Reviews

Anticoagulants and pregnancy: When are they safe?

Cleveland Clinic Journal of Medicine. 2009 February;76(2):113-127

References

Chang J, Elam-Evans LD, Berg CJ, et al. Pregnancy-related mortality surveillance-United States, 1991–1999. MMWR Surveill Summ 2003; 52:1–8.
Lewis G, Drife JO, Clutton-Brock T, et al. Why Mothers Die, 2000–2002. The Sixth Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. London: RCOG Press, 2004.
Health Canada. Special Report on Maternal Mortality and Severe Morbidity in Canada—Enhanced Surveillance: The Path to Prevention. Ottawa: Minister of Public Works and Government Services Canada, 2004. www.phac-aspc.gc.ca/rhs-ssg/srmm-rsmm/page1-eng.php. Accessed 11/26/2008.
Stein PD, Hull RD, Kayali F, et al. Venous thromboembolism in pregnancy: 21-year trends. Am J Med 2004; 117:121–125.
Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet 1999; 353:1258–1265.
Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353:1167–1173.
Gherman RB, Goodwin TM, Leung B, et al. Incidence, clinical characteristics, and timing of objectively diagnosed venous thromboembolism during pregnancy. Obstet Gynecol 1999; 94:730–734.
Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997; 337:688–698.
Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334:677–681.
Koopman MM, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group. N Engl J Med 1996; 334:682–687.
Simonneau G, Sors H, Charbonnier B, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l’Embolie Pulmonaire. N Engl J Med 1997; 337:663–669.
Hull RD, Raskob GE, Brant RF, et al. Low-molecular-weight heparin vs heparin in the treatment of patients with pulmonary embolism. American-Canadian Thrombosis Study Group. Arch Intern Med 2000; 160:229–236.
Sanson BJ, Lensing AW, Prins MH, et al. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81:668–672.
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; 106:401–407.
Melissari E, Parker CJ, Wilson NV, et al. Use of low molecular weight heparin in pregnancy. Thromb Haemost 1992; 68:652–656.
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. Thromb Res 1984; 34:557–560.
Forestier F, Daffos F, Rainaut M, Toulemonde F. Low molecular weight heparin (CY 216) does not cross the placenta during the third trimester of pregnancy. Thromb Haemost 1987; 57:234.
Barbour LA, Oja JL, Schultz LK. A prospective trial that demonstrates that dalteparin requirements increase in pregnancy to maintain therapeutic levels of anticoagulation. Am J Obstet Gynecol 2004; 191:1024–1029.
Smith MP, Norris LA, Steer PJ, Savidge GF, Bonnar J. Tinzaparin sodium for thrombosis treatment and prevention during pregnancy. Am J Obstet Gynecol 2004; 190:495–501.
Ellison J, Walker ID, Greer IA. Antenatal use of enoxaparin for prevention and treatment of thromboembolism in pregnancy. BJOG 2000; 107:1116–1121.
Sarig G, Brenner B. Monitoring of low molecular weight heparin (LMWH) in pregnancy. Thromb Res 2005; 115 suppl 1:84–86.
Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents during pregnancy: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004; 126 suppl 3:627S–644S.
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; 332:1330–1335.
Hassell K. The management of patients with heparin-induced thrombocytopenia who require anticoagulant therapy. Chest 2005; 127 suppl 2:1S–8S.
Barbour LA, Kick SD, Steiner JF, et al. A prospective study of heparin-induced osteoporosis in pregnancy using bone densitometry. Am J Obst Gynecol 1994; 170:862–869.
Douketis JD, Ginsberg JS, Burrows RF, Duku EK, Webber CE, Brill-Edwards P. The effects of long-term heparin therapy during pregnancy on bone density. A prospective matched cohort study. Thromb Haemost 1996; 75:254–257.
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. Thromb Haemost 2002; 87:182–186.
Carlin AJ, Farquharson RG, Quenby SM, Topping J, Fraser WD. Prospective observational study of bone mineral density during pregnancy: low molecular weight heparin versus control. Hum Reprod 2004; 19:1211–1214.
