CURRENT CONCEPTS OF ANTICOAGULANT THERAPY IN PREGNANCY

PRESCRIBING IN PREGNANCY

0889-8545/97 $0.00

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CURRENT CONCEPTS OF ANTICOAGULANT THERAPY IN PREGNANCY Linda A. Barbour, MD, MSPH

Pregnant women are subjected to a fivefold increased risk of venous thrombosis during pregnancy and are more likely to die from this disease after a live birth than from any other cause in the United States5 Thromboembolism also accounts for the largest number of maternal deaths in Wales and and data from Sweden during the period 1980 to 1988 also confirmed embolism as the leading cause of maternal death.56 Multiple changes in the coagulation system account for the hypercoagulable state of pregnancy, including increases in clotting factors, decreases in natural inhibitors of coagulation, changes in the fibrinolytic system, increases in venous stasis, and vascular injury at delivery from placental separation, cesarean section, or infection.'O As a consequence, antithrombotic therapy in pregnancy is used for the treatment of acute events, the prophylaxis of patients with a history of events, the prevention and treatment of systemic embolization in women with valvular disease, and as prophylaxis against fetal loss and thrombosis in women with the antiphospholipid antibody syndrome. Despite the gravity of this problem in pregnant women, treatment guidelines are nondefinitive and often contradictory because the evidence upon which recommendations can be based is largely derived from retrospective studies. Pregnant women are usually excluded from prospective treatment studies owing to concerns that antithrombotic agents pose risks for both maternal and fetal complications. This article critically appraises the literature on the

From the Departments of Medicine and Obstetrics and Gynecology, University of Colorado Health Sciences Center, Denver, Colorado OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA

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VOLUME 24 * NUMBER 3 SEPTEMBER 1997

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maternal and fetal effects of anticoagulants, including low-molecularweight heparin (LMWH) and thrombolytic agents; discusses controversial guidelines from expert panels; and offers recommendations for their use in pregnancy. EPIDEMIOLOGY Although thromboembolism accounts for significant morbidity and mortality in pregnant and postpartum women, the absolute risk of a symptomatic venous thrombosis in a patient without any risk factors is fairly small at 0.5 to 3.0 per 1000 when considering only studies using 90 Women with a history of thromboemradiographic documentati~n.~~, bolic events are at an increased risk for recurrence when they become pregnant and pose a unique problem to the practitioner in regards to management. Estimates of recurrence are extremely imprecise because they are based on retrospective studies subject to inaccurate reporting. In addition, they do not stratify women on the basis of risk factors and circumstances surrounding the event. Recent observations in nonpregnant patients confirm that patients who present with idiopathic deep vein thrombosis (DVT) have a much higher recurrence rate than 73 patients who develop DVT in association with a transient risk factor.42, In addition, women with underlying hypercoagulable states, including the recent discovery of hereditary resistance to activated protein C, also have a higher recurrence risk.25 Unfortunately, estimates of recurrence in pregnancy are not stratified by any risk factors and are derived primarily from two retrospective studies. A 12% recurrence risk was first reported in a highly quoted questionnaire study administered to 84 women, but the events were poorly documented and recall bias threatens the validity of this estimate.6 A second study of 87 pregnancies in 72 women, whose first documented event occurred primarily in the context of pregnancy or oral contraceptive use, reported an anteparturn recurrence rate of 7.5% to 10.5%.'04 The prophylactic failures occurred in the second trimester in women given 5000 units of heparin subcutaneously every 12 hours, which may be inadequate. Preventive treatment in pregnancy has been another area of unresolved debate. Early data gathered in England and Wales as well as by the Mayo Clinic in the 1950s and 1960s suggested that postpartum events were much more frequent than anteparturn events.', 88 However, lengthy hospitalizations and bed rest were standard of care for uncomplicated vaginal deliveries at that time. More recent studies have demonstrated that antepartum DVT is at least as common as postpartum DVT (Table 1) and can occur at any time during gestation, although pulmonary emboli (PE) remains more common p o s t p a r t ~ m . ~In~a, recent ~~,~~ cohort study of 60 women with antepartum DVT, 22% occurred during the first trimester, 47% during the second trimester, and 31% during the third trimester.O Interestingly, all 60 events involved the left leg, and this

12 93 60

TengbornIo4 Rutherfordgo(abstract) Ginsberg"

Only anteparturn events reported

67 75

Only anteparturn events reported

36 78

("/.I

22

51

37

12 33 24

1st (%)

47

35 33 41

2nd (%)

31

53 33 35

3rd (%)

Antepartum Events Occurring During Trimesters

'Only proportion of anteparturn events occurring first trimester are reported. t82% of postpartum emboli occurred after cesarean delivery. DVT = deep venous thromboses; PE = pulmonary emboli.

77 23 17

Primary Author

Aaro' Hellgren52 BergqvistI3

Events (n)

DVT Antepartum

Table 1. TIMING OF EVENTS IN PREGNANCY

33 25

64 22

DVT Postpartum (%.)

34

23

PE Antepartum (%)

66t

77

("M

PE Postpartum

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predominance of left-sided events is corroborated in the l i t e r a t ~ r e Io4 . ~ In ~, the largest series of nearly 170,000 pregnant women, 75% of all DVTs occurred anteparturn, whereas 66% of the PE occurred postpartum, the vast majority after cesarean delivery (see Table 1).9O Of all DVTs occurring anteparturn, 51% occurred by 15 weeks' gestation. Earlier postpartum ambulation and discharge of patients from the hospital may have resulted in a relative decrease in postpartum events as compared to antepartum events. Other factors that significantly increase thromboembolic risk in addition to cesarean section include increased age and parity, obesity, prolonged bed rest, operative procedures, the postphlebitic syndrome, and, as mentioned, a history of unprecipitated thromboses or hypercoagulable states that are acquired or congenital.'O WARFARIN Warfarin produces its anticoagulant effect by interfering with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide). Vitamin K plays a crucial role in the gamma-carboxylation of glutamic acid residues of the vitamin K-dependent coagulation factors (prothrombin or factor 11, VII, IX,and X), thereby providing these factors with important binding sites for calcium and phospholipids. Unless they are carboxylated, they are unable to bind calcium or phospholipids, resulting in defective hemostasis. In addition, warfarin limits the carboxylation of the regulatory proteins (protein C and protein S) and as a result impairs the function of these anticoagulant proteins. Progress has been made in the control of warfarin therapy because of the importance of reporting the prothrombin time (PT) results as an international normalized ratio (INR), which takes into account the various sensitivities of commercial thromboplastins. As a result, the anticoagulant activity as measured by the INR is closely equivalent from laboratory to laboratory, and the results from studies reporting the INR can be generalized to other patient populations. In clinical practice, it must be remembered that warfarin causes the plasma concentrations of functional factor VII and protein C to fall quickly because of their short half-lives (6 to 8 hours), whereas decreases in other clotting factors are delayed for 24 to 48 hours. Thus, when warfarin therapy is first started, the initial anticoagulant effect (an increase in the INR because of reduced factor VII concentrations) precedes the antithrombotic effect (because of reduced prothrombin concentrations) by about 24 hours. It is also associated with a transient hypercoagulable state because protein C, which also has a short half-life, is reduced quickly. For the same reason, loading with Coumadin (warfarin) is ineffective and often unsafe. If heparin is discontinued early because the INR is in the therapeutic range, the patient might be at risk for extension of the thrombosis, given prothrombin is not yet inhibited and the anticoagulant protein C is low. It is safer to start with an estimated dose of about 5 mg of Coumadin and give heparin concurrently for at least 4 to 5 days, at which time patients have

