Pregnancy in patients with prosthetic valves: The effects of anticoagulation mother, fetus, and neonate
heart on
Maternal and fetal complications in a consecutive serjes of 60 pregnancies in 49 patients with prosthetic heart valves were prospectively evaluated. Group 1 consisted of 40 pregnancies in 31 patients who were taking oral anticoagulants. No oral anticoagulation was used in 20 pregnancies in 19 patients (group 2). In group 1 there were three instances of acute valvular thrombosis during the 35 pregnancies in patients with mechanical prostheses, with two maternal deaths. There were two episodes of cerebral embolism, one in group 1 and one in group 2. Patients with isolated aortic valve replacement had fewer maternal complications (2 of 13) than patients with isolated mitral valve replacement (15 of 42) without statistical significance. Severe bioprosthesis dysfunction occurred in 4 of 25 pregnancies (one rupture and three stenosis) with two maternal deaths, one in the puerperium and the other in the postoperative period of cardiac surgery during pregnancy. When analyzing obstetric events we observed seven spontaneous abortions and one hydatidiform mole. All spontaneous abortions occurred in group 1. The incidences of prematurity and low birth weight were significantly higher in group 1 than in group 2 (46.6% vs lOS%, p < 0.05, and 50% vs lOS%, p < 0.05, respectively). Moreover, there was a significant association between prematurity and the mother’s New York Heart Association functional class (61.5% in classes Ill and IV vs 22.2% in classes I and II, p < 0.05). There were five neonatal deaths, all in group 1 (p = NS vs group 2). Three infants had warfarin-related congenital defects. We conclude that pregnancy in patients with artificial valves is a high-risk situation for both the fetus and the mother. (AM HEART J 1992;124:413.)
Daniel Born, Eulogio E. Martinez, Pedro A. M. Almeida, Dirceu V. Santos, Antonio C. C. Carvalho, Antonio F. Moron, Celia H. Miyasaki, Sergio D. Moraes, and John A. Ambrose S&o Paulo, Brazil, and New York, N.Y.
Pregnancy creates several problems for patients with artificial heart valves. Maternal and fetal morbidity are increased especially in patients with mechanical valves who require oral anticoagulation.1-6 In patients with a biological prosthesis in whom oral anticoagulation is not required, maternal and fetal morbidity and mortality appear to be lessened.7-g There is still a high incidence of rheumatic heart disease in Brazil, and a growing population of young women have undergone cardiac surgery and valve replacement. In this article we describe our experience in the management of pregnant women with a cardiac valve prosthesis at a large hospital in Sao Paulo. The maternal and fetal complications in a consecutive seFrom the Department Division of Cardiology, Received Reprint Paula 4/1/38090
of Cardiology, Department
for publication requests: SP 04512,
Eulogio Brazil.
May
Escola Paulista de Medicina; and the of Medicine, Mount Sinai Hospital.
17. 1991;
E. Martinez,
accepted MD,
Rua
Jan. 20. 1992. Escobar
Ortiz,
699, Sao
ries of 60 pregnancies in 49 patients were prospectively evaluated. Although previous studies on pregnancy in patients with artificial valves have reported an increased incidence of fetal and newborn complications, this report also considers the relationship between fetal complications and the functional cardiac status of the mother. METHODS
The same cardiologist prospectively evaluated all patients seenin the outpatient clinics of the Medical School of the Federal University of SBoPaulo between June 1981 and August 1988.Most patients werefirst seenin the clinic after the third month of gestation. In all patients valve replacement wasperformed before pregnancy for symptomatic rheumatic valve disease.The most often usedmechanical valves were Lillehei-Kaster valves in 16 patients and Starr-Edwards valves in eight. The biological valves used (25 in 23 patients) were Carpentier-Edwards valves in six patients, dura mater in six, bovine pericardium valves in seven, and other porcine bioprosthesesin six. The valves were provided by the Brazilian National Health Institute 413
414
Born et al.
