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Use of Antithrombotic Agents During Pregnancy : The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy FREE TO VIEW

Shannon M. Bates, MDCM, FRCPC; Ian A. Greer, MD, FRCP (Glas Edin London), FRCOG; Jack Hirsh, MD, FCCP; Jeffrey S. Ginsberg, MD, FRCPC, Chair
Author and Funding Information

Correspondence to: Jeffrey S. Ginsberg, MD, FCCP, HSC 3X28, McMaster University Medical Center, 1200 Main St West, Hamilton, ON L8N 325; e-mail: ginsbergj@mcmaster.edu



Chest. 2004;126(3_suppl):627S-644S. doi:10.1378/chest.126.3_suppl.627S
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This chapter about the use of antithrombotic agents during pregnancy is part of the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients’ values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S–187S). Among the key recommendations in this chapter are the following: for women requiring long-term vitamin K antagonist therapy who are attempting pregnancy, we suggest performing frequent pregnancy tests and substituting unfractionated heparin (UFH) or low molecular weight heparin (LMWH) for warfarin when pregnancy is achieved (Grade 2C). In women with acute venous thromboembolism (VTE), we recommend adjusted-dose LMWH throughout pregnancy or IV UFH for at least 5 days, followed by adjusted-dose UFH or LMWH for the remainder of the pregnancy and at least 6 weeks postpartum (Grade 1C+). In patients with a single episode of VTE associated with a transient risk factor that is no longer present, we recommend antepartum clinical surveillance and postpartum anticoagulants (Grade 1C). In patients with a single episode of VTE and thrombophilia or strong family history of thrombosis and not receiving long-term anticoagulants, we suggest antepartum prophylactic or intermediate-dose LMWH or minidose or moderate-dose UFH, plus postpartum anticoagulants (Grade 2C). In patients with multiple (two or more) episodes of VTE and/or women receiving long-term anticoagulants, we suggest antepartum adjusted-dose UFH or adjusted-dose LMWH followed by long-term anticoagulants postpartum (Grade 2C). For pregnant patients with antiphospholipid antibodies (APLAs) and a history of two or more early pregnancy losses or one or more late pregnancy losses, preeclampsia, intrauterine growth retardation, or abruption, we suggest antepartum aspirin plus minidose or moderate-dose UFH or prophylactic LMWH (Grade 2B). We suggest one of the following approaches for women with APLAs without prior VTE or pregnancy loss: surveillance, minidose heparin, prophylactic LMWH, and/or low-dose aspirin, 75 to 325 mg/d (all Grade 2C). In women with prosthetic heart valves, we recommend adjusted-dose bid LMWH throughout pregnancy (Grade 1C), aggressive adjusted-dose UFH throughout pregnancy (Grade 1C), or UFH or LMWH until the thirteenth week and then change to warfarin until the middle of the third trimester before restarting UFH or LMWH (Grade 1C). In high-risk women with prosthetic heart valves, we suggest the addition of low-dose aspirin, 75 to 162 mg/d (Grade 2C).

Fatal pulmonary embolism (PE) remains a leading cause of maternal mortality in the Western world.1Maternal mortality from PE can be reduced in two ways: (1) by investigating women aggressively when they present with a clinical suspicion of deep vein thrombosis (DVT) or PE, and treating those with a diagnosis of venous thromboembolism (VTE); and (2) by prophylaxis of those who have an increased risk for DVT and/or PE. Both approaches are problematic for several reasons, the former because the symptoms and signs compatible with DVT and PE are common during pregnancy and are usually nonthrombotic in origin, reflecting physiologic changes rather than VTE. In support of this, the prevalence of DVT in a study2of consecutive pregnant patients presenting with a clinical suspicion was < 10%, compared to approximately 25% in studies36 of nonpregnant populations. Further, in a study by Chan and colleagues,7only 2 of 113 pregnant subjects (1.8%) with suspected PE had high-probability ventilation perfusion lung scan results; 83 patients (73%) had normal perfusion scan results, and 28 patients (25%) had nondiagnostic scans, compared to approximately 10 to 30% of nonpregnant patients who present with suspected PE.89 Potential alterations in the utility of tests used to diagnose DVT produced by the compressive effects of the gravid uterus on the iliac vein contribute to the diagnostic challenge. In addition, there is concern about performing procedures (such as isotope lung and spiral CT scanning) that expose the fetus to radiation. Prophylaxis of DVT and PE is problematic because it involves long-term parenteral unfractionated heparin (UFH) or low molecular weight heparin (LMWH). Both are expensive, inconvenient, and painful to administer, and are associated with risks for bleeding, osteoporosis, and heparin-induced thrombocytopenia (HIT), although these complications, particularly HIT, are very uncommon with LMWH. Furthermore, rational administration of prophylaxis depends on identifying those women who have an increased risk of thrombosis and accurately quantifying this risk. Until recently, reliable information on the true incidence of recurrence in pregnant women with a single prior VTE event was not available. In addition, although many women with prior VTE have an identifiable laboratory abnormality associated with thrombophilia, the significance of these abnormalities and the management of such individuals remain controversial.

Since our last review, new information has been published on the management of pregnant women with prior VTE, the management of VTE in pregnancy, the safety of LMWH during pregnancy (particularly with regard to osteoporosis), the difficulties of managing pregnant women with prosthetic heart valves, and the relation between thrombophilia and fetal loss, intrauterine growth restriction (IUGR), and preeclampsia. In this chapter, we will review the management of thromboembolic complications during pregnancy, with particular emphasis on important new studies. Table 11A describes the search and eligibility criteria for the studies considered in each section of the recommendations that follow.

The true incidence of VTE associated with pregnancy is unknown, but there is a strong clinical impression that the risk is increased compared to nonpregnant individuals.1011 There does not appear to be a preponderance of VTE in any trimester, although there is a striking predisposition for DVT to occur in the left leg (approximately 90%),12possibly because during pregnancy there is an exaggeration of the compressive effects on the left iliac vein by the right iliac artery where they cross.13 The increased risk for VTE persists postpartum; available evidence suggests that the risk of VTE is higher after cesarean section (particularly emergency cesarean section) than after vaginal delivery.11

Anticoagulant therapy is indicated during pregnancy for the prevention and treatment of VTE, for the prevention and treatment of systemic embolism in patients with mechanical heart valves and, often in combination with aspirin, for the prevention of pregnancy complications in women with antiphospholipid antibodies (APLAs) or other thrombophilia and previous pregnancy complications. Given the paucity of data regarding the efficacy of anticoagulants during pregnancy, recommendations about their use during pregnancy are based largely on extrapolations from data from nonpregnant patients, from case reports, and from case series of pregnant patients. The antithrombotics currently available for the prevention and treatment of VTE and arterial thromboembolism include heparin and heparin-like compounds (UFH, LMWH, and heparinoids), coumarin derivatives, and aspirin. The “direct” thrombin inhibitors, such as hirudin, cross the placenta and have not yet been evaluated during pregnancy and, therefore, will not be further discussed.

Based on safety data, a heparin-related compound (LMWH or UFH) is the anticoagulant of choice during pregnancy for situations in which its efficacy is established. There is accumulating experience with the use of LMWHs and heparinoids, both in pregnant and nonpregnant patients, for the prevention and treatment of VTE.1428 Based on the results of large clinical trials in nonpregnant patients, LMWH and heparinoids (danaparoid sodium) are at least as effective and safe as UFH for the treatment of patients with acute proximal DVT,2325 and for the prevention of DVT in patients who undergo surgery.26 There is evidence that LMWH (and heparinoids) do not cross the placenta,2930 and an overview and large series of cases concluded that LMWH was safe for the fetus.22,31

LMWHs have potential advantages over UFH during pregnancy because they cause less HIT,32 have a longer plasma half-life and a more predictable dose response than UFH,27 with the potential for once-daily administration, and are likely associated with a lower risk of heparin-induced osteoporosis.3334 Allergic skin reactions to both LMWH and UFH can occur.21,35 These take the form of itchy, erythematous infiltrated plaques, which may resolve when preparations are switched, although cross-reactivity can occur. As HIT can present with isolated skin manifestations, this entity should be excluded when skin lesions develop.

