Background: Pregnancy is associated with an increased risk of thrombosis in women with mechanical prosthetic heart valves. Effective anticoagulation is therefore critical in such patients but remains problematic, since oral anticoagulation and both unfractionated and low-molecular-weight heparin may be associated with important fetal and maternal side effects.
Purpose: To review information related to the use of anticoagulation with both warfarin and heparin and reassess the safety and efficacy of these therapies in pregnant women with mechanical prosthetic heart valves.
Data source and selection: A MEDLINE search from 1966 to October 2003 for English and non-English language articles that reported the use of anticoagulation in pregnancy was conducted. Articles were included if they reported use of anticoagulation in pregnancy with emphasis on those that included women with mechanical prosthetic heart valves.
Conclusions: Anticoagulation prophylaxis with both warfarin and heparin (unfractionated heparin and low-molecular-weight heparin) may be associated with important fetal and maternal side effects. Optional regimens for the treatment of low-risk and high-risk patients are proposed to minimize potential complications.
McGehee W . Anticoagulation in pregnancy. In Elkayam U, Gleicher N, (eds), Cardiac Problems in Pregnancy, 3rd edition. New York: Wiley-Liss, 1998, pp 407-417
2.
Elkayam U , Khan SS. Pregnancy in the patient with an artificial heart valve. In Elkayam U, Gleicher N, (eds), Cardiac Problems in Pregnancy, 3rd edition. New York: Wiley-Liss, 1998, pp 61-78
3.
Born D , Martinez EE, Almeida PA, et al. Pregnancy in patients with prosthetic heart valves: The effects of anticoagulation on mother, fetus and neonate. Am Heart J124:413-417, 1992
4.
Sbarouni E , Oakley CM. Outcome of pregnancy in women with valve prostheses. Br Heart J71:196-201, 1994
5.
Hanania G , Thomas D, Michel PL, et al. Pregnancy in patients with heart valve prosthesis. A French retrospective cooperative study (155 cases). Arch Mal Coeur87:429-437, 1994
6.
Lee CN , Wu CC, Lin PY, et al. Pregnancy following cardiac prosthetic valve replacement. Obstet Gynecol83:353-356, 1994
7.
Salazar E , Izaguirre R, Verdejo J, et al. Failure of adjusted doses of subcutaneous heparin to prevent thromboembolic phenomena in pregnant patients with mechanical cardiac valve prostheses. J Am Coll Cardiol27:1698-1703, 1996
8.
Meschengieser SS , Fondevila CG, Santarelli MT, et al. Anticoagulation in pregnant women with mechanical heart valve prostheses. Heart82:23-26, 1999
9.
Sadler L , McCowan L, White H, et al. Pregnancy outcomes and cardiac complications in women with mechanical, bioprosthetic and homograft valves. Br J Obstet Gynecol107:245-253, 2000
10.
Rowan JA , McCowan LM, Raudkivi PJ, et al. Enoxaparin treatment in women with mechanical heart valves during pregnancy. Am J Obstet Gynecol185:633-637, 2001
11.
Elkayam U . Anticoagulation in pregnant women with prosthetic heart valves: A double jeopardy. J Am Coll Cardiol27:1704-1706, 1996
12.
Elkayam U . Pregnancy through a prosthetic heart valve. J Am Coll Cardiol33:1642-1645, 1999
13.
Hung L , Rahimtoola SH. Prosthetic heart valves and pregnancy. Circulation107:1240-1246, 2003
14.
Barbour LA , Pickard J. Controversies in thromboembolic disease during pregnancy: A critical review. Obstet Gynecol86:621-633, 1995
15.
Dahlman TC . Osteoporotic fractures and the recurrence of thromboembolism during pregnancy and the puerperium in 184 women undergoing thromboprophylaxis with heparin. Am J Obstet Gynecol168:1265-1270, 1993
16.
Vongpatanasin W , Hillis LD, Lange RA. Prosthetic heart valves. N Engl J Med335:407-416, 1996
17.
Gohlke-Barwolf C , Acar J, Oakley C, et al. Guidelines for prevention of thromboembolic events in valvular heart disease. Study group of the working group on valvular heart disease of the European Society of Cardiology. Eur Heart J16:1320-1330, 1995
18.
Bonow RO , Carabello B, DeLeon AC, et al. ACC/AHA guidelines for the management of patients with valvular heart disease. J Am Coll Cardiol32:1486-1588, 1998
19.
Chan WS , Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves. A systemic review of the literature. Arch Intern Med160:191-196, 2000
20.
