Anticoagulants and Thrombolytics During Pregnancy Susan M. Ramin, Kirk D. Ramin, and Larry C. Gilstrap

Although venous thromboembol i sm is a rare complicat ion o f pregnancy, it is one o f the leading causes o f maternal mortality. As many as 40% o f asymptomatic w o m e n with deep venous thrombosis may indeed have a pulmonary embol ism. Therefore , pregnant w o m e n with thromboembol ic disease, a history o f thromboembol i c disease, or those who are at increased risk o f thromboembol i sm (me- chanical cardiac valve prostheses, antithrombin II, or protein C or S deficient) should receive antico- agulant therapy. The choice o f anticoagulant therapy in a pregnant w o m a n 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 o f anticoagu- lants and thrombolytics in pregnant women. Copyright �9 1997 by W.B. Saunders Company

V enous th romboembol i sm has been re- por ted to cause as many as 120,000 deaths

in the Uni ted States per year. 1 It is also one of the leading causes of maternal deaths dur ing pregnancy. 2'3 For example, Berg et al 4 repor ted that pu lmonary 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 unt rea ted deep ve- nous thrombosis are at risk for pu lmonary 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, p regnan t women with th romboembol ic disease, a history of th romboembol ic disease, or who are at increased risk of such (ie, ant i throm- bin II or prote in C or S deficient) should receive ant icoagulant therapy. Although such therapy is not without risks to both m o t he r and fetus, the benefits of anticoagulation obviously outweigh potential risks.

Spec i f i c A n t i c o a g u l a n t s

Coumarin Derivatives

Warfarin sodium (coumadin) is a coumarin anti- coagulant and works primarily by depressing vita- min K - d e p e n d e n t 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- por ted to occur in 10% to 25% of fetuses ex- posed in the first trimester. TM The most critical t ime of exposure appears to be between the sixth and ninth weeks of ges ta t ion]

Although it used to be c o m m o n practice to use coumarin derivatives after the first trimester, it is now well documen ted that second- and third- tr imester exposure may also lead to adverse ef- fects, such as microcephaly, blindness, deafness, and growth restriction. 7 The latter anomalies are probably related to hemor rhage 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 coumar in 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 administrat ion and the sig- nificant side effects associated with prot rac ted

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

hepar in use, warfarin is the ideal anticoagulant to use during the pos tpar tum per iod for mainte- nance therapy in most women.

Heparin

Compared with warfarin, hepar in is a relatively large molecule with a molecular weight ranging f rom 4,000 to 6,000 for low-molecular-weight hepar in 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, hepar in does not cross the placenta in any appreciable amoun t and thus should not be associated with direct adverse fetal effects. Thus, hepar in is the drug of choice for the t rea tment or prevent ion of th romboembol i sm dur ing pregnancy. How- ever, women requir ing hepar in may have an in- crease in the f requency of adverse pregnancy outcomes, such as prematur i ty and neonatal deaths. For example, Nageot te et al H repor ted 15 (13%) adverse pregnancy outcomes (prema- turity, neonatal death, stillbirth, and spontane- ous abortion) in a study of 135 pregnancies in which hepar in was used. Such pregnancy losses may be the result of the condit ion being treated and not the hepar in itself. In a review of 77 women requir ing hepar in dur ing pregnancy, there was no increase in the f requency of still- births, prematurity, neonatal deaths, or congeni- tal anomalies. 12

It would appear that low-molecular-weight hepar in also does not cross the placenta. 1~'~4 In studies involving more than 60 pregnancies in which low-molecular-weight hepar in was used, there were no increase in adverse fetal effects. ~- 17 Low-molecular-weight hepar in was also not found to be teratogenic in animal studies. 18

Although hepar in is not associated with te- ratogenic or adverse fetal effects, it may cause

significant adverse maternal effects. Probably the most c o m m o n 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 Thrombocy topen ia has been repor ted in patients treated with low-mo- lecular-weight heparin, ~~ a l though Sturridge et a121 found no association with platelet count and one preparat ion, enoxaparin.

Hepar in has also been repor ted to be associ- ated with a reversible osteopenia when used in large doses over a protracted per iod of time. ~~ Ginsberg et a122 repor ted decreased bone density as an effect of heparin, but none of the patients had fractures. In a study of 184 women receiving prophylactic hepar in dur ing pregnancy Dahl- man 23 repor ted osteoporotic vertebral fractures in 2.2% of women.

Finally, women on ant icoagulant therapy are at risk for hemor rhage at the time of delivery and dur ing the pos tpar tum period. The antico- agulant effect of hepar in can be corrected with p ro tamine sulfate. A general " ru le of t h u m b " is 0.5 mg of p ro tamine for every 100 units o f hepa- rin. Fortunately, p ro tamine is rarely needed for the p regnan t woman on hepar in therapy.