Casele HL, Laifer SA. Prospective evaluation of bone density in pregnant women receiving the low molecular weight heparin enoxaparin sodium. J Matern Fetal Med 2000; 9:122–125.
Casele H, Haney EI, James A, Rosene-Montella K, Carson M. Bone density changes in women who receive thromboprophylaxis in pregnancy. Am J Obstet Gynecol 2006; 195:1109–1113.
Horlocker TT, Wedel DJ, Benzon H, et al. Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med 2003; 28:172–197.
Hirsh J, Dalen JE, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119 suppl 1:8S–21S.
Levine MN, Raskob G, Beyth RJ, Kearon C, Schulman S. Hemorrhagic complications of anticoagulant treatment: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004; 126 suppl 3:287S–310S.
Holmes LB. Teratogen-induced limb defects. Am J Med Genet 2002; 112:297–303.
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.
Pauzner R, Dulitzki M, Langevitz P, Livneh A, Kenett R, Many A. Low molecular weight heparin and warfarin in the treatment of patients with antiphospholipid syndrome during pregnancy. Thromb Haemost 2001; 86:1379–1384.
Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355:1295–1302.
Patrono C, Coller B, FitzGerald GA, Hirsh J, Roth G. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 suppl 3:234S–264S.
Duley L, Henderson-Smart DJ, Knight M, King JF. Antiplatelet agents for preventing preeclampsia and its complications. Cochrane Database Syst Rev. 2004; ( 1):CD004659.
Coomarasamy A, Honest H, Papaioannou S, Gee H, Khan KS. Aspirin for prevention of preeclampsia in women with historical risk factors: a systematic review. Obstet Gynecol 2003; 101:1319–1332.
Caritis SN, Sibai BM, Hauth J, et al, and the National Institute of Child Health and Human Development Network of Maternal Fetal Medicine Units. Low-dose aspirin to prevent preeclampsia in women at high risk. N Engl J Med 1998; 338:701–705.
Rai R, 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). BMJ 1997; 314:253–257.
Kozer E, Nikfar S, Costei A, Boskovic R, Nulman I, Koren G. Aspirin consumption during the first trimester of pregnancy and congenital anomalies: a meta-analysis. Am J Obstet Gynecol 2002; 187:1623–1630.
Sebastian C, Scherlag M, Kugelmass A, Schechter E. Primary stent implantation for acute myocardial infarction during pregnancy: use of abciximab, ticlopidine, and aspirin. Cathet Cardiovasc Diagn 1998; 45:275–249.
Wilson AM, Boyle AJ, Fox P. Management of ischaemic heart disease in women of child-bearing age. Intern Med J 2004; 34:694–697.
Klinzing P, Markert UR, Liesaus K, Peiker G. Case report: successful pregnancy and delivery after myocardial infarction and essential thrombocythemia treated with clopidogrel. Clin Exp Obstet Gynecol 2001; 28:215–216.
Danhof M, de Boer A, Magnani HN, Stiekema JC. Pharmacokinetic considerations on Orgaran (Org 10172) therapy. Haemostasis 1992; 22:73–84.
Tardy-Poncet B, Tardy B, Reynaud J, et al. Efficacy and safety of danaparoid sodium (ORG 10172) in critically ill patients with heparin-associated thrombocytopenia. Chest 1999; 115:1616–1620.
Lagrange F, Vergnes C, Brun JL, et al. Absence of placental transfer of pentasaccharide (fondaparinux, Arixtra) in the dually perfused human cotyledon in vitro. Thromb Haemost 2002; 87:831–835.
Dempfle CE. Minor transplacental passge of fondapinux in vivo. N Engl J Med 2004; 350:1914.
Magnani HN. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with orgaran (Org 10172). Thromb Haemost 1993; 70:554–561.
Lindhoff-Last E, Kreutzenbeck HJ, Magnani HN. Treatment of 51 pregnancies with danaparoid because of heparin intolerance. Thromb Haemost 2005; 93:63–69.
Greinacher A, Eckhardt T, Mussmann J, Mueller-Eckhardt C. Pregnancy complicated by heparin associated thrombocytopenia: management by a prospectively in vitro selected heparinoid (Org 10172). Thromb Res 1993; 71:123–126.
Schindewolf M, Mosch G, Bauersachs RM, Lindhoff-Last E. Safe anticoagulation with danaparoid in pregnancy and lactation. Thromb Haemost 2004; 92:211.
