CLINICAL OBSTETRICS AND GYNECOLOGY Volume 55, Number 3, 774787 r 2012, Lippincott Williams & Wilkins

Prevention and Treatment of Venous Thromboembolism in Pregnancy

ANDRA H. JAMES, MD, MPH Department of Obstetrics and Gynecology, Division of MaternalFetal Medicine, Duke University Medical Center, Durham, North Carolina

Abstract: During pregnancy, women have a 4- to 5fold increased risk of thromboembolism. Candidates for anticoagulation in pregnancy include women with current thrombosis, a history of thrombosis, risk factors for postpartum thrombosis, and some women with thrombophilia and a history of poor pregnancy outcome. Although, there are no large trials of anticoagulants in pregnancy and recommendations for their use are based on case series and the opinion of experts, observational studies demonstrate the benefit of heparins in reducing the risk of recurrent thromboembolism in pregnancy. A practical approach to the prevention and treatment of thromboembolism in pregnancy is outlined. Key words: thromboembolism, pregnancy, postpartum, anticoagulation, heparin

During pregnancy, women have a 4- to 5fold increased risk of thromboembolism compared with women who are not pregnant.1,2 Eighty percent of thromboembolic
Correspondence: Andra H. James, MD, MPH, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Virginia, P.O. Box 800712, Charlottesville, VA 22908. E-mail: andra.james@virginia.edu Dr James has received research funding from Grifols.
CLINICAL OBSTETRICS AND GYNECOLOGY /

events in pregnancy are venous3 with an absolute risk of venous thromboembolism (VTE) during pregnancy of between 0.5 and 2.0 per 1000 women.39 VTE accounts for 1.1 deaths per 100,000 deliveries,3 or 10% of all maternal deaths in the United States.10 The main reason for the increased risk of thromboembolism in pregnancy is hypercoagulability, which has likely evolved to protect women from the bleeding challenges of miscarriage and childbirth. In Western Europe and the United States, where hemorrhage is successfully treated or prevented, a leading cause of maternal death is thromboembolic disease.10 This article provides information on diagnosis, management, and prevention of thromboembolism, particularly VTE, during pregnancy.

Pregnancy-associated Changes and VTE

Seventy-five to 80% of pregnancy-associated VTE is deep vein thrombosis (DVT)
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Thrombembolism in Pregnancy and 20%-25%3,7,11 is pulmonary embolism (PE). Approximately half of these events occur during pregnancy and half occur postpartum.3,8 When DVT occurs during pregnancy, it is more likely to be proximal,12,13 massive,12 and in the left lower extremity.1315 This left-sided predominance is thought to be due to a relative stenosis of the left common iliac vein where it lies between the lumbar vertebral body and the right common iliac artery, but the true mechanism is unknown. The risk of VTE may be higher in the third compared with the first and second trimesters,2,8 but the increased risk of VTE is clearly present from the first trimester,8,1416 even before many of the anatomic changes of pregnancy take place. Compared with pregnancy, the risk of VTE is even higher postpartum. During the first 6 weeks postpartum, the risk is 20-fold to 80fold higher1,2 and during the first week postpartum, the risk is 100-fold higher.1

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changes in terms of their contribution to VTE are a decrease in the natural anticoagulant protein S and an increase in coagulation factors such as fibrinogen, factor VIII and von Willebrand factor that promote hemostasis.25,26

Risk Factors for VTE During Pregnancy

The strongest personal risk factor for VTE in pregnancy is a history of thrombosis. Fifteen to 25% of thromboembolic events in pregnancy are recurrent events. Besides a history of thrombosis, the next strongest personal risk factor for VTE in pregnancy is thrombophilia.3,15 Thrombophilia is present in 20%-50%2729 of women who experience VTE during pregnancy and the postpartum period. Both acquired and inherited thrombophilia increase the risk of VTE. The risk conferred by type of thrombophilia was systematically reviewed by Robertson et al30 and is summarized in Table 1. In the last decade, several large population-based studies have identified other patient characteristics, medical conditions, and pregnancy complications that increase the risk of pregnancy-associated VTE.3,68,21,31,32 The odds ratios and confidence intervals for these risk factors are summarized in Table 2. In general, the patient characteristics (advanced maternal age, African American race,

