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Fetal deaths and malformations associated with the use of coumarin derivatives in pregnancy
Fetal deaths and malformations associated with the use of coumann derivatives 1n pregnancy A critical rev1ew
DANIEL K. BLOOMFIELD, M.D.* Cleveland, Ohio The literature which relates the use of oral anticoagulants during pregnancy to fetal wastage and malformation has been reviewed. Fatal fetal or neonatal hemorrhage has occurred only in instances where the limits of the therapeutic range were seriously exceeded or where the coumarin drug was not discontinued sufficiently prior to labor. The evidence for coumarin drugs causing nonhemorrhagic intrauterine death is not convincing and may be due to the bias of selective
reporting. A possibility exists that warfarin sodium may be teratogenic.
T o T R E A T o R not to treat the pregnant patient with coumarin derivatives remains a problem to this day. In 1968, Beller1 stated "It is felt in this institution that the number of published case reports of fetal death due to hemorrhage are sufficient enough to contraindicate the use of coumarins and indandiones during pregnancy." VillaSanta 2 states that "Previous use of coumarin derivatives is the only constant factor associated with perinatal death in thrombophlebitis of pregnancy." On the other hand, Finnerty and MacKay3 concluded "The use of anticoagulant therapy in antepartum thrombolic disorders dramatically reduces maternal mortality and morbidity without serious risks of maternal hemorrhagic complications. In several intrauterine deaths attributed to anticoagulant therapy, causation was not clearly established, and the risk of well-controlled therapy may have been over emphasized." This view is supported by Aaro, Johnson and Juergens4 who state that "Our experience has led us to believe that the danger to the
fetus is minimal when the coumarin compounds are carefully administered and the mother's prothrombin time is vvell con-
trolled in the therapeutic range." To a cardiologist, faced with the problem of maintaining anticoagulant therapy in pregnant patients with prosthetic heart valves, the contrary views quoted above prove disconcerting. The purpose of this paper is to review critically the reports of perinatal death or malformation associated with coumarin therapy. Methods and results Sixteen case reports in ten articles 5 • 14 relating to fetal or neonatal death and malformation associated with coumarin and indandione therapy have been reviewed. Table I is a summary of the 16 cases. The reports were studied to determine whether a direct relationship betv:een oral anticoagulant therapy and perinatal death or malformation was established by the presence of hemorrhage in fetus or newborn. In the classifications A and B in Table I are (A) fatal hemorrhage in the fetus was confirmed or deemed highly probable by autopsy and (B) fatal hemor-
From the Division of Medicine, Mt. Sinai Hospital. *Address: Mt. Sinai Hos{Jital. 1800 East 105th Street, Cleveland,· Ohio 44106.
rhage in the fetus vvas excluded or deemed
unlikely by autopsy. 883
July 15, 1970 Amer. ]. Obstet. Gynee'.
884 Bloomfield
Table I. Summary of intrauterine or neonatal death and malformations associated with coumarin drugs
Case
1 2 3 4 5 6
7 8 9 10 11 12 13 14 15 16
Reference
Case No. in reference
5 6 7
1 1 1 2 1
7 8
9
i
iO 11 8 8 8 12
3 2 3 4 1 2 3 1 1
i2 12 13 14
I
Therapeutic class*
I
Death (D) of malformation (M)
Maternal labor on or within 7 days of therapy
Coumarin drugs proved responsible for death or mal/ormation
A. Associated with fatal hemorrhage in ihe feius 1 D Yes 2 D No 0 Yes D 0 D Yes D 2 No D No
Yes Yes Yes Yes Yes Doubtful
B. Not aswciated with fatal hemorrhage in the fetus D Yes No 2 D 2 No D No 2 D ? No M 0 No D 0 D No 1 D No No 0 M 0 No M
No No No No No No No No Possible Possible
*0, Therapeutic ranges properly kept. I, Therapeutic ranges exceeded on occasion. 2, Therapeutic range probably seriously exceeded.