Harenberg J. Treatment of a woman with lupus and thromboembolism and cutaneous intolerance to heparins using fondaparinux during pregnancy. Thromb Res 2007; 119:385–388.
Wijesiriwardana A, Lees DA, Lush C. Fondaparinux as anticoagulant in a pregnant woman with heparin allergy. Blood Coagul Fibrinolysis 2006; 17:147–149.
Mazzolai L, Hohlfeld P, Spertini F, Hayoz D, Schapira M, Duchosal MA. Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy. Blood 2006; 108:1569–1570.
Hawkins D, Evans J. Minimizing the risk of heparin-induced osteoporosis during pregnancy. Expert Opin Drug Saf 2005; 4:583–590.
Brill-Edwards P, Ginsberg JS, Gent M, et al. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of clot in this pregnancy study group. N Engl J Med 2000; 343:1439–1444.
Martinelli I, Legnani C, Bucciarelli P, Grandone E, De Stefano V, Mannucci PM. Risk of pregnancy-related venous thrombosis in carriers of severe inherited thrombophilia. Thromb Haemost 2001; 86:800–803.
De Stefano V, Martinelli I, Rossi E, Battaglioli T, Za T, Mannucci PM, Leone G. The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis. Br J Haematol 2006; 135:386–391.
Barbour LA, Smith JM, Marlar RA. Heparin levels to guide thromboembolism prophylaxis during pregnancy. Am J Obstet Gynecol 1995; 173:1869–1873.
Ensom MH, Stephenson MD. Pharmacokinetics of low molecular weight heparin and unfractionated heparin in pregnancy. J Soc Gynecol Investig 2004; 11:377–383.
Crowther MA, Berry LR, Monagle PT, Chan AK. Mechanisms responsible for the failure of protamine to inactivate low-molecular-weight heparin. Br J Haematol 2002; 116:178–186.
Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med 1997; 336:1506–1511.
Thomas LA, Summers RR, Cardwell MS. Use of Greenfield filters in pregnant women at risk for pulmonary embolism. South Med J 1997; 90:215–217.
Maclean PS, Tait RC. Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options. Drugs 2007; 67:1429–1440.
Information from LactMed: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT, LactMed Record Number: 279. Accessed 11/26/2008.
Gerhardt A, Scharf RE, Beckmann MW, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000; 342:374–380.
Hirsch DR, Mikkola KM, Marks PW, et al. Pulmonary embolism and deep venous thrombosis during pregnancy or oral contraceptive use: prevalence of factor V Leiden. Am Heart J 1996; 131:1145–1148.
Dizon-Townson DS, Nelson LM, Jang H, Varner MW, Ward K. The incidence of the factor V Leiden mutation in an obstetric population and its relationship to deep vein thrombosis. Am J Obstet Gynecol 1997; 176:883–886.
McColl MD, Ramsay JE, Tait RC, et al. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost 1997; 78:1183–1188.
Kupferminc MJ, Fait G, Many A, Gordon D, Eldor A, Lessing JB. Severe preeclampsia and high frequency of genetic thrombophilic mutations. Obstet Gynecol 2000; 96:45–49.
Kupferminc MJ, Eldor A, Steinman N, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340:9–13.
Robertson L, Wu O, Langhorne P, et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006; 132:171–196.
Brenner B, Hoffman R, Blumenfeld Z, Weiner Z, Younis JS. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost 2000; 83:693–697.
Carp H, Dolitzky M, Inbal A. Thromboprophylaxis improves the live birth rate in women with consecutive recurrent miscarriages and hereditary thrombophilia. J Thromb Haemost 2003; 1:433–438.
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; 103:3695–3699.
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 1996; 27:1698–1703.
Iturbe-Alessio I, Fonseca MC, Mutchinik O, Santos MA, Zajarias A, Salazar E. Risks of anticoagulant therapy in pregnant women with artificial heart valves. N Engl J Med 1986; 315:1390–1393.
Rowan JA, McCowan LM, Raudkivi PJ, North RA. Enoxaparin treatment in women with mechanical heart valves during pregnancy. Am J Obstet Gynecol 2001; 185:633–637.
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 2004; 92:747–751.