Table
I. Patient population
American
GFOU~
1
GFOUp
With anticoagulation
Pregnancies Patients Age (yr) Primigravid Multigravid Time from surgery pregnancy (mo) Digitalis and/or diuretic MVR AoVR MVR and AoVR Mechanical Biological Biological and mechanical MVR, Mitral significant.
valve
to
40 31 30 9 31 65
:!
WithOUt anticoagulation
NS NS NS NS
20 19 27 4 16 55
37 (92.55,)
NS
19 (95%)
27 9 4 34 5 1
NS NS NS
15 (75’r ) 4 (2O’i.j 1 (ifi’;,)
replacement:
p 6 (22.5@; ) (77.5%) p 47
(67.5’;) (22.54,) (lo”;) (85% ) (ST, (2.5”;)
AoVR,
p < 0.05 p < 0.05
NS
p 5 (20”
)
August 1992 Heart Journal
7 (22.2c1 bt 8 (61.fjC< )
Lou) birth weight 10 (27.7’;,
7 (53.8’;
Stillbirth
Neonatal mortalit)
Birth
defects
,$
1
5
4
)
1
0
0
therapy.
All seven spontaneous abortions mothers who were in functional
occurred in group 1 class I or II.
DISCUSSION
It is generally accepted that in patients with prosthetic heart valves who require continuous anticoagulation with coumarin-like drugs (i.e., all patients with mechanical valves and patients with bioprosthetic valves in atria1 fibrillation), risk to the fetus is increased during pregnancy. In addition, there is an increased risk of spontaneous abortion and stillbirths.11-13 The latter may be related to intrauterine hemorrhage associated with excessive anticoagulation. Published reports suggest that the risk of perinatal hemorrhage from second- and third-trimester exposure to oral anticoagulants is 5 % to 10 70 ,14 and the risk of malformations is also increased.14q l5 The most common fetal malformations are warfarin embryopathy and central nervous system abnormalities. The incidence of warfarin embryopathy varies from 3.5 7; to 5 7; .3,16-18 Whereas fetal complications increase in women who continue oral anticoagulation therapy,s lg maternal complications appear to be decreased if oral anticoagulation is continued during pregnancy.7, 13*so Salazar et a1.6 found a significantly higher incidence of thromboembolic phenomena in women in whom antiplatelet agents were substituted for oral anticoagulants throughout pregnancy. Even when subcutaneous heparin has been substituted for oral anticoagulants early in pregnancy, there have been reports of maternal thromboembolic complications.l”, 2o However, subcutaneous heparin in higher doses to maintain a partial thromboplastin time >1.5 times the control value has been recommended1 and is reported to be associated with a low risk of thromboembolic complications l2 when used in the first trimester and in the last 2 weeks of gestation. In our study there was an 8.5 % incidence of valve thrombosis in mechanical valves, in spite of the fact that the target prothrombin times were somewhat longer than those currently accepted in the United States (2 to 2.5 times the control values in our study vs 1.5 to 2
times the control value). The frequency of valve thrombosis might have been even higher if we had used the lower target prothrombin times. Moreover, two of the three mechanical valve thromboses in the present study occurred in patients in whom anticoagulation was inadequate. Although it has been suggested that coumarin-like drugs should be omitted in the first trimester and during the last 1 or 2 weeks of pregnancy because of fetal risk,15, 22,23 this is often impossible, especially in third-world countries where pregnant women rarely seek medical attention before the second trimester. Therefore in our study population coumarin-like drugs were not routinely omitted during the first trimester. The study population reported here is one of the largest in the literature. Our findings confirm the higher incidence of fetal and newborn complications in women treated with oral anticoagulants (Group 1). Women who were not receiving coumarin (bioprosthetic valves in sinus rhythm) had a lower incidence of fetal complications. Spontaneous abortion and