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often reached an INR of 2.0 and, if not, adjust the Coumadin dose 54 acc~rdingly.~~, In pregnancy, coumarin derivatives cross the placenta and have the potential to cause both bleeding in the fetus and teratogenicity. An embryopathy similar to chondromalacia punctata (stippled epiphyses and nasal and limb hypoplasia) has been reported to affect 0 to 67% of 19, fetuses when exposed during the sixth to twelfth week of ge~tati0n.l~. 69, 94, 112 The huge splay in the reported incidence of embryopathy can be partly explained by the dose of warfarin used at the critical period of embryogenesis, whether very minor abnormalities were reported, and whether a clinical geneticist versus general practitioner examined the neonate. A large number of studies have found warfarin-induced embryopathy to occur much less frequently than originally reported, esti18, 50, 70, 81, 93, 94 The skeletal abnormalities associated mated at 5% to with the embryopathy are thought to be secondary to vitamin Ks involvement in the post-translational modification of proteins enabling them to bind calcium rather than to hemorrhagic complications. Although avoidance of exposure during the first 6 to 12 weeks of gestation can avoid the risk of skeletal embryopathy, bleeding can occur in the fetus at any time, resulting in a high fetal loss rate. In addition, central nervous system (CNS) abnormalities, including dorsal midline dysplasia, midline cerebellar atrophy, and ventral midline dysplasia, have been reported. As a consequence, optic atrophy, microcephaly, or mental retardation may occur. The immature fetal liver produces low concentrations of vitamin K-dependent clotting factors, resulting in a much stronger anticoagulant effect of warfarin during a period of rapid growth in the fetus. The fetal loss rate from the use of warfarin is high, 83, lo8; however, no adjustments are made for ranging from 8% to 50%14, confounding maternal morbidity, which is often valvular heart disease. Warfarin is contraindicated after 34 to 36 weeks, when the combination of the anticoagulant effect and trauma of delivery can lead to serious bleeding in the neonate. A review of 1325 pregnancies from 186 studies reported a 16.9% incidence of adverse outcomes with the use of warfarin during pregnancy, compared to a 3% incidence with heparin, after excluding pregnancies with confounding maternal comorbid conditions and prematurity with normal outcomes." However, selection bias may affect the accuracy of this figure. Treatment with warfarin during pregnancy is usually restricted to patients with mechanical heart valves between 12 to 34 weeks, owing to the significant failure rate with therapeutic heparin, as will be discussed. Warfarin may be given to lactating mothers and has been approved as compatible with nursing by the American Academy of Pediatricians. Small studies have found no warfarin activity in breast milk or infant 77 Little or no warfarin diffuses into breast milk because it cir~ulation.~~, is highly protein bound, and that which is not exists in its ionized form, which is not lipid soluble.

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HEPARIN

Heparin is the anticoagulant of choice during pregnancy because it is a very large molecule that does not cross the placenta. Heparin is a glycosaminoglycan, and commercial heparins are obtained from porcine gut or bovine lung and have molecular weights of up to 40,000 daltons. Its major anticoagulant effect is attributable to a unique pentasaccharide with a high-affinity binding sequence to antithrombin I11 (AT-111) that is present in only one third of heparin molecules. The anticoagulant effect of heparin is mediated largely through its interaction with AT-111. It produces a confirmational change in AT-I11 that markedly accelerates its ability to inactivate the coagulation enzymes thrombin (factor IIa), factor Xa, and factor IXa. A retrospective study of 100 consecutive pregnancies in which heparin was used reported that the rate of adverse fetal and neonatal outcomes was comparable to that in normal ~ r e g n a n c i e sUnfractionated .~~ heparin, however, needs to be given parenterally, and its antithrombotic effect is more difficult to maintain for extended periods of time when given subcutaneously. Although heparin is safest for the fetus, the mother is at risk for two adverse outcomes in addition to bleeding risks or inadequate levels of anticoagulation: heparin-induced thrombocytopenia and heparin-induced osteoporosis. Thrombocytopenia is a well-recognized complication of heparin therapy for which two forms are described. An early, nonimmune thrombocytopenia can occur 2 to 5 days after starting therapy and is thought to be secondary to direct weak activation by heparin, but is not associated with any adverse clinical s e q ~ e l a eIn . ~ contrast, ~ the immune form of heparin-induced thrombocytopenia (HIT) is secondary to heparin-dependent IgG antiplatelet antibodies resulting in serotonin-induced platelet aggregation and a substantial risk of thrombotic complicathe incidence of serologically confirmed HIT was t i o n ~ .lO9 ~ ~Recently , investigated in a large clinical trial comparing unfractionated heparin (7500 units twice daily) with LMWH (Enoxaparin, 30 mg twice daily) for prophylaxis following elective hip surgery."O The incidence of HIT was approximately 1%at 7 days and 3% at 14 days in the unfractionated heparin group, and 0% in those receiving LMWH. Other prospective studies using therapeutic doses have reported similar incidences.*,49, 65, 84,85 The incidence of HIT is lower with porcine mucosal heparin than bovine lung.65HIT usually occurs between 5 and 15 days after beginning heparin therapy, but it has been reported within hours of beginning therapy in patients who have been previously exposed to heparin, especially within the last 3 months.65A fall in platelet count without overt thrombocytopenia can herald HIT-associated thrombosis; thus, patients on heparin should receive frequent platelet counts between 5 and 15 days after initiating therapy. Because HIT is a highly prothrombotic disorder, heparin must be stopped and an alternative strategy must be implemented. LMWHs may cross-react immunologically with unfractionated heparin. A low-molecular-weight heparinoid, danaparoid so-

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dium (Orgaran), was efficacious in 93% of 88 patients with heparininduced thrombocytopenia and t h r o m b ~ s i s . ~ ~ Heparin-induced osteoporosis is a more common concern of heparin use during pregnancy. Symptomatic fractures from heparin-induced osteoporosis in pregnancy have been reported in less than a dozen cases: 51, 57,100, 111,113 but the subclinical incidence appears to be significant. In one series of 184 women undergoing heparin prophylaxis, the incidence of symptomatic fractures was 2.2%.26 One fracture occurred as early as 7 weeks in a patient on only 15,000 units per day. The largest retrospective radiographic study using postpartum spine or hip radiographs suggested that 17% of pregnant women treated with prophylactic heparin showed evidence of osteopenia.28 Prospective trials using bone densitometry have also documented this phenomenon at a subclinical level. In one series by this author: 5 of 14 pregnant women exposed to heparin, versus 0 of 14 pregnant controls, developed at least a 10% decrease from their baseline proximal femur values when measured immediately postpartum. Although bone density improved after discontinuation of heparin postpartum, a statistically significant decrease in mean bone density remained at 6 months postpartum, suggesting that this phenomenon may not be entirely reversible. Another study using single photon absorptiometry of the wrist also demonstrated an overall reduction of approximately 5% in 39 pregnant women.29Lumbar spine bone density measured postpartum in 25 women who received heparin during pregnancy, versus 25 pregnant controls, demonstrated a 7% lower bone density in the heparin group, which was significant. In a number of studies, there was no clear doseresponse relationship? 28, 29, 34, 47 although older studies have suggested a possible dose-response effect. Heparin delivery during pregnancy is often problematic because of increasing heparin requirements in pregnancy and difficulty maintaining an anticoagulant effect with subcutaneous heparin during the course of pregnancy. Increases in heparin-binding proteins (e.g., von Willebrands’s factor), plasma volume, renal clearance, and heparin degradation by the placenta may result in reduced bioavailability of subcutaneous heparin. Some patients may require up to 40,000 units of heparin intravenously in a 24-hour period to maintain a therapeutic activated partial thromboplastin time (APTT). Doses as high as 20,000 units every 8 hours may be required to achieve a therapeutic APTT (1% to 2% times control) throughout the dosing interval using subcutaneous heparin, given its reduced bioavailability compared to intravenous heparin.lO,l5 Two recent studies have suggested that 5000 units every 12 hours may be inadequate prophylaxis during the second and third trimester because of increasing heparin requirements in pregnancy. Although 5000 units every 12 hours may be adequate prophylaxis in medical patients who are not undergoing high-risk procedures such as hip or knee surgery, 5000 units every 12 hours may be insufficient in pregnant women, and prophylactic failures have occurred using this regimen.lo4 Both studies evaluated the amount of heparin necessary to achieve

