Advertisement
Canadian Journal of Cardiology

Anticoagulation Regimens During Pregnancy in Patients With Mechanical Heart Valves: A Systematic Review and Meta-analysis

Published:November 12, 2015DOI:https://doi.org/10.1016/j.cjca.2015.11.005

      Abstract

      Background

      Managing anticoagulation in pregnant women with mechanical heart valves remains challenging. Our aim was to evaluate the effectiveness and safety of 4 regimens in these women.

      Methods

      Relevant studies published before June 2015 were collected in several databases and analyzed with RevMan version 5.3 and SPSS version 19.0. Four regimens were defined as follows: a regimen of a vitamin K antagonist (VKA) throughout pregnancy; a heparin (H)/VKA regimen using VKAs except for unfractionated heparin (UFH) or low molecular weight heparin (LMWH) during 6-12 weeks of pregnancy; a LMWH regimen of adjusted LMWH doses throughout pregnancy; and a UFH regimen of adjusted UFH doses throughout pregnancy. The low warfarin dose in the VKA regimen was defined as 5 mg/d or less.

      Results

      Fifty-one studies comprising 2113 pregnancies in 1538 women were included. The rate of fetal wastage was significantly higher in the high warfarin dose subgroup than in the low dose one. Compared with the H/VKA regimen, the rate of maternal major thromboembolic event in the low-dose VKA regimen group was significantly lower, although the fetal outcomes were similar. Compared with the H/VKA regimen, the rate of fetal wastage in the LMWH regimen group was significantly lower, and the maternal outcomes were similar. The UFH regimen presented the worst maternal and fetal outcomes.

      Conclusions

      In the absence of large prospective trials, this meta-analysis showed that the VKA regimen should be best for pregnant women with a low warfarin dose, and the H/VKA regimen might be reasonable for those with a high warfarin dose. The LMWH regimen could be used for those who refuse VKA.

      Résumé

      Introduction

      Le traitement anticoagulant chez les femmes enceintes munies de valvules cardiaques mécaniques demeure problématique. Notre objectif était d’évaluer l'efficacité de quatre traitements différents chez ces femmes.

      Méthodes

      Une série d’études pertinentes publiées avant juin 2015 ont été recueillies dans diverses bases de données et analysées à l'aide de la version 5.3 du logiciel RevMan et de la version 19.0 du logiciel SPSS. Les quatre traitements consistaient respectivement en: 1) l'administration d'un antagoniste de la vitamine K (AVK) pendant toute la grossesse; 2) l'administration d'héparine (H) et d'un AVK, c'est-à-dire un traitement à base d'un AVK auquel se substituait un traitement par une héparine non fractionnée (HNF) ou une héparine de faible poids moléculaire (HFPM) pendant 6 à 12 semaines de la grossesse; 3) l'administration d'héparine de faible poids moléculaire dont la dose était ajustée au besoin pendant toute la grossesse; et 4) l'administration d'héparine non fractionnée dont la dose était ajustée au besoin pendant toute la grossesse. Administrée en concomitance avec le traitement par l’AVK, une faible dose de warfarine était définie comme une dose de 5 mg ou moins de warfarine par jour.

      Résultats

      Cinquante et une études portant sur 2113 grossesses chez 1538 femmes ont été retenues. Le taux de perte du fœtus était significativement plus élevé chez le sous-groupe de femmes recevant une dose importante de warfarine par rapport à celui qui recevait une faible dose de warfarine. Comparativement aux femmes traitées par l'héparine et l’AVK, l'incidence des événements thromboemboliques graves a été significativement inférieure chez celles traitées par un AVK à faible dose, mais les effets pour les fœtus ont été comparables. Par rapport au groupe traité par l'héparine et l’AVK, l'incidence de perte du fœtus a été significativement moindre dans le groupe traité par l’HFPM, tandis que les effets pour les mères ont été semblables. C'est le traitement par l’HNF qui entraîné les pires résultats tant pour les mères que pour les fœtus.