A. Hemorrhagic deaths. Hemorrhagic death and thus coumarin toxicity was established in 6 of 16 cases. However, when these 6 cases are analyzed by therapeutic classification further information is yielded. Therapeutic ranges were exceeded in the ____ , f_ r r • ro " • rnou1ers or 't or tne o cases, ano 1n ~ cases the overdose was deemed serious. Case 1 is a clear case of fetal hemorrhage during the delivery process. The mother's prothrombin time was 33 per cent on the day of delivery and fell to 16 per cent shortly after delivery. The prothrombin time of the dying infant was less than 10 per cent. In Case 2, the author states "none of the (prothrombin time) determinations were abnormally high" but showed data with the maternal prothrombin time reaching 65 seconds on two occasions (control, 14 to 17 seconds) 42 days and 30 days before the presumed day of fetal death. Cases 3 and 4 occurred in twins delivered 1 week after the mother's oral anticoagulant therapy had been discontinued. Five days before labor the proth.rombin time of the mother \vas t\vice con.. trol, and the next day the maternal A
1
n
prothrombin time was 20 seconds (control, 15 seconds). It is likely in these cases that the fetal prothrombin time did not recover with the same speed as the mother's prothrombin time and the stress of labor initiated the fatal hemorrhages. In Case 5, a maternal prothrombin time as high as 44.6 seconds was recorded when the therapeutic range was listed as 18 to 25 seconds. Hemoglobin stains were noted in many of the fetal organs at autopsy. Case 6 is the only case involving hemorrhage in which there was no serious coumarin excess, and in which the trauma of labor did not play a role. However, in Case 6, there was advanced maternal disease, and the role of coumarin as a cause of death is doubtful. The mother was a 42year-old woman with rheumatic heart disease, pulmonary edema, and pulmonary embolism. Intrauterine death was caused by separation of the placenta at a time when the prothrombin time was 44 seconds ( therapeutic range, 27 to 35 seconds). Fetal hemorrhage vvas found only in the thymus gland.
Coumarin derivatives m pregnancy
Volume 107 Number6
885
Table II. Summary of factors related to nonhemorrhagic death or malformation Trimester (1, 2, 3) of: NonprescripCase No.
Coumarin
Prescription drugs
tion
Idrugs I Past
obstetric history
Complicating maternal disease*
ResponsiPossibility of bility coumarin of for death birth or malfor1 trauma I mationt
7
3
N.D.t
N.D. 1-0-0-1
Diabetes mellitus
2+
0
8
2
N.D.
N.D. 43-year-old primipara
Anemia
0
1+
9
2
N.D.
N.D. Grav. 5; one spontaneous abortion
None
0
1+
10
3
N.D.
N.D. Grav. 10; one spontaneous abortion, 2 intrauterine deaths
Vomiting, acidosis 3 weeks before fetal death
0
1+
11
2
N.D.
N.D. N.D.
N.D.
0
0
12
2,3
Meticorten-1,2,3, N.D. Pre-eclampsia with intrauterine death at 26 weeks
Lupus erythematosus
0
1+
13
2,3
None
N.D. Neonatal death at 12 hours
None
0
1+
14
2,3
Heparin-2
N.D. 4-0-0-4
None
0
1+
15
1,2,3
Digitoxin-1,2,3 Sulfisoxazole-1, 2,3 Heparin-3 Isoxsuprine-3
N.D. None
Positive STS, allergic to penicillin; rheumatic heart disease
0
1+
16
1,2,3
Penicillin-! ,2,3
N.D. N.D.
Negative for syphilis
0
1+
*Other than thrombophlebitis, pulmonary embolism, or prosthetic heart valve. t0-3+; 0 Impossible, 1+ possible but unlikely or with incomplete evidence; 2+ :j:N.D. = n?t documented.
=
=
Therefore, not a single reported case of hemorrhagic fetal death due to coumarin drug therapy could be found which could not be explained either by excessive dosage, failure to discontinue the drug in adequate time for labor, or the presence of advanced rna ternal disease. B. Nonhemorrhagic deaths and anomalies . It is difficult to establish a cause and effect relationship between coumarin derivatives and perinatal death or congenital malformation when hemorrhage is not a factor. The papers were reviewed for documentation of other maternal drugs, both prescribed and nonprescribed, the maternal past history, the presence or absence of complicating maternal disease, and the possibility of birth injury. 'Table II is a summary of such information from the 10 cases of
=
probable, 3+
proved.