Vitale N , De Feo M, De Santo LS, et al. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. J Am Coll Cardiol33:1637-1641, 1999
21.
Physician’s Desk Reference 2001, Medical Economics Company, Inc.New Jersey, p 1138
22.
Wesseling J , Van Driel D, Heymans HS, et al. Coumarins during pregnancy: Long-term effects on growth and development of school-age children. Thrombosis Hemost85:609-613, 2001
23.
Evans W , Laifer SA, McNanley TJ, et al. Management of thromboembolic disease associated with pregnancy. J Maternal Fetal Med6:21-27, 1997
24.
Laurent P , Dussarat GV, Bonal J, et al. Low molecular weight heparins: A guide to their optimum use in pregnancy. Drugs62:463-477, 2002
Omri A , Delaloye JF, Andersen H, et al. Low molecular weight heparin Novo (LHN-1) does not cross the placenta during the second trimester of pregnancy. Thromb Hemost61:55-56, 1989
27.
Harenberg J , Schneider D, Heilmann L, et al. Lack of antifactor Xa activity in umbilical cord vein samples after subcutaneous administration of heparin or low molecular mass heparin in pregnant women. Haemostasis23:314-320, 1993
28.
Weitz JI . Low-molecular-weight heparins. N Engl J Med337:688-698, 1997
29.
Melandri G , Semprini F, Cervi V, et al. Comparison of efficacy of low molecular weight heparin (parnaparin) with that of unfractionated heparin in the presence of activated platelets in healthy subjects. Am J Cardiol72:450-454, 1993
30.
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 Med332:1330-1335, 1995
31.
Fausett MB , Vogtlander M, Lee RM, et al. Heparin-induced thrombocytopenia is rare in pregnancy. Am J Obstet Gynecol185:148-152, 2001
32.
Spandorfer JM , Lynch S, Weitz HH, et al. Use of enoxaparin for the chronically anticoagulated patient before and after procedures. Am J Cardiol84:478-480, 1999
33.
Galla JM , Fuhs BE. Outpatient anticoagulation protocol for mechanical valve recipients undergoing non-cardiac surgery. J Am Coll Cardiol. 135:531A, 2000
34.
Montalescot G , Polle V, Collet JP, et al. Low molecular weight heparin after mechanical heart valve replacement. Circulation101:1083-1086, 2000
35.
Johnson J , Turpie AG. Temporary discontinuation of oral anticoagulants: Role of low molecular weight heparin [abstract]. Thromb Haemost2323, 2001
36.
Arnaout MS , Kazma H, Khalil A, et al. Is there a safe anticoagulation protocol for pregnant women with prosthetic valves? Clin Exp Obst Gyn25:101-104, 1998
37.
Lee LH , Liauw PC, Ng AS. Low molecular weight heparin for thromboprophylaxis during pregnancy in 2 patients with mechanical mitral valve replacement. Thromb Haemost76:628-630, 1996
38.
Berndt N , Khan I, Gallo R. A complication in anticoagulation using low-molecular weight heparin in a patient with a mechanical valve prosthesis. A case report. J Heart Valve Dis9:844-846, 2000
39.
Ellison J , Thomson AJ, Walker ID, et al. Use of enoxaparin in a pregnant woman with a mechanical heart valve prosthesis. Br J Obstet Gynecol108:757-759, 2001
40.
Idir M , Madonna F, Roudant R. Collapse and massive pulmonary edema secondary to thrombosis of a mitral mechanical heart valve prosthesis during low-molecular weight heparin therapy. J Heart Valve Dis8:303-304, 1999
41.
Lev-Ran O , Kramer A, Gurevitch J, et al. Low-molecular-weight heparin for prosthetic heart valves: Treatment failure. Ann Thorac Surg69:264-266, 2000
42.
Oles D , Berryessa R, Campbell K, et al. Emergency redo mitral valve replacement in a 27-year-old pregnant female with a clotted prosthetic mitral valve, preoperative fetal demise and postoperative ventricular assist device: A case report. Perfusion16:159-164, 2001
43.
Tenconi PM , Gatti L, Acacia B. Low molecular weight heparin in pregnant women with mechanical heart valve prosthesis: A case report [abstract]. Thromb Haemost734, 1997
44.
Naqvi TZ , Foster E. Anticoagulation during pregnancy. Curr Womens Health Rep2:95-104, 2002
45.
Data on file, Aventis Pharmaceuticals
46.
Leyh RT , Fischer S, Ruhparwar, et al. Anticoagulant therapy in pregnant women with mechanical heart valves. Arch Gynecol Obstet268:1-4, 2003
47.