Physiological Changes Associated With VTE in Pregnancy

The physiological changes that accompany pregnancy and childbirth that are associated with VTE include increased venous distention17 and decreased venous outflow,18,19 mechanical obstruction by the uterus,20 decreased mobility2124 and vascular injury,20 but the most important

TABLE 1. Absolute Risk of Venous Thromboembolism Conferred by Inherited Thrombophilia30

Thrombophilia Odds Ratios

Factor V Leidenhomozygosity Factor V Leidenheterozygosity Prothrombin gene mutationhomozygosity Prothrombin gene mutationheterozygosity Protein C deficiency Protein S deficiency Antithrombin deficiency

34.40 (9.86, 120.05) 8.32 (5.44, 12.0) 26.36 (1.24, 559.29) 6.80 (2.46, 18.77) 4.76 (2.15, 10.57) 2.19 (1.48, 6.00) 4.76 (2.15, 10.57)

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James
Medical Conditions and Complications of Pregnancy and Delivery Associated With an Increased Risk of Venous Throembolism in Pregnancy
Knight32 (Pulmonary Embolism Only)
1.3 (0.8, 2.1) 1.7 (1.3, 2.3) antenatal 0.8 (0.5, 1.2) antenatal 1.9 (1.2, 3.0) postnatal 1.4 (1.2, 1.6) 1.3 (0.7, 2.3) 5.1 (2.5, 10.5) 7.1 (6.2, 8.3) 6.7 (4.4, 10.1) 8.7 (5.8, 13.0) 4.4 (3.4, 5.7) 5.3 (2.1, 13.5) BMI >30 2.0 (1.4, 2.7) 1.8 (1.4, 2.3) 2.1 (1.2, 4.0) BMI >30

TABLE 2.

Lindqqvist et al6
Patient characteristics Age >35 Nulliparity Para 2 Para Z2 Para Z3 African American race Nonwhite Medical conditions Heart disease Sickle cell disease Systemic lupus erythematosus Obesity 1.3 (1.0, 1.7) 1.8 (1.2, 2.7) 1.5 (1.1, 1.9)

Danilenko- Simpson James Dixon et al21 et al7 et al3

1.5 (1.1, 2.2) 0.9 (0.37, 2.2) 1.4 (1.2, 1.8)

Larsen et al31

Jacobsen et al8

2.4 (1.8, 3.1)

Diabetes Hypertension History of superficial 10.0 (1.3, 78) thrombophlebitis Smoking 1.4 (1.1, 1.9) 2.5 (1.3, 4.7) for Z 10 per day Surgery in pregnancy Complications of pregnancy and delivery Assisted reproduction Multiple gestation 1.8 (1.1, 3.0) 7.0 (0.36, 135) Hyperemesis Gestational diabetes Antepartum hemorrhage Preeclampsia Cesarean delivery

1.7 (1.4, 2.1) 2.7 (1.5, 4.9)

0.9 (0.6, 1.5)

6.0 (0.6, 57.7) 4.4 (2.6, 7.5) antenatal 2.7 (1.6, 4.5) antenatal 4.0 (2.0, 8.9) antenatal 2.3 (1.8, 2.8)

1.6 (1.2, 2.1) 2.5 (2.0, 3.2)

2.9 (2.1, 3.9) 3.6 (3.0, 4.3)

1.0 (0.15, 7.1) 1.2 (0.9, 1.5) 2.6 (1.9, 3.4)

0.9 (0.7, 1.0) 2.1 (1.8, 2.4)

3.8 (2.8, 5.1) postnatal 2.7 (1.8, 4.0) planned 4.0 (3.0, 5.3) emergency

Postpartum infection Postpartum hemorrhage Transfusion BMI indicates body mass index.