nonhemorrhagic death and anomaly noted in Table I. In 4 of the 7 cases there was no mention of other drug ingestion and in none of the 7 were nonprescription remedies listed. Three cases seemed entirely unrelated to coumarin therapy. In Case 7 the infant weighed 10.5 pounds and died 12 hours after a prolonged and difficult delivery from a diabetic mother. Autopsy showed a tentorial tear. The mother of Case 10, who already had a history of two previous intrauterine deaths, suffered a violent illness with prolonged vomiting and acidosis during the thirty-third week of gestation. In Case 12 the mother had a history of pre-eclampsia. Following this a diagnosis of lupus erythematosus disseminata was made. Analysis of the remaining 4 cases (Cases
886 Bloomfield
8, 9, 13, and 14) reveals a tenuous relationship to coumarin at best. In Case 8 the mother was an anemic 43-year-old primipara. Only Case 14 had a completely normal past history. The problem of \varfarin sodium as a teratogenic agent is raised by Cases 15 and 16. In Case 15, the child was born with optic atrophy, nasal hypoplasia, and mental retardation. The mother, a 24-year-old Negro woman, was known to have syphilis. She was last treated 18 months prior to the current pregnancy. She had a persistently positive serologic test for syphilis. Because of rheumatic heart disease and a prosthetic mitral valve, she was maintained on the drugs indicated in Table II. As stated above, nonprescription drugs were not documented in her case. It would be difficult to ascribe the congenital anomalies to warfarin with any degree of assurance were it not for Case 16. Case 16 is the second case report of nasal bridge hypoplasia associated with warfarin therapy. In this case, there is less complicating disease, and the only additional drugs documented in the first trimester of pregnancy are digitalis leaf and benzathine penicillin G. Again nonprescription drugs in the first trimester pregnancy were not recorded. Case 11 was born with optic atrophy, microcephaly, and cerebral agenesis. The authors 8 clearly document that oral anticoagulants were not started until the twenty-fourth week of gestation, a time well after these organs were formed. Unfortunately, the case was collected in a review. 2 It should be discarded as not having any relationship to the coumarin drugs. Comment
The experimental work of Quick showed that the fetal and newborn pup is far more sensitive to dicumarol than its parent. He succinctly advised "the use of dicumarol in a pregnant woman is strictly contraindicated."15 Kraus, Perlow, and Singer16 confirmed Quick's findings in rabbits. The greater reduction in the prothrombin concentration of the blood in the offspring of a coumarin-fed mother appears true in the
July 15, 1970
Amer.
J. Obstet. Gynec.
few human cases where maternal and newborn prothrombin concentrations have been measured. 5' 10 Nevertheless, hemorrhagic death associated with proper maternal oral anticoagulant therapy is rare. Perhaps this is due to phenomena pointed out by Beller1 that the fetus and newborn have a compensation mechanism for the inadequate production rate of coagulation factors in the liver. Despite the deficiency of coagulation factors, the bleeding and clotting time in the newborn is even shorter than in normal aduits. Evidence relating coumarin drug therapy to hemorrhagic intrauterine and neonatal death is well documented. This is not to say that the coumarin drugs cannot be used safely during pregnancy. In every instance of hemorrhagic death of the fetus or neonate reviewed above, seriously excessive maternal prothrombin times were pres·ent prior to the death, or the infant was subjected to the trauma of labor without prior effort having been made to correct the infant prothrombin deficiency. In each case the fetal death was preventable in the light of current knowledge. Evidence relating the coumarin drug therapy to nonhemorrhagic fetal death is less than convincing. Note in Table II, that there are 4 intrauterine or neonatal deaths in the obstetric histories of the 8 cases where docu-
mentation is given. These earlier losses occurred without coumarin drugs. This is an unusually high incidence for routine obstetric histories and suggests other factors besides oral anticoagulants were involved in the iosses associated with the coumarin treatment. Failure to document nonprescription and other varieties of drug therapy during pregnancy was almost universal. The pharmacology literature emphasizes the enormous drug appetite of the American public. Masland, Sarason, and Gladwin17 reported from the figures collected in a collaborative study of 1,377 women, that the average drug consumption was four drugs per woman, and this did not include nutritional supplements and simple home remedies. The favorites on this list include