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prophylactic heparin levels using anti-Xa assays because prophylactic doses of heparin usually do not increase the APTT, given its low sensitivity to small doses of heparin. DahlmanZ7first documented that when heparin is measured as antifactor Xa activity (heparin assay), which can be detected at very low heparin concentrations, pregnant women required higher doses to achieve the same prophylactic level that 5000 units every 12 hours would achieve in the nonpregnant population. By using a chromogenic assay to measure anti-Xa activity, he noted that the average dose needed to achieve a prophylactic level (0.08 to 0.15 U/mL) was 8200 units subcutaneously every 12 hours as measured 3 hours after the morning dose of heparin (peak heparin level). This author also found that standard doses of 5000 units given subcutaneously every 12 hours was inadequate to achieve a prophylactic anti-Xa activity level between 0.05 and 0.25 U/mL during pregnancy. In five of nine second-trimester pregnancies, 7500 units given subcutaneously every 12 hours was inadequate to attain this range. In 6 of 13 third-trimester pregnancies, greater than 10,000 units every 12 hours was needed." Given the decreased bioavailability of heparin during pregnancy, intravenous doses and subcutaneous doses may need to be higher in pregnancy for both prophylactic and therapeutic anticoagulation. Administering heparin through a programmable pump subcutaneously has theoretic merit to minimize the fluctuation in levels of anticoagulation when given as single injections every 8 to 12 hours, especially in the context of acute thromboembolism or valvular heart disease. However, data supporting this approach are minimal and the most recent study using an automated pump was limited to a retrospective, paired case-controlled study of 16 women with a history of thromboembolic disease that was unclear as to how recent or remote.% Although the mean daily dose of heparin delivered by the subcutaneous pump was higher, there was no definable goal of therapy. There were two complications in the intermittent subcutaneous group (hematoma and site infection), while none occurred in the subcutaneous infusion pump group; however, the latter had the advantage of regular weekly home visits by a perinatal nurse. Delivering heparin through a subcutaneous Teflon catheter that can be left in place for 1 week has also recently become available in order to avoid two or three injections a day.3 A small randomized crossover trial reported favorable results; however, patients did not use the catheter longer than a 2-week duration at a time. Further longer-term studies are needed to better define any advantage that programmable pumps or indwelling catheters may have in various high-risk populations (acute DVT and mechanical valve prostheses) before recommendations can be made on their efficacy. LOW-MOLECULAR-WEIGHT HEPARIN There is mounting evidence in nonpregnant individuals, based on the results of large randomized clinical trials, that LMWHs are at least

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as effective and safe, and probably more so, than unfractionated heparin for the treatment of patients with acute proximal DVT and for the prevention of DVT in patients undergoing surgery and orthopedic 98 LMWHs have several advantages over unfractionated procedures.42, heparin (UH). Their half-lives are longer and there is less protein binding; the dose response is more predictable, allowing the drug to be administered in fixed doses without laboratory monitoring in the nonpregnant population; they have been shown to be more effective than UH in preventing recurrence of clot and they are less likely to cause major bleeding because of minimal effects on platelets and vascular permeability. LMWHs are derived from standard heparin by either chemical or enzymatic depolymerization to yield fragments that are approximately one third the size of heparin, with a mean molecular weight of 4000 to 5000 daltons. Depolymerization of heparin into low-molecular-weight fragments results in less of an ability to catalyze thrombin inhibition because there are few molecules that contain the essential 18 saccharides necessary to bind thrombin and AT-I11 simultaneously. However, because the inhibition of factor Xa by AT-I11 does not require heparin to form a ternary complex, LMWHs have more antifactor Xa activity relative to antifactor IIa (thrombin) activity. As a result, the APTT does not correlate well with the anticoagulant effect of LMWH and instead antifactor Xa levels (heparin levels) must be used. In contrast to UH, LMWH does not bind to numerous plasma proteins, including histidine-rich glycoprotein (HRGP), platelet factor 4 (PF4), von Willebrand’s factor (VWF), and endothelial cell receptors. As a result, it does not have a saturation kinetics phase of elimination as does UH. UH’s initial elimination is thought to be due to protein and endothelial binding resulting in a dose-dependent half-life and dosedependent bioavailability. At low doses, UH’s bioavailability is low (15%)and half-life shorter (30 minutes); at high doses, the bioavailability is high (90%) and the half-life increases (150 minutes). Because LMWH does not bind to plasma proteins, the bioavailability is greater and unchanged at different doses. Because it has a reduced interaction with platelets and causes less vascular permeability, it results in less microvascular bleeding and heparin-induced thrombocytopenia. Experience using LMWH in pregnancy is largely from European countries and it has been conclusively demonstrated that it does not 87 Both Enoxaparin and Dalteparin (Fragcross into fetal circ~lation.~~, min) have been used as prophylactic agents in pregnant women, and anti-Xa levels have been monitored given the increased volume of distribution and glomerular filtration rate of pregnancy, which may necessitate higher doses. Between 2500 U and 20,000 U of Dalteparin have been administered as single or divided doses for prophylaxis depending on anti-Xa activity measured 2 to 6 hours after subcutaneous administrat i ~ n ?59,~ 78, , 87 as has 20 to 40 mg of Enoxaparin once a day.41,lo2Efficacy trials with sufficient numbers comparing prophylaxis with LMWH versus UH have not been done, and there is minimal reported experience

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using LMWH for treatment of acute DVT in pregnan~y.5~ Whether or not LMWH causes less heparin-induced osteoporosis is unknown. One study suggested a decreased risk of osteopenia when used in the longterm management of nonpregnant individuals in comparison to UH.79 Limited data in pregnancy suggested that LMWH caused a decrease in bone density of the spine;96however, bone density also decreased in normal pregnancy, which is in contrast to other investigators who have not found bone density to decrease in normal ~regnancy.~, 99 Unfortunately, there have been case reports of LMWH causing osteoporosis, 59 and animal studies have been ~onflicting.~~, Trials in pregnancy are sorely needed owing to the longer half-life and improved bioavailability of LMWH, especially in the setting of acute DVT given the extreme difficulty in maintaining a therapeutic anticoagulant effect throughout the dosing interval when using UH, in spite of 8-hour injections.'O Because the molecular weight and activity of LMWHs vary widely depending on the preparation, individual preparations need to be tested independently during pregnancy. Each of the available products alter the antifactor Xa activity to slightly different amounts and must be calibrated against a standard LMWH compound in use. Unfortunately, trials in the United States have excluded pregnant women for the use of LMWH in the past. THROMBOLYTIC THERAPY

Thrombolytic agents dissolve thrombi by activating plasminogen to the active agent plasmin. Plasmin then degrades fibrin in thrombus to soluble peptides. Circulating plasmin degrades soluble fibrinogen. Streptokinase (SK), urokinase (UK), and tissue plasminogen activator (TPA) are the three thrombolytic agents currently available for use in thromboembolism. Traditionally, thrombolytic therapy has been considered a relative contraindication during pregnancy, owing to the concerns of maternal and fetal hemorrhage. Therefore, there are no controlled trials using SK, UK, or TPA, and there are not likely to be any in the future. Indications for thrombolytic therapy for the treatment of thromboembolism outside of pregnancy are restricted to acute massive pulmonary embolism in patients hemodynamically unstable or patients with extensive iliofemoral thrombosis and a low risk of bleeding. Unfortunately, thrombolytic therapy is less effective in dissolving thrombus in venous thromboemboli in comparison to coronary thrombi. Only partial dissolution appears to be the rule because venous thromboemboli are older, larger, and more organized than coronary thrombi.6O The incidence of major (clinically significant)hemorrhage in patients treated with thrombolytic therapy for acute venous thrombosis in the nonpregnant literature ranges between 6% and 30%, a threefold greater incidence than with heparin Unfortunately, direct infusion into a leg vein or pulmonary artery has not been shown definitively to