Other measures

Women on anticoagulant therapy who are at risk of recurrent venous thromboembolism should be encouraged to wear elastic compression stockings. Intermittent pneumatic compression of the legs via automated devices may be considered for women hospitalized for any reason or on bedrest.

Whichever measures are used, a high index of suspicion and a low threshold for investigating for recurrent thrombosis should be maintained throughout pregnancy and the puerperium.

PERIPARTUM AND POSTPARTUM MANAGEMENT OF ANTICOAGULATION

Heparin therapy must be interrupted temporarily during the immediate peripartum interval to minimize the risk of hemorrhage and to allow for the option of regional anesthesia. As mentioned earlier, because of the theoretical risk of paraspinal hemorrhage in women receiving heparin who undergo epidural or spinal anesthesia, the American Society of Regional Anesthesia guidelines advise waiting to insert the needle at least 10 to 12 hours after the last prophylactic dose of LMWH, and at least 24 hours after the last therapeutic dose. ³¹

The guidelines state that neuraxial anesthesia is not contraindicated in patients on prophylactic unfractionated heparin. ³¹

To facilitate use of regional anesthesia in these women, therefore, options include:

Electively stopping LMWH 24 hours before planned induction of labor
Electively stopping prophylactic-dose LMWH or unfractionated heparin at about 38 weeks of gestation, to await spontaneous labor, or
Switching therapeutic or prophylactic LMWH to unfractionated heparin at about 36 weeks of gestation, with instructions to discontinue the injections in the earliest stages of spontaneous labor. This aims to shorten the heparin-free period required before neuraxial anesthesia while minimizing maternal thrombotic risk.

Additional advantages to using unfractionated heparin peripartum include the option of obtaining a rapid aPTT measurement to confirm the absence of a significant ongoing heparin effect prior to regional anesthesia or delivery, and the ability to completely reverse the heparin effect with protamine sulfate if major bleeding occurs. LMWHs are only partially reversible. ⁶⁴

Interrupting anticoagulation after an initial thrombotic event

If therapeutic anticoagulation must be interrupted for labor within 1 month of the initial thrombotic event, the risk of recurrent thrombotic complications is high ⁶⁵; these women must be observed very carefully and may benefit from intravenous heparin before and after delivery. They may even merit placement of a temporary vena cava filter (particularly if less than 2 weeks have elapsed since the venous thromboembolic event and in women with a large deep venous clot burden), a procedure that has been used safely but little studied in pregnant women. ⁶⁶

Fluoroscopic guidance may be needed for filter placement. This exposes the fetus to radiation, but the low-level exposure at this late gestational age is unlikely to pose a significant risk. The filter may be removed within 1 to 2 weeks postpartum, assuming there are no ongoing contraindications to anticoagulation.

In the rare woman with antithrombin deficiency and a recent or prior thrombotic event, giving antithrombin concentrate during the peripartum (heparin-free) interval has been described and may be considered under the guidance of a hematologist. ⁶⁷

Ongoing anticoagulation is essential postpartum, as the puerperium is the period of highest day-to-day risk of thromboembolic events: about one-third of pregnancy-associated events occur during these 6 to 12 weeks. ² Heparin should be resumed 6 to 12 hours after delivery, once hemostasis is confirmed.