Volume 107
Coumarin derivatives
m pregnancy
887
Number 6
aspmn, antihistamines, tranquilizers, antiemetics, laxatives, and nasal decongestants. While the reports cited in Table II cannot be entirely discounted, it seems that these reports are the result of a natural bias directed toward reporting the intrauterine death when a patient is taking oral anticoagulants and ignoring such a death when it occurs in the course of routine care. A similar problem arises in the case of malformations. Saddle-nose deformity has appeared in 2 patients with prosthetic valves treated with warfarin sodium through the first trimester of pregnancy. Syphilis, the classical producer of saddle-nose, could not be excluded as an etiologic agent in the first instance. 14 In the second case/ 5 serologic tests for syphilis were negative in mother and child. The authors failed to document any home remedies that may have been taken by the mother. They also failed to mention the possibility of syphilis in the previously reported case of saddle-nose deformity to which they refer. Since reports of successful pregnancies of patients with prosthetic valves treated with coumarin drugs are still infrequent, the interesting teratogenic possibility of saddle-nose deformity has yet to be defined. Subject to the above discussion we conclude that coumarin drugs can safely be used in the antepartum period. 3 • 4 There are two requirements. ( 1) the therapeutic range should not be exceeded and ( 2) the drug should be discontinued long enough before delivery to allow the fetal prothrombin con-
REFERENCES
1. Beller, F. K.: Clin. Obstet. Gynec. 11: 290, 1968. 2. VillaSanta, U.: AMER. J. 0BsTET. GvNEC. 93: 142, 1965. 3. Finnerty, J. J., and MacKay, B. R.: Obstet. Gynec. 19: 405, 1962. 4. Aaro, L. A., Johnson, T. R., and Juergens, J. L.: AM:ER. J. 0BSTET. GYNEC. 97: 514, 1967. 5. von Sydow, G.: Nord. M:ed. 109: 1171, 1947. 6. Sachs, J. J., and Labate, J. S.: AMER. J. 0BSTET. GYNEC. 57: 965, 1949.
tent to return to a safe level. Unfortunately, the exact answer to the second requirement is not known at present. The cases of Gordon and Dean 7 indicated that 7 days is not long enough. Kerber, Warr, and Richardson14 S\vitched from \Yarfarin sodium to daily heparin at 7 months' gestation. Although a congenital malformation was present, there was no evidence of neonatal hemorrhage. Johnson and associates18 in reporting 2 uncomplicated cases advocate the use of oral anticoagulants until one month before delivery at which time they are discontinued. In summary it would seem that oral anticoagulants can be used safely until 4 weeks before term, at which time, the drug should be switched to heparin. While heparin has theoretical advantages over coumarin drugs which have been discussed by others/ the paper of Bennett and Oakley19 grimly documents that precipitous flight from oral anticoagulants to heparin during pregnancy can be disasterous. Because oral anticoagulants remain the drug of choice for the routine care of most patients with prosthetic valves, the onset of pregnancy will introduce the possible risk of teratogenesis. 13 • 14 The nasal bridge and associated defects found in 2 cases to date relate to early pregnancy so that such harm will already be done before the pregnancy comes to the attention of the physician. From that point until one month before term the proper use of oral anticoagulants is indicated and safe. Nothing in this review of literature contradicts this opinion.
7. Gordon, R. R., and Dean, T.: Brit. M:ed. J. 2: 719, 1955. 8. Quenneville, G., Burton, B., McDevitt, E., and Wright, I. S.: AMER. J. OssTET. GvNEc. 77: 135, 1959. 9. Mahairas, G. H., and Weingo1d, A. B.: AMER. J. 0BSTET. GYNEC. 85: 234, 1963. 10. Wright, H. P.: J. Obstet. Gynaec. Brit. Emp. 58: 272, 1951. 11. Blum, M.: AMER. J. 0BSTET. GYNEC. 73: 440, 1957. 12. Epstein, W. A.: J. Mt. Sinai Hosp. 26: 562, 1959.
888
Bloomfield
13. Disaia, P. J.: Obstet. Gynec. 28: 469, 1966. 14. Kerber, I. J., Warr, 0. S., and Richardson, C.: ]. A. M. A. 203: 223, 1968. 15. Quick, A. J.: J. Bioi. Chern. 163: 371, 1946. 16. Kraus, A. P., Perlow, S., and Singer, K.: J. A.M. A. 139: 158, 1949. 17. Masland, R. L., Sarason, S. B., and Glad-
Amer.
J.
July 15, 1970 Obstet. Gynec.
win, T.: Mental Subnormality, New York, 1958, Basic Books. 18. Johnson, A. S., Meyers, M. P., Eckhouse, A. S., Bacher, B., and Limia, A.: Mich. Med. 65: 718, 1966. 19. Bennett, G. G., and Oakley, C. M.: Lancet 1: 616, 1968.
