Anticoagulants and Thrombolytics During Pregnancy Susan M. Ramin, Kirk D. Ramin, and Larry C. Gilstrap
Although venous thromboembol ism is a rare complication of pregnancy, it is one of the leading causes of maternal mortality. As many as 40% of asymptomatic women with deep venous thrombosis may indeed have a pulmonary embolism. Therefore, pregnant women with thromboembol ic disease, a history of thromboembol ic disease, or those who are at increased risk o f thromboembol ism (me- chanical cardiac valve prostheses, antithrombin II, or protein C or S deficient) should receive antico- agulant therapy. The choice of anticoagulant therapy in a pregnant woman as well as the dose and duration will depend on the specific condit ion being treated. Although anticoagulant therapy is beneficial, it is not without risks to both mother and fetus. This article discusses the use of anticoagu- lants and thrombolytics in pregnant women. Copyright 9 1997 by W.B. Saunders Company
V enous thromboembol ism has been re- ported to cause as many as 120,000 deaths in the United States per year. 1 It is also one of the leading causes of maternal deaths during pregnancy. 2'3 For example, Berg et al 4 reported that pulmonary embolism was responsible for 11% of pregnancy-related deaths in the United States for the years 1987 through 1990. Almost one fourth of women with untreated deep ve- nous thrombosis are at risk for pulmonary embo- lism, which in turn, is associated with a 15% mor- tality rate. 5 Even somewhat more worrisome is that up to 40% of asymptomatic women with deep venous thrombosis may actually have a pul- monary embolus. 6
Thus, pregnant women with thromboembol ic disease, a history of thromboembol ic disease, or who are at increased risk of such (ie, antithrom- bin II or protein C or S deficient) should receive anticoagulant therapy. Although such therapy is not without risks to both mother and fetus, the benefits of anticoagulation obviously outweigh potential risks.
Speci f ic Ant icoagulants
Warfarin sodium (coumadin) is a coumarin anti- coagulant and works primarily by depressing vita- min K -dependent clotting factors (II, VII, IX, and X). Because of its relatively small molecular weight, warfarin and its derivatives readily cross the placenta. Maternal warfarin therapy may cause both teratogenic and fetal affects. The te- ratogenic effects, known collectively as the "fetal
warfarin syndrome," consist of nasal hypoplasia, stippled epiphyses, and growth restriction. Em- bryopathy associated with warfarin has been re- ported to occur in 10% to 25% of fetuses ex- posed in the first trimester. TM The most critical time of exposure appears to be between the sixth and ninth weeks of gestation]
Although it used to be common practice to use coumarin derivatives after the first trimester, it is now well documented that second- and third- trimester exposure may also lead to adverse ef- fects, such as microcephaly, blindness, deafness, and growth restriction. 7 The latter anomalies are probably related to hemorrhage into the fetal tissues. The teratogenic and adverse fetal effects are summarized in Table 1. v
Warfarin may also be associated with abortion, fetal death in utero, and prematurity. In the re- view by Hall et al 7 of 418 pregnancies in which coumarin derivatives were used, there were 36 (8.6%) spontaneous abortions, 32 (7.7%) still- births, and 11 (2.6%) newborns with embryopa- thy.
Warfarin therapy does not appear to cause adverse effects to the breast-feeding neonate and is thus not contraindicated. 9'1~ In fact, because of the oral route of administration and the sig- nificant side effects associated with protracted
From the Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX; and the Department of Obstetrics and Gynecology, Mayo Medical Center, Rochester, MN. Address reprint requests to Susan M. Ramin, MD, Department of Obstetrics and Gynecology, University of Texas Southwestern Medi- cal Center, 5323 Harry Hines Blvd, Dallas, TX 75235-9032. Copyright 9 1997 by W.B. Saunders Company 0146-0005/97/2102-0005505.00/0
Seminars in Perinatology, Vol 21, No 2 (April), 1997: pp 149-153 149
150 Ramin, Ramin, and Gilstrap
Table 1. Teratogenic and Adverse Fetal Effects of Coumarin Derivatives
Nasal hypoplasia Stippled epiphyses Agenesis of corpus callosum Dandy-Walker malformations Microcephaly Blindness Deafness Growth restriction Developmental delay
Adapted from data from Hall JG, et al. 7
heparin use, warfarin is the ideal anticoagulant to use during the postpartum period for mainte- nance therapy in most women.