      Conclusion

      En l'absence d'importantes études prospectives, cette méta-analyse a permis de déterminer que le traitement par un AVK est vraisemblablement le plus approprié pour les femmes enceintes recevant une faible dose de warfarine, tandis que celui par l’H/AVK pourrait être jugé acceptable pour les femmes enceintes traitées par une forte dose de warfarine. Le traitement par l’HFPM pourrait pour sa part être offert aux femmes enceintes qui refusent de prendre un AVK.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Canadian Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Sun J.C.
        • Davidson M.J.
        • Lamy A.
        • Eikelboom J.W.
        Antithrombotic management of patients with prosthetic heart valves: current evidence and future trends.
        Lancet. 2009; 374: 565-576
        • Nishimura R.A.
        • Otto C.M.
        • Bonow R.O.
        • et al.
        2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
        J Am Coll Cardiol. 2014; 63: 2438-2488
        • Guyatt G.H.
        • Akl E.A.
        • Crowther M.
        • et al.
        Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
        Chest. 2012; 141: 7S-47S
        • Regitz-Zagrosek V.
        • Blomstrom Lundqvist C.
        • Borghi C.
        • et al.
        • European Society of Gynecology
        • Association for European Paediatric Cardiology
        • German Society for Gender Medicine
        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.
        Eur Heart J. 2011; 32: 3147-3197
        • 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. 2000; 160: 191-196
        • James A.H.
        • Brancazio L.R.
        • Gehrig T.R.
        • et al.
        Low molecular-weight heparin for thromboprophylaxis in pregnant women with mechanical heart valves.
        J Matern Fetal Neonatal Med. 2006; 19: 543-549
        • 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
        • Stroup D.F.
        • Berlin J.A.
        • Morton S.C.
        • et al.
        Meta-analysis of observational studies in epidemiology: a proposal for reporting: meta-analysis of observational studies in epidemiology (MOOSE) group.
        JAMA. 2000; 283: 2008-2012
        • Castellano J.M.
        • Narayan R.L.
        • Vaishnava P.
        • Fuster V.
        Anticoagulation during pregnancy in patients with a prosthetic heart valve.
        Nat Rev Cardiol. 2012; 9: 415-424
        • Zeng X.
        • Zhang Y.
        • Kwong J.S.
        • et al.
        The methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review.
        J Evid Based Med. 2015; 8: 2-10
        • Wallis Sean A.
        Binomial confidence intervals and contingency tests: mathematical fundamentals and the evaluation of alternative methods.
        J Quant Linguis. 2013; 20: 178-208
        • Begg C.B.
        • Mazumdar M.
        Operating characteristics of a rank correlation test for publication bias.
        Biometrics. 1994; 50: 1088-1101
        • Egger M.
        • Davey Smith G.
        • Schneider M.
        • et al.
        Bias in meta-analysis detected by a simple, graphical test.
        BMJ. 1997; 315: 629-634
        • Casanegra P.
        • Avilés G.
        • Maturana G.
        • Dubernet J.
        Cardiovascular management of pregnant women with a heart valve prosthesis.
        Am J Cardiol. 1975; 36: 802-806
        • Ibarra-Perez C.
        • Arevalo-Toledo N.
        • Alvarez-de la Cadena O.
        • Noriega-Guerra L.
        The course of pregnancy in patients with artificial heart valves.
        Am J Med. 1976; 61: 504-512
        • Limet R.
        • Grondin C.M.
        Cardiac valve prostheses, anticoagulation, and pregnancy.
        Ann Thorac Surg. 1977; 23: 337-341
        • Lutz D.J.
        • Noller K.L.
        • Spittell Jr., J.A.
        • Danielson G.K.
        • Fish C.R.
        Pregnancy and its complications following cardiac valve prostheses.
        Am J Obstet Gynecol. 1978; 131: 460-468
        • Chen W.W.
        • Chan C.S.
        • Lee P.K.