Fetal Complications of Anticoagulants During Pregnancy

There are two potential fetal complications of maternal anticoagulant therapy: teratogenicity and bleeding. Neither UFH36 nor LMWH2930 cross the placenta; therefore, these agents do not have the potential to cause fetal bleeding or teratogenicity, although bleeding at the uteroplacental junction is possible. Several studies22,31,3738 strongly suggest that UFH/LMWH therapy is safe for the fetus.

In contrast, coumarin derivatives cross the placenta and have the potential to cause both bleeding in the fetus and teratogenicity.37,39 Coumarin derivatives can cause an embryopathy, consisting of nasal hypoplasia and/or stippled epiphyses, after in utero exposure to vitamin K antagonists (VKAs) during the first trimester of pregnancy, and CNS abnormalities after exposure to such drugs during any trimester.,39 It is probable that these agents are safe during the first 6 weeks of gestation, but there is a risk of embryopathy if coumarin derivatives are taken between 6 weeks and 12 weeks of gestation.39Although one cohort study40 reported that the use of coumarins during the second and third trimester was not associated with major risks for abnormalities in growth and long-term development of offspring, the authors did note that neurodevelopmental problems were found more often in children exposed to coumarins in the second and third trimester of pregnancy. In addition, VKAs cause an anticoagulant effect in the fetus, which is a concern, particularly at the time of delivery, when the combination of the anticoagulant effect and trauma of delivery can lead to bleeding in the neonate.

Maternal Complications of Anticoagulant Therapy During Pregnancy

In a cohort study,38 the rate of major bleeding in pregnant patients treated with UFH therapy was 2%, which is consistent with the reported rates of bleeding associated with heparin therapy in nonpregnant patients41and with warfarin therapy42when used for the treatment of DVT. During pregnancy, the activated partial thromboplastin time (aPTT) response to heparin is often attenuated because of increased levels of factor VIII and fibrinogen.43Adjusted-dose subcutaneous (SC) UFH can cause a persistent anticoagulant effect at the time of delivery, which can complicate its use prior to labor.44 In a small study,44 an anticoagulant effect persisted for up to 28 h after the last injection of adjusted-dose SC UFH, resulting in deliveries that were complicated by a prolonged aPTT. The mechanism for this prolonged effect is unclear. Bleeding complications appear to be very uncommon with LMWH.1422,28,34,45

HIT

Approximately 3% of nonpregnant patients receiving UFH acquire immune, IgG-mediated thrombocytopenia, which is frequently complicated by extension of preexisting VTE or new arterial thrombosis.32 This should be differentiated from an early, benign, transient thrombocytopenia that can occur with initiation of UFH. Diagnosing immune thrombocytopenia is often difficult because definitive platelet-activation assays are not widely available and turnaround times are slow. It should be suspected when the platelet count falls to < 100 × 109/L or < 50% of the baseline value 5 to 15 days after commencing heparin, or sooner with recent heparin exposure.,32 In pregnant women who acquire HIT and require ongoing anticoagulant therapy, use of the heparinoid danaparoid sodium is recommended because it is an effective antithrombotic agent,25 does not cross the placenta, and has much less cross-reactivity with UFH and, therefore, less potential to produce recurrent HIT than LMWH.46

Heparin-Induced Osteoporosis

Long-term heparin therapy has been reported to cause osteoporosis in both laboratory animals and humans.4751 A number of studies have attempted to quantify the risk of osteoporosis when heparin is administered for periods of ≥ 1 month. In general, symptomatic vertebral fractures have been reported to occur in approximately 2 to 3% of the patient population, and significant reductions in bone density have been reported in up to 30% of patients receiving long-term UFH.47Dahlman48 studied 184 women receiving long-term prophylactic UFH therapy during pregnancy, and reported a 2.2% incidence of vertebral fracture. In contrast, in a small randomized trial, Monreal et al33 reported spinal fractures in 6 of 40 nonpregnant patients (15%) receiving 10,000 IU UFH SC bid for a period of 3 to 6 months. The higher incidence of osteoporotic fractures in the latter study33 is probably due to the fact that these patients were significantly older than those in the study by Dahlman et al.48

In animal studies, UFH has been shown to cause a dose-dependent loss of cancellous bone through decreasing rates of bone formation and increased bone resorption.49Animal models demonstrating that heparin is sequestered in the bone for extended periods also suggest that heparin-induced osteoporosis may not be rapidly reversible.50

Several lines of evidence now suggest that LMWHs have a lower risk of osteoporosis than heparin. In the study by Monreal et al,33dalteparin, 5,000 IU anti-Xa SC bid, was compared with UFH, 10,000 IU SC bid, in 80 patients with DVT. Both treatments were administered for a period of 3 to 6 months. Six of the 40 patients (15%; 95% confidence interval [CI], 6 to 30%) who received UFH acquired spinal fractures compared with only 1 of 40 patients (3%; 95% CI, 0 to 11%) receiving dalteparin. Further, in a randomized trial34 comparing UFH and dalteparin for thromboprophylaxis in pregnancy that measured bone mineral density in the lumbar spine for up to 3 years after delivery, bone density did not differ between healthy control subjects and the dalteparin group. Density was significantly lower in the UFH group when compared to both control subjects and dalteparin-treated women. Multiple logistic regression found that the type of heparin therapy was the only independent factor associated with reduced bone mass.34 Cohort studies31 have also reported no association with osteoporosis and LMWH therapy. A study51 using an animal model of heparin-induced osteoporosis support the hypothesis that LMWHs cause less osteoporosis than UFH. When rats were treated with once-daily SC injections of either UFH (1.0 U/g or 0.5 U/g) or LMWH (tinzaparin 1.0 U/g or 0.5 U/g) for a period of 32 days, both treatments decreased cancellous bone volume in a dose-dependent fashion, but UFH caused significantly more cancellous bone loss than LMWH.

Use of Anticoagulants in the Nursing Mother

Heparin and LMWHs are not secreted into breast milk and can be safely administered to nursing mothers.52There have been two convincing reports5354 that warfarin does not induce an anticoagulant effect in the breast-fed infant when the drug is given to a nursing mother. Therefore, the use of warfarin in women who require postpartum anticoagulant therapy is also safe, and women using this drug should be encouraged to breast feed.

Safety of Aspirin During Pregnancy

Potential complications of aspirin during pregnancy include birth defects and bleeding in the neonate and in the mother. Both a metaanalysis55and a large randomized trial56 that enrolled > 9,000 patients reported that low-dose (60 to 150 mg/d) aspirin therapy administered during the second and third trimesters of pregnancy in women at risk for pregnancy-induced hypertension or IUGR was safe for the mother and fetus. Thus, based on current evidence, low-dose aspirin (< 150 mg/d) during the second and third trimesters appears to be safe. The safety of higher doses of aspirin and/or aspirin ingestion during the first trimester remains uncertain.