Compared with warfarin, heparin is a relatively large molecule with a molecular weight ranging from 4,000 to 6,000 for low-molecular-weight heparin to as high as 20,000 to 30,000 for stan- dard heparin. It is also a highly charged mole- cule. Because of these two facts, heparin does not cross the placenta in any appreciable amount and thus should not be associated with direct adverse fetal effects. Thus, heparin is the drug of choice for the treatment or prevention of thromboembol ism during pregnancy. How- ever, women requiring heparin may have an in- crease in the frequency of adverse pregnancy outcomes, such as prematurity and neonatal deaths. For example, Nageotte et al H reported 15 (13%) adverse pregnancy outcomes (prema- turity, neonatal death, stillbirth, and spontane- ous abortion) in a study of 135 pregnancies in which heparin was used. Such pregnancy losses may be the result of the condition being treated and not the heparin itself. In a review of 77 women requiring heparin during pregnancy, there was no increase in the frequency of still- births, prematurity, neonatal deaths, or congeni- tal anomalies. 12
It would appear that low-molecular-weight heparin also does not cross the placenta. 1~'~4 In studies involving more than 60 pregnancies in which low-molecular-weight heparin was used, there were no increase in adverse fetal effects. ~- 17 Low-molecular-weight heparin was also not found to be teratogenic in animal studies. 18
Although heparin is not associated with te- ratogenic or adverse fetal effects, it may cause
significant adverse maternal effects. Probably the most common adverse effect is thrombocyto- penia, which may occur in up to 15% of women. 19 It usually does not develop until after 3 to 5 days of therapy and appears to be an auto- immune phenomena. 19 Thrombocytopenia has been reported in patients treated with low-mo- lecular-weight heparin, ~~ although Sturridge et a121 found no association with platelet count and one preparation, enoxaparin.
Heparin has also been reported to be associ- ated with a reversible osteopenia when used in large doses over a protracted period of time. ~~ Ginsberg et a122 reported decreased bone density as an effect of heparin, but none of the patients had fractures. In a study of 184 women receiving prophylactic heparin during pregnancy Dahl- man 23 reported osteoporotic vertebral fractures in 2.2% of women.
Finally, women on anticoagulant therapy are at risk for hemorrhage at the time of delivery and during the postpartum period. The antico- agulant effect of heparin can be corrected with protamine sulfate. A general "rule of thumb" is 0.5 mg of protamine for every 100 units of hepa- rin. Fortunately, protamine is rarely needed for the pregnant woman on heparin therapy.
Thromboly t i cs
Streptokinase, atteplase (tissue plasminogen ac- tivator), and urokinase are the major thrombo- lytics currently available. No large studies have examined their use during pregnancy. Uroki- nase was not associated with an increase in mal- formations in mice and rats in doses several times the usual human dose. 24
In a recent review of more than 30 reports involving 172 pregnant women treated with thrombolytics, Turrentine et a125 reported a ma- ternal mortality of 1% to 2% and hemorrhagic complications in 8.1%. In addition, there were approximately 6% pregnancy losses.
Although there is currently no evidence that thrombolytics are teratogenic, they may be asso- ciated with a risk of bleeding as high as 27%. a9 Moreover, there appears to be no advantage of thrombolytics in either short- or long-term mor- bidity or mortality. 19'26
It would seem reasonable to conclude that thrombolytics should be reserved for clinical sit- uations in which other agents are not effective.
Anticoagulants and Thrombolytics in Pregnancy 151
Table 2. Anficoagulation Therapy for Acute Thrombolytic Disease in Pregnancy
Heparin for 5-10 days 5,000 IU as initial bolus and 1,000 IU/h as continuous intravenous infusion or
amount to maintain PTT at 1.5 to 2.5 times control, or
5,000 IU intravenous every 4 hours intermittently, or 10,000 IU subcutaneously every 8 hours or 20,000
units every 12 hours Maintain PTT at 1.5 to 2.5 times control or plasma
heparin level of 0.1 to 0.2 IU/mL Follow-up
Subcutaneous heparin, 5,000 IU every 8 to 12 hours or doses to maintain PTT at 1.5 times control
Continue for 2 to 6 weeks postpartum (coumadin can be substituted for heparin)
Abbreviation: PTT, partial thromboplastin time. Data from Rutherford and PhelauS; Toglia and Weyl~ and Cunningham et al. ~7
The choice, as well as the dose and duration, of anticoagulant therapy during pregnancy mostly depends on the specific condition that is being treated.