        • Wang R.Y.
        • Wong V.C.
        Pregnancy in patients with prosthetic heart valves: an experience with 45 pregnancies.
        QJM. 1982; 203: 358-365
        • O’Neill H.
        • Blake S.
        • Sugrue D.
        • Macdonald D.
        Problems in the management of patients with artificial valves during pregnancy.
        Br J Gynecol Obstet. 1982; 89: 940-943
        • Salazar E.
        • Zajarias A.
        • Gutierrez N.
        • Iturbe I.
        The problem of cardiac valve prostheses, anticoagulants, and pregnancy.
        Circulation. 1984; 70: I169-I177
        • Guidozzi F.
        Pregnancy in patients with prosthetic cardiac valves.
        S Afr Med J. 1984; 65: 961-963
        • Javares T.
        • Coto E.O.
        • Maiques V.
        • et al.
        Pregnancy after heart valve replacement.
        Int J Cardiol. 1984; 5: 731-739
        • Matorras R.
        • Reque J.A.
        • Usandizaga J.A.
        • et al.
        Prosthetic heart valve and pregnancy. A study of 59 cases.
        Gynecol Obstet Invest. 1985; 19: 21-31
        • Iturbe-Alessio I.
        • Fonseca M.C.
        • Mutchinik O.
        • et al.
        Risks of anticoagulant therapy in pregnant women with artificial heart valves.
        N Engl J Med. 1986; 315: 1390-1393
        • Pavankumar P.
        • Venugopal P.
        • Kaul U.
        • et al.
        Pregnancy in patients with prosthetic cardiac valve. A 10-year experience.
        Scand J Thorac Cardiovasc Surg. 1988; 22: 19-22
        • Sareli P.
        • England M.J.
        • Berk M.R.
        • et al.
        Maternal and fetal sequelae of anticoagulation during pregnancy in patients with mechanical heart valve prostheses.
        Am J Cardiol. 1989; 63: 1462-1465
        • Ayhan A.
        • Yapar E.G.
        • Yüce K.
        • et al.
        Pregnancy and its complications after cardiac valve replacement.
        Int J Gynaecol Obstet. 1991; 35: 117-122
        • Bron D.
        • Martines E.E.
        • Almeida P.A.
        • et al.
        Pregnancy in patient with prosthetic heart valves the effect of anticoagulation on mother, fetus and neonatal.
        Am Heart J. 1992; 124: 413-417
        • Lee C.N.
        • Wu C.C.
        • Lin P.Y.
        • Hsieh F.J.
        • Chen H.Y.
        Pregnancy following cardiac prosthetic valve replacement.
        Obstet Gynecol. 1994; 83: 353-356
        • Meschengieser S.S.
        • Fondevila C.G.
        • Santarelli M.T.
        • Lazzari M.A.
        Anticoagulation in pregnant women with mechanical heart valve prostheses.
        Heart. 1999; 82: 23-26
        • Ashour Z.A.
        • Shawky H.A.
        • Hassan Hussein M.
        Outcome of pregnancy in women with mechanical valves.
        Tex Heart Inst J. 2000; 27: 240-245
        • Sadler L.
        • McCowan L.
        • White H.
        • et al.
        Pregnancy outcomes and cardiac complications in women with mechanical, bioprosthetic and homograft valves.
        BJOG. 2000; 107: 245-253
        • Hassouna A.
        • Allam H.
        Limited dose warfarin throughout pregnancy in patients with mechanical heart valve prosthesis: a meta-analysis.
        Interact Cardiovasc Thorac Surg. 2014; 18: 797-806
        • Hassouna A.
        • Allam H.
        Oral anticoagulation therapy during pregnancy in patients with mechanical mitral valves: a prospective study.
        Cardiovasc Surg. 2001; 9: 478-481
        • Al-Lawati A.A.
        • Venkitraman M.
        • Al-Delaime T.
        • Valliathu J.
        Pregnancy and mechanical heart valves replacement; dilemma of anticoagulation.
        Eur J Cardiothorac Surg. 2002; 22: 223-227
        • Cotrufo M.
        • De Feo M.
        • De Santo L.S.
        • et al.
        Risk of warfarin during pregnancy with mechanical valve prostheses.
        Obstet Gynecol. 2002; 99: 35-40
        • Vitale N.
        • De Feo M.
        • De Santo L.S.
        • et al.
        Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves.