1.0 Management Of Women Receiving Long-term VKA Therapy Who Are Considering Pregnancy

As described above VKAs have the potential to cause teratogenicity.37,39 It appears that the risk of fetal complications is reduced if coumarin derivatives are stopped before the sixth week of gestation.39 Women receiving VKA therapy should be counseled about the risks of warfarin therapy and pregnancy before pregnancy occurs. If pregnancy is still desired, two options can be considered: (1) performance of frequent pregnancy tests and substitution of adjusted-dose UFH or LMWH for warfarin when pregnancy is achieved, or (2) replacement of warfarin with UFH or LMWH before conception is attempted. Both approaches have limitations; the first assumes that warfarin is safe during the first 4 to 6 weeks of gestation and requires a reliable patient. The second increases the duration of exposure to heparin and, therefore, is costly and exposes the patient to a higher risk of osteoporosis (at least with UFH). We suggest the first approach because it is convenient and appears to be safe.

Recommendation

1.1. For women requiring long-term VKA therapy who are attempting pregnancy, we suggest performing frequent pregnancy tests and substituting UFH or LMWH for warfarin when pregnancy is achieved (Grade 2C).

2.0 Treatment of VTE During Pregnancy

There are now many well-designed randomized trials and meta-analyses2324 comparing IV UFH and SC LMWH for the treatment of acute DVT and PE in nonpregnant patients. They show that LMWH is at least as safe and effective as UFH. There are also studies5759 in nonpregnant patients showing that long-term LMWH (and UFH) are as effective and safe as warfarin for the prevention of recurrent VTE. Therefore, in the pregnant patient with acute VTE, two alternative approaches are reasonable: (1) IV UFH followed by at least 3 months of SC LMWH or adjusted-dose SC UFH, or (2) adjusted-dose SC UFH or LMWH can be used both for initial and long-term treatment. With UFH, doses should be adjusted to prolong a mid-interval aPTT into the therapeutic range (adjusted-dose SC heparin).

As discussed above, better bioavailabilty, a better safety profile with regard to osteoporosis and thrombocytopenia compared to UFH, and the inconvenience associated with the need for frequent aPTT monitoring of UFH make LMWH the preferred option for most patients. Thus, in view of the totality of the data, we endorse the use of LMWH for initial and long-term treatment of acute VTE in pregnant women. If one of these agents is used for acute treatment of VTE, a weight-adjusted dose regimen (as per the recommendations of the manufacturer) should be used. However, as the half-life of LMWH is decreased in pregnancy, twice-daily regimens are probably preferable to once-daily dosing. As the pregnancy progresses (and most women gain weight), the potential volume of distribution for LMWH changes. Two options are available to deal with this. The first is to simply change the dose in proportion to the weight change.60The second is to perform regular anti-factor Xa levels 3 to 4 h after the morning dose, and adjust the dose of LMWH to achieve an anti-Xa level of approximately 0.5 to 1.2 U/mL.6162 However, clinical experience suggests that few dose adjustments are required, and monitoring may not be necessary or need only be done infrequently.

It remains unclear whether the dose of LMWH or UFH can be reduced after an initial period of full anticoagulation. It has been suggested that therapeutic levels of anticoagulation should be maintained throughout pregnancy and the puerperium because of the ongoing risk of recurrent VTE during this time period. However, regimens in which the intensity of therapy is reduced after initial full-dose anticoagulation may reduce the risks of anticoagulant-related bleeding and heparin-induced osteoporosis, and have been successfully used in patients with contraindications to warfarin33 and in patients with underlying malignancy.63 Although there have been no studies directly comparing these two types of dosing strategies in pregnant women, this type of modified dosing regimen may be useful in pregnant women at increased risk of bleeding or osteoporosis.

In order to avoid an unwanted anticoagulant effect during delivery (especially with neuroaxial anesthesia) in women receiving adjusted-dose SC UFH therapy,44 it is suggested that heparin be discontinued 24 h prior to elective induction of labor or cesarean section. If spontaneous labor occurs in women receiving adjusted-dose SC UFH, careful monitoring of the aPTT is required. If it is markedly prolonged near delivery, protamine sulfate may be required to reduce the risk of bleeding. Although bleeding complications appear to be very uncommon with LMWH,1422,28,34,45 we suggest the same approach to women receiving “therapeutic doses” of LMWH as in those receiving adjusted-dose UFH, namely discontinuing LMWH 24 h prior to elective induction of labor or cesarean section.

If the woman is deemed to have a very high risk of recurrent VTE (eg, proximal DVT within 2 weeks), therapeutic IV UFH can be initiated and discontinued 4 to 6 h prior to the expected time of delivery in order to limit the duration of time without therapeutic anticoagulation. In addition or alternatively, a temporary inferior vena cava filter can be inserted within a week of elective induction or cesarean section and removed postpartum. Postpartum anticoagulants should be administered for at least 6 weeks.

Recommendations

2.1. In women with acute VTE, we recommend either adjusted-dose LMWH throughout pregnancy or IV UFH (bolus followed by a continuous infusion to maintain the aPTT in the therapeutic range) for at least 5 days, followed by adjusted-dose UFH or LMWH for the remainder of the pregnancy. Anticoagulants should be administered for at least 6 weeks postpartum (Grade 1C+).

2.2. In women receiving adjusted-dose LMWH or UFH therapy, we recommend discontinuing the heparin 24 h prior to elective induction of labor (Grade 1C).

3.0 Prevention of VTE During Pregnancy

When evaluating women who are deemed to have an increased risk of VTE, it is important to first critically examine the evidence that the women indeed had VTE and/or have thrombophilia placing them at increased risk of VTE. Once this is done, based on laboratory and clinical data, the women can be broadly categorized as follows: (1) single episode of VTE associated with a transient risk factor; (2) single idiopathic episode of VTE and not receiving long-term anticoagulants; (3) single episode of VTE and thrombophilia (confirmed laboratory abnormality) and not receiving long-term anticoagulants; (4) multiple (two or more) episodes of VTE and/or receiving long-term anticoagulants (eg, single episode of VTE—either idiopathic or associated with thrombophilia); and (5) no prior VTE and thrombophilia (confirmed laboratory abnormality). Risk assessment for each patient should be individualized. For example, a woman with a single episode of VTE in association with a transient risk factor might be managed more aggressively if she requires bed rest or is morbidly obese or has a family history of VTE.

3.1 Prior VTE and pregnancy

Women with a history of VTE (with or without thrombophilia) are believed to have a higher risk of recurrence in subsequent pregnancies. Estimates of the rate of recurrent venous thrombosis during pregnancy in women with a history of VTE have varied between zero and 13%.6467 The higher of these estimates has prompted authorities (including the American College of Chest Physicians) to recommend anticoagulant prophylaxis during pregnancy and the postpartum period in women with a history of VTE. However, the risk is likely to be lower than has been suggested by some of these studies because objective testing was used uncommonly to confirm the diagnosis of recurrent VTE, thereby resulting in a substantial overdiagnosis of recurrence. Furthermore, the higher estimates of the frequency of recurrence are from retrospective studies6667 of nonconsecutive patients, whereas the lower estimates come from prospective, albeit small (n = 20, n = 59), studies.6465

In order to obtain a reliable estimate of the true incidence of recurrence in women with prior VTE, Brill-Edwards and Ginsberg68 performed a prospective study of 125 pregnant women with a single previous episode of objectively diagnosed VTE. Antepartum heparin was withheld, and anticoagulants (usually warfarin with a target international normalized ratio [INR] of 2.0 to 3.0 with an initial short course of UFH or LMWH) were administered in the postpartum period for 4 to 6 weeks. The antepartum recurrence rate was 2.4% (95% CI, 0.2 to 6.9%). Ninety-five patients underwent blood testing to identify thrombophilia. There were no recurrences in the 44 patients (0%; 95% CI, 0.0 to 8.0%) who did not have thrombophilia and had a previous episode of thrombosis that was associated with a temporary risk factor. Patients with abnormal test results and/or a previous episode of thrombosis that was idiopathic (unprovoked) had an antepartum recurrence rate of 5.9% (95% CI, 1.2 to 16%). Based on these results, antepartum heparin prophylaxis is not routinely recommended in women without thrombophilia whose previous episode of thrombosis was associated with a temporary risk factor. However, this decision should be considered on an individual basis, taking all risk factors for VTE into account. Further studies are needed to determine whether prophylaxis is warranted in patients with laboratory thrombophilia and/or a previous episode of idiopathic thrombosis.

