American Heart Journal March, 1972, Volume 83, Number 3

Editorial

Anticoagulants in pregnancy:

A review of indications and complications

J. Hirsh, M.D., F.R.A.C.P. J. F. Cade, M.D., Ph.D., M.R.A.C.P. A. S. Gallus, M.B., M.R.A.C.P.

Hamilton, Ontario, Canada

mhe use of anticoagulant drugs during A pregnancy presents a therapeutic di-

lemma. This is because anticoagulant therapy is sometimes indicated in preg- nancy yet treatment with either heparin or the vitamin K antagonists may present difficulties. Heparin is safe for the fetus because it does not cross the placenta, but it is inconvenient for long-term use. On the other hand, the vitamin K antagonists cross the placenta and may therefore predispose to fetal or neonatal damage. This problem will be considered by discuss- ing first the maternal indications and then the fetal and maternal complications of anticoagulant therapy.

Maternal indications

Venous thromboembolism. Venous throm- boembolism is a serious complication of pregnancy’ z2 and, although uncommon,3r4 has become one of the chief causes of maternal deaths in Western communities.5 It is generally accepted that anticoagulant therapy reduces the morbidity and mor- tality rates in nonpregnant patients with deep venous thrombosis or pulmonary embolism.@ Because of the thrombotic tendency during pregnancy,g-ll it might be

expected that venous thromboembolism would be more serious for the pregnant than for the nonpregnant patient. Indeed this appears to be borne out by data ac- cumulated from reported cases2*3s12 which indicate that the death rate of untreated antepartum thromboembolism is at least 15 per cent. On the other hand, the death rate of antepartum thromboemboiism among reported cases treated with anti- coagulants is less than one per cent2s3*12 which, even allowing for possible selection bias, is significantly less than in untreated patients.

Prosthetic heart valve replacement. Sys- temic embolization is the most important late complication of prosthetic heart valve replacement. r3-16 Improvements in valve design appear to have reduced but not eliminated this complication16~17 so that, at present, many patients with prosthetic heart valves are treated with anticoagulant drugs for life. Although anticoagulant ther- apy does not provide absolute protection against systemic embolization, particularly in patients with mitral valve prostlleses,16B18 it does significantly reduce the incidence of this complication.16~18~1g~20 The thrombotic tendency of pregnancy is likely to increase

From the Departments of Medicine and Pathology, McMaster University, Hamilton, Ontario, Canada. Received for publication Feb. 22, 1971. Reprint requests to: Dr. J. Hirsh, Department of Pathology. St. Joseph’s Hospital, 50 Charlton Ave., East, Hamilton,

Ontario, Canada.

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302 H&h, Cade, and Gallus Am. Head J. March, 1972

the risk of emboli, so that the indication for anticoagulant therapy is at least as strong in the pregnant as in the nonpregnant patient.

Recent investigations in nonpregnant patients with prosthetic heart valves sug- gested that drugs which interfere with platelet function may be effective in pre- venting embolic complications.‘*J1 These drugs may eventually replace the anti- coagulants currently used for this purpose but their effects on the fetus would require careful evaluation before their use could be safely recommended during pregnancy.

Fetal complications

Fetal hemorrhage. There is good evidence both in the experimental anima122,23 and in human subjects22J4 that heparin does not cross the placenta to any measureable de- gree and does not therefore predispose to fetal hemorrhage. On the other hand, the vitamin K antagonists (oral anticoagulants) cross the placenta (see below) and are therefore potentially dangerous to the fetus. For this reason the vitamin K antagonists have been considered to be contraindicated during pregnancy,2,25n26 although this view has recently been questioned.24 Since the risk of fetal hemorrhage is central to the problem of anticoagulant therapy in preg- nancy, it will be considered in some detail.

EXPERIMENTAL FINDINGS IN ANIMALS. In early experiments, both Quick27 and Kraus and associates28 demonstrated a high inci- dence of fetal hemorrhage and death when coumarin was administered to pregnant dogs and rabbits. In both of these studies, the fetuses were delivered at a time when their coagulation system was severely im- paired because large doses of the drug were given until term.

A more recent study2g confirmed these findings but the results further suggested that bleeding in the fetus with abnormally depressed vitamin K dependent coagula- tion factors is related to the trauma of delivery. Thus, when pregnant rabbits were given coumadin from approximately one week after conception until term, they gave birth to litters of stillborn fetuses all with widespread hemorrhage. On the other hand, there was no evidence of fetal or neonatal hemorrhage if delivery was performed by cesarean section or if the drug was stopped

four or five days before spontaneous de- livery.