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improve efficacy or reduce bleeding in comparison to systemic infusion because all of these agents cause systemic activation of fibrinolysis and a body-wide thrombolytic effect. Although some trials suggest that early use of a thrombolytic agent can decrease subsequent pain, swelling, loss of venous valves, and the incidence of the postphlebitic syndrome, conflicting findings necessitate prospective trials with long-term outcomes.6o, Reports of thrombolytic therapy in pregnancy in the world's literature are limited to fewer than 200 cases,'07 and in the vast majority, SK was used. SK and TPA do not cross the placenta in animals, and in vivo studies show that negligible amounts of SK reach the fetal circulation, given an absence of activation of the fetal fibrinolytic system, when administered to mothers immediately before delivery. No studies of the in vivo human placental transfer of UK or TPA have been published. UK has not been shown to be teratogenic in rats; however, it does cross the placenta. Complications of thrombolytic therapy have included primarily maternal hemorrhage, preterm delivery, and fetal loss. The vast experience has been with SK; however, there are case reports using UK and TPA.66, 67, lo7 A significant risk of intraparturn or postpartum hemorrhage may occur if therapy is given at the time of delivery (8.1% compared with 2% for therapeutic heparin). There is concern about the use of thrombolytic agents in the first trimester because of a theoretic risk of interference with placental implantation as a result of fibrinolysis of the fibrin layer between chorionic villi and myometrium. In the seven reported cases of first-trimester use, only one reported fetal loss.'O7 Although most reported cases of fetal loss later in pregnancy did not seem to be directly related to thrombolytic therapy, there have been reports of fetal death caused by abruptio placentae and intracranial hemorrhage in a newborn whose mother had received TPA. In addition, concern over premature labor being triggered by activation of circulating plasminogen has restricted use. Despite these concerns, an extensive recent review1O7noted the pregnancy loss rate in patients receiving lytic therapy to be only 5.8%, which included two maternal deaths. Although the available data suggest that thrombolytic agents are not teratogenic and do not carry a prohibitive fetal risk when given in appropriate situations, there are no controlled trials, efficacy is unproved, and there is a definite increased risk of bleeding complications. Thrombolytic therapy is relatively contraindicated at delivery or within the first 1 to 2 weeks postpartum.

VALVULAR HEART DISEASE

The optimal management of women of childbearing potential with valvular disease is especially controversial given the paucity of prospective data on the efficacy and safety of antithrombotic therapy for prosthetic valves, reports of therapeutic heparin failures resulting in signifi-

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cant morbidity, and the concerns that bioprosthetic heart valves may deteriorate at an accelerated rate during pregnancy.35 What is clear is that low-dose heparin or antiplatelet agents alone are inadequate prophylaxis in patients with prosthetic valves. The group at highest risk for thrombosis appears to be women with older generation valves such as the Starr Edwards and Bjork-Shiley valves in the 35 The newer mechanical prostheses (Medtronic-Hall mitral p~sition.'~, and St. Jude Medical) may be somewhat less thrombogenic, and it may be erroneous to generalize outcomes from studies primarily using one type of valve p r o ~ t h e s i sAdditionally, .~~ many of the studies are retrospective in design and it is impossible to ascertain the level of anticoagulation. This is especially important given the fact that contemporary APTT reagents are more sensitive to the anticoagulant effect of heparin. Thus, a minimum APTT ratio of only 1.5 times control is likely to be inadequate, although traditionally considered to be a "therapeutic" level. Although heparin is clearly the anticoagulant of choice in pregnancy for venous thrombosis, reports of therapeutic heparin failures and valvular thrombosis in pregnant women have recently brought into question its efficacy in patients with mechanical heart valves. A number of investigators have reported therapeutic heparin failures, at times resulting in fatal massive thromboses despite attempts to maintain the APTT at least 21~pregnan1.5 times c 0 n t r o 1 . In ~ a~small ~ ~ retrospective ~ ~ ~ ~ ~ series ~ ~ ~of ~ cies in 16 women after mechanical valve replacement, six of seven episodes of thrombosis occurred while the patients were on heparin.I7 Additionally, in the largest retrospective series of 151 pregnancies in 133 women with mechanical valves, there were 13 valve thrombo~es.9~ Ten of the 13 thromboses occurred in women taking heparin, and 12 of the 13 thromboses involved the mitral valve. In neither series was it clear that the women were therapeutic on heparin at the time of their thromboses; however, as discussed, it is extremely difficult to maintain the APTT 2 to 2% times control throughout the dosing interval using subcutaneous heparin during pregnancy. Lastly, it is unclear whether tissue valves are associated with improved pregnancy outcome because of the significant failure rate of these valves in young women. A number of retrospective series have suggested that up to one third of tissue valves deteriorated either during pregnancy or shortly thereafter.7,94 Others have suggested that the longterm performance of bioprostheses in pregnant women is not significantly different in women who have never experienced a pregnancy.'jz A large retrospective study in France analyzed 155 pregnancies in 103 women50with prosthetic heart valves. One hundred and eight mechanical prostheses and 74 bioprostheses were exposed to the risk of pregnancy. Among 108 women with mechanical valves, 16 thromboembolic events occurred, 13 in the mitral position. Twelve of the thromboses occurred under heparin, three under warfarin, and one when a patient had been withdrawn from anticoagulant therapy. The thromboembolic events that occurred under warfarin were always associated with an

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error in the therapeutic regimen itself, which was not the case with heparin treatment. For the 12 thromboembolic events that occurred under heparin, the coagulation intensity at the time of the accident was unknown in four cases, inadequate in four cases, but was apparently satisfactory in the other four. The thromboembolic risk under heparin was estimated to be four times higher than with warfarin. Among 74 bioprostheses, seven suffered premature failure. Eighty percent of the women with bioprostheses had normal deliveries, as compared to 53% of those with mechanical valves. All four maternal deaths were in the mechanical valve group, and three of four were attributed to thrombosis of the valve. The risk of spontaneous abortions was four times higher in patients requiring anticoagulants, and miscarriages were twice as frequent when warfarin was given during the first trimester than when heparin was initiated early. Given the lack of prospective well-controlled trials to determine the optimal management of women with valvular heart disease during pregnancy, there are insufficient grounds to make definite recommendations about optimal antithrombotic therapy or the choice between bioprosthetic and mechanical heart valves. Although a bioprosthesis may afford a better pregnancy outcome, structural valve failure during pregnancy carries a high mortality and women are faced with the risk of a known surgical reintervention within 10 to 15 years after replacement. TREATMENT RECOMMENDATIONS Acute Thromboembolism

Acute thromboembolism during pregnancy requires IV anticoagulation for approximately 5 to 10 days, followed by every 8 to 12 hours subcutaneous injections to prolong the APTT at least 1?h times control throughout the dosing interval. Appropriate dosing is typically established using a weight-based protocol in nonpregnant patients. The starting dose for nonpregnant individuals is 18 U/kg/hr as a heparin infusion after an 80 U/kg bolus in order to avoid inadequate dosing and recurrent thromboemb~lism.~~ Although the Fourth American College of Chest Physicians (ACCP) Conference on Antithrombotic Therapp recommends that after IV anticoagulation, subcutaneous heparin can be given every 12 hours for treatment of DVT or PE, and that the midinterVal AMT can be used to adjust heparin therapy, there is insufficient evidence in pregnancy that every-12-hour dosing with midinterval assessments confers an adequate level of anticoagulant therapy. Confirming that a midinterval APTT is 1% times normal has been shown to predict an adequate level of anticoagulation throughout most of the dosing interval in the nonpregnant populations6;however, changes in heparin metabolism throughout pregnancy may shorten its half-life.15 An alternative strategy is to aim for a 2- to 3-hour peak at 2 to 2.5 times normal and a trough at least 10 to 15 seconds above The

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Table 2. PROPHYLACTIC OPTION FOR ANTICOAGULATION BASED ON CONSENSUS PANELS ~