9.0 (1.1, 71) 5.0 (0.58, 43)

4.1 (2.9, 5.7) 1.3 (1.1, 1.6) 7.6 (6.2, 9.4)

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Thrombembolism in Pregnancy obesity) and medical conditions (heart disease, lupus, sickle cell disease, diabetes, hypertension, smoking) that are risk factors for VTE or suspected to be risk factors for VTE in the general population are risk factors for VTE in pregnancy and the postpartum period.

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thrombosis while fully anticoagulated are at an increased risk of maternal mortality and should be counseled accordingly. Most other women with a history of thrombosis, however, can be counseled that their risks are manageable, are reduced with anticoagulation and are not a contraindication to pregnancy.

Candidates for Anticoagulation During Pregnancy

Despite the increased risk of VTE during pregnancy and the postpartum period, most women do not require anticoagulation. In most cases, the risks of anticoagulation outweigh the benefits. Women who may benefit from anticoagulation in pregnancy are those whose risk of VTE outweighs the risks of bleeding complications, which have been reported to be as high as 2%.3336 Women who are believed to benefit from anticoagulation in pregnancy include women with current thrombosis, most women with a history of thrombosis, or women who have risk factors for postpartum VTE. In recent studies, the rate of recurrent VTE in women who did not receive anticoagulation has been reported to range from 2.4% to 12.2%.27,37,38 In women who did receive anticoagulation, the rate of recurrent VTE has been reported to range from 0% to 5.5%.34,35,37,39 Some women without a history of thrombosis, but with an acquired or inherited thrombophilia, may also benefit from anticoagulation in pregnancy. Ideally, evaluation of the woman who may require anticoagulation during pregnancy should occur before conception, or at least early in pregnancy. Women with very high risk conditions such as mechanical heart valves, chronic thromboembolic pulmonary hypertension, a history of myocardial infarction, permanent occlusion of a major vessel such as an iliac vein, or a history of recurrent

Anticoagulant Medication to Prevent VTE During Pregnancy

Women who are fully anticoagulated before pregnancy will likely need to continue. They should be counseled about the harmful effects of warfarin on the fetus and offered the opportunity to be converted to lowmolecular-weight heparin before conception, especially as the rate of miscarriage among women taking warfarin is 15%-56%.4046 Women with a history of thrombosis who have not had a complete thrombophilia work-up may undergo testing. A complete thrombophilia work-up includes testing for both antiphospholipid antibodies (anticardiolipin, lupus anticoagulant and anti-b 2 glycoprotein 1) and for inherited thrombophilia (factor V Leiden, the prothrombin gene mutation, protein C, protein S, and antithrombin). Although the results of thrombophilia testing will not generally alter a recommendation for (or against) anticoagulation in pregnancy, the results may alter the intensity from low or prophylactic dosing to full, weight-based, adjusted-dose or therapeutic dosing. Unique aspects of anticoagulation in pregnancy include both maternal and fetal issues. Warfarin, historically the preferred agent for long-term anticoagulation outside of pregnancy, has potentially harmful fetal effects that include a 5%33% reported risk of stillbirth,41,4446 up to a 30% (depending on the series) reported risk of congenital anomalies or warfarin embryopathy,4145,4749 a 2% reported risk www.clinicalobgyn.com

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James from the ACOG Practice Bulletin,67 and the Duke Comprehensive Thrombosis and Hemostasis Center guidelines are included in Table 4. With the exception of the tinzaparin protocol, the full, weight-based, adjusted-dose or therapeutic lowmolecularweight heparin regimens are generally administered every 12 hours, which is supported by the pharmacokinetics of these agents in pregnancy.5660 Although a retrospective study of once daily versus twice daily dosing of lowmolecular-weight heparin for VTE in pregnancy found no recurrent VTE in 125 women, 66% of whom received once daily lowmolecular-weight heparin,70 another study comparing once daily versus twice daily tinzaparin for the treatment of VTE in pregnancy found that a higher than recommended dosage was required in women who took tinzaparin only