OBSERVATIONS IN HUMANS. Experimental observations were made in human patients by von Runge and Hartert30 and von Mertz and Breitner31 who gave coumarin to twelve women before they underwent legal abor- tions. They were unable to find evidence of fetal hemorrhage. Although there are a number of reports of fetal effects of coumarins administered during pregnancy, accurate analysis of the fetal risk is impossible because of the selection bias which is inevitably associated with case reports. Villasanta recently reviewed the reported cases of antepartum thrombo- phlebitis treated with oral anticoagulants and concluded that these drugs should not be used during pregnancy because of the risk of fetal hemorrhage. However, evalu- ation of those case reports in which ade- quate details were available suggested to us24 that oral anticoagulants may not in- crease the risk of fetal hemorrhage unless they are taken until term or in excessive doses. Thus, among the ten women still receiving oral anticoagulants at the for- tieth week of gestation, there were five instances of perinatal hemorrhage, of which four were fatal (two fetal and two neona- tal).’ On the other hand, in 47 women given oral anticoagulants at an early stage of pregnancy, there were 13 deaths but only one was clearly due to hemorrhage.

These views were supported by a prospec- tive investigation by Hirsh and associatesZ4 of the effects of anticoagulants given during pregnancy in 15 cases. Ten of these patients were treated with vitamin K antagonists at some time during pregnancy. In all of these, treatment was well controlled and was stopped at least three weeks before labor. In none was there evidence of fetal or neonatal hemorrhage. Bloomfield also concluded that fatal fetal or neonatal hemorrhage occurred only when the thera- peutic range was exceeded or when the coumarin drug was continued until term. More recently, Fillmore and McDevitt,33 in a retrospective analysis of 36 pregnan- cies during which coumarin compounds were administered, noted that fetal com- plications occurred only when the pro- thrombin time was excessively prolonged or if there was a past history of abnormal

Volunte 83 Number 3 Anticoagulants in pregnancy 303

pregnancies. They concluded that cou- marin compounds do not usually produce fetal damage if carefully administered to women with a normal obstetrical history.

REVERSIBILITY OF FETAL HYPOCOAGULA-

BILITY. There is both experimenta12g~34 and clinicalz4 evidence that depression of the vitamin K dependent coagulation factors in the fetus caused by the placental passage of oral anticoagulant drugs is reversible. Studies in pregnant rabbits2g have shown that if delivery occurs four to five days after stopping the administration of cou- marin to the mother, the fetal vitamin K dependent coagulation factors are normal at birth. Vitamin K given to the mother enhances the rate of increase of fetal clotting factors.34

In human patients, neonatal coagulation tests were normal when long-term oral anticoagulant therapy was discontinued three weeks before delivery.24 However, the minimum time required for fetal coagula- tion factors to return to normal after oral anticoagulant drugs have been withdrawn is unknown. This information would be important in helping to determine how long oral anticoagulants can be given during pregnancy without endangering the fetus during labor.

Other fetal damage. The possibility that oral anticoagulants produce fetal damage by means other than depression or vitamin K dependent coagulation factors requires serious consideration. Kraus and associ- ates28 found a number of poorly developed fetuses in pregnant rabbits given coumarin but this finding is difficult to interpret because abnormal fetuses may also be found in untreated rabbits.35 Observations in human subjects are equally difficult to assess. It is possible that the 12 nonhemor- rhagic fetal deaths reviewed by Villasanta were due to vitamin K antagonists. Re- cently, nasal bone malformations have been reported in two cases wherein the mother was given warfarin in the first two months of pregnancy.36 However, one of these neonates also had optic atrophy and the mother had syphilis.

Maternal complications

Despite the theoretical risk, there is no evidence that anticoagulants in therapeutic doses increase the incidence of uterine

hemorrhage either before, during, or after normal delivery.114s37 On the other hand, increased bleeding may be expected from sites of trauma such as spontaneous vaginal tears or episiotomy, or in patients with uterine atonia or retained placenta.24 In a recent prospective study,24 seven patients had a prolonged clotting time due to heparin therapy at delivery. Of these, three developed hematomas of the episiotomy and one, who had an atonic uterus, a post- partum hemorrhage which required blood transfusion.

Therapeutic recommendations

It is difficult to define a regimen of anti- coagulant therapy during pregnancy that is safe, practical, and effective. Ideally, patients requiring anticoagulant therapy during pregnancy should be treated with heparin, both because this drug is thought to be more effective in patients with throm- boembolic disease8 and because it is safer for the fetus. However, since heparin must be given parenterally, its long-term use is impractical in most patients. Furthermore, there is evidence that heparin in doses of greater than 15,000 units per day for six months or more may predispose to osteopo- rosis.38 Concentrated heparin administered by subcutaneous injection has been used successfully on a long-term basis in selected patients,3g but in most cases oral vitamin K antagonists provide the only practical means of achieving satisfactory long-term anticoagulant therapy.