Based on the currently available studies, there are two general approaches to the antepartum management of pregnant patients with previous VTE who require active prophylaxis with UFH or LMWH. One randomized trial and several recent cohort studies1422,69 reported low recurrence rates with the use of prophylactic once-daily LMWH. Given the benefits of LMWH, it is the preferred choice. For prophylaxis of VTE during pregnancy, several dose regimens of LMWHs have been used. Common regimens that have been reported in a randomized trial34 (comparing the effects of LMWH and UFH on bone density), cohort studies and case series include subcutaneous enoxaparin; dalteparin, 5,000 U q24h69; and dose-adjusted LMWH to achieve a peak anti-Xa level of 0.2 to 0.6 U/mL.1922 Although all of the studies reported low recurrence rates, none were placebo-controlled trials; therefore, the recurrence rates might have been low without prophylaxis.

SC UFH, 5,000 U q12h, is effective and safe for the prevention of VTE in high-risk nonpregnant patients,70 and its use has been recommended in pregnant patients. However, there is concern that a dose of 5,000 U SC q12h may be insufficient in high-risk situations because it does not reliably produce detectable heparin levels. There are also published data that more intense heparin therapy, in doses that produce plasma heparin levels (measured as anti-factor Xa activity) of 0.1 to 0.2 U/mL, is associated with low recurrence rates in pregnant women with previous VTE.48 Thus, where UFH is employed for prophylaxis in pregnancy, higher doses are often used, such as 10,000 IU bid. Until comparative studies are performed, it is not possible to make definitive recommendations about which prophylactic regimen of UFH should be used (if active prophylaxis is chosen).

Repeated screening during the antepartum period with noninvasive tests for DVT, such as compression ultrasonography, is not justified for two reasons. In these patients, even with a sensitivity of 96% and a specificity of 98%, the positive predictive value of compression ultrasonography would be only 10%, if we postulate that the prevalence of recurrent VTE during pregnancy is approximately 5%. Second, the timing of screening with ultrasound is problematic. Even if performed as often as weekly, a woman could still acquire clinically important recurrence 2 to 3 days after a normal ultrasound. Thus, women at risk of VTE should not be screened routinely with regular noninvasive tests. Instead, we recommend they be investigated aggressively if symptoms suspicious of DVT or PE occur.

Recommendations

3.1.1. In patients with a single episode of VTE associated with a transient risk factor that is no longer present, we recommend clinical surveillance and postpartum anticoagulants (Grade 1C). If the previous event is pregnancy or estrogen-related or there are additional risk factors (such as obesity), we suggest antenatal anticoagulant prophylaxis (Grade 2C).

3.1.2. In patients with a single idiopathic episode of VTE who are not receiving long-term anticoagulants, we suggest prophylactic LMWH, or minidose UFH or moderate-dose UFH, or clinical surveillance plus postpartum anticoagulants (Grade 2C).

3.1.3. In patients with a single episode of VTE and thrombophilia (confirmed laboratory abnormality) or strong family history of thrombosis and not receiving long-term anticoagulants, we suggest prophylactic or intermediate-dose LMWH or mini-dose or moderate-dose UFH, plus postpartum anticoagulants (Grade 2C).

3.1.4. In antithrombin-deficient women, compound heterozygotes for prothrombin G20210A and factor V Leiden and homozygotes for these conditions with a history of VTE, we suggest intermediate-dose LMWH prophylaxis or moderate-dose UFH (Grade 2C).

3.1.5. In patients with multiple (two or more) episodes of VTE and/or women receiving long-term anticoagulants (eg, single episode of VTE—either idiopathic or associated with thrombophilia) we suggest adjusted-dose UFH or adjusted-dose LMWH followed by resumption of long-term anticoagulants postpartum (Grade 2C).

3.1.6. In all women with previous DVT, antenatally and postpartum, we suggest use of graduated elastic compression stockings (Grade 2C).

See summary of recommendations for definitions of dosing regimens.

3.2 Thrombophilia and VTE associated with pregnancy

Approximately 50% of gestational VTEs are associated with heritable thrombophilia.11 Studies7182 have provided estimates for the risk of gestational VTE in women with thrombophilia. The relative risks or odds ratios (ORs) for gestational thrombosis in women with antithrombin deficiency, heterozygosity for the factor V Leiden or prothrombin gene mutations, and homozygosity for the C667T methylene tetrahydrofolate reductase (MTHFR) mutation (thermolabile variant), after adjusting for other key variables, are presented in Tables 2, 3 . Variability in these risk estimates is likely the result of small sample sizes; as well as differences in study methodology (case control,71,7374,82 vs cohort72,75), the characteristics of control subjects (parous age-matched women without a history of thrombosis82 vs age-matched women without a history of thrombosis with or without previous pregnancy71 vs healthy women with at least one previous pregnancy without thrombosis74 vs the general population73), and the factors adjusted for in calculating risk estimates (parity74 vs age, body mass index, oral contraceptive use, protein C and S activity, and antithrombin activity, and presence of factor V Leiden, prothrombin G20210A, or MTHFR 677TT genotype71). Although not systematically examined in any of these studies, persistent APLAs76 are probably also associated with an increased risk of VTE during pregnancy and the puerperium.

In a study of 119 women with gestational VTE and 233 control subjects, Gerhardt et al71 also provided a positive predictive value for each thrombophilia, assuming an underlying rate of VTE of 0.66/1,000 pregnancies, consistent with estimates from Western populations.11 These values were 1:500 for individuals heterozygous for the factor V Leiden mutation, 1:200 for those heterozygous for the prothrombin 20210A allele, and 4.6:100 for double heterozygotes. In a similar analysis, a retrospective study72 of 72,000 pregnancies, in which women with venous thrombosis were assessed for thrombophilia and where the underlying prevalence of these defects in the population was known, showed that the risk of thrombosis was 1:437 for women with the factor V Leiden mutation, 1:113 for those with protein C deficiency, 1:2.8 for women with type 1 antithrombin deficiency, and 1:42 for those with type 2 antithrombin deficiency.

Given that the background rate of VTE during pregnancy is approximately 1:1000,11 the absolute risk of VTE remains modest for the majority of these thrombophilias, except antithrombin deficiency, homozygosity for the factor V Leiden mutation, and combined defects. The absolute risk of pregnancy-associated VTE has been reported to range from 9 to 16% in homozygotes for the factor V Leiden mutation.7780 Double heterozygosity for the factor V Leiden and prothrombin gene mutations has been reported to have an absolute risk of pregnancy-associated VTE of 4.0% (95% CI, 1.4 to 16.9%).79 These data suggest that women with antithrombin deficiency or homozygosity for the factor V Leiden mutation, as well as double heterozygotes, should be managed more aggressively than those with other inherited thrombophilias, especially in symptomatic kindreds.