of hydrocephalus from fetal or neonatal intracranial hemorrhage,48,50 a 14% reported risk of adverse neurological outcome,51 and a 4% reported risk of low intelligence quotient.51 Consequently, warfarin is rarely prescribed during pregnancy. The exceptional case is the patient at a high risk of mortality from thrombosis who may not be sufficiently anticoagulated with either heparin or lowmolecular-weight heparin, such as the patient with mechanical heart valves. The preferred agents for anticoagulation in pregnancy are heparin compounds. Neither heparin nor lowmolecular-weight heparin crosses the placenta5254 and both are considered safe in pregnancy.36 During pregnancy, both unfractionated heparin and lowmolecular-weight heparins have shorter half-lives and lower peak plasma concentrations, usually necessitating higher doses and more frequent administration to maintain peak and sustained concentrations.5560 There are few comparative studies in pregnancy, but in nonpregnant patients, lowmolecular-weight heparin has been associated with fewer side effects than unfractionated heparin.61Potential advantages of lowmolecular-weight heparin are less bleeding, a more predictable response, a lower risk of heparin-induced thrombocytopenia,35,36 a longer half-life, less bone loss,62 less risk of allergic reaction,63 less bruising,64 and less risk of bacterial contamination due to multidose vials.65 In contrast, a disadvantage of low molecular-weight heparins, besides their greater cost, is their longer half-life, which becomes an issue at the time of delivery. There are no large trials of anticoagulants in pregnancy and recommendations for their use are based on case series and the opinion of experts. Best-evidence recommendations have recently been published by the American College of Obstetricians and Gynecologists (ACOG)66,67 and the American College of Chest Physicians.61 A simplified strategy for identifying candidates for anticoagulation is included in Table 3. Regimens www.clinicalobgyn.com

TABLE 3. Candidates for Anticoagulation

Candidates for full-dose anticoagulation Current thrombosis On life-long anticoagulation Antiphospholipid syndrome with a history of thrombosis Candidates for intermediate or full-dose anticoagulation (high-risk thrombophilia) Antithrombin deficiency with antithrombin level<60% Homozygosity for the factor V Leiden or the prothrombin gene mutation Compound heterozygosity for the factor V Leiden mutation and the prothrombin gene mutation Candidates for low-dose anticoagulation History of thrombosis not requiring life-long anticoagulation History of the antiphospholipid syndrome without thrombosis (with the addition of aspirin 81 mg/d) History of arterial thrombosis (with the addition of aspirin 81 mg/d) Candidates for 3-6 wk low-dose anticoagulation postpartum History of thrombophilia (not high-risk) and no history of thrombosis History of thrombosis in the setting of transient risk factors (not estrogen-related)

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TABLE 4.
Regimens

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Protocols for Thromboprophylaxis in Pregnancy

ACOG Practice Bulletin67 Duke Womens Hemostasis and Thrombosis Clinic Protocol68,69

Unfractionated heparin Mini-dose Low dose Prophylactic dose

5000 U sc q 12 h 5000-10,000 U sc q 12 h 5000-7500 U sc q 12 h first trimester 7500-10,000 U sc q 12 h second trimester 10,000 U sc q 12 h in the third trimester unless aPTT is elevated Intermediate or moderate dose 10,000 U sc q 12 h or more o target Adjusted dose aPTT in the therapeutic range Full dose, or (1.5-2.5, 6 h after injection) Therapeutic dose Lowmolecular-weight heparin Prophylactic dose or Enoxaparin 40 mg sc qd Low dose Dalteparin 5000 U sc qd Tinzaparin 4500 U sc qd Intermediate or moderate dose Weight-adjusted dose or Enoxaparin 1 mg/kg bid Full dose or Dalteparin 100 U/kg q 12 h or Therapeutic dose 200 U/kg 1 24 h Tinzaparin 175 mg U/kg qd

5000 U sc q 12 h<8 wk 7500 U sc q 12 h 8-28 wk 10,000 U sc q 12 h> 28 wk

q 8 h to target mid-interval aPTT in therapeutic range Enoxaparin 40 mg qd or 30 mg bid before 28 wk then Enoxaparin 40 mg bid after 28 wk Enoxaparin 40 mg bid Enoxaparin 1 mg/kg bid with target of antifactor Xa level of 0.6-1.0 with monthly levels

aPTT indicates activated partial thromboplastin time; sc, subcutaneously.