DANIEL K. BLOOMFIELD, M.D.* Cleveland, Ohio The literature which relates the use of oral anticoagulants during pregnancy to fetal wastage and malformation has been reviewed. Fatal fetal or neonatal hemorrhage has occurred only in instances where the limits of the therapeutic range were seriously exceeded or where the coumarin drug was not discontinued sufficiently prior to labor. The evidence for coumarin drugs causing nonhemorrhagic intrauterine death is not convincing and may be due to the bias of selective
reporting. A possibility exists that warfarin sodium may be teratogenic.
T o T R E A T o R not to treat the pregnant patient with coumarin derivatives remains a problem to this day. In 1968, Beller1 stated "It is felt in this institution that the number of published case reports of fetal death due to hemorrhage are sufficient enough to contraindicate the use of coumarins and indandiones during pregnancy." VillaSanta 2 states that "Previous use of coumarin derivatives is the only constant factor associated with perinatal death in thrombophlebitis of pregnancy." On the other hand, Finnerty and MacKay3 concluded "The use of anticoagulant therapy in antepartum thrombolic disorders dramatically reduces maternal mortality and morbidity without serious risks of maternal hemorrhagic complications. In several intrauterine deaths attributed to anticoagulant therapy, causation was not clearly established, and the risk of well-controlled therapy may have been over emphasized." This view is supported by Aaro, Johnson and Juergens4 who state that "Our experience has led us to believe that the danger to the
fetus is minimal when the coumarin compounds are carefully administered and the mother's prothrombin time is vvell con-
trolled in the therapeutic range." To a cardiologist, faced with the problem of maintaining anticoagulant therapy in pregnant patients with prosthetic heart valves, the contrary views quoted above prove disconcerting. The purpose of this paper is to review critically the reports of perinatal death or malformation associated with coumarin therapy. Methods and results Sixteen case reports in ten articles 5 • 14 relating to fetal or neonatal death and malformation associated with coumarin and indandione therapy have been reviewed. Table I is a summary of the 16 cases. The reports were studied to determine whether a direct relationship betv:een oral anticoagulant therapy and perinatal death or malformation was established by the presence of hemorrhage in fetus or newborn. In the classifications A and B in Table I are (A) fatal hemorrhage in the fetus was confirmed or deemed highly probable by autopsy and (B) fatal hemor-
From the Division of Medicine, Mt. Sinai Hospital. *Address: Mt. Sinai Hos{Jital. 1800 East 105th Street, Cleveland,· Ohio 44106.
rhage in the fetus vvas excluded or deemed
unlikely by autopsy. 883
July 15, 1970 Amer. ]. Obstet. Gynee'.
884 Bloomfield
Table I. Summary of intrauterine or neonatal death and malformations associated with coumarin drugs
Case
1 2 3 4 5 6
7 8 9 10 11 12 13 14 15 16
Reference
Case No. in reference
5 6 7
1 1 1 2 1
7 8
9
i
iO 11 8 8 8 12
3 2 3 4 1 2 3 1 1
i2 12 13 14
I
Therapeutic class*
I
Death (D) of malformation (M)
Maternal labor on or within 7 days of therapy
Coumarin drugs proved responsible for death or mal/ormation
A. Associated with fatal hemorrhage in ihe feius 1 D Yes 2 D No 0 Yes D 0 D Yes D 2 No D No
Yes Yes Yes Yes Yes Doubtful
B. Not aswciated with fatal hemorrhage in the fetus D Yes No 2 D 2 No D No 2 D ? No M 0 No D 0 D No 1 D No No 0 M 0 No M
No No No No No No No No Possible Possible
*0, Therapeutic ranges properly kept. I, Therapeutic ranges exceeded on occasion. 2, Therapeutic range probably seriously exceeded.