stillbirths occurred only in patients receiving oral anticoagulants. In addition, the incidence of prematurity and low birth weight was also increased in mothers treated with oral anticoagulation. The reasons for the higher incidence of prematurity in mothers receiving coumarin-like drugs are not fully understood. There was a significant increase in the incidence of prematurity in mothers with functional class III or IV heart failure versus classes I and II. This is the first study to report such a finding, which is possibly related to some adverse effects of maternal heart failure on intrauterine physiology. It is interesting that we did not find an increase in maternal complications among patients receiving oral anticoagulants. Except, in two women with valve thrombosis and presumed inadequate anticoagulation, most complications (heart failure and arrhythmias) occurred in women with mitral valves, prostheses and these did not appear to be related to the presence of anticoagulation. Aortic valve prostheses were better tolerated during
Volume Number
124 2
pregnancy than mitral valve prostheses. The higher incidence of atria1 arrhythmias and thromboembolic complications seen in general with mitral prostheses probably explains this finding in our study population. As in other seriess,g> l3 of pregnant women with prosthetic valves, we found that bioprosthetic valves without anticoagulation were associated with a lower incidence of fetal complications. Even though pregnancy is accompanied by a hypercoagulable state, bioprosthetic valves in sinus rhythm do not appear to require coumarin during pregnancy. We conclude that pregnancy in patients with artificial heart valves is risky for both the fetus and the mother. Prematurity has been shown to be more frequent in pregnancies in which the mother has severe heart failure and/or receives oral anticoagulants during the gestational period. Low birth weight is also more frequent among infants born of mothers treated with anticoagulants. These results suggest as in prior studies that it is the anticoagulation status of the mother that is most important and that bioprosthetic valves when feasible are preferable for women who desire children. REFERENCES
1. Ben-Ismail M, Abid F, Trabelsi S, Taktak M, Fekih M. Cardiac valve prostheses, anticoagulation and pregnancy. Br Heart J 1986;55:101-5. 2. Chen WWC, Chan CS, Lee PK, Wang RYC, Wong VCW. Pregnancy in patients with prosthetic heart valves: an experience with 45 pregnancies. Q J Med 1982;51:358-65. 3. Hirsh J, Cade JF, O’Sullivan EF. Clinical experience with anticoagulant therapy during pregnancy. Br Med J 1970;1:270-3. 4. Iturbe-Alescio I. Fonseca MC, Mutchinik 0, Santos MA, Zajarias A, Salazar E. Risks of anticoagulant therapy in pregnant women with artificial heart valves. N Engl J Med 1986; 315:1390-3. 5. Lutz DJ, Noller KL, Spittel Jr JR, Danielson GK, Fish CR. Pregnancy and complications following cardiac valve prostheses. Am J Obstet Gynecol 1978;131:460-6. 6. Salazar E, Zajaria A, Gutierrez N, Iturbe I. The problem of cardiac valve prostheses, anticoagulants, and pregnancy. Circulation 1984;7O(suppl 1):1169-77.
Anticoagulation
effects on pregnancy
417
7. Bortolotti U, Milan0 A, Mazzucco A, Valfre C, Russo R, Valente M, Schivazappa L, Thiene G, GaIIucci V. Pregnancy in patients with a porcine valve bioprotheses. Am J Cardiol 1982;50:1051-4. 8. Denbow CE, Matadial L, Sivapragasam S, Spencer H. Pregnancy in patients after homograft cardiac valve replacement. Chest 1983;83:540-2. 9. Deviri E, Levinsky L, Yechezkel M, Levy MJ. Pregnancy after valve replacement with porcine xenograft prostheses. Surg Gynecol Obstet 1985;160:437-43. 10. Capurro H, Knochezky S, Fonseca D, Caldero-Barcia R. A simplified method for diagnosis of gestational age in the newborn infant. J Pediatr 1978;93:120-2. 