        J Am Coll Cardiol. 1999; 33: 1637-1641
        • Nassar A.H.
        • Hobeika E.M.
        • Abd Essamad H.M.
        • et al.
        Pregnancy outcome in women with prosthetic heart valves.
        Am J Obstet Gynecol. 2004; 191: 1009-1013
        • Geelani M.A.
        • Singh S.
        • Verma A.
        • et al.
        Anticoagulation in patients with mechanical valves during pregnancy.
        Asian Cardiovasc Thorac Ann. 2005; 13: 30-33
        • Khamooshi A.J.
        • Kashfi F.
        • Hoseini S.
        • et al.
        Anticoagulation for prosthetic heart valves in pregnancy. Is there an answer?.
        Asian Cardiovasc Thorac Ann. 2007; 15: 493-496
        • Kim K.H.
        • Jeong D.S.
        • Ahn H.
        Anticoagulation in pregnant women with a bileaflet mechanical cardiac valve replacement.
        Heart Surg Forum. 2007; 10: 267-270
        • Lee J.H.
        • Park N.H.
        • Keum D.Y.
        • et al.
        Low molecular weight heparin treatment in pregnant women with a mechanical heart valve prosthesis.
        J Korean Med Sci. 2007; 22: 258-261
        • Akhtar R.P.
        • Abid A.R.
        • Zafar H.
        • Cheema M.A.
        • Khan J.S.
        Anticoagulation in pregnancy with mechanical heart valves: 10-year experience.
        Asian Cardiovasc Thorac Ann. 2007; 15: 497-501
        • Shannon M.S.
        • Edwards M.B.
        • Long F.
        • et al.
        Anticoagulant management of pregnancy following heart valve replacement in the United Kingdom, 1986-2002.
        J Heart Valve Dis. 2008; 17: 526-532
        • McLintock C.
        • McCowan L.M.
        • North R.A.
        Maternal complications and pregnancy outcome in women with mechanical prosthetic heart valves treated with enoxaparin.
        BJOG. 2009; 116: 1585-1592
        • Suri V.
        • Keepanasseril A.
        • Aggarwal N.
        • et al.
        Mechanical valve prosthesis and anticoagulation regimens in pregnancy: a tertiary centre experience.
        Eur J Obstet Gynecol Reprod Biol. 2011; 159: 320-323
        • 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: 1008-1013
        • Samiei N.
        • Kashfi F.
        • Khamoushi A.
        • et al.
        Pregnancy outcome after mechanical mitral valve replacement: a prospective study.
        J Teh Univ Heart Ctr. 2012; 7: 117-120
        • Khamoushi A.J.
        • Kashfi F.
        • Hosseini S.
        • et al.
        Anti-coagulation during pregnancy in women with mechanical heart valves: a prospective study.
        Int J Fertil Steril. 2011; 5: 47-51
        • Sillesen M.
        • Hjortdal V.
        • Vejlstrup N.
        • et al.
        Pregnancy with prosthetic heart valves—30 years’ nationwide experience in Denmark.
        Eur J Cardiothorac Surg. 2011; 40: 448-454
        • Sbarouni E.
        • Oakley C.M.
        Outcome of pregnancy in women with valve prostheses.
        Br Heart J. 1994; 71: 196-201
        • van Hagen I.M.
        • Roos-Hesselink J.W.
        • Ruys T.P.
        • 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: 132-142
        • Bhutta S.Z.
        • Aziz S.
        • Korejo R.
        Pregnancy following cardiac surgery.
        J Pak Med Assoc. 2003; 53: 407-413
        • Bouhout I.
        • Poirier N.
        • Mazine A.
        • et al.
        Cardiac, obstetric, and fetal outcomes during pregnancy after biological or mechanical aortic valve replacement.
        Can J Cardiol. 2014; 30: 801-807
        • Harenberg J.
        • Huhle G.
        • Piazolo L.
        • Giese C.
        • Heene D.L.
        Long-term anticoagulation of outpatients with adverse events to oral anticoagulants using low-molecular-weight heparin.
        Semin Thromb Hemost. 1997; 23: 167-172
        • Bauersachs R.
        • Lindhoff-Last E.
        Anticoagulation of pregnant women with mechanical heart valves using low-molecular weight heparin.
        Arch Intern Med. 2003; 163: 2788-2789
        • Abildgaard U.
        • Sandset P.M.
        • Hammerstrøm J.
