromboembolic disease in pregnancy. The Lancet 1998;352:1904.Google Scholar
  53. 53.
    Casele HL, Laifer SA, Woelkers DA, et al. Changes in the pharmacokinetics of the low molecular weight heparin enoxaparin sodium during pregnancy. Am J Obstet Gynecol 1999;181:1113–1117.CrossRefPubMedGoogle Scholar
  54. 54.
    Crowther MA, Spitzer K, Julian J, et al. Pharmacokinetic profile of a low-molecular weight (Reviparin) in pregnant patients: a prospective cohort study. Thromb Res 2000;98:133–134.CrossRefPubMedGoogle Scholar
  55. 55.
    Sephton V, Farquharson RG, Topping J, et al. A longitudinal study of maternal dose response to low molecular weight heparin in pregnancy. Obstet Gynecol 2003;101:1307–1311.CrossRefPubMedGoogle Scholar
  56. 56.
    Lee AYY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146–153.PubMedGoogle Scholar
  57. 57.
    Checketts MR, Wildsmith JAW. Central nerve block and thromboprophylaxis - is there a problem ? British Journal of Anaesthesia 1999;82:164–167PubMedGoogle Scholar
  58. 58.
    Horlocker TT. Wedel DJ. Spinal and epidural blockade and perioperative low molecular weight heparin: smooth sailing on the Titanic. Anaesthetic Analgesia 1998;86:1153–1156Google Scholar
  59. 59. website with consensus statement on anticoagulants and neuraxial anaesthesia from the American Society of Regional Anesthesia).
  60. 60.
    Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. Arch Intern Med 2000;160:191–196.CrossRefPubMedGoogle Scholar
  61. 61.
    Oran B, Lee-Paritz A, Ansell J. Low molecular weight heparin for the prophylaxis of thromboembolism in women with prosthetic mechanical heart valves during pregnancy. Thromb Haemost. 2004;94:747–751.Google Scholar
  62. 62.
    Ginsberg JS, Chan W, Bates SM, Kaatz S. Anticoagulation of pregnant women with mechanical heart valves. Arch Intern Med, 2003;163:694–698.CrossRefPubMedGoogle Scholar
  63. 63.
    Greer IA, Hunt BJ. Low molecular weight heparin in pregnancy: Current issues. British Journal of Haematology 2004;128:593–601.Google Scholar
  64. 64.
    Greer IA. The challenge of thrombophilia in maternal-fetal medicine. New England Journal of Medicine. 2000;342:424–425.CrossRefPubMedGoogle Scholar
  65. 65.
    Greer IA. The use of LMWH in pregnancies at risk: new evidence or perception? J Thromb Haemost 2005;3(4):781–782.CrossRefGoogle Scholar
  66. 66.
    Derksen RHWM, Khamashta MA, Branch DW. Management of the obstetric antiphospholipid syndrome. Arthritis Rheumatism 2004;50:1028–1039.CrossRefPubMedGoogle Scholar
  67. 67.
    Greer IA. Thrombophilia: implications for pregnancy outcome. Thromb Res 2003;109(2-3):73–81.CrossRefPubMedGoogle Scholar
  68. 68.
    Kovalevsky G, Gracia CR, Berlin JA, Sammel MD, Barnhart KT. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss. Arch Intern Med 2004;164: 558–563.CrossRefPubMedGoogle Scholar
  69. 69.
    Laude I et al. Circulating procoagulant microparticles in women with unexplained pregnancy loss: A new insight. Thromb Hemost 2001;85:18–21.Google Scholar
  70. 70.
    Quenby S. Mountfield S. Cartwright JE. Whitley GS. Vince G. Effects of low-molecular-weight and unfractionated heparin on trophoblast function. Obstetrics & Gynecology 2004;104(2):354–361.Google Scholar
  71. 71.
    Gris JC, Mercier E, Quere I, et al. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder. Blood 2004;103(10):3695–3699.CrossRefPubMedGoogle Scholar
  72. 72.
    Brenner B, Hoffman R, Blumenfeld Z, Weiner Z, Younis J. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost 2000;83:693–697.PubMedGoogle Scholar
  73. 73.
    Brenner B. Clinical management of thrombophilia-related placental vascular complication. Blood 2004;103:4003-4009.PubMedGoogle Scholar
  74. 74.
    Greer IA. Procoagulant microparticles: new insights and opportunities in pregnancy loss? Thromb Haemostas 2001;85:3–4.Google Scholar
  75. 75.
    Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss treatment with heparin and low-dose aspirin is superior to low dose aspirin alone. Am J Obstet Gynaecol 1996;174:1584–1589.Google Scholar
  76. 76.
    Rai RS, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). Brit Med J 1997;314:253–256.PubMedGoogle Scholar
  77. 77.
    Pattison NS, Chamley LW, Birdsall M, Zanderigo AM, Lideell HS, McDougall J. Does aspirin have a role in improving pregnancy outcome for women with the antiphospholipid syndrome? A randomised controlled trial. Am J Obstet Gynecol 2000;183:1008–1012CrossRefPubMedGoogle Scholar
  78. 78.
    Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomised, controlled trial of treatment. Obstet Gynecol 2002;100:408–13.PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Division of Developmental Medicine, Maternal and Reproductive Medicine, Glasgow Royal InfirmaryUniversity of GlasgowScotlandU.K.

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