Acute thrombophlebitis is often difficult to diag- nose, especially in the pregnant woman. Al- though many clinicians are hesitant to perform venography in pregnancy because of the fear of radiation exposure, it remains the "gold stan- dard" for confirming the diagnosis of thrombo- phlebitis during pregnancy. Once the diagnosis is made, heparin should be started in an initial bolus of 5,000 U followed by a constant infusion of 1,000 U or higher per hour to maintain the activated partial thromboplastin time (aPTT) at 1.5 to 2.5 times the control. 5,a~ Intravenous hepa- rin is generally continued for 5 to 10 days (Table 2). 5'1~ Following this initial therapy, heparin can then be given subcutaneously every 12 hours to maintain the aPTT (measured at 6 hours after the last injection) at 1.5 times the control until delivery, a~ Most recommend continuing antico- agulation for at least 6 weeks postpartum. This can be accomplished with coumadin.
History of Thromboembolism
The exact recurrence risk of thromboembolism in a subsequent pregnancy is unknown but has
been estimated to be 4% to 15%. 28'29 Recently, it has been recommended that in subsequent pregnancies women with a history of thrombo- embolism be given subcutaneous heparin in a dose of 5,000 IU every 12 hours. 9 In a study of 184 pregnant women receiving prophylactic sub- cutaneous heparin (mean dose 13,000 to 40,000 IU per 24 hours), Dahlman 2~ reported a recur- rence of thromboembolism of 2.7%. z~
It would also seem reasonable to use low-mo- lecular-weight heparin in pregnant women at risk for thromboembolism. However, there are no large, randomized studies regarding the effi- cacy of such therapy. The dose of one form of low-molecular-weight heparin, enoxaparin, is 30 mg subcutaneous twice a day. Some clinicians recommend a once-a-day dose. This form of hep- arin is easy to use and comes in packages of 10 prefilled syringes of 30 mg each.
Pregnant women with pulmonary emboli should receive full anticoagulation as previously de- scribed. These women should remain on antico- agulants throughout pregnancy and for at least 6 weeks postpartum. An argument can logically be made to maintain these women on "thera- peutic" doses of subcutaneous heparin through- out pregnancy. Again, coumadin can be used for the postpartum period even if the mother is breast-feeding.
Cardiac Valve Prosthesis
Most women with artificial heart valve prostheses are maintained on coumadin when not preg- nant. In a study of more than 200 pregnancies in 156 women, Salazar et al so reported three ma- ternal mortalities and a 25% incidence of cere- bral embolism in the 68 pregnancies treated only with antiplatelet agents in the first trimester. In 128 pregnancies in which coumadin was used, 8% had warfarin embryopathy and 28% ended in abortion.
Iturbe-Alessio et al ~1 prospectively studied 72 pregnant women with artificial heart valves. In 23 women, heparin 5,000 U twice a day from weeks 6 through 12 was used. In 12 women, hep- arin was used from week 7 through week 12. The remaining 37 women were detected after the first trimester and received coumadin continu- ously throughout gestation. Heparin was used
152 Ramin, Ramin, and Gilstrap
the last 2 weeks of pregnancy in most of the women. Three women suffered thrombosis of a tilting-disk mitral valve prosthesis, two of which were fatal. Although there were no differences in the rate of spontaneous abortions, the rate of coumarin embryopathy was 25% and 29.6% in the second and third groups. None of the women in the first group had evidence of em- bryopathy. The authors concluded that low-dose heparin does not protect against prosthetic valve thrombosis and that coumadin provides effective protection.
Because of the risk of coumadin embryopathy and the risk of recurrent embolism and death in pregnant women with artificial heart valves, Ginsberg and Hirsh 12 recommend subcutaneous heparin every 12 hours in sufficient doses to maintain the aPTT at 1.5 times control values. These women can be switched to coumadin dur- ing the postpartum period.
Salazar et a132 reported further on the failure of heparin to prevent valve thrombosis with me- chanical valves in pregnancy. They followed 40 pregnancies in 37 women with prosthetic valves. These women received subcutaneous heparin from weeks 6 to 12 and the last 2 weeks of preg- nancy. Heparin was given every 8 hours in the first 36 cases and every 6 hours in the other 4. The dose was adjusted to keep the aPTT at 1.5 to 2.5 times control. Coumadin was used in the remainder of pregnancy and postpartum. There was one neonatal death caused by cerebral hem- orrhage and a spontaneous abortion rate of 37.5 %. No cases of coumarin-induced embryopa- thy were detected. There were two cases of fatal thrombosis of mitral tilting-disk prosthesis dur- ing heparin therapy. The findings of this study are concerning even while adequate anticoagula- tion with heparin fatal events occurred. Consid- eration of continuous coumadin therapy is sug- gested by the authors. Clearly, further larger prospective studies are needed to define the best management of pregnant women with prosthetic valves.
The major concern in the management of pregnant women with prosthetic valves is elimi- nating the occurrence of valve thrombosis while maintaining the optimal outcome for the fetus. One approach would be to consider the age and reproductive status of the woman at the time of valve placement....