T h r o m b o l y t i c s

Streptokinase, atteplase (tissue plasminogen ac- tivator), and urokinase are the major thrombo- lytics currently available. No large studies have examined their use dur ing pregnancy. Uroki- nase was not associated with an increase in mal- formations in mice and rats in doses several times the usual h u m a n dose. 24

In a recent review of more than 30 reports involving 172 p regnan t women treated with thrombolytics, Turrent ine et a125 repor ted 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 e i ther 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 o ther 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

Specific Conditions

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

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 r ecommend 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 1 5 % . 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.

Pulmonary Embolism

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 coumar in 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 hepar in 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 p regnan t women with artificial hear t valves, Ginsberg and Hirsh 12 r e c o m m e n d subcutaneous hepar in 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 pos tpar tum period.

Salazar et a132 repor ted fur ther on the failure of hepar in to prevent valve thrombosis with me- chanical valves in pregnancy. They followed 40 pregnancies in 37 women with prosthetic valves. These women received subcutaneous hepar in f rom weeks 6 to 12 and the last 2 weeks of preg- nancy. Hepar in was given every 8 hours in the first 36 cases and every 6 hours in the o ther 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 abort ion 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 hepar in therapy. The findings of this study are concerning even while adequate anticoagula- tion with hepar in fatal events occurred. Consid- eration of continuous coumadin therapy is sug- gested by the authors. Clearly, fur ther larger prospective studies are needed to define the best m a n a g e m e n t of p regnan t women with prosthetic valves.

The major concern in the m a n a g e m e n t of p regnan t 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 . Sbarouni and Oakley 33 assessed the outcomes of 151 pregnancies in 133 women with mechanical valves and 63 pregnancies in 49

women with bioprostheses. All but one woman with a mechanical valve used anticoagulants dur- ing pregnancy compared with 17% with a bio- prosthetic valve. The incidence of stillbirths and spontaneous abortions did not differ between the two groups. W o m e n with mechanical valves suffered 13 valve thromboses (4 fatal), 8 embolic events (2 fatal), and 7 bleeds. Most of the compli- cations occurred while using heparin, but fatal valve thrombosis occurred in a woman who re- fused anticoagulation. There were no deaths in the bioprosthetic valve group, but 35% required rep lacement during or after pregnancy owing to failure of the valve. Lee et a134 conf i rmed these findings in a retrospective review of 151 pregnan- cies in 88 women. They concluded that porcine valves resulted in fewer fetal and maternal com- plications; however, pregnancy may accelerate the degenerative process of bioprosthesis.

Intrapartum Management In t rapar tum m a n a g e m e n t is most precarious in those women with mechanical cardiac valve pros- theses or a recent pu lmonary embolism. Contin- uing therapeutic intravenous hepar in through labor appears to be the most appropr ia te man- agement plan. Currently, regional analgesia is not r e c o m m e n d e d in light of the possible devel- o p m e n t of an epidural hematoma. Anticoagula- tion should be terminated when the woman reaches the active phase of labor, and therapy should be resumed within 6 hours of vaginal de- livery. Ideally, the woman who is on coumadin should be converted to intravenous hepar in be- fore labor to avoid delivery of an anticoagulated infant. In the woman who is on coumadin when labor ensues before conversion to heparin, con- sideration of cesarean section to reduce the risk of fetal intracerebral hemor rhage must be given. Cotrufo et a135 managed 20 women with cardiac valve prosthesis by cont inuous coumadin until 38 weeks' gestation. The coumadin was s topped 48 hours before delivery and reinstituted 24 hours thereafter. They observed no increased risk of morbidity or mortality to ei ther the mo the r or fetus. The data f rom Salazar et al a2 in those women with mechanical valves in the mi- tral position contradicts the use of subcutaneous heparin.

Summary The risk of th romboembol i sm and its t rea tment pose great risks to the mo the r and her fetus. The

Anticoagulants and Thrombolytics in Pregnancy 153

fetus is at risk for possible spontaneous abortion and coumadin embryopathy. The mother is at risk for one of three even t s - - r ecu r ren t throm- boembolism, hemorrhage, or osteoporosis. Ide- ally, women should be counseled about these risks before pregnancy. Management plans should be made and clearly recorded in the woman's record. The caregivers involved (cardiologists, perinatologists, hematologists, and anesthesiologists) should all be included in management discussions. It is through the col- laborative efforts of all that risks to the mother and her fetus can be kept to a minimum.

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