11. Javares T, Coto EO, Maiques V, Rincon A, Such M, Caffarena JM. Pregnancy after heart valve replacement. Int J Cardiol 198+5:731-g. 12. Lee PK, Wang RYC, Chow JSF, Cheng KL, Wong VCW, Chang TK. Combined use of warfarin and adjusted subcutaneous heparin during pregnancy in patients with an artificial heart valve. J Am Co11 Cardiol 1986;8:221-4. 13. Oakley C. Valve prostheses and pregnancy. Br Heart J 1987;58:303-5. 14. Stevenson RE, Burton M, Ferlauto GJ, Taylor HA. Hazards oforalanticoagulantsduringpregnancy. JAMA1980;243:154951. 15. Hall JG, Pauli M, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980;68:122-40. 16. Berman LB, Aledort L. Anticoagulation in pregnancy. In: Elkayan U, Gleicher N,. eds. Cardiac problems in pregnancy: diagnosis and management of maternal and fetal disease. New York: Alan R. Liss, Inc., 1982:261-72. 17. Fillmore SJ, McDevitt E. Effects of coumarin compounds on the fetus. Ann Intern Med 1970;73:731-5. 18. Harrison EC, Roschke EJ. Pregnancy in patients with cardiac valve prostheses. Clin Obstet Gynecol1975;18:107-23. 19. Bloomfield DK. Fetal deaths and malformations associated with the use of coumarin derivates in pregnancy. Am J Obstet Gynecol 1970;107:883-8. 20. Matorras R, Reque JA, Usandizaga JA, Minquez JA, Larrea JL, Nunez L. Prosthetic heart valve and pregnancy-a study of 59 cases. Gynecol Obstet Invest 1985;19:21-31. 21. Chesebro JH, Adams PC, Fuster V. Antithrombotic therapy in patients with valvular heart disease and prosthetic heart valves. J Am Co11 Cardiol 1986;8(suppl B):4i-56B. 22. Ibarra-Perez C. Arevalo-Toledo N.De La Cadena OA. NorienaGuerra L. The’course of pregnancy in patients with artifiGa1 heart valves. Am J Med 1976;61:504-12. 23. Larrea JL, Nunez L, Reque JA, Aguado MG, Matorras R, Minquez JA. Pregnancy and mechanical valve prostheses: a high risk situation for the mother and the fetus. Ann Thorac S&g 1983;36:459-63.
heart on
Maternal and fetal complications in a consecutive serjes of 60 pregnancies in 49 patients with prosthetic heart valves were prospectively evaluated. Group 1 consisted of 40 pregnancies in 31 patients who were taking oral anticoagulants. No oral anticoagulation was used in 20 pregnancies in 19 patients (group 2). In group 1 there were three instances of acute valvular thrombosis during the 35 pregnancies in patients with mechanical prostheses, with two maternal deaths. There were two episodes of cerebral embolism, one in group 1 and one in group 2. Patients with isolated aortic valve replacement had fewer maternal complications (2 of 13) than patients with isolated mitral valve replacement (15 of 42) without statistical significance. Severe bioprosthesis dysfunction occurred in 4 of 25 pregnancies (one rupture and three stenosis) with two maternal deaths, one in the puerperium and the other in the postoperative period of cardiac surgery during pregnancy. When analyzing obstetric events we observed seven spontaneous abortions and one hydatidiform mole. All spontaneous abortions occurred in group 1. The incidences of prematurity and low birth weight were significantly higher in group 1 than in group 2 (46.6% vs lOS%, p < 0.05, and 50% vs lOS%, p < 0.05, respectively). Moreover, there was a significant association between prematurity and the mother’s New York Heart Association functional class (61.5% in classes Ill and IV vs 22.2% in classes I and II, p < 0.05). There were five neonatal deaths, all in group 1 (p = NS vs group 2). Three infants had warfarin-related congenital defects. We conclude that pregnancy in patients with artificial valves is a high-risk situation for both the fetus and the mother. (AM HEART J 1992;124:413.)
Daniel Born, Eulogio E. Martinez, Pedro A. M. Almeida, Dirceu V. Santos, Antonio C. C. Carvalho, Antonio F. Moron, Celia H. Miyasaki, Sergio D. Moraes, and John A. Ambrose S&o Paulo, Brazil, and New York, N.Y.