Hyperhomocysteinemia is associated with an increased risk of VTE in nonpregnant subjects.81 The data regarding homozygosity for MTHFR C677T in this situation is less definitive. It is also unclear whether homozygotes for MTHFR C677T have an increased risk of VTE during pregnancy and the puerperium.71,73,82As clinical events in homozygotes are likely to reflect the interaction of the genotype with a relative deficiency of vitamins such as B12 and folic acid, the absence of an association of this genotype with gestational VTE may reflect pregnancy-related physiologic reduction in homocysteine levels, and/or the effects of folic acid supplements that are now taken widely by women in pregnancy for prevention of neural tube defects.83

The antepartum management of pregnant women with known thrombophilia and no prior VTE remains controversial because of our limited knowledge of the natural histories of various thrombophilias and a lack of trials of VTE prophylaxis. We are unaware of prospective data addressing the issue of the incidence of VTE in a large group of pregnant women with thrombophilia and no prior VTE.

Recommendations

3.2.1. In antithrombin-deficient women, compound heterozygotes for prothrombin G20210A and factor V Leiden, and homozygotes for these conditions with no prior VTE, we suggest active prophylaxis (Grade 2C).

3.2.2. In all other patients with no prior VTE and thrombophilia (confirmed laboratory abnormality), we suggest surveillance or prophylactic LMWH or minidose UFH, plus postpartum anticoagulants (Grade 2C).

See summary of recommendations for definitions of dosing regimens.

3.3 VTE associated with cesarean section

Available data suggests that the risk of VTE is higher after cesarean section (especially emergent surgery) than after vaginal delivery.11 The presence of additional risk factors for pregnancy-associated VTE (for example, prior VTE, thrombophilia, age > 35 years, obesity, prolonged bed rest, and concomitant acute medical illness) may exacerbate this risk. It has been recommended that graduated compression stockings be used during and after cesarean section in patients considered to be at “moderate risk” of VTE and that LMWH or UFH prophylaxis be added in those thought to be at “high risk.”84However, there is insufficient good quality data to provide information as to the benefits associated with these interventions.8586

4.0 Thrombophilia and Pregnancy Complications

It has been suggested that maternal thrombophilias are associated with pregnancy complications, including fetal loss, IUGR, preeclampsia, abruption, and intrauterine death.87There have now been many case-control and cohort studies8898 examining the relationship between some heritable thrombophilias and miscarriage. The results of the studies are inconsistent, reflecting different populations, small sample size, varying case definition, potential selection bias, and retrospective design. These issues have, at least in part, been resolved by a recent meta-analysis99 of 31 cohort, case-control, and cross-sectional studies, in which the quality of the data was regarded as strong or moderate. This analysis reported an association between fetal loss and the presence of factor V Leiden, activated protein C resistance, protein S deficiency, and prothrombin G20210A.99 For heterozygosity for the factor V Leiden mutation, pooled ORs were 1.73 (95% CI, 1.18 to 2.54) for nonrecurrent fetal loss, 2.01 (95% CI, 1.13 to 3.58) for recurrent loss before 13 weeks, and 3.26 (95% CI, 1.82 to 5.83) for nonrecurrent late loss (after 19 weeks). For heterozygosity for the prothrombin G20210A allele, ORs were 2.15 (95% CI, 1.18 to 3.54) for recurrent fetal loss, 2.32 (95% CI, 1.12 to 4.79) for recurrent loss before 13 weeks, and 2.30 (95% CI, 1.09 to 4.87) for nonrecurrent late loss. Protein S deficiency was associated with an OR of 7.39 (95% CI, 1.28 to 42.83) for nonrecurrent late fetal loss. However, protein C and antithrombin deficiency, as well as homozygosity for MTHFR C677T, were not associated with recurrent or nonrecurrent fetal loss.

One systematic review and meta-analysis100reported a significant association between preeclampsia and the factor V Leiden mutation (heterozygotes and homozygotes), heterozygosity for the prothrombin G20210A allele, homozygosity for MTHFR C677T, and protein C and S deficiency. However, a more recent meta-analysis published in conjunction with a large population-based study did not find an association between preeclampsia and the presence of factor V Leiden, prothrombin G20210A, homozygosity for MTHFR C677T or platelet collagen receptor α2β1C807T.101 Although there was no overall association between preeclampsia and these thrombophilic states, there was an association between severe preeclampsia and heterozygosity for the factor V Leiden mutation and homozygosity for MTHFR C677T, with pooled ORs of 2.84 (95% CI, 1.95 to 4.14) and 1.50 (95% CI, 1.02 to 2.23), respectively. The reasons underlying these differences in results with regard to the association between thrombophilia and preeclampsia are unclear. It may reflect different diagnostic criteria, small sample size, and reporting bias, as many studies had relatively low levels of heterozygosity for factor V Leiden in the control groups studied. Nonetheless, these data suggest that while prothrombotic genotypes might not be causative factors for preeclampsia, they could be linked to the severity of disease expression once the condition arises.

A previous systematic review and meta-analysis100 reported significant associations between IUGR and heterozygosity for the prothrombin G20210A allele, homozygosity for MTHFR C6777, and protein S deficiency. However a large, methodologically rigorous case-control study102 has cast doubt on the association between IUGR and thrombophilia. This study of 493 newborns with IUGR and 472 controls found no increase in the risk of IUGR among mothers homozygous for MTHFR C677T, or those heterozygous for factor V Leiden or prothrombin G20210A with ORs of 1.55 (95% CI, 0.83 to 2.90), 1.18 (95% CI, 0.54 to 2.35), and 0.92 (95% CI, 0.36 to 2.35), respectively. Even when the birth weight centile was reduced to the fifth centile and the analysis repeated, there was no relationship with underlying thrombophilia, suggesting that, in contrast to preeclampsia, there is no association between thrombophilia and disease severity. However, there was an association between MTHFR C677T homozygosity and IUGR in the subgroup of mothers not receiving vitamin supplements (OR, 12.3; 95% CI, 1.2 to 126.2). Thus, the lack of association between IUGR and MTHFR C677T homozygosity may reflect the widespread use of multivitamin preparations containing folic acid in pregnancy, which could influence homocysteine levels. This emphasizes the need for consideration of plasma homocysteine, rather than the MTHFR genotype alone, as a possible risk factor for pregnancy complications. In addition, this study102 reported no association between the fetal genotype for thrombophilia and IUGR. The difference between this study and previous reports lie in its large sample size, which contained more patients than the total analyzed in the metaanalysis described above.

In view of these data, women with recurrent pregnancy loss, a second trimester miscarriage, or a history of intrauterine death or severe or recurrent preeclampsia should be screened for underlying congenital thrombophilias. However, in contrast to patients with APLA syndrome with recurrent miscarriage, where a combination of heparin and low-dose aspirin has been shown to be effective in reducing miscarriage rates, there are no convincing data to indicate whether such antithrombotic therapy is beneficial in women with congenital thrombophilia and pregnancy complications. Nevertheless, since many of these women also have an increased risk of VTE, antithrombotic therapy should be considered in this population. Randomized trials are assessing the value of this therapy in women with recurrent pregnancy loss and underlying thrombophilia. Although hyperhomocysteinemia has not been associated with DVT in pregnancy,73 hyperhomocysteinemia98 and reduced serum folic acid concentrations appear to be risk factors for recurrent spontaneous miscarriage; therefore, folic acid supplementation may be beneficial in such patients.