~

~

~~~

~~

American College of Chest Physicians, 1995 Grade C Recommendations Previous thrornboernbolic event: Heparin 5000 U q 12h OR Heparin adjusted to level of 0.1-0.2 IU/rnL OR Clinical surveillance with periodic CUS AND Warfarin prophylaxis postpartum for 4-6 weeks Mechanical prosthetic valves: Heparin q 12 SC to prolong 6h post injection

APTT into therapeutic range OR Adjusted dose heparin until 13th week, warfarin (target INR 2.5-3.0) until middle of 3rd trimester, then adjusted dose heparin until delivery AND Low dose aspirin (80-100 rng) should be considered with either regimen

British Society for Haematology Guidelines, 1992 Heparin 5000 U q 12h 1st and 2nd trimesters. Previous thrornboernbolic event: Increase 3rd trimester to prolong rnidinterval APlT 1.5X OR Heparin 10,000 U q 12h throughout pregnancy unless heparin level >0.3 IU/rnL Maternal and Neonatal Haemostasis Working Party of the Haemostasis Thrombosis Task, 1992 Previous single event without Careful antenatal surveillance with prophylaxis thrornbophilia or risk factors: intrapartum and 6 wks postpartum OR Heparin 7500-1 0,000 q 12h throughout pregnancy (and prophylaxis postpartum) CUS = Compression ultrasonography.

ACCP recommends a continuation of therapeutic anticoagulation for the remainder of pregnancy; however, there are no studies comparing therapeutic versus prophylactic anticoagulation after an initial 3 months of full therapeutic anticoagulation. Almost all investigators agree that prophylaxis should be used in the postpartum period for at least 6 weeks and that warfarin can be given. The APTT can be used to gauge the adequacy of anticoagulation for acute thromboembolism with the exception of patients with the antiphospholipid antibody syndrome. In this circumstance, a heparin level should be used in order to document an anti-Xa activity of 0.3 to 0.7 U/mL using a chromogenic a~say.5~ Another situation in which the heparin level might be useful is in pregnant patients requiring extremely high doses of heparin to increase the APTT. Because factor VIII increases in the setting of acute inflammation as well as in pregnancy, high levels of factor VIII may result in less of a prolongation in the APTT.55In this situation, a heparin level may be checked to determine whether the antiXa activity is in the therapeutic range.

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Thromboembolic Prophylaxis

Only one randomized controlled trial has been published evaluating the efficacy of prophylactic heparin in patients with a previous thrombotic history, but the sample size was too small to provide any definitive conclusions.57As is evident by the completely different approaches for prophylaxis offered by the ACCP (Table 2), there are insufficient data to strongly advocate one prophylaxis strategy above another. Disappointingly, recommendations from the British Society for Haematology Guidelines and the Maternal and Neonatal Haemostasis Working Party of the Haemostasis Thrombosis Task (see Table 2) provide further con76 tradictory recommendations.20, It has been increasingly recognized in the nonpregnant literature that patients with a transient and identifiable risk factor (orthopedic surgery, skeletal or major trauma) who sustain a DVT are at a much lower risk of recurrence than patients with an unavoidable or permanent risk factor.60For this reason, this author recommends antithrombotic prophylaxis for patients who have had a previous event while on oral contraceptive (OCPs), during pregnancy, or unprovoked. Women who had a prior event associated with a known high-risk provocation (orthopedic surgery or skeletal or major trauma), who do not have any evidence of chronic venous insufficiency, and who do not have a positive family history of thrombosis may be candidates for surveillance antepartum and warfarin prophylaxis postpartum. However, a hypercoagulable evaluation including APC resistance should first be done to rule out a congenital or acquired hypercoagulable state. Such an approach of clinical surveillance and periodic CUS (compression ultrasonagraphy) to detect asymptomatic proximal DVT is unstudied and is likely to be fraught with failure because the sensitivity of CUS to detect proximal asymptomatic DVT is as low as 38% in orthopedic trials.63Therefore, this author believes that anticoagulation prophylaxis should at least be discussed with all individuals with a previous event, even if not recommended, so as to outline the possible limitations of the surveillance strategy. Although the ACCP offered two different approaches to the dosing of prophylactic heparin (5000 q 12 hours or adjusted to achieve a heparin level of 0.1 to 0.2 U/mL), this author’s study has confirmed the inadequacy of 5000 units every 12 hours during pregnancy to attain prophylactic heparin levels” and failures have been reported using this approach.104Although there are no efficacy trials available supporting any level of heparin prophylaxis, increasing the heparin to attain a peak or midinterval level of 0.1 to 0.2 U/mL would at least confirm a detectable anticoagulant effect. Alternatively, if heparin levels are not available, using 7500 to 10,000 units every 12 hours throughout pregnancy and checking the APTT to make sure it is not significantly prolonged also seems to be a relatively safe approach. Heparin levels or the APTT should be checked near term because of the possibility of decreasing heparin requirements near delivery, possibly as a result of decreasing

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heparinase activity from placental aging.l' Confirming that the APTT is not significantly elevated at term may be prudent given recent data suggesting that women on therapeutic heparin may have an elevated APTT as long as 24 hours after a subcutaneous dose.4 Women should be given supplemental calcium during pregnancy; however, this does not appear to prevent heparin-induced osteoporosis. Fortunately, symptomatic osteoporosis appears uncommon. North American trials are clearly needed for both the acute treatment and prophylaxis of pregnant women with thromboembolic events. Although the experience in European countries with LMWH for prophylaxis is extensive and many practitioners are using it as the agent of choice for prophylaxis, prospective trials in the United States are lacking. Most important clinically are trials using LMWH for treatment of acute DVT in pregnancy. Given the extreme difficulty in maintaining a therapeutic anticoagulant effect with standard heparin throughout pregnancy, the greater bioavailability and longer half-life of LMWH is sorely needed. It is hoped that a reduction in heparin-induced osteoporosis, heparin-induced thrombocytopenia, and bleeding complications will also be substantiated.

Thromboembolic Prophylaxis for Mechanical Heart Valves There is no consensus regarding the optimal anticoagulation prophylaxis in pregnant patients with mechanical heart valves given the risks of fetal wastage from warfarin prophylaxis administered any time during pregnancy and the risk of valve thrombosis in women on therapeutic heparin. The ACCP recommends that one of two approaches can be taken: therapeutic heparin throughout pregnancy versus therapeutic heparin in the first trimester and the latter half of the third trimester with warfarin instituted at weeks 14 to 34." The former avoids the risk of fetopathic effects such as CNS abnormalities, hemorrhage, and stillbirth, but is associated with a higher risk of valvular thrombosis. If therapeutic heparin is given, the APTT should be increased to 2 times control throughout the dosing interval rather than only 1%times control. This is very problematic and likely to require injections at least every 8 hours or delivery through a pump. Recommending warfarin any time during pregnancy is difficult because the manufacturer of warfarin does not support its use in pregnancy. Unfortunately, there are no reported trials using therapeutic LMWH for this indication. This author believes that warfarin is best avoided if possible unless the patient has failed heparin or is unable to comply with the extremely intensive and frequent monitoring that is required using therapeutic heparin. Patients with Bjork-Shiley or Starr-Edwards valves in the mitral position are perhaps most likely to fail therapeutic heparin prophylaxis.