A. Hemorrhagic deaths. Hemorrhagic death and thus coumarin toxicity was established in 6 of 16 cases. However, when these 6 cases are analyzed by therapeutic classification further information is yielded. Therapeutic ranges were exceeded in the ____ , f_ r r • ro " • rnou1ers or 't or tne o cases, ano 1n ~ cases the overdose was deemed serious. Case 1 is a clear case of fetal hemorrhage during the delivery process. The mother's prothrombin time was 33 per cent on the day of delivery and fell to 16 per cent shortly after delivery. The prothrombin time of the dying infant was less than 10 per cent. In Case 2, the author states "none of the (prothrombin time) determinations were abnormally high" but showed data with the maternal prothrombin time reaching 65 seconds on two occasions (control, 14 to 17 seconds) 42 days and 30 days before the presumed day of fetal death. Cases 3 and 4 occurred in twins delivered 1 week after the mother's oral anticoagulant therapy had been discontinued. Five days before labor the proth.rombin time of the mother \vas t\vice con.. trol, and the next day the maternal A
1
n
prothrombin time was 20 seconds (control, 15 seconds). It is likely in these cases that the fetal prothrombin time did not recover with the same speed as the mother's prothrombin time and the stress of labor initiated the fatal hemorrhages. In Case 5, a maternal prothrombin time as high as 44.6 seconds was recorded when the therapeutic range was listed as 18 to 25 seconds. Hemoglobin stains were noted in many of the fetal organs at autopsy. Case 6 is the only case involving hemorrhage in which there was no serious coumarin excess, and in which the trauma of labor did not play a role. However, in Case 6, there was advanced maternal disease, and the role of coumarin as a cause of death is doubtful. The mother was a 42year-old woman with rheumatic heart disease, pulmonary edema, and pulmonary embolism. Intrauterine death was caused by separation of the placenta at a time when the prothrombin time was 44 seconds ( therapeutic range, 27 to 35 seconds). Fetal hemorrhage vvas found only in the thymus gland.
Coumarin derivatives m pregnancy
Volume 107 Number6
885
Table II. Summary of factors related to nonhemorrhagic death or malformation Trimester (1, 2, 3) of: NonprescripCase No.
Coumarin
Prescription drugs
tion
Idrugs I Past
obstetric history
Complicating maternal disease*
ResponsiPossibility of bility coumarin of for death birth or malfor1 trauma I mationt
7
3
N.D.t
N.D. 1-0-0-1
Diabetes mellitus
2+
0
8
2
N.D.
N.D. 43-year-old primipara
Anemia
0
1+
9
2
N.D.
N.D. Grav. 5; one spontaneous abortion
None
0
1+
10
3
N.D.
N.D. Grav. 10; one spontaneous abortion, 2 intrauterine deaths
Vomiting, acidosis 3 weeks before fetal death
0
1+
11
2
N.D.
N.D. N.D.
N.D.
0
0
12
2,3
Meticorten-1,2,3, N.D. Pre-eclampsia with intrauterine death at 26 weeks
Lupus erythematosus
0
1+
13
2,3
None
N.D. Neonatal death at 12 hours
None
0
1+
14
2,3
Heparin-2
N.D. 4-0-0-4
None
0
1+
15
1,2,3
Digitoxin-1,2,3 Sulfisoxazole-1, 2,3 Heparin-3 Isoxsuprine-3
N.D. None
Positive STS, allergic to penicillin; rheumatic heart disease
0
1+
16
1,2,3
Penicillin-! ,2,3
N.D. N.D.
Negative for syphilis
0
1+
*Other than thrombophlebitis, pulmonary embolism, or prosthetic heart valve. t0-3+; 0 Impossible, 1+ possible but unlikely or with incomplete evidence; 2+ :j:N.D. = n?t documented.
=
=
Therefore, not a single reported case of hemorrhagic fetal death due to coumarin drug therapy could be found which could not be explained either by excessive dosage, failure to discontinue the drug in adequate time for labor, or the presence of advanced rna ternal disease. B. Nonhemorrhagic deaths and anomalies . It is difficult to establish a cause and effect relationship between coumarin derivatives and perinatal death or congenital malformation when hemorrhage is not a factor. The papers were reviewed for documentation of other maternal drugs, both prescribed and nonprescribed, the maternal past history, the presence or absence of complicating maternal disease, and the possibility of birth injury. 'Table II is a summary of such information from the 10 cases of
=
probable, 3+
proved.