References

Chang J, Elam-Evans LD, Berg CJ, et al. Pregnancy-related mortality surveillance-United States, 1991–1999. MMWR Surveill Summ 2003; 52:1–8.
Lewis G, Drife JO, Clutton-Brock T, et al. Why Mothers Die, 2000–2002. The Sixth Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. London: RCOG Press, 2004.
Health Canada. Special Report on Maternal Mortality and Severe Morbidity in Canada—Enhanced Surveillance: The Path to Prevention. Ottawa: Minister of Public Works and Government Services Canada, 2004. www.phac-aspc.gc.ca/rhs-ssg/srmm-rsmm/page1-eng.php. Accessed 11/26/2008.
Stein PD, Hull RD, Kayali F, et al. Venous thromboembolism in pregnancy: 21-year trends. Am J Med 2004; 117:121–125.
Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet 1999; 353:1258–1265.
Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353:1167–1173.
Gherman RB, Goodwin TM, Leung B, et al. Incidence, clinical characteristics, and timing of objectively diagnosed venous thromboembolism during pregnancy. Obstet Gynecol 1999; 94:730–734.
Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997; 337:688–698.
Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334:677–681.
Koopman MM, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group. N Engl J Med 1996; 334:682–687.
Simonneau G, Sors H, Charbonnier B, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l’Embolie Pulmonaire. N Engl J Med 1997; 337:663–669.
Hull RD, Raskob GE, Brant RF, et al. Low-molecular-weight heparin vs heparin in the treatment of patients with pulmonary embolism. American-Canadian Thrombosis Study Group. Arch Intern Med 2000; 160:229–236.
Sanson BJ, Lensing AW, Prins MH, et al. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81:668–672.
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; 106:401–407.
Melissari E, Parker CJ, Wilson NV, et al. Use of low molecular weight heparin in pregnancy. Thromb Haemost 1992; 68:652–656.
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. Thromb Res 1984; 34:557–560.
Forestier F, Daffos F, Rainaut M, Toulemonde F. Low molecular weight heparin (CY 216) does not cross the placenta during the third trimester of pregnancy. Thromb Haemost 1987; 57:234.
Barbour LA, Oja JL, Schultz LK. A prospective trial that demonstrates that dalteparin requirements increase in pregnancy to maintain therapeutic levels of anticoagulation. Am J Obstet Gynecol 2004; 191:1024–1029.
Smith MP, Norris LA, Steer PJ, Savidge GF, Bonnar J. Tinzaparin sodium for thrombosis treatment and prevention during pregnancy. Am J Obstet Gynecol 2004; 190:495–501.
Ellison J, Walker ID, Greer IA. Antenatal use of enoxaparin for prevention and treatment of thromboembolism in pregnancy. BJOG 2000; 107:1116–1121.
Sarig G, Brenner B. Monitoring of low molecular weight heparin (LMWH) in pregnancy. Thromb Res 2005; 115 suppl 1:84–86.
Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents during pregnancy: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004; 126 suppl 3:627S–644S.
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; 332:1330–1335.
Hassell K. The management of patients with heparin-induced thrombocytopenia who require anticoagulant therapy. Chest 2005; 127 suppl 2:1S–8S.
Barbour LA, Kick SD, Steiner JF, et al. A prospective study of heparin-induced osteoporosis in pregnancy using bone densitometry. Am J Obst Gynecol 1994; 170:862–869.
Douketis JD, Ginsberg JS, Burrows RF, Duku EK, Webber CE, Brill-Edwards P. The effects of long-term heparin therapy during pregnancy on bone density. A prospective matched cohort study. Thromb Haemost 1996; 75:254–257.
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. Thromb Haemost 2002; 87:182–186.
Carlin AJ, Farquharson RG, Quenby SM, Topping J, Fraser WD. Prospective observational study of bone mineral density during pregnancy: low molecular weight heparin versus control. Hum Reprod 2004; 19:1211–1214.
Casele HL, Laifer SA. Prospective evaluation of bone density in pregnant women receiving the low molecular weight heparin enoxaparin sodium. J Matern Fetal Med 2000; 9:122–125.
Casele H, Haney EI, James A, Rosene-Montella K, Carson M. Bone density changes in women who receive thromboprophylaxis in pregnancy. Am J Obstet Gynecol 2006; 195:1109–1113.
Horlocker TT, Wedel DJ, Benzon H, et al. Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med 2003; 28:172–197.
Hirsh J, Dalen JE, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119 suppl 1:8S–21S.