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Thromboembolic Prophylaxis in Hypercoagulable Disorders

Patients with a thromboembolic history and a positive family his-

tory of thrombosis have a 15% to 25% risk of an identifiable hypercoagulable disorder and should be evaluated with a hypercoagulable panel that assesses congenital AT-111, protein C, and protein S deficiency, all of which are autosomal dominant with variable p e n e t r a n ~ e .In ~ ~one kindred of protein C-deficient individuals with thrombotic tendencies, all of the women presented with their first event while on OCPs or during pregnancy.lffiProtein S deficiency cannot be diagnosed in pregnancy because protein S levels begin to fall in the first trimester.21,36 The recent recognition of APC resistance as an even more common heritable condition necessitates that this also be evaluated, especially in patients with recurrent thrombosis or a positive family history of thrombo~is.'~~ One series in Sweden reported nearly 60% of all patients with thromboembolism in pregnancy, and 30% of patients on OCPs were found to have abnormal clotting studies for APC re~istance.~~ However, the clotting assay for APC may be unreliable in pregnancy. Therefore, a factor V Leiden assay should be obtained to identify definitively patients with this mutation. Patients with a history of thromboembolism who are found to have AT-111, protein C, or protein S deficiency are at an appreciable risk of recurrent thrombosis based on retrospective data and should be prophylaxed in pregnancy.23Whether low dose or therapeutic doses of heparin should be used in these populations is unclear; however, patients with AT-111 deficiency have a 12% to 70% risk of recurrent thrombosis and therapeutic doses of heparin and AT-I11 concentrate may need to be given.l2,23, 92, 95 Patients with protein C deficiency may have a 7% to 25% risk of recurrence, and low-dose or therapeutic regimens have 23 Warfarin prophylaxis may be used in the postparbeen advocated.12r2*, tum period but should be started in conjunction with heparin because protein C has a shorter half-life than some of the vitamin K-dependent clotting factors. Finally, patients with protein S deficiency appear to have a greater postpartum than antepartum risk of thrombosis.23Prospective trials with adequate numbers, however, are lacking. In contrast to patients with a history of thrombosis and who are found to be deficient in one of these natural anticoagulants, a European trial in the Netherlands and Italy found that women with heritable deficiencies of AT-I11 or proteins S or C, and who had not had a thrombotic event themselves, were not at greatly increased risk during pregnancy and the postpartum period compared to those with a history of events.40In a series of 60 women identified with a factor deficiency who underwent 169 pregnancies, 4.1% developed a DVT in pregnancy or the postpartum period compared to 0.5% of controls (nondeficient individuals with family histories of thrombosis). Thus, women who are found to be deficient in AT-111 or proteins C or S, who have not had a history of thromboembolism, are at less risk than deficient individuals

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with a history of thromboembolism, but certainly at a higher risk than the normal pregnant population. Interestingly, most of these events were found to occur in the third trimester and postpartum. All the events in the patients with protein S deficiency occurred postpartum, although the sample size was small in each group and not all the events were radiographically documented. Trials looking at thrombosis risk with the factor V Leiden deficiency in pregnancy are in progress. Given the lack of large prospective data, therapeutic anticoagulation of individuals with AT-I11 and protein C deficiency with a history of thromboembolism seems reasonable.12,8o Prophylactic anticoagulation also seems reasonable in patients with protein S deficiency or APC resistance with a previous event. Patients with AT-I11 deficiency should receive prophylaxis even without an event; however, it is less clear what to recommend for 8o A strong family patients with protein C deficiency without an event.12* history of thrombosis would indicate a need for prophylaxis because many women present with their first clot in pregnancy. Postpartum prophylaxis should at least be offered to patients with protein S deficiency without a history of thrombosis. Patients with the acquired antiphospholipid antibody syndrome characterized by recurrent fetal loss or thrombosis have been treated with a combination of steroids, heparin, and/or low-dose aspirin with variable success.16,74* 89 Women with a history of thrombosis may be candidates for therapeutic rather than prophylactic heparin therapy and low-dose aspirin, although there are few data to support any given regimen.@,lo5 Steroids are less frequently used and heparin given at prophylactic to therapeutic doses (depending on a prior history of thrombosis) has been advocated because prednisone was found to be associated with premature rupture of membranes, preterm delivery, and preeclampsia in the only small randomized trial." SUMMARY

The optimal use of anticoagulants during pregnancy will continue to be controversial until appropriate randomized controlled and prospective trials with adequate sample sizes are completed. The relative low frequency of thromboembolic events, the concerns about maternal and fetal safety of both treatment and withholding treatment, and the reservations about prospectively enrolling pregnant women in treatment trials has sadly dissuaded the appropriate study of this life-threatening condition. North American trials that enroll pregnant women to evaluate the efficacy of LMWH are of preeminent importance owing to their superior bioavailability, ease in dosing, longer half-life, and side effect profile. Similarly, trials evaluating the optimal management of women of childbearing age with valvular disease are critical to reduce the considerable maternal and fetal morbidity and mortality associated with these pregnancies. Such definitive studies will need to be multicenter in design and it is hoped that the National Institutes of Health initiative to

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enroll pregnant women in clinical trials will at last be realized in the near future.

References 1. Aaro LA, Juergens J L Thrombophlebitis associated with pregnancy. Am J Obstet Gynecol109:1128-1133, 1971 2. Aarskog D, Aksnes L: Low 1,25-dihydroxy vitamin D in heparin-induced osteopenia. Lancet 2650651, 1980 3. Anderson DR, Ginsberg JS, Brill-Edwards P, et al: The use of an indwelling Teflon catheter for subcutaneous heparin administration during pregnancy. A randomized crossover study. Arch Intern Med 153:841-844, 1993 4. Anderson DR, Ginsberg JS, Burrows R, et al: Subcutaneous heparin during pregnancy: A need for concern at the time of delivery. Thromb Haemost 65248-250, 1991 5. Atrash HK, Koonin LM, Lawson HW,et al: Maternal morbidity in the United States 1979-1986. Obstet Gynaecol 761055-1060, 1990 6. Badaracco MA, Vessey MP: Recurrence of venous thromboembolic disease and use of oral contraceptives. BMJ 1215-217, 1974 7. Badduke R, Jamieson WRE, Miyaqishima RT, et al: Pregnancy and childbearing in a population with biologic valve prostheses. Thorac Cardiovasc Surg 102179-186,1991 8. Bailey RT, Ursick JA, Heim KL, et a 1 Heparin associated thrombocytopenia: A prospective comparison of bovine lung heparin, manufactured by a new process, a porcine intestinal heparin. Drug Intell Clin