APLAs can be detected using clotting assays (lupus anticoagulant/nonspecific inhibitor) or immunoassays (anticardiolipin antibodies), and have been reported to occur in systemic lupus erythematosus, with use of certain drugs and in apparently healthy individuals.103 There is convincing evidence that the presence of APLAs is associated with an increased risk of thrombosis76 and pregnancy loss.104105 Thus, pregnant women with APLAs should be considered at risk for both of these complications. In addition, women with recurrent pregnancy loss should be screened for the presence of APLAs prior to, or during the early part of, pregnancy. The management of pregnant women with APLAs is problematic because few clinical trials evaluating therapy have been performed. A relatively large (n = 202) placebo-controlled, randomized trial105showed no benefit to using aspirin and prednisone in pregnant women with prior pregnancy losses and one or more autoantibodies (94 of 202 women [40%] had APLAs). Two randomized trials106107 compared aspirin and heparin to aspirin alone, and showed improved fetal survival with heparin and aspirin. Results of published case series107a,107b suggest that LMWH is efficacious in pregnant women with APLAs and fetal loss; currently, we and others are performing randomized trials evaluating the efficacy and safety of LMWH in pregnant women with APLAs. While available data suggest that aspirin and heparin is the regimen of choice for the prevention of pregnancy loss in pregnant women with APLAs and multiple previous pregnancy losses, it is likely that LMWH will also be effective. A more recent study,45 however, found no difference in outcome when these women were randomized to low-dose aspirin with LMWH or low-dose aspirin alone.

Pregnant women with APLAs (particularly “high-titer” anticardiolipin antibodies and/or lupus anticoagulants), no pregnancy losses, but previous venous thrombosis should be considered candidates for UFH or LMWH therapy, especially if they are already receiving long-term anticoagulant therapy. Women with APLAs and neither previous venous thrombosis nor pregnancy losses should probably still be considered to have an increased risk of VTE, and should be managed either with careful clinical surveillance for VTE or prophylactic UFH or LMWH.

Recommendations

4.1. For women with recurrent pregnancy loss (three or more miscarriages) and women with prior severe or recurrent preeclampsia, abruptions, or otherwise unexplained intrauterine death, we suggest screening for congenital thrombophilia and APLAs (Grade 2C).

4.2. For pregnant patients with APLAs and a history of multiple (two or more) early pregnancy losses or one or more late pregnancy losses, preeclampsia, IUGR, or abruption, we suggest administration of antepartum aspirin plus minidose or moderate-dose UFH or prophylactic LMWH (Grade 2B).

4.3. For women who are homozygous for thermolabile variant (C677T) of MTHFR, we suggest folic acid supplements prior to conception or, if already pregnant, as soon as possible, and throughout pregnancy (Grade 2C).

4.4. For women with a congenital thrombophilic deficit and recurrent miscarriages, a second-trimester or later loss, severe or recurrent preeclampsia, or abruption, we suggest low-dose aspirin therapy plus either minidose heparin or prophylactic LMWH therapy (Grade 2C). We also suggest that postpartum anticoagulants be administered to these women (Grade 2C).

4.5. Patients with APLAs and a history of venous thrombosis are usually receiving long-term oral anticoagulation therapy because of the high risk of recurrence. During pregnancy, we recommend adjusted-dose LMWH or UFH therapy plus low-dose aspirin and resumption of long-term oral anticoagulation therapy postpartum (Grade 1C).

4.6. Patients with APLAs and no prior VTE or pregnancy loss should be considered to have an increased risk for the development of venous thrombosis and, perhaps, pregnancy loss. We suggest one of the following approaches for these women: surveillance, minidose heparin, prophylactic LMWH, and/or low-dose aspirin, 75 to 162 mg/d (all Grade 2C).

5.0 Management of Pregnant Women With Prosthetic Heart Valves

Pregnant women with prosthetic heart valves pose a problem because of the lack of reliable data regarding the efficacy and safety of antithrombotic therapy during pregnancy. A retrospective survey108 describing outcomes in pregnant women with mechanical heart valves concluded the following: warfarin was safe and not associated with embryopathy, and heparin was associated with more thromboembolic and bleeding complications than warfarin.

In order to examine the validity of these conclusions and explore optimum antithrombotic regimens, Chan and colleagues109 performed a systematic review of the literature examining fetal and maternal outcomes of pregnant women with prosthetic heart valves. Since no randomized trials were identified, the overview consisted of prospective and retrospective cohort studies. Pooled estimates of maternal and fetal risks associated with the following three commonly used approaches were determined: (1) use of VKAs throughout pregnancy (in widespread use in Europe), (2) replacement of VKAs with UFH from 6 to 12 weeks, and (3) UFH use throughout pregnancy. In both VKA-containing regimens, heparin was commonly used close to term in order to avoid delivery of an anticoagulated fetus. Outcomes included pregnancy loss, fetopathic effects (including warfarin embryopathy), as well as maternal bleeding, thromboembolic complications, and death.

The use of VKAs throughout pregnancy was associated with warfarin embryopathy in 6.4% of live births (Table 4 ). The substitution of heparin at or prior to 6 weeks eliminated this risk. Overall the rates of fetal wastage (spontaneous loss, stillbirths, and neonatal deaths) were similar in the three groups. The overall pooled maternal mortality rate was 2.9% (Table 5 ). Major bleeding occurred in 2.5% of all pregnancies, mostly at the time of delivery (Table 6 ). The regimen associated with the lowest risk of valve thrombosis/systemic embolism (3.9%) was the use of VKAs throughout; using UFH only between 6 weeks and 12 weeks gestation was associated with an increased risk of valve thrombosis (9.2%) [Table 5].

This analysis suggests that VKAs are more efficacious than UFH for thromboembolic prophylaxis of women with mechanical heart valves in pregnancy; however, coumarins increase the risk of embryopathy. Substituting VKAs with heparin between 6 weeks and 12 weeks reduces the risk of fetopathic effects but possibly subjects the woman to an increased risk of thromboembolic complications. The reported high rates of thromboembolism with UFH might be explained by inadequate dosing and/or the use of an inappropriate target therapeutic range. The use of low-dose UFH is inadequate; the use of adjusted-dose UFH warrants aggressive monitoring and appropriate dose adjustment. Contemporary aPTT reagents are more sensitive to the anticoagulant effect of heparin; therefore, a minimum target aPTT ratio of 1.5 times the control is likely to be inadequate. A target aPTT ratio of at least twice the control should be attained.110

Reports of LMWH use in pregnant women with prosthetic heart valves are starting to appear,111117 and many physicians now use these agents during pregnancy in women with mechanical valves. Treatment failures have been reported,114117 and the use of LMWH for this indication has recently become controversial due to a warning from a LMWH manufacturer regarding their safety in this situation.118 This warning was based on an undisclosed number of postmarketing reports of thrombosed valves in patients receiving this LMWH, as well as the results of a very small randomized trial of pregnant women with prosthetic valves. In this study,18 which was stopped after 12 patients were enrolled, pregnant women were randomized to receive either LMWH or UFH and warfarin administered sequentially. Although few details are available, according to the manufacturer, two of seven women treated with LMWH acquired valve thrombosis and outflow obstruction causing maternal and fetal deaths. Given the small numbers of patients enrolled in the study and the inability to determine accurate incidence rates from postmarketing data, the true incidence of valve thrombosis in pregnant women with mechanical valves treated with LMWH remains unknown.

All anticoagulant therapies used in this situation are associated with significant risks, but clearly, women with prosthetic heart valves require anticoagulation during pregnancy. Coumarins are contraindicated in pregnancy in North America due to fetal concerns. UFH has significant maternal side effects, and there are reports that it lacks efficacy, albeit when associated with doses of UFH that were likely to be inadequate. LMWH, with its good safety profile for mother and baby, should not be discarded in this situation until there are better comparative data. It is important to remember that the failures of UFH and LMWH reported in the literature do not exclude the possibility that these medications, if administered in high doses and aggressively monitored, would be effective.