once a day58 and another retrospective study of the once-a-day tinzaparin regimen found 2 unusual thrombotic complications among 37 pregnancies.71 Close observation (assessment of signs and symptoms of thrombosis at routine prenatal visits) may be an option for women with a history of thrombosis in the setting of transient risk factors such as injury or immobility,61,66,67 but in 1 series, women with a history of thrombosis in the setting of transient risk factors had a rate of recurrence in pregnancy (8/94 = 8.5%) that was equal to or higher than the rate of recurrence in women with a history of unprovoked thrombosis (0/15 = 0%).38 Therefore, if these women do not receive anticoagulation during pregnancy, they should at least be considered for thromboprophylaxis during the first 3 weeks postpartum, the period of highest risk of pregnancy-related VTE.1,2,8

At the present time, there are insufficient data on new anticoagulants to justify their use in pregnancy. Although a recent retrospective study of fondaparinux, a synthetic pentasaccharide, found no untoward effects of fondaparinux use during the first trimester on mother or infant,72 anticoagulant activity has been detected in umbilical cord blood of exposed fetuses.73 Nonetheless, as danaparoid, a heparinoid, is unavailable in the United States, fondaparinux may be the anticoagulant of choice in cases of severe cutaneous allergies or heparin-induced thrombocytopenia in pregnancy.74 The 4 new oral agents for long-term anticoagulation, the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban have not been studied in pregnancy. Even in a noncontinuing pregnancy, however, the lack of a reversing agent for these www.clinicalobgyn.com

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James vein thrombosis is not suspected, compression ultrasonography can be repeated in 3 days. When results are negative or equivocal and an iliac vein thrombosis is suspected, magnetic resonance direct thrombus imaging may be used75 (Fig. 1). Ddimers do not distinguish between pregnant women with and without VTE.76 The diagnosis of new onset PE is similar to that in the nonpregnant individual. Both ventilation/perfusion (V/Q) scanning and computed-tomographic pulmonary angiography (CT pulmonary angiography) give relatively low radiation exposure to the fetus.75 There are concerns, however, about maternal radiation exposure with CT pulmonary angiography. Estimates of radiation absorption by maternal

anticoagulants would preclude their use during gestation.

Diagnosing and Managing New VTE

The 2 most common initial symptoms, present in >80% of women with pregnancy-associated DVT, are pain and swelling in an extremity.15 A difference in calf circumference of 2 or more centimeters is particularly suggestive of DVT in a lower extremity.16 When signs or symptoms suggest new onset DVT, the recommended initial diagnostic test is compression ultrasonography of the proximal veins.66 When results are negative and iliac

Suspect Lower Extremity DVT

Compression Ultrasonography of Lower Extremity(ies)

Results?

Negative

Equivical and/or Suspect Iliac Vessel Process

Positive

Still With Concerns?

MRI of Iliac Veins

No

Yes Repeat Compression Ultrasonography in 3 Days

Results?

Positive

Negative

Follow

Treat

FIGURE 1. Algorithm for diagnosis of deep vein thrombosis (courtesy of Leo Brancazio, MD).

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Thrombembolism in Pregnancy breast tissue are 10 mGy compared with 0.28 mGy for a V/Q scan and each 1 mGy of radiation exposure is associated with an increase of breast cancer by an additional 1 in 50,000 women.75 A risk of this small magnitude must be weighed against the potential consequences of withholding CT pulmonary angiography and failing to make a proper diagnosis. A recent study concluded that a chest x-ray (CXR) could be used as a discriminator to reduce the likelihood of nondiagnostic test results and increase the likelihood of diagnostic test results in the evaluation of pregnancy-associated PE. Pregnant women with a negative CXR were more likely to have a diagnostic test result with a V/Q scan and pregnant women with an abnormal CXR were more likely to have a diagnostic test result with CT pulmonary angiography.77 Recently published guidelines by the American Thoracic Society, the Society of Thoracic Radiology, and endorsed by the ACOG, recommend a V/Q scan as the next imaging test in women with suspected