Pharmacol20374-378, 1986 9. Barbour L, Kick S, Steiner J, et al: A prospective study of heparin-induced osteoporosis in pregnancy using bone densitometry. Am J Obstet Gynecol 170:862-869,1994 10. Barbour LA, Pickard JA: Controversies in thromboembolic disease during pregnancy: A critical review. Obstet Gynecol 86:621-633, 1995 11. Barbour LA, Smith JM, Marlan RA: Heparin levels to guide thromboembolism prophylaxis during pregnancy. Am J Obstet Gynecol 173:1869-1873, 1995 12. Bauer KA: Management of patients with hereditary defects predisposing to thrombosis including pregnant women. Thromb Haemost 74(1):94100, 1995 13. Bergqvist A, Bergqvist D, Holbook T Deep vein thrombosis during pregnancy: A prospective study. Acta Obstet Gynecol Scand 62443448, 1983 14. Born D, Martinez EE, Almeida PAM, et al: Pregnancy in patients with prosthetic heart valves: The effects of anticoagulation on mother, fetus, neonate. Am Heart J 124:413417, 1992 15. Brancazio LR, Roperti KA, Stierer R, et al: Pharmacokinetics and pharmacodynamics of subcutaneous heparin during the early third trimester of pregnancy. Am J Obstet Gynecol 173:1240-1245, 1995 16. Branch DW, Silver RM, Blackwell JL, et al: Outcome of treated pregnancies in women with antiphospholipid antibody syndrome: An update of the Utah experience. Obstet Gynecol 80614420, 1992 17. Caruso A, De Carolis S, Ferrazzani S, et al: Pregnancy outcome in women with cardiac valve prosthesis. Eur J Obstet Gynecol Reprod Biol 547-11, 1994 18. Chen WWC, Chan CS, Lee PK, et al: Pregnancy in patients with prosthetic heart valves: An experience with 45 pregnancies. J Med 203:358-365, 1982 19. Chong MKB, Harvey D, deSwiet M: Follow-up study of children whose mothers were treated with warfarin during pregnancy. Br J Obstet Gynaecol 91:1070-1073, 1984 20. Colvin BT, Barrowcliff Tw: The British Society for Haematology guidelines on the use and monitoring of heparin 1992: Second revision. J Clin Pathol46:97-103, 1993 21. Comp PC, Thumau GR, Welsh J, et al: Functional and immunologic protein S levels are decreased during pregnancy, delivery and the puerperium. Blood 68:881-885,1986 22. Conard S, Horellou MH, VanDreden P, et al: Pregnancy and congenital deficiency in antithrombin I11 or protein C [abstract]. Thromb Haemost 5839, 1987 23. Conard J, Horellou MH, Van Dredan P, et al: Thrombosis and pregnancy in congenital

518

BARBOUR

deficiencies in antithrombin 111, protein C or protein S: Study of 78 women. Thromb Haemost 63:319-320, 1990 24. Cowchock S, Reece A, Balaban D, et al: Repeated fetal losses associated with antiphospholipid antibodies: A collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am J Obstet Gynecol 1661318-1323, 1992 25. Dahlback B: Inherited thrombophilia: Resistance to activated protein C as a pathogenic factor for venous thromboembolism. Blood 85:607-614, 1995 26. Dahlman TC: Osteoporotic fractures and the recurrence of thromboembolism during pregnancy and the puerperium in 184 women undergoing thromboprophylaxis with heparin. Am J Obstet Gynecol 168:1265-1270, 1993 27. Dahlman TC, Hellgren MS, Blomback M: Thrombosis prophylaxis in pregnancy with use of subcutaneous heparin adjusted by monitoring heparin concentrations in plasma. Am J Obstet Gynecol 16L420-425, 1989 28. Dahlman TC, Lindvall N, Hellgren M Osteopenia in pregnancy during long-term heparin treatment: A radiological study post-partum. Br J Obstet Gynaecol 97221228, 1990 29. Dahlman TC, Sjoberg HE, Ringertz H Bone mineral density during long-term prophylaxis with heparin in pregnancy. Am J Obstet Gynecol 1701315-1320, 1994 30. de Boer K, Heyboer H, ten Cate JW, et al: Low molecular weight heparin treatment in a pregnant woman with allergy to standard heparins and heparanoid. Thromb Haemost 61:148, 1989 31. DeLoughery TG, Goodnight SH: The hypercoagulable states; Diagnosis and management. Semin Vasc Surg 6:66-74, 1993 32. Demers C, Ginsberg J: Deep venous thrombosis and pulmonary embolism in pregnancy. Clin Chest Med 13:645456, 1992 33. DHSS Report on Confidential Enquiries into Maternal Deaths in England and Wales 1986-1988. London, HMSO, 1991 34. Douketis JD, Ginsberg JS, Burrows RF, et al: The effects of long-term heparin therapy during pregnancy on bone density. Thromb Haemost 75(2):254-257, 1996 35. Elkayam U: Anticoagulation in pregnant women with prosthetic heart valves: A double jeopardy. J Am Coll Cardiol 27(7):170&1706, 1996 36. Faught W, Gamer P, Jones G, et al: Changes in protein C and protein S levels in normal pregnancy. Am J Obstet Gynecol 172147-150, 1995 37. Fejgin MD, Lourwood DL: Low molecular weight heparins and their use in obstetrics and gynecology. Obstet Gynecol Surv 49(5):424-431, 1994 38. Floyd RC, Gookin KS, Hess LW, et al: Administration of heparin by subcutaneous infusion with a programmable pump. Am J Obstet Gynecol 165:931-933, 1991 39. Forestier F: Absence of transplacental Fragmin(Kabi) during second and third trimesters of pregnancy. Thromb Haemost 67180-181, 1992 40. Friederich PW, Sanson B-J, Simioni P, et a1 Frequency of pregnancy-related venous thromboembolism in anticoagulant factor-deficient women: Implications for prophylaxis. Ann h t e m Med 125:955-960, 1996 41. Gillis S, Shushan A, Eldor A: Use of low molecular weight heparin for prophylaxis and treatment of thromboembolism in pregnancy. Int J Gynecol Obstet 39:297-301, 1993 42. Ginsberg JS Management of venous thromboembolism. N Engl J Med 335(24):18161828,1996 43. Ginsberg JS, Brill-Edwards P, Burrows RF, et a1 Venous thrombosis during pregnancy: Leg and trimester of presentation. Thromb Haemost 67519-520, 1992 44. Ginsberg JS, Hirsh J: Use of antithrombotic agents during pregnancy. Chest 108(Suppl):4305-4311, 1995 45. Ginsberg JS, Hirsch J, Turner DC, et al: Risks to the fetus of anticoagulant therapy during pregnancy. Thromb Haemost 61:197-203, 1989 46. Ginsberg JS, Kowalchuk G, Hirsch J, et al: Heparin therapy during pregnancy: Risks to the fetus and mother. Arch h t e m Med 149:2233-2236,1989 47. Ginsberg JS, Kowalchuk G, Hirsh J, et al: Heparin effect on bone density. Thromb Haemost 64:286-289,1990 48. Golby AJ, Bush EC, DeRook FA, et al: Failure of high dose heparin to prevent

CURRENT CONCEPTS OF ANTICOAGULANT THERAPY IN PREGNANCY

519

recurrent cardioembolic strokes in a pregnant patient with a mechanical heart valve. Neurology 422204-2206, 1992 49. Green D Heparin-induced thrombocytopenia. Med J Aust 144(suppl):37-39, 1986 50. Hanania G, Thomas D, Michel PL, et al: Pregnancy and prosthetic heart valves: A French cooperative retrospective study of 155 cases. Eur Heart J 151651-1658, 1994 51. Haram K, Hervig T, Thordarson H, et a1 Osteopenia caused by heparin treatment in pregnancy. Acta Obstet Gynecol Scand 72674-675, 1993 52. Hellgren M, Nygards EB: Long-term therapy with subcutaneous heparin during pregnancy. Gynecol Obstet Invest 13:76-89, 1982 53. Hellgren M, Svensson PJ, Dahlback B: Resistance to activated protein C as a basis for venous thromboembolism associated with pregnancy and oral contraceptives. Am J Obstet Gynecol 173210-213, 1995 54. Hirsh J, Dalen J, Deykin D, et a1 Oral anticoagulants: Mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 108(4)(suppl):231-246,1995 55. Hirsh J, Raschke R, Warkentin TE, et a1 Heparin: Mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 108(4)(suppl):258-275, 1995 56. Hogberg U, Innala E, Sandstrom A: Maternal mortality in Sweden. Obstet Gynecol 84:240-244, 1994 57. Howell R, Fidler J, Letsky E, et al: The risks of antenatal subcutaneous heparin prophylaxis: A controlled trial. Br J Obstet Gynaecol 901124-1128, 1983 58. Hull RD, Raskob GE, Carter CJ: Serial impedance plethysmography in pregnant patients with clinically suspected deep-vein thrombosis. Ann Intern Med 112663667,1990 59. Hunt PJ, Doughty HA, Majumdar G, et al: Thrombophylaxis with low molecular weight heparin (fragmin) in high-risk pregnancies. Thromb Haemost 77(1):39-43,1997 60. Hyers T, Hull RD, Wey JG: Antithrombotic therapy for venous thromboembolic