Pregnancy creates several problems for patients with artificial heart valves. Maternal and fetal morbidity are increased especially in patients with mechanical valves who require oral anticoagulation.1-6 In patients with a biological prosthesis in whom oral anticoagulation is not required, maternal and fetal morbidity and mortality appear to be lessened.7-g There is still a high incidence of rheumatic heart disease in Brazil, and a growing population of young women have undergone cardiac surgery and valve replacement. In this article we describe our experience in the management of pregnant women with a cardiac valve prosthesis at a large hospital in Sao Paulo. The maternal and fetal complications in a consecutive seFrom the Department Division of Cardiology, Received Reprint Paula 4/1/38090
of Cardiology, Department
for publication requests: SP 04512,
Eulogio Brazil.
May
Escola Paulista de Medicina; and the of Medicine, Mount Sinai Hospital.
17. 1991;
E. Martinez,
accepted MD,
Rua
Jan. 20. 1992. Escobar
Ortiz,
699, Sao
ries of 60 pregnancies in 49 patients were prospectively evaluated. Although previous studies on pregnancy in patients with artificial valves have reported an increased incidence of fetal and newborn complications, this report also considers the relationship between fetal complications and the functional cardiac status of the mother. METHODS
The same cardiologist prospectively evaluated all patients seenin the outpatient clinics of the Medical School of the Federal University of SBoPaulo between June 1981 and August 1988.Most patients werefirst seenin the clinic after the third month of gestation. In all patients valve replacement wasperformed before pregnancy for symptomatic rheumatic valve disease.The most often usedmechanical valves were Lillehei-Kaster valves in 16 patients and Starr-Edwards valves in eight. The biological valves used (25 in 23 patients) were Carpentier-Edwards valves in six patients, dura mater in six, bovine pericardium valves in seven, and other porcine bioprosthesesin six. The valves were provided by the Brazilian National Health Institute 413
414
Born et al.
Table
I. Patient population
American
GFOU~
1
GFOUp
With anticoagulation
Pregnancies Patients Age (yr) Primigravid Multigravid Time from surgery pregnancy (mo) Digitalis and/or diuretic MVR AoVR MVR and AoVR Mechanical Biological Biological and mechanical MVR, Mitral significant.
valve
to
40 31 30 9 31 65
:!
WithOUt anticoagulation
NS NS NS NS
20 19 27 4 16 55
37 (92.55,)
NS
19 (95%)
27 9 4 34 5 1
NS NS NS
15 (75’r ) 4 (2O’i.j 1 (ifi’;,)
replacement:
p 6 (22.5@; ) (77.5%) p 47
(67.5’;) (22.54,) (lo”;) (85% ) (ST, (2.5”;)
AoVR,
p < 0.05 p < 0.05
NS
p 5 (20”
)
August 1992 Heart Journal
7 (22.2c1 bt 8 (61.fjC< )
Lou) birth weight 10 (27.7’;,
7 (53.8’;
Stillbirth
Neonatal mortalit)
Birth
defects
,$
1
5
4
)
1
0
0
therapy.
All seven spontaneous abortions mothers who were in functional
occurred in group 1 class I or II.