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PE and a normal CXR, and CT pulmonary angiography in women with suspected PE and an abnormal CXR.78 Availability of V/Q scan is limited, however, so that CT pulmonary angiography will often be the diagnostic test of choice. Figure 2 illustrates the American Thoracic Society/Society of Thoracic Radiology diagnostic algorithm for suspected PE in pregnancy. Nonpregnant patients with DVT can usually be managed as outpatients, but pregnant patients, who tend to have large clots, are usually admitted to the hospital. Lowmolecular-weight heparin is used for the initial treatment of DVT. Although lowmolecular-weight heparin is sometimes used for the initial treatment of PE, it has not been as well studied in this situation. When patients with PE appear to be stable, however, they can be switched from intravenous unfractionated heparin to lowmolecular-weight heparin in anticipation of discharge from the hospital.

FIGURE 2. American Thoracic Society/Society of Thoracic Radiology diagnostic algorithm for suspected pulmonary embolism in pregnancy. CXR indicates chest x-ray; V/Q, ventilation/ perfusion. From Leung et al.78 Reprinted with permission of the American Thoracic Society. Copyright r 2012 American Thoracic Society.

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James converted from lowmolecular-weight heparin to unfractionated heparin in the last month of pregnancy or sooner if delivery appears imminent. The purpose of converting women to unfractionated heparin, which is shorter acting, is not primarily to reduce the risk of obstetrical or surgical bleeding at the time of delivery, but rather to reduce the risk of epidural or spinal hematoma with regional anesthesia. The American Society of Regional Anesthesia and Pain Medicine (ASRA) guidelines recommend against needle placement for neuraxial blockade within 10-12 hours after the last low dose, or 24 hours after the last full dose of lowmolecular-weight heparin.82 There is no contraindication to needle placement in patients receiving regimens of 5000 U of unfractionated heparin twice daily, but the safety of needle placement in patients receiving 10,000 U twice daily, or more frequent dosing, is unknown. In such cases, the ASRA recommends assessment on an individual basis.82 Should a woman start labor while taking unfractionated heparin, the heparin will usually clear within 4-6 hours. Clearance can be verified by an aPTT. Heparin, however, does have the potential for causing a persistent anticoagulant effect4 and, therefore, whenever reasonable, should be withheld 12-24 hours before anticipated delivery or regional anesthetic. Reversal of heparin is rarely required, though, and is not indicated for low-dose heparin. Although the use of pneumatic compression devices for the prevention of pregnancy-associated thrombosis has not been studied, extrapolating from perioperative data, placement of pneumatic compression devices is recommended for women whose anticoagulation has temporarily been discontinued.

Monitoring Anticoagulation During Pregnancy

When used in full, weight-based, adjusteddose or therapeutic intensity to treat or prevent VTE, it is not clear whether the dose of lowmolecular weight heparin needs to be adjusted. On the basis of small studies demonstrating the need for increased low molecular-weight heparin to maintain antifactor Xa levels in the 0.6-1.0 U/mL range, some experts advocate the performance of periodic (every 1-3 mo) antifactor Xa levels 4-6 hours after injection, but other studies have shown that few women actually require increased doses when lowmolecularweight heparin is used.61 Patients converted to subcutaneous unfractionated heparin in the last month of pregnancy should have an activated partial thromboplastin time (aPTT) checked once or twice a week and their dose of heparin adjusted to maintain the mid-dose aPTT at the lower end of the therapeutic range. Patients receiving lowintensity anticoagulation should not need any monitoring, but checking an antifactor Xa level or aPTT 1 week after starting therapy or making a dose change can verify that the patient is not overly anticoagulated on the low dose. Guidelines recommend platelet counts every 2 or 3 days during the first 2 weeks of unfractionated heparin therapy, but do not recommend routine platelet counts in obstetric patients who are receiving only lowmolecular-weight heparin.61 There are potential fetal and maternal benefits of anticoagulation. Although there have been studies documenting improved pregnancy outcomes with anticoagulation in women with a history of thrombosis or thrombophilia,79,80 providers should still develop a plan for fetal surveillance for these women.81