disease. Chest 108(4)(suppl):S335-351, 1995 61. Iturbe-Alesio I, del Carmen Fonseca M, Mutchinik 0, et al: Risks of anticoagulant therapy in pregnant women with artificial heart valves. N Engl J Med 221390-1393, 1986 62. Jamieson WRE, Miller DC, Akins CW, et al: Pregnancy and bioprostheses: Influence on structural valve deterioration. Ann Thorac Surg 6O(suppl):S282-287, 1995 63. Jongbloets LMM, Lensing AWA, Koopman MMW, et al: Limitations of compression ultrasound for the detection of symptomless postoperative deep vein thrombosis. Lancet 343:1142-1144, 1994 64. Kakkar W, Lawrence D Hemodynamic and clinical assessment after therapy of acute deep vein thrombosis. Am 1Surg 10:54-63, 1985 65. King DJ, Kelton JG: Heparin-associatedu thrombocytopenia. Ann Intern Med 100535540, 1984 66. Gamer WB, Belfort M, Saade G, et al: Successful urokinase treatment of massive pulmonary embolism in pregnancy. Obstet Gynecol 866604562, 1995 67. LaValleur J, Williams PI? Use of urokinase in pregnancy. Postgrad Med 99(5):269273, 1996 68. Leclerk JR, Geerts W, Panju A, et al: Management of antithrombin 111 deficiency during pregnancy without administration of antithrmbin 111. Thromb Res 41:567573, 1986 69. Lecura F, Desnos M, Taurelle R Anticoagulant therapy in pregnancy: Report of 54 cases. Acta Obstet Gynecol Scand 75(3):217-221, 1996 70. Lee Chien-Nan, Wu Chih-Cheng, Lin Ping-Yi, et al: Pregnancy following cardiac prosthetic valve replacement. Obstet Gynecol83:353-356, 1994 71. L'e Orme M, Lewis PJ, deSwiet M, et al: May mothers given warfarin breast-feed their infants? BMJ 1:1564-1565, 1977 72. Levine MN, Goldhaber SZ, Gore JM, et al: Hemorrhagic complications of thrombolytic therapy in the treatment of myocardial infarction and venous thromboembolism. Chest 108(4):S291-301, 1995 73. Levine MN, Hirsh J, Gent M, et a1 Optimal duration of oral anticoagulant therapy:

520

BARBOUR

A randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis. Thromb Haemost 74:60&611, 1995 74. Lockshin MD: Which patients with antiphospholipid antibody should be treated and how? Rheum Dis Clin North Am 19:235-247,1993 75. Magnani HN: Heparin-induced thrombocytopenia (HIT): An overview of 230 patients treated with Orgaran (Org 10172). Thromb Haemost 70:554-561, 1993 76. Maternal and Neonatal Haemostasis Working Party of the Haernostasis and Thrombosis Task Guidelines on the presentation, investigation, and management of thrombosis associated with pregnancy. J Clin Pathol 46:489-496, 1993 77. McKenna R, Cole E, Vasan U: Is warfarin sodium contraindicated in the lactating mother? J Pediatr 103:325-327, 1983 78. Melissari E, Parker CJ, Wilson NV, et al: Use of low molecular weight heparin in pregnancy. Thromb Haemost 68:652456, 1992 79. Monreal M, Lafoz E, Olive A, et al: Comparison of subcutaneous unfractionated heparin with low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin. Thromb Haemost 71:7-11, 1994 80. Montella KR. Hypercoagulable states in pregnancy. In Current Obstetric Medicine, vol2. Chicago, Mosby-Year Book, 1993, pp 141-162 81. Oakley CM. Anticoagulants in pregnancy. Br Heart J 74(2):107-111, 1995 82. Omri A, Delaloye JF, Anderson H, et al: Low molecular weight heparin Novo (LHN1) does not cross the placenta during the second trimester of pregnancy. Thromb Haemost 61:55-56, 1989 83. Pavankumar P, Venugopal P, Kaul U, et al: Pregnancy in patients with prosthetic cardiac valve: A 10-year experience. Scand J Thorac Cardiovasc Surg 22:19-22, 1988 84. Powers PJ, Kelton JG, Carter CJ: Studies on the frequency of heparin-associated thrombocytopenia. Thromb Res 33:439443, 1984 85. Rao AK, White GC, Sherman L, et al: Low incidence of thrombocytopenia with porcine mucosal heparin. Arch Intern Med 149:1285-1288, 1989 86. Raskob GE, Hull RD, LeClere JR, et al: Sustained therapeutic heparinization by subcutaneous administration for the primary treatment of acute venous thrombosis [abstract]. Circ 7O(suppl 2):360, 1984 87. Rasmussen C, Wadt B, Jacobsen B: Thromboembolic prophylaxis with low molecular weight heparin during pregnancy. Int J Gynecol Obstet 147121-125, 1994 88. Report on confidential enquiries into maternal deaths in England and Wales 19761978: London, Her Majesty's Stationery Office, 1980 89. Rosove MH, Tabsh K, Wasserstrum N, et al: Heparin therapy for pregnant women with lupus anticoagulant or anticardiolipin antibodies. Obstet Gynecol 75630434, 1990 90. Rutherford S, Montoro M, McGehee W, et al: Thromboembolic disease associated with pregnancy: An 11 year review [abstract]. Am J Obstet Gynecol 164:286, 1991 91. Salazar E, Izaguirre R, Verdejo J, et al: Failure of adjusted doses of subcutaneous heparin to prevent thromboembolic phenomena in pregnant patients with mechanical cardiac valve prostheses. J Am Coll Cardiol27(7):1698-1703, 1996 92. Samson D, Stirling Y, Woolf L, et al: Management of planned pregnancy in a patient with congenital antithrombin 111 deficiency. Br J Haematol 56:243-249, 1984 93. Sareli P, England MJ, Berk MR, et al: Maternal and fetal sequelae of anticoagulation during pregnancy in patients with mechanical heart valve prostheses. Am J Cardiol 63462465,1989 94. Sbarouni E, Oakley C: Outcome of pregnancy in women with valve prostheses. Br Heart J 71:196-201, 1994 95. Schwartz RS, Bauer KA, Rosenberg RD, et al: Clinical experience with antithrombin 111 concentrate in treatment of congenital and acquired deficiency of antithrombin. Am J Med 87(suppI 38):535-605, 1989 96. Shefras J, Farquharson RG: Bone density in pregnant women receiving heparin. Eur J Obstet Gynecol65:171-174, 1996 97. Sipes SL, Weiner CP: Venous thromboembolic disease in pregnancy. Semin Perinatol 14103-118,1990 98. Siragusa S, Cosmi B, Piovella F, et al: Low-molecular-weight heparins and unfraction-

CURRENT CONCEITS OF ANTICOAGULANT THERAPY IN PREGNANCY

521

ated heparin in the treatment of patients with acute venous thromboembolism: Results of a meta-analysis. Am J Med 100:269-277, 1996 99. Sowers M, Crutchfield M, Jannausch M, et al: A prospective evaluation of bone mineral change in pregnancy. Obstet Gynecol 77841-845, 1991 100. Squires JW, Pinch LW Heparin-induced spinal fractures. JAMA 241:2417-2418, 1979 101. Stevenson RE, Burton OM, Ferlauto GJ, et al: Hazards of oral anticoagulants during pregnancy. JAMA 243:1549-1551,1980 102. Sturridge F, de Swiet M, Letsky E: The use of low molecular weight heparin for thromboprophylaxis in pregnancy. Br J Obstet Gynaecol 101:69-71, 1994 103. Svensson PJ, Dahlback B: Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 330:517-521, 1994 104. Tengbom L, Bergqvist D, Matzsch T, et al: Recurrent thromboembolism in pregnancy and puerperium. Am J Obstet Gynecol28:107-118, 1985 105. Toglia MR, Wey JG: Venous thromboembolism during pregnancy. N Engl J Med 335(2):108-114, 1996 106. Trauscht-Van Horn JJ, Capeless EL, Easterling TR, et al: Pregnancy loss and thrombosis with protein C deficiency. Am J Obstet Gynecol 167968-972, 1992 107. Turrentine MA, Braems G, Ramirez M M Use of thrombolytics for the treatment of thromboembolic disease during pregnancy. Obstet Gynecol Surv 50(7):534-541, 1995 108. Vitali E, Donateli F, Quaini E, et al: Pregnancy in patients with mechanical prosthetic in 57 patients. J Cardiovasc heart valve: Our experiences regarding 98 -pregnancies Surg 27221-227, 198'6 109. Warkentin TE, Kelton TG: Heuarin-induced thrombocvtouenia. In Annual Review of Medicine. Palo Alto, CA, A k u a l Reviews Inc, 1989, pp i1-44 110. Warkentin TE, Mark N, Hirsh J, et al: Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 332:1330-1335, 1995 111. Wise PH, Hall AJ: Heparin-induced osteopenia in pregnancy. BMJ 3:llO-111, 1980 112. Wong V, Chen CH, Chan KC: Fetal and neonatal outcome of exposure to anticoagulants during pregnancy. Am J Med Genet 45:17-21, 1993 113. Zimran A, Shilo S, Fisher D, et al: Histomorphometric evaluation of reversible heparin-induced osteoporosis in pregnancy. Arch Intern Med 46:386-388, 1986

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