Levine MN, Raskob G, Beyth RJ, Kearon C, Schulman S. Hemorrhagic complications of anticoagulant treatment: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004; 126 suppl 3:287S–310S.
Holmes LB. Teratogen-induced limb defects. Am J Med Genet 2002; 112:297–303.
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.
Pauzner R, Dulitzki M, Langevitz P, Livneh A, Kenett R, Many A. Low molecular weight heparin and warfarin in the treatment of patients with antiphospholipid syndrome during pregnancy. Thromb Haemost 2001; 86:1379–1384.
Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355:1295–1302.
Patrono C, Coller B, FitzGerald GA, Hirsh J, Roth G. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 suppl 3:234S–264S.
Duley L, Henderson-Smart DJ, Knight M, King JF. Antiplatelet agents for preventing preeclampsia and its complications. Cochrane Database Syst Rev. 2004; ( 1):CD004659.
Coomarasamy A, Honest H, Papaioannou S, Gee H, Khan KS. Aspirin for prevention of preeclampsia in women with historical risk factors: a systematic review. Obstet Gynecol 2003; 101:1319–1332.
Caritis SN, Sibai BM, Hauth J, et al, and the National Institute of Child Health and Human Development Network of Maternal Fetal Medicine Units. Low-dose aspirin to prevent preeclampsia in women at high risk. N Engl J Med 1998; 338:701–705.
Rai R, 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). BMJ 1997; 314:253–257.
Kozer E, Nikfar S, Costei A, Boskovic R, Nulman I, Koren G. Aspirin consumption during the first trimester of pregnancy and congenital anomalies: a meta-analysis. Am J Obstet Gynecol 2002; 187:1623–1630.
Sebastian C, Scherlag M, Kugelmass A, Schechter E. Primary stent implantation for acute myocardial infarction during pregnancy: use of abciximab, ticlopidine, and aspirin. Cathet Cardiovasc Diagn 1998; 45:275–249.
Wilson AM, Boyle AJ, Fox P. Management of ischaemic heart disease in women of child-bearing age. Intern Med J 2004; 34:694–697.
Klinzing P, Markert UR, Liesaus K, Peiker G. Case report: successful pregnancy and delivery after myocardial infarction and essential thrombocythemia treated with clopidogrel. Clin Exp Obstet Gynecol 2001; 28:215–216.
Danhof M, de Boer A, Magnani HN, Stiekema JC. Pharmacokinetic considerations on Orgaran (Org 10172) therapy. Haemostasis 1992; 22:73–84.
Tardy-Poncet B, Tardy B, Reynaud J, et al. Efficacy and safety of danaparoid sodium (ORG 10172) in critically ill patients with heparin-associated thrombocytopenia. Chest 1999; 115:1616–1620.
Lagrange F, Vergnes C, Brun JL, et al. Absence of placental transfer of pentasaccharide (fondaparinux, Arixtra) in the dually perfused human cotyledon in vitro. Thromb Haemost 2002; 87:831–835.
Dempfle CE. Minor transplacental passge of fondapinux in vivo. N Engl J Med 2004; 350:1914.
Magnani HN. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with orgaran (Org 10172). Thromb Haemost 1993; 70:554–561.
Lindhoff-Last E, Kreutzenbeck HJ, Magnani HN. Treatment of 51 pregnancies with danaparoid because of heparin intolerance. Thromb Haemost 2005; 93:63–69.
Greinacher A, Eckhardt T, Mussmann J, Mueller-Eckhardt C. Pregnancy complicated by heparin associated thrombocytopenia: management by a prospectively in vitro selected heparinoid (Org 10172). Thromb Res 1993; 71:123–126.
Schindewolf M, Mosch G, Bauersachs RM, Lindhoff-Last E. Safe anticoagulation with danaparoid in pregnancy and lactation. Thromb Haemost 2004; 92:211.
Harenberg J. Treatment of a woman with lupus and thromboembolism and cutaneous intolerance to heparins using fondaparinux during pregnancy. Thromb Res 2007; 119:385–388.
Wijesiriwardana A, Lees DA, Lush C. Fondaparinux as anticoagulant in a pregnant woman with heparin allergy. Blood Coagul Fibrinolysis 2006; 17:147–149.
Mazzolai L, Hohlfeld P, Spertini F, Hayoz D, Schapira M, Duchosal MA. Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy. Blood 2006; 108:1569–1570.
Hawkins D, Evans J. Minimizing the risk of heparin-induced osteoporosis during pregnancy. Expert Opin Drug Saf 2005; 4:583–590.
Brill-Edwards P, Ginsberg JS, Gent M, et al. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of clot in this pregnancy study group. N Engl J Med 2000; 343:1439–1444.
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A young pregnant woman with shortness of breath

Anticoagulants and pregnancy: When are they safe?

References

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Interrupting anticoagulation after an initial thrombotic event

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