Recommendations for Management at the Time of Delivery

Women on either full-dose, moderate-dose, or low-dose anticoagulation may be www.clinicalobgyn.com

Management of Anticoagulation Postpartum

The American College of Chest Physicians guidelines recommend that patients

Thrombembolism in Pregnancy with at least 1 additional risk factor in addition to cesarean delivery have thromboprophylaxis with pneumatic compression devices, graduated elastic stockings or lowmolecular-weight heparin61 and patients with multiple risk factors for DVT or PE receive thromboprophylaxis with either pneumatic compression devices or graduated elastic stockings and lowmolecular-weight heparin.61 Recently published ACOG guidelines recommend pneumatic compression devices for every woman undergoing cesarean delivery and pneumatic compression devices plus pharmacologic thromboprophylaxis for women undergoing cesarean delivery who have multiple risk factors.67 Obviously, any patient receiving thromboprophylaxis during pregnancy should receive thromboprophylaxis postpartum. Additional measures should be considered for certain women at particularly high risk of thrombosis at the time of delivery. Women who have antithrombin deficiency may be candidates for antithrombin concentrates peripartum. Women who have had DVT in the previous 2-4 weeks before delivery may be candidates for placement of a temporary vena caval filter with removal postpartum.83,84 Other women who may be candidates for vena caval filter placement during pregnancy include women with recurrent VTE despite full anticoagulation.84 The optimum time to restart anticoagulation postpartum is not known. A reasonable approach to minimize bleeding complications is resumption of anticoagulation no sooner than 6-12 hours after vaginal delivery or 12-24 hours after cesarean delivery, depending on the risk of thrombosis versus the risk of bleeding complications. Current recommendations by ASRA are resumption of prophylactic lowmolecular-weight heparin no sooner than 2 hours after epidural removal.82 As the optimal interval for resumption of therapeutic anticoagulation after epidural removal is unclear, 12

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hours is reasonable. Pneumatic compression devices should be left in place until the patient is ambulatory and until anticoagulation is restarted. After postpartum bleeding has subsided, which may be 1 or 2 weeks after delivery, women who require >6 weeks of anticoagulation may be bridged to warfarin, which, like lowmolecular-weight heparin,85 is also compatible with breastfeeding.8689 Bridging to warfarin requires women to take 2 anticoagulants simultaneously. Bridging sooner than 2 weeks postpartum may contribute to delayed postpartum hemorrhage. For women who require only 6 weeks of anticoagulation postpartum, the utility of warfarin is limited, as warfarin frequently requires 1-2 weeks of administration before a therapeutic range is attained. Consequently, many patients opt to remain on low molecular-weight heparin for the 6-week period. With respect to the 4 new oral anticoagulants, there are no data about their presence in human breast milk. Women who have experienced VTE during the current pregnancy will likely need to remain on anticoagulation for >6 weeks after delivery. Some experts recommend at least 3-6 months depending on the nature of the original thrombosis and the circumstances surrounding the event. Estrogen containing contraceptives are generally contraindicated for women with thrombophilia or a history of thrombosis who are not anticoagulated, but progestin-only contraceptives have not been found to significantly increase the risk of thrombosis and are, therefore, generally allowed.90

Summary
During pregnancy, women have a 4-fold to 5-fold increased risk of thromboembolism compared with nonpregnant women. Every woman is at risk of VTE in pregnancy. Some women are at greater risk than others. Every patient should be www.clinicalobgyn.com