To summarize, there are still insufficient grounds to make definitive recommendations about optimal antithrombotic therapy in pregnant patients with mechanical heart valves because properly designed studies have not been performed. Substantial concern remains about the fetal safety of warfarin, the efficacy of subcutaneous heparin and of LMWH in preventing thromboembolic complications, and the risks of maternal bleeding with various regimens. European experts have recommended warfarin therapy throughout pregnancy in view of the reports of bad maternal outcomes with heparin and their impression that the risk of embryopathy with coumarin derivatives has been overstated.108 Although this latter approach is reasonable, it is fraught with medicolegal concerns, because the package insert states that warfarin is contraindicated during pregnancy. We believe that warfarin should be avoided between 6 weeks and 12 weeks of gestation (to avoid embryopathy) and close to term (to avoid delivery of an anticoagulated fetus). Although the risks associated with warfarin during the remainder of pregnancy have been considered smaller, the recent association with neurodevelopment problems with mid-pregnancy exposure must also be considered.40

It appears reasonable to use one of the following three regimens: (1) either LMWH or UFH between 6 weeks and 12 weeks and close to term only, and to use VKAs at other times (despite medicolegal concerns); (2) aggressive dose-adjusted UFH throughout pregnancy; or (3) aggressive adjusted-dose LMWH throughout pregnancy. Before any of these approaches is used, it is crucial to explain the risks carefully to the patient. If warfarin is used, the dose should be adjusted to attain a target INR of 3.0 (range, 2.5 to 3.5); a lower therapeutic range of 2.0 to 3.0 can be used in patients with bileaflet aortic valves, provided they do not have atrial fibrillation or left ventricular dysfunction. If used, SC UFH should be initiated in high doses (17,500 to 20,000 U q12h) and adjusted to prolong a 6-h postinjection aPTT into the therapeutic range; strong efforts should be made to ensure an adequate anticoagulant effect. Adjusted-dose LMWHs are a reasonable substitute for UFH because they appear to reduce the risk of bleeding and osteoporosis and do not cross the placenta. Although further information is required about dosing for this indication, we recommend that LMWH be administered twice daily and dosed to achieve anti-Xa levels of 1.0 to 1.2 U/mL 4 to 6 h after SC injection. Extrapolating from data in nonpregnant patients with mechanical valves receiving warfarin therapy,119 for some high-risk women, the addition of aspirin, 75 to 162 mg/d, can be considered in an attempt to reduce the risk of thrombosis, recognizing that it increases the risk of bleeding.

Recommendations

In women with prosthetic heart valves, we recommend:

5.1. Adjusted-dose bid LMWH throughout pregnancy in doses adjusted either to keep a 4-h postinjection anti-Xa heparin level at approximately 1.0 to 1.2 U/mL (preferable) or according to weight (Grade 1C), or

5.2. Aggressive adjusted-dose UFH throughout pregnancy, ie, administered SC q12h in doses adjusted to keep the mid-interval aPTT at least twice control or to attain an anti-Xa heparin level of 0.35 to 0.70 U/mL (Grade 1C), or

5.3. UFH or LMWH (as above) until the thirteenth week, change to warfarin until the middle of the third trimester, and then restart UFH or LMWH (Grade 1C).

Remark: Long-term anticoagulants should be resumed postpartum with all regimens.

5.4. In women with prosthetic heart valves at high risk, we suggest the addition of low-dose aspirin, 75 to 162 mg/d (Grade 2C).

Anticoagulant therapy is indicated during pregnancy for the prevention and treatment of VTE, in patients with mechanical heart valves, and for the prevention of pregnancy complications in women with APLAs or hereditary thrombophilia and prior pregnancy complications.

VKAs are fetopathic, but the true risks of the warfarin embryopathy and CNS abnormalities remain unknown. There is considerable evidence that warfarin may not be fetopathic when administered in the first 6 weeks of gestation. Although there is considerable evidence that warfarin embryopathy occurs only when VKAs are administered between the sixth week and the twelfth week of gestation, concerns have been raised recently about long-term neurocognitive effects of warfarin on children exposed to during the mid-trimester of pregnancy. VKAs should be avoided in the weeks before delivery because of the risk of serious perinatal bleeding caused by the trauma of delivery to the anticoagulated fetus. The safety of aspirin during the first trimester of pregnancy is still a subject of debate. Although doubt has been raised about the effectiveness of heparin or LMWH for the prevention of systemic embolism in patients with mechanical heart valves, the observed failures could have been caused by inadequate dosing. Finally, the optimum management of pregnant women with thrombophilia (and prior pregnancy complications and/or prior VTE) is unknown, but trials of anticoagulant therapy are ongoing.

When describing the various regimens of UFH and LMWH, we will use the following short forms:

  • Minidose UFH: UFH 5,000 U SC q12h

  • Moderate-dose UFH: UFH SC q12h in doses adjusted to target an anti-Xa level of 0.1 to 0.3 U/mL.

  • Adjusted-dose UFH: UFH SC q12h in doses adjusted to target a mid-interval aPTT into the therapeutic range.

  • Prophylactic LMWH: eg, dalteparin 5,000 U SC q24h, or enoxaparin 40 mg SC q24 h (although at extremes of body weight modification of dose may be required).

  • Intermediate-dose LMWH: eg, dalteparin 5,000 U SC q12h, or enoxaparin 40 mg SC q12h.

  • Adjusted-dose LMWH: weight-adjusted, full-treatment doses of LMWH administered once or twice daily (eg, dalteparin 200 U/kg, or tinzaparin 175 U/kg qd, or dalteparin 100 U/kg q12h, or enoxaparin 1 mg/kg q12 h). As the half-life of LMWH is shorter in pregnancy, twice-daily dosing is preferable, at least in the initial treatment phase.

  • Postpartum anticoagulants: warfarin for 4 to 6 weeks with a target INR of 2.0 to 3.0, with initial UFH or LMWH overlap until the INR is ≥ 2.0.

  • In addition, the term surveillance refers to clinical vigilance and aggressive investigation of women with symptoms suspicious of DVT or PE.

1.0 Management of Women Receiving Long-Term Vitamin K Antagonist Therapy Who Are Considering Pregnancy

1.1. For women requiring long-term VKA therapy who are attempting pregnancy, we suggest performing frequent pregnancy tests and substituting UFH or LMWH for warfarin when pregnancy is achieved (Grade 2C).

2.0 Treatment of VTE During Pregnancy

2.1. In women with acute VTE, we recommend either adjusted-dose LMWH throughout pregnancy or IV UFH (bolus followed by a continuous infusion to maintain the aPTT in the therapeutic range) for at least 5 days, followed by adjusted-dose UFH or LMWH for the remainder of the pregnancy. Anticoagulants should be administered for at least 6 weeks postpartum (Grade 1C+).

2.2. In women receiving adjusted-dose LMWH or UFH therapy, we recommend discontinuing the heparin 24 h prior to elective induction of labor (Grade 1C).

3.0 Prevention of VTE During Pregnancy
3.1 Prior VTE and pregnancy

3.1.1. In patients with a single episode of VTE associated with a transient risk factor that is no longer present, we recommend clinical surveillance and postpartum anticoagulants (Grade 1C). If the previous event is pregnancy or estrogen-related or there are additional risk factors (such as obesity), we suggest antenatal anticoagulant prophylaxis (Grade 2C).

3.1.2. In patients with a single idiopathic episode of VTE who are not receiving long-term anticoagulants, we suggest prophylactic LMWH, or minidose UFH, or moderate-dose UFH, or clinical surveillance plus postpartum anticoagulants (Grade 2C).