DISCUSSION
It is generally accepted that in patients with prosthetic heart valves who require continuous anticoagulation with coumarin-like drugs (i.e., all patients with mechanical valves and patients with bioprosthetic valves in atria1 fibrillation), risk to the fetus is increased during pregnancy. In addition, there is an increased risk of spontaneous abortion and stillbirths.11-13 The latter may be related to intrauterine hemorrhage associated with excessive anticoagulation. Published reports suggest that the risk of perinatal hemorrhage from second- and third-trimester exposure to oral anticoagulants is 5 % to 10 70 ,14 and the risk of malformations is also increased.14q l5 The most common fetal malformations are warfarin embryopathy and central nervous system abnormalities. The incidence of warfarin embryopathy varies from 3.5 7; to 5 7; .3,16-18 Whereas fetal complications increase in women who continue oral anticoagulation therapy,s lg maternal complications appear to be decreased if oral anticoagulation is continued during pregnancy.7, 13*so Salazar et a1.6 found a significantly higher incidence of thromboembolic phenomena in women in whom antiplatelet agents were substituted for oral anticoagulants throughout pregnancy. Even when subcutaneous heparin has been substituted for oral anticoagulants early in pregnancy, there have been reports of maternal thromboembolic complications.l”, 2o However, subcutaneous heparin in higher doses to maintain a partial thromboplastin time >1.5 times the control value has been recommended1 and is reported to be associated with a low risk of thromboembolic complications l2 when used in the first trimester and in the last 2 weeks of gestation. In our study there was an 8.5 % incidence of valve thrombosis in mechanical valves, in spite of the fact that the target prothrombin times were somewhat longer than those currently accepted in the United States (2 to 2.5 times the control values in our study vs 1.5 to 2
times the control value). The frequency of valve thrombosis might have been even higher if we had used the lower target prothrombin times. Moreover, two of the three mechanical valve thromboses in the present study occurred in patients in whom anticoagulation was inadequate. Although it has been suggested that coumarin-like drugs should be omitted in the first trimester and during the last 1 or 2 weeks of pregnancy because of fetal risk,15, 22,23 this is often impossible, especially in third-world countries where pregnant women rarely seek medical attention before the second trimester. Therefore in our study population coumarin-like drugs were not routinely omitted during the first trimester. The study population reported here is one of the largest in the literature. Our findings confirm the higher incidence of fetal and newborn complications in women treated with oral anticoagulants (Group 1). Women who were not receiving coumarin (bioprosthetic valves in sinus rhythm) had a lower incidence of fetal complications. Spontaneous abortion and stillbirths occurred only in patients receiving oral anticoagulants. In addition, the incidence of prematurity and low birth weight was also increased in mothers treated with oral anticoagulation. The reasons for the higher incidence of prematurity in mothers receiving coumarin-like drugs are not fully understood. There was a significant increase in the incidence of prematurity in mothers with functional class III or IV heart failure versus classes I and II. This is the first study to report such a finding, which is possibly related to some adverse effects of maternal heart failure on intrauterine physiology. It is interesting that we did not find an increase in maternal complications among patients receiving oral anticoagulants. Except, in two women with valve thrombosis and presumed inadequate anticoagulation, most complications (heart failure and arrhythmias) occurred in women with mitral valves, prostheses and these did not appear to be related to the presence of anticoagulation. Aortic valve prostheses were better tolerated during
Volume Number
124 2
pregnancy than mitral valve prostheses. The higher incidence of atria1 arrhythmias and thromboembolic complications seen in general with mitral prostheses probably explains this finding in our study population. As in other seriess,g> l3 of pregnant women with prosthetic valves, we found that bioprosthetic valves without anticoagulation were associated with a lower incidence of fetal complications. Even though pregnancy is accompanied by a hypercoagulable state, bioprosthetic valves in sinus rhythm do not appear to require coumarin during pregnancy. We conclude that pregnancy in patients with artificial heart valves is risky for both the fetus and the mother. Prematurity has been shown to be more frequent in pregnancies in which the mother has severe heart failure and/or receives oral anticoagulants during the gestational period. Low birth weight is also more frequent among infants born of mothers treated with anticoagulants. These results suggest as in prior studies that it is the anticoagulation status of the mother that is most important and that bioprosthetic valves when feasible are preferable for women who desire children. REFERENCES
1. Ben-Ismail M, Abid F, Trabelsi S, Taktak M, Fekih M. Cardiac valve prostheses, anticoagulation and pregnancy. Br Heart J 1986;55:101-5. 2. Chen WWC, Chan CS, Lee PK, Wang RYC, Wong VCW. Pregnancy in patients with prosthetic heart valves: an experience with 45 pregnancies. Q J Med 1982;51:358-65. 3. Hirsh J, Cade JF, O’Sullivan EF. Clinical experience with anticoagulant therapy during pregnancy. Br Med J 1970;1:270-3. 4. Iturbe-Alescio I. Fonseca MC, Mutchinik 0, Santos MA, Zajarias A, Salazar E. Risks of anticoagulant therapy in pregnant women with artificial heart valves. N Engl J Med 1986; 315:1390-3. 5. Lutz DJ, Noller KL, Spittel Jr JR, Danielson GK, Fish CR. Pregnancy and complications following cardiac valve prostheses. Am J Obstet Gynecol 1978;131:460-6. 6. Salazar E, Zajaria A, Gutierrez N, Iturbe I. The problem of cardiac valve prostheses, anticoagulants, and pregnancy. Circulation 1984;7O(suppl 1):1169-77.