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James
6. Lindqvist P, Dahlback B, Marsal K. Thrombotic risk during pregnancy: a population study. Obstet Gynecol. 1999;94:595599. 7. Simpson EL, Lawrenson RA, Nightingale AL, et al. Venous thromboembolism in pregnancy and the puerperium: incidence and additional risk factors from a London perinatal database. BJOG. 2001;108:5660. 8. Jacobsen AF, Skjeldestad FE, Sandset PM. Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium a register-based case-control study. Am J Obstet Gynecol. 2008;198:233e1-7. 9. Liu S, Rouleau J, Joseph KS, et al. Epidemiology of pregnancy-associated venous thromboembolism: a population-based study in Canada. J Obstet Gynaecol Can. 2009;31:611620. 10. Berg CJ, Callaghan WM, Syverson C, et al. Pregnancy-related mortality in the United States, 1998 to 2005. Obstet Gynecol. 2010;116:13021309. 11. Blanco-Molina A, Rota LL, Di Micco P, et al. Venous thromboembolism during pregnancy, postpartum or during contraceptive use. Thromb Haemost. 2010;103:306311. 12. Ulander VM, Lehtola A, Kaaja R. Long-term outcome of deep venous thrombosis during pregnancy treated with unfractionated heparin or low molecular weight heparin. Thrombosis Res. 2003; 111:239242. 13. Chan WS, Spencer FA, Ginsbergm JS. Anatomic distribution of deep vein thrombosis in pregnancy. CMAJ. 2010;182:657660. 14. Ray JG, Chan WS. Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the period of risk and the leg of presentation. Obstet Gynecol Surv. 1999;54:265271. 15. James AH, Tapson VF, Goldhaber SZ. Thrombosis during pregnancy and the postpartum period. Am J Obstet Gynecol. 2005;193:216219. 16. Chan WS, Lee A, Spencer FA, et al. Predicting deep venous thrombosis in pregnancy: out in LEFt field? Ann Intern Med. 2009;151:8592. 17. Rabhi Y, Charras-Arthapignet C, Gris JC, et al. Lower limb vein enlargement and spontaneous blood flow echogenicity are normal sonographic findings during pregnancy. J Clin Ultrasound. 2000;28:407413. 18. Gordon M. Maternal physiology in pregnancy. In: Gabbe S, Niebyl J, Simpson J. eds. Normal and Problem Pregnancies. New York: Churchill Livingstone; 2002: 6392. 19. Macklon NS, Greer IA, Bowman AW. An ultrasound study of gestational and postural changes in the deep venous system of the leg in pregnancy. Br J Obstet Gynaecol. 1997;104:191197. 20. Whitty J, Dombrowski M. Respiratory diseases in pregnancy. In: Gabbe S, Niebyl J, Simpson J. eds.

asked about a personal history of thrombosis, ideally before conception, or at least early in pregnancy. Patients should be assessed for other risk factors for thrombosis at the beginning of pregnancy, during pregnancy, and at the time of delivery. Women who would benefit from anticoagulation in pregnancy are those whose risk of morbidity and mortality from VTE is at least greater than the risk of bleeding complications from anticoagulation. Candidates include women with current VTE, a history of VTE, risk factors for postpartum VTE, and some women with thrombophilia and a history of poor pregnancy outcome. There are no large trials of anticoagulants in pregnancy and recommendations for their use are based on case series and the opinion of experts. At the time of delivery, anticoagulation can be manipulated to reduce the risk of bleeding complications while minimizing the risk of thrombosis.

References
1. Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med. 2005;143: 697706. 2. Pomp ER, Lenselink AM, Rosendaal FR, et al. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost. 2008;6:632637. 3. James AH, Jamison MG, Brancazio LR, et al. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol. 2006;194: 13111315. [Epub April 21, 2006]. 4. Andersen BS, Steffensen FH, Sorensen HT, et al. The cumulative incidence of venous thromboembolism during pregnancy and puerperiuman 11 year Danish population-based study of 63,300 pregnancies. Acta Obstet Gynecol Scand. 1998;77: 170173. 5. Gherman RB, Goodwin TM, Leung B, et al. Incidence, clinical characteristics, and timing of objectively diagnosed venous thromboembolism during pregnancy. Obstet Gynecol. 1999;94 (5 pt 1): 730734.

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Thrombembolism in Pregnancy
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