        • Gjestvang F.T.
        • Tveit A.
        Management of pregnant women with mechanical heart valve prosthesis: thromboprophylaxis with low molecular weight heparin.
        Thromb Res. 2009; 124: 262-267
        • Rowan J.A.
        • McCowan L.M.
        • Raudkivi P.J.
        • North R.A.
        Enoxaparin treatment in women with mechanical heart valves during pregnancy.
        Am J Obstet Gynecol. 2001; 185: 633-637
        • Quinn J.
        • Klemperer K.V.
        • Brooks R.
        • 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. 2009; 94: 1608-1612
        • Yinon Y.
        • Siu S.C.
        • Warshafsky C.
        • et al.
        Use of low molecular weight heparin in pregnant women with mechanical heart valves.
        Am J Cardiol. 2009; 104: 1259-1263
        • Saeed C.R.
        • Frank J.B.
        • Pravin M.
        • et al.
        A prospective trial showing the safety of adjusted-dose enoxaparin for thromboprophylaxis of pregnant women with mechanical prosthetic heart valves.
        Clin Appl Thromb Hemost. 2011; 17: 313-319
        • Goland S.
        • Schwartzenberg S.
        • Fan J.
        • et al.
        Monitoring of anti-Xa in pregnant patients with mechanical prosthetic valves receiving low-molecular-weight heparin: peak or trough levels?.
        J Cardiovasc Pharmacol Ther. 2014; 19: 451-456
        • Berresheim M.
        • Wilkie J.
        • Nerenberg K.A.
        • Ibrahim Q.
        • Bungard T.J.
        A case series of LMWH use in pregnancy: should trough anti-Xa levels guide dosing?.
        Thromb Res. 2014; 134: 1234-1240
        • Mihaljevic T.
        • Paul S.
        • Leacche M.
        • et al.
        Valve replacement in women of childbearing age: influences on mother, fetus and neonate.
        J Heart Valve Dis. 2005; 14: 151-157
        • Kawamata K.
        • Neki R.
        • Yamanaka K.
        • et al.
        Risks and pregnancy outcome in women with prosthetic mechanical heart valve replacement.
        Circ J. 2007; 71: 211-213
        • Tanaka H.
        • Tanaka K.
        • Kamiya C.
        • et al.
        Analysis of anticoagulant therapy by unfractionated heparin during pregnancy after mechanical valve replacement.
        Circ J. 2014; 78: 878-881
        • Elkayam U.
        • Goland S.
        The search for a safe and effective anticoagulation regimen in pregnant women with mechanical prosthetic heart valves.
        J Am Coll Cardiol. 2012; 59: 1116-1118
        • McLintock C.
        Anticoagulant therapy in pregnant women with mechanical prosthetic heart valves: no easy option.
        Thromb Res. 2011; 127: S56-S60
        • Vahanian A.
        • Alfieri O.
        • Andreotti F.
        • et al.
        • Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology
        • European Association for Cardio-Thoracic Surgery
        Guidelines on the management of valvular heart disease The Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery.
        Eur Heart J. 2012; 33: 2451-2496
        • De Santo L.S.
        • Romano G.
        • Della Corte A.
        • et al.
        Mechanical aortic valve replacement in young women planning on pregnancy maternal and fetal outcomes under low oral anticoagulation, a pilot observational study on a comprehensive pre-operative counseling protocol.
        J Am Coll Cardiol. 2012; 59: 1110-1115
        • Bian C.E.
        • Wei Q.
        • Liu X.
        Influence of heart-valve replacement of warfarin anticoagulant therapy on perinatal outcomes.
        Arch Gynecol Obstet. 2012; 285: 347-351
        • Cotrufo M.
        • De Luc T.S.
        • Calabro R.
        • Mastrogiovanni G.
        • Lama D.
        Coumarin anticoagulation during pregnancy in patients with mechanical valve prostheses.
        Eur J Cardiothorac Surg. 1991; 5: 300-305
        • Friedrich E.
        • Hameed A.B.
        Fluctuations in anti-factor Xa levels with therapeutic enoxaparin anticoagulation in pregnancy.
        J Perinatol. 2010; 30: 253-257