nonhemorrhagic death and anomaly noted in Table I. In 4 of the 7 cases there was no mention of other drug ingestion and in none of the 7 were nonprescription remedies listed. Three cases seemed entirely unrelated to coumarin therapy. In Case 7 the infant weighed 10.5 pounds and died 12 hours after a prolonged and difficult delivery from a diabetic mother. Autopsy showed a tentorial tear. The mother of Case 10, who already had a history of two previous intrauterine deaths, suffered a violent illness with prolonged vomiting and acidosis during the thirty-third week of gestation. In Case 12 the mother had a history of pre-eclampsia. Following this a diagnosis of lupus erythematosus disseminata was made. Analysis of the remaining 4 cases (Cases
886 Bloomfield
8, 9, 13, and 14) reveals a tenuous relationship to coumarin at best. In Case 8 the mother was an anemic 43-year-old primipara. Only Case 14 had a completely normal past history. The problem of \varfarin sodium as a teratogenic agent is raised by Cases 15 and 16. In Case 15, the child was born with optic atrophy, nasal hypoplasia, and mental retardation. The mother, a 24-year-old Negro woman, was known to have syphilis. She was last treated 18 months prior to the current pregnancy. She had a persistently positive serologic test for syphilis. Because of rheumatic heart disease and a prosthetic mitral valve, she was maintained on the drugs indicated in Table II. As stated above, nonprescription drugs were not documented in her case. It would be difficult to ascribe the congenital anomalies to warfarin with any degree of assurance were it not for Case 16. Case 16 is the second case report of nasal bridge hypoplasia associated with warfarin therapy. In this case, there is less complicating disease, and the only additional drugs documented in the first trimester of pregnancy are digitalis leaf and benzathine penicillin G. Again nonprescription drugs in the first trimester pregnancy were not recorded. Case 11 was born with optic atrophy, microcephaly, and cerebral agenesis. The authors 8 clearly document that oral anticoagulants were not started until the twenty-fourth week of gestation, a time well after these organs were formed. Unfortunately, the case was collected in a review. 2 It should be discarded as not having any relationship to the coumarin drugs. Comment
The experimental work of Quick showed that the fetal and newborn pup is far more sensitive to dicumarol than its parent. He succinctly advised "the use of dicumarol in a pregnant woman is strictly contraindicated."15 Kraus, Perlow, and Singer16 confirmed Quick's findings in rabbits. The greater reduction in the prothrombin concentration of the blood in the offspring of a coumarin-fed mother appears true in the
July 15, 1970
Amer.
J. Obstet. Gynec.
few human cases where maternal and newborn prothrombin concentrations have been measured. 5' 10 Nevertheless, hemorrhagic death associated with proper maternal oral anticoagulant therapy is rare. Perhaps this is due to phenomena pointed out by Beller1 that the fetus and newborn have a compensation mechanism for the inadequate production rate of coagulation factors in the liver. Despite the deficiency of coagulation factors, the bleeding and clotting time in the newborn is even shorter than in normal aduits. Evidence relating coumarin drug therapy to hemorrhagic intrauterine and neonatal death is well documented. This is not to say that the coumarin drugs cannot be used safely during pregnancy. In every instance of hemorrhagic death of the fetus or neonate reviewed above, seriously excessive maternal prothrombin times were pres·ent prior to the death, or the infant was subjected to the trauma of labor without prior effort having been made to correct the infant prothrombin deficiency. In each case the fetal death was preventable in the light of current knowledge. Evidence relating the coumarin drug therapy to nonhemorrhagic fetal death is less than convincing. Note in Table II, that there are 4 intrauterine or neonatal deaths in the obstetric histories of the 8 cases where docu-
mentation is given. These earlier losses occurred without coumarin drugs. This is an unusually high incidence for routine obstetric histories and suggests other factors besides oral anticoagulants were involved in the iosses associated with the coumarin treatment. Failure to document nonprescription and other varieties of drug therapy during pregnancy was almost universal. The pharmacology literature emphasizes the enormous drug appetite of the American public. Masland, Sarason, and Gladwin17 reported from the figures collected in a collaborative study of 1,377 women, that the average drug consumption was four drugs per woman, and this did not include nutritional supplements and simple home remedies. The favorites on this list include