Anticoagulation
effects on pregnancy
417
7. Bortolotti U, Milan0 A, Mazzucco A, Valfre C, Russo R, Valente M, Schivazappa L, Thiene G, GaIIucci V. Pregnancy in patients with a porcine valve bioprotheses. Am J Cardiol 1982;50:1051-4. 8. Denbow CE, Matadial L, Sivapragasam S, Spencer H. Pregnancy in patients after homograft cardiac valve replacement. Chest 1983;83:540-2. 9. Deviri E, Levinsky L, Yechezkel M, Levy MJ. Pregnancy after valve replacement with porcine xenograft prostheses. Surg Gynecol Obstet 1985;160:437-43. 10. Capurro H, Knochezky S, Fonseca D, Caldero-Barcia R. A simplified method for diagnosis of gestational age in the newborn infant. J Pediatr 1978;93:120-2. 11. Javares T, Coto EO, Maiques V, Rincon A, Such M, Caffarena JM. Pregnancy after heart valve replacement. Int J Cardiol 198+5:731-g. 12. Lee PK, Wang RYC, Chow JSF, Cheng KL, Wong VCW, Chang TK. Combined use of warfarin and adjusted subcutaneous heparin during pregnancy in patients with an artificial heart valve. J Am Co11 Cardiol 1986;8:221-4. 13. Oakley C. Valve prostheses and pregnancy. Br Heart J 1987;58:303-5. 14. Stevenson RE, Burton M, Ferlauto GJ, Taylor HA. Hazards oforalanticoagulantsduringpregnancy. JAMA1980;243:154951. 15. Hall JG, Pauli M, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980;68:122-40. 16. Berman LB, Aledort L. Anticoagulation in pregnancy. In: Elkayan U, Gleicher N,. eds. Cardiac problems in pregnancy: diagnosis and management of maternal and fetal disease. New York: Alan R. Liss, Inc., 1982:261-72. 17. Fillmore SJ, McDevitt E. Effects of coumarin compounds on the fetus. Ann Intern Med 1970;73:731-5. 18. Harrison EC, Roschke EJ. Pregnancy in patients with cardiac valve prostheses. Clin Obstet Gynecol1975;18:107-23. 19. Bloomfield DK. Fetal deaths and malformations associated with the use of coumarin derivates in pregnancy. Am J Obstet Gynecol 1970;107:883-8. 20. Matorras R, Reque JA, Usandizaga JA, Minquez JA, Larrea JL, Nunez L. Prosthetic heart valve and pregnancy-a study of 59 cases. Gynecol Obstet Invest 1985;19:21-31. 21. Chesebro JH, Adams PC, Fuster V. Antithrombotic therapy in patients with valvular heart disease and prosthetic heart valves. J Am Co11 Cardiol 1986;8(suppl B):4i-56B. 22. Ibarra-Perez C. Arevalo-Toledo N.De La Cadena OA. NorienaGuerra L. The’course of pregnancy in patients with artifiGa1 heart valves. Am J Med 1976;61:504-12. 23. Larrea JL, Nunez L, Reque JA, Aguado MG, Matorras R, Minquez JA. Pregnancy and mechanical valve prostheses: a high risk situation for the mother and the fetus. Ann Thorac S&g 1983;36:459-63.