Brennand JE , Walker ID, Greer IA. Anti-activated factor X profiles in pregnant women receiving antenatal thromboprophylaxis with enoxaparin. Acta Haematol101:53-55, 1999
48.
Casele HL , Laifer SA, Woelkers DA, et al. Changes in the pharmacokinetics of low-molecular-weight heparin enoxaparin sodium during pregnancy. Am J Obstet Gynecol181:1113-1117, 1999
49.
Blomback M , Bremme K, Hellgren M, et al. A pharmacokinetic study of dalteparin (Fragmin) during late pregnancy. Blood Coagul Fibrinolysis9:343-350, 1998
Hirsh J , Warkentin TE, Raschke R, et al. Heparin and low-molecular-weight heparin: Mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest114:489S-510S, 1998
54.
Volles DF , Ancell CJ, Michael KA, et al. Establishing an institution-specific therapeutic range for heparin. Am J Health Syst Pharm55:2002-2006, 1998
55.
Laposata M , Green D, Van Cott EM, et al. College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulation therapy: The clinical use and laboratory monitoring of low-molecular-weight heparin, danaparoid, hirudin and related compounds, and argatroban. Arch Pathol Lab Med122:799-807, 1998
56.
Duplaga BA , Rivers CW, Nutescu E. Dosing and monitoring of low-molecular-weight heparins in special populations. Pharmacotherapy21:218-234, 2001
57.
Campbell PJ , Tirvengadum MA, Pickering W, et al. HEP-TEST: A suitable method for monitoring heparin during pregnancy. Clin Laboratory Haematol21:193-199, 1999
58.
Klein SM , Slaughter TF, Vail PT, et al. Thromboelastography as a perioperative measure of anticoagulation resulting from low molecular weight heparin: A comparison with anti-Xa concentrations. Anesth Analg. 91:1091-1095, 2000
59.
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. Am J Obstet Gynecol176:1062-1068, 1997
60.
Collet JP , Montalescot G, Lison L, et al. Percutaneous coronary intervention after subcutaneous enoxaparin pre-treatment in patients with unstable angina pections. Circulation103:658-663, 2001
61.
Anonymous . Dose-ranging trial of enoxaparin for unstable angina: Results of TIMI 11A. The Thrombolysis in Myocardial Infarction (TIMI) 11A Trial Investigators. J Am Coll Cardiol29:1474-1482, 1997
62.
Ginsberg JS , Greer I, Hirsh J. Use of antithrombotic agents during pregnancy. Sixth Consensus Conference on antithrombotic therapy. Chest119:122S-131S, 2001
63.
Stein PD , Alpert JS, Bussey HI, et al. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest119:220S-227S, 2001
64.
Thorp JA , White RD, Westergom KL, et al. Intracranial hemorrhage (ICH) in premature infants. Epidemiology and Prevention. CNS Drugs1999
65.
Thorp JA , Poskin MF, McKenzie DR, et al. Perinatal factors predicting severe intracranial hemorrhage. Am J Perinatal14:631-636, 1997
66.
Ginsberg JS , Chan WS, Bates SH, et al. Anticoagulation of pregnant women with mechanical heart valves. Arch Int Med163:694-698, 2003
67.
Anderson DR , Ginsberg JS, Burrows R, et al. Subcutaneous heparin therapy during pregnancy: A need for concern at the time of delivery. Thromb Haemost65:248-250, 1991
68.
Barbour L , Lehahal P, Oja J, et al. A prospective trial demonstrating dalteparin requirements increase in pregnancy to maintain therapeutic levels of anticoagulation. Am J Obstet Gynecol (in press).
69.
Bombeli T , Raddatz Mueller P, Fehr J. Evaluation of an optimal dose of low-molecular-weight heparin for thrromboprophylaxis in pregnant women at risk of thrombosis using coagulation activation markers. Haemostasis31:90-98, 2001
70.
Turpie AG , Gent M, Laupacis A, et al. A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement. N Engl J Med329:524-529, 1993
71.
Cappelleri JC , Fiore LD, Brophy MT, et al. Efficacy and safety of combined anticoagulant and antiplatelet therapy versus anticoagulant monotherapy after mechanical heart-valve replacement: A metaanalysis. Am Heart J130:547-552, 1995
72.
Meschengieser SS , Fondevila CG, Frontroth J, et al. Low-intensity oral anticoagulation plus low-dose aspirin versus high-intensity oral anticoagulation alone: a randomized trial in patients with mechanical prosthetic heart valves. J Thorac Cardiovasc Surg113:910-916, 1997