Volume 107
Coumarin derivatives
m pregnancy
887
Number 6
aspmn, antihistamines, tranquilizers, antiemetics, laxatives, and nasal decongestants. While the reports cited in Table II cannot be entirely discounted, it seems that these reports are the result of a natural bias directed toward reporting the intrauterine death when a patient is taking oral anticoagulants and ignoring such a death when it occurs in the course of routine care. A similar problem arises in the case of malformations. Saddle-nose deformity has appeared in 2 patients with prosthetic valves treated with warfarin sodium through the first trimester of pregnancy. Syphilis, the classical producer of saddle-nose, could not be excluded as an etiologic agent in the first instance. 14 In the second case/ 5 serologic tests for syphilis were negative in mother and child. The authors failed to document any home remedies that may have been taken by the mother. They also failed to mention the possibility of syphilis in the previously reported case of saddle-nose deformity to which they refer. Since reports of successful pregnancies of patients with prosthetic valves treated with coumarin drugs are still infrequent, the interesting teratogenic possibility of saddle-nose deformity has yet to be defined. Subject to the above discussion we conclude that coumarin drugs can safely be used in the antepartum period. 3 • 4 There are two requirements. ( 1) the therapeutic range should not be exceeded and ( 2) the drug should be discontinued long enough before delivery to allow the fetal prothrombin con-
REFERENCES
1. Beller, F. K.: Clin. Obstet. Gynec. 11: 290, 1968. 2. VillaSanta, U.: AMER. J. 0BsTET. GvNEC. 93: 142, 1965. 3. Finnerty, J. J., and MacKay, B. R.: Obstet. Gynec. 19: 405, 1962. 4. Aaro, L. A., Johnson, T. R., and Juergens, J. L.: AM:ER. J. 0BSTET. GYNEC. 97: 514, 1967. 5. von Sydow, G.: Nord. M:ed. 109: 1171, 1947. 6. Sachs, J. J., and Labate, J. S.: AMER. J. 0BSTET. GYNEC. 57: 965, 1949.
tent to return to a safe level. Unfortunately, the exact answer to the second requirement is not known at present. The cases of Gordon and Dean 7 indicated that 7 days is not long enough. Kerber, Warr, and Richardson14 S\vitched from \Yarfarin sodium to daily heparin at 7 months' gestation. Although a congenital malformation was present, there was no evidence of neonatal hemorrhage. Johnson and associates18 in reporting 2 uncomplicated cases advocate the use of oral anticoagulants until one month before delivery at which time they are discontinued. In summary it would seem that oral anticoagulants can be used safely until 4 weeks before term, at which time, the drug should be switched to heparin. While heparin has theoretical advantages over coumarin drugs which have been discussed by others/ the paper of Bennett and Oakley19 grimly documents that precipitous flight from oral anticoagulants to heparin during pregnancy can be disasterous. Because oral anticoagulants remain the drug of choice for the routine care of most patients with prosthetic valves, the onset of pregnancy will introduce the possible risk of teratogenesis. 13 • 14 The nasal bridge and associated defects found in 2 cases to date relate to early pregnancy so that such harm will already be done before the pregnancy comes to the attention of the physician. From that point until one month before term the proper use of oral anticoagulants is indicated and safe. Nothing in this review of literature contradicts this opinion.
7. Gordon, R. R., and Dean, T.: Brit. M:ed. J. 2: 719, 1955. 8. Quenneville, G., Burton, B., McDevitt, E., and Wright, I. S.: AMER. J. OssTET. GvNEc. 77: 135, 1959. 9. Mahairas, G. H., and Weingo1d, A. B.: AMER. J. 0BSTET. GYNEC. 85: 234, 1963. 10. Wright, H. P.: J. Obstet. Gynaec. Brit. Emp. 58: 272, 1951. 11. Blum, M.: AMER. J. 0BSTET. GYNEC. 73: 440, 1957. 12. Epstein, W. A.: J. Mt. Sinai Hosp. 26: 562, 1959.
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13. Disaia, P. J.: Obstet. Gynec. 28: 469, 1966. 14. Kerber, I. J., Warr, 0. S., and Richardson, C.: ]. A. M. A. 203: 223, 1968. 15. Quick, A. J.: J. Bioi. Chern. 163: 371, 1946. 16. Kraus, A. P., Perlow, S., and Singer, K.: J. A.M. A. 139: 158, 1949. 17. Masland, R. L., Sarason, S. B., and Glad-
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win, T.: Mental Subnormality, New York, 1958, Basic Books. 18. Johnson, A. S., Meyers, M. P., Eckhouse, A. S., Bacher, B., and Limia, A.: Mich. Med. 65: 718, 1966. 19. Bennett, G. G., and Oakley, C. M.: Lancet 1: 616, 1968.