3.1.3. In patients with a single episode of VTE and thrombophilia (confirmed laboratory abnormality) or strong family history of thrombosis and not receiving long-term anticoagulants, we suggest prophylactic or intermediate-dose LMWH, or mini-dose or moderate-dose UFH, plus postpartum anticoagulants (Grade 2C).

3.1.4. In antithrombin-deficient women, compound heterozygotes for prothrombin G20210A and factor V Leiden and homozygotes for these conditions with a history of VTE, we suggest intermediate-dose LMWH prophylaxis or moderate-dose UFH (Grade 2C).

3.1.5. In patients with multiple (two or more) episodes of VTE and/or women receiving long-term anticoagulants (eg, single episode of VTE—either idiopathic or associated with thrombophilia) we suggest adjusted-dose UFH or adjusted-dose LMWH followed by resumption of long-term anticoagulants postpartum (Grade 2C).

3.1.6. In all women with previous DVT, antenatally and postpartum, we suggest use of graduated elastic compression stockings (Grade 2C).

3.2 Thrombophilia and venous thromboembolism associated with pregnancy

3.2.1. In antithrombin-deficient women, compound heterozygotes for prothrombin G20210A and factor V Leiden, and homozygotes for these conditions with no prior VTE, we suggest active prophylaxis (Grade 2C).

3.2.2. In all other patients with no prior VTE and thrombophilia (confirmed laboratory abnormality), we suggest surveillance or prophylactic LMWH or minidose UFH, plus postpartum anticoagulants (Grade 2C).

4.0 Thrombophilia and Pregnancy Complications

4.1. For women with recurrent pregnancy loss (three or more miscarriages) and women with prior severe or recurrent preeclampsia, abruptions, or otherwise unexplained intrauterine death, we suggest screening for congenital thrombophilia and APLAs (Grade 2C).

4.2. For pregnant patients with APLAs and a history of multiple (two or more) early pregnancy losses or one or more late pregnancy losses, preeclampsia, IUGR, or abruption, we suggest administration of antepartum aspirin plus minidose or moderate-dose UFH or prophylactic LMWH (Grade 2B).

4.3. For women who are homozygous for thermolabile variant (C677T) of MTHFR, we suggest folic acid supplements prior to conception or, if already pregnant, as soon as possible, and throughout pregnancy (Grade 2C).

4.4. For women with a congenital thrombophilic deficit and recurrent miscarriages, a second-trimester or later loss, severe or recurrent preeclampsia, or abruption, we suggest low-dose aspirin therapy plus either minidose heparin or prophylactic LMWH therapy (Grade 2C). We also suggest that postpartum anticoagulants be administered to these women (Grade 2C).

4.5. Patients with APLAs and a history of venous thrombosis are usually receiving long-term oral anticoagulation therapy because of the high risk of recurrence. During pregnancy, we recommend adjusted-dose LMWH or UFH therapy plus low-dose aspirin and resumption of long-term oral anticoagulation therapy postpartum (Grade 1C).

4.6. Patients with APLAs and no prior VTE or pregnancy loss should be considered to have an increased risk for the development of venous thrombosis and, perhaps, pregnancy loss. We suggest one of the following approaches for these women: surveillance, mini-dose heparin, prophylactic LMWH, and/or low-dose aspirin, 75 to 162 mg daily (all Grade 2C).

5.0 Prophylaxis in Patients with Mechanical Heart Valves

In women with prosthetic heart valves, we recommend:

5.1. Adjusted-dose, twice-daily LMWH throughout pregnancy in doses adjusted either to keep a 4-h postinjection anti-Xa heparin level at approximately 1.0 to 1.2 U/mL (preferable) or according to weight (Grade 1C), or

5.2. Aggressive adjusted-dose UFH throughout pregnancy: ie, administered SC q12h in doses adjusted to keep the mid-interval aPTT at least twice control or to attain an anti-Xa heparin level of 0.35 to 0.70 U/mL (Grade 1C), or

5.3. UFH or LMWH (as above) until the thirteenth week, change to warfarin until the middle of the third trimester, and then restart UFH or LMWH (Grade 1C).

Remark: Long-term anticoagulants should be resumed postpartum with all regimens.

5.4. In women with prosthetic heart valves at high risk, we suggest the addition of low-dose aspirin, 75 to 162 mg/d (Grade 2C).

Abbreviations: APLA = antiphospholipid antibody; aPTT = activated partial thromboplastin time; CI = confidence interval; DVT = deep vein thrombosis; HIT = heparin-induced thrombocytopenia; INR = international normalized ratio; IUGR = intrauterine growth restriction; LMWH = low molecular weight heparin; MTHFR = methylene tetrahydrofolate reductase; OR = odds ratio; PE = pulmonary embolism; SC = subcutaneous; UFH = unfractionated heparin; VKA = vitamin K antagonist; VTE = venous thromboembolism

Table Graphic Jump Location
Table 1. Question Definition and Eligibility Criteria for the Use of Antithrombotic Agents During Pregnancy*
Table Graphic Jump Location
Table 1A. Continued
* 

RCT = randomized controlled trial.

Table Graphic Jump Location
Table 2. Risk of VTE in Pregnancy in Patients With Thrombophilia*
* 

Data are presented as OR (95% CI).

Table Graphic Jump Location
Table 3. Risk of VTE in Pregnancy or Puerperium in Patients With Thrombophilia*
* 

Data are presented as OR or relative risk (95% CI).

Table Graphic Jump Location
Table 4. Frequency of Fetal Complications Reported With Various Anticoagulation Regimens*
* 

Data are from Chan et al,109 and are presented as No./total (%).

Table Graphic Jump Location
Table 5. Frequency of Maternal Complications Reported With Various Anticoagulation Regimens*
* 

Data are from Chan et al,109 and are presented as No./total (%).

Table Graphic Jump Location
Table 6. Pooled Frequency of Bleeding Complications Reported From all Studies of Pregnant Women With Prosthetic Valves (Irrespective of Antithrombotic Regimen)*
* 

Data are from Chan et al.109

The National Institute for Clinical Excellence, Scottish Executive Health Department and Department of Health, Social Services and Public Safety: Northern Ireland. Confidential Enquiries into Maternal Deaths in the United Kingdom 1997–99. London: TSO, 2001. Available at: http://www.cemach.org.uk/publications/CEMDreports/cemdrpt.pdfhttp://www.cemach.org.uk/publications/CEMDreports/cemdrpt.pdf. Accessed July 2003.
 
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Figures

Tables

Table Graphic Jump Location
Table 1. Question Definition and Eligibility Criteria for the Use of Antithrombotic Agents During Pregnancy*
Table Graphic Jump Location
Table 1A. Continued
* 

RCT = randomized controlled trial.

Table Graphic Jump Location
Table 2. Risk of VTE in Pregnancy in Patients With Thrombophilia*
* 

Data are presented as OR (95% CI).

Table Graphic Jump Location
Table 3. Risk of VTE in Pregnancy or Puerperium in Patients With Thrombophilia*
* 

Data are presented as OR or relative risk (95% CI).

Table Graphic Jump Location
Table 4. Frequency of Fetal Complications Reported With Various Anticoagulation Regimens*
* 

Data are from Chan et al,109 and are presented as No./total (%).

Table Graphic Jump Location
Table 5. Frequency of Maternal Complications Reported With Various Anticoagulation Regimens*
* 

Data are from Chan et al,109 and are presented as No./total (%).

Table Graphic Jump Location
Table 6. Pooled Frequency of Bleeding Complications Reported From all Studies of Pregnant Women With Prosthetic Valves (Irrespective of Antithrombotic Regimen)*
* 

Data are from Chan et al.109

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