The use of the oral anticoagulant drugs should be avoided in the first trimester because of possible teratogenic effects. Their use is also best avoided in the last three weeks before term because of the risk of perinatal hemorrhage should premature labor occur. At these times, heparin should be used when anticoagulant therapy is indi- cated. Oral anticoagulants probably carry little risk at other times if their adminis- tration is carefully monitored to avoid overdosage.

Treatment with anticoagulant drugs is probably indicated for the duration of preg- nancy in patients with iliofemoral venous thrombosis, recurrent venous thrombosis, pulmonary embolism, and prosthetic heart valves. This is because these patients are exposed to both local and general pre-

304 Hirsh, Cade, and Gullus Am. Hcurt 1. March, 1972

disposing factors to further thromboembo- lism throughout pregnancy. On the other hand, patients with single episodes of calf vein thrombosis are probably less vulner- able to recurrence and in these it may be sufficient to treat the acute episode with intravenous heparin and to follow the pa- tient carefully for any evidence of recur- rence. Using this approach, the authors have treated 14 patients with anticoagu- lants during 15 pregnancies without any maternal deaths and with no fetal or neonatal complications.24

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REFERENCES

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Wisch, N.: Role of anticoagulants in preventing embolization from prosthetic heart valves, J.A.M.A. 202:282, 1967. Pansegrau, D. G., Rosenfeld, IV. C., Calvelo, M. G., Kioschos, J. M., and Kroetz, F. W.: The management of patients with prosthetic heart valves, Med. Cl&. N. Amer. 52:1133, 1968. Harker. L. A.. and Slichter. S. 1.: Studies of platelet and fibrinogen kinetics in patients with prosthetic heart valves, New Eng. J. Med. 283:1302, 1970. Flessa, H. C., Kapstrom, A. B., Glueck, H. I., and Will, J. J.: Placental transport of heparin, Amer. J. Obstet. Gynec. 93:570, 1965. Cade, J. F., and Hirsh, J.: Unpublished obser- vations. Hirsh, J., Cade, J. F., and O’Sullivan, E. F.: Clinical experience with anticoagulant therapy during pregnancy, Brit. Med. J. 1:270, 1970. Douglas, A. S.: Anticoagulant therapy, Oxford, 1962, Blackwell Scientific Publications, pp. 248, 312. Johnson, S. A., and Greenwalt, T. J.: Coagula- tion and transfusion in clinical practice, Bos- ton, 1965, Little, Brown & Company, pp. 116, 157. Quick, A. J.: Experimentally induced changes in the orothrombin level of the blood. III. Prothrombin concentration of newborn pups of a mother given dicumarol before parturition, J. Biol. Chem. 164:371, 1946. Kraus, A. P., Perlow, S., and Singer, K.: Danger of dicoumarol treatment in pregnancy, J.AA.M.,4. 139:758, 1949. Hirsh, J., Cade, J. F., and Gallus, A. S.: Fetal effects of coumadin administered during preg- nancy. Blood 36:623, 1970. von kunge, H., and Hartert, I.: Methodische und klinische Erfahruneen bei der Thera- pie nut AntikoagulantienlYGynaecologia (Basel) 138:110, 1954. von Mertz, W. R., and Breitner, J.: Wirkung der Dicumarine auf den Fetus und auf das Neugeborene, Geburtsh. Frauenheilk. 16:426, 19.56. Bloomheld, D. K. : Fetal deaths and malforma- tions associated with the use of coumarin de- rivatives in pregnancy, Amer. J. Obstet. Gyncc. 107:883, 1970. Fillmore, S. J., and McDevitt, E.: Effects of

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coumarin compounds in the fetus, Ann. Intern. Med. 73:731, 1970.

34. Cade, J. F., Hirsh, J., and Gallus, A. S.: Un- published observations.

35. Cade, J. F., and Hirsh, J.: Unpublished obser- vations.

36. Kerber, I. J., Warr, 0. S., and Richardson, C.: Pregnancy in a patient with a prosthetic mitral valve. Associated with a fetal anomaly at- tributed to warfarin sodium, J.A.M.A. 203:223, 1968.

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37. Taylor, J. J.: Antepartum thromboembolism, Postgrad. Med. J. 41:80, 1965.

38. Griffith, G. C., Nichols, G., Asher, J. D., and Flanagan, B.: Heparin osteoporosis, J.A.M.A. 193:85, 1965.

39. Hirsh, J., O’Sullivan, E. F., Gallus, A. S., and Martin, M.: Evaluation of subcutaneous cal- cium heparin therapy in the treatment of thromboembolic disease, Med. J. Aust. l:lS, 1970.