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Thromboembolism in Pregnancy

WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).

The risk of symptomatic venous thrombosis during pregnancy is between 0.5 and 3.0 per 1,000 women. Pulmonary embolism (PE) is a leading cause of maternal deaths in the United States. During pregnancy women have a five-fold increased risk of venous thromboembolism (VTE), compared to non-pregnant women. The prevalence and severity of this condition warrants consideration of anticoagulant therapy in pregnancy for women at risk for VTE.

The purpose of this document is to review the current literature on the prevention and management of thromboembolism in obstetric patients. It offers evidence-based recommendations to address the most clinically relevant issues in the management of these patients.

Introduction:

Numerous changes in the coagulation system account for the hyper-coagulable state associated with pregnancy. Half of women, who have thrombotic events during pregnancy, possess an underlying congenital or acquired thrombophilia. The most common thrombophilias in the Caucasian population are the factor V Leiden mutation, which has a prevalence of 5% in this population, and the prothrombin gene mutation G20210A, which has a prevalence of 2% in this population. In approximately 50% of patients with a hereditary thrombophilia, the initial thrombotic event occurs in the presence of an additional risk factor such as pregnancy, oral contraceptive use, orthopedic trauma, immobilization, or surgery (1).

Risk of Thromboembolism during Pregnancy:

It was believed that the risk of venous thrombosis was greatest in the third trimester and immediate postpartum period; however, more recent studies using objective criteria for diagnosis have found that antepartum deep vein thrombosis (DVT) is at least as common as postpartum thrombosis and occurs with equal frequency in all three trimesters. Pulmonary embolism (PE) is more common in postpartum period. Women with a history of thromboembolism have an increased risk of recurrence when they become pregnant; however, recurrence rate based primarily on two retrospective studies are 7.5% to 12% (2).

Pregnancy-associated changes in coagulation are:

  • Increase in clotting factors (I, VII, VIII, IX, X)
  • Decrease in protein S
  • Decrease in fibrinolytic activity
  • Increase venous stasis
  • Vascular injury associated with delivery
  • Increase activation of platelets
  • Resistance to activated protein C

Risk Factors for Deep Vein Thrombosis and Thromboembolic Disorders:

  • Prior history of Deep Vein Thrombosis (DVT)
  • Hereditary Thrombophilia - Factor V Leiden mutation, AT-III deficiency, Protein C deficiency, Protein S deficiency, Hyperhomocystinemia, Prothrombin gene mutation.
  • Mechanical heart valve
  • Atrial fibrillation
  • Trauma/ prolonged immobilization/ major surgery
  • Antiphospholipid syndrome

Evaluation and Laboratory Tests:

The following tests may be ordered to evaluate the risk for thromboembolic events in women with a history of thrombosis, a family history of thrombosis, or a first-degree relative with a specific mutation (3):

  • Lupus anticoagulant (for women with a personal history of VTE)
  • Anticardiolipin antibodies (for women with a personal history of VTE)
  • Factor V Leiden mutation
  • Prothrombin G20210A
  • AT-III antigen activity levels
  • Fasting homocysteine levels or the MTHFR mutation
  • Protein C antigen activity levels
  • Protein S antigen activity levels (free and total)

It is important to note that physiologic changes in normal pregnancy result in marked alterations in protein S and activated protein C resistance, which is associated with the factor V Leiden mutation; therefore, deferral of testing until after pregnancy may be warranted. Also, testing for AT-III, protein C, and protein S in the setting of extensive clotting, warfarin use, or heparin administration may result in falsely low values. DNA testing for the factor V Leiden, prothrombin G20210A mutation, and the MTHFR mutation are reliable in pregnancy.

Diagnosis of Deep Vein Thrombosis (DVT) in Pregnancy:

A high index of suspicion is required for the diagnosis of DVT in pregnancy because some of the symptoms of DVT are similar to the common symptoms of pregnancy. Non-invasive testing for DVT includes compression ultrasound (CUS), which uses firm compression with the ultrasound transducer probe to detect an intraluminal filling defect and impedance plethysmography (IPG), which measures impedance flow with pneumatic cuff inflation around the thigh. In the symptomatic nonpregnant patient, IPG has a sensitivity of 83% and specificity of 92% of detecting proximal DVT.

If clinical suspicion is high and noninvasive test results are negative, limited venography with abdominal shielding that results in fetal exposure less than 0.05 rads should be considered. If iliac or pelvic thrombosis is suspected, full venography can be performed (bilateral venography without shielding results in fetal exposure <1.0 rads). Diagnosis of pelvic vein thrombosis and venography is widespread, MRI may become the imaging modality of choice in these circumstances, but its role still is not well defined in the pregnant patients (4).

Diagnosis of Pulmonary Embolism (PE):

The diagnosis of PE has traditionally been evaluated initially with ventilation-perfusion scanning (V/Q). A V/Q scan results in minimal radiation exposure to the fetus (<0.1 rads). However, any outcome other than high probability or normal requires further testing because of insufficient accuracy to rule out PE in patients for which there is a high clinical suspicion. Unfortunately, about 40-60% of V/Q scans are non-diagnostic in the non-pregnant population, and further evaluation becomes necessary. If non-invasive testing (IPG, CUS) reveals a proximal DVT, then anticoagulation therapy can be initiated. If the results of these tests are negative, but clinical suspicion is high, then pulmonary angiography should be considered (5).

Sensitivity and specificity of spiral computed tomography (CT) in non-pregnant patients for central pulmonary artery embolus are approximately 94%. It also may detect abnormalities other than PE responsible for symptoms (pleural effusions, consolidation, emphysema, pulmonary masses) and may be more specific in patients with underlying cardiopulmonary disease. CT may be useful for diagnosing PE; however, there is still difficulty reliability identifying emboli below the segmental level. Magnetic resonance angiography also may be promising, but current technology limits adequate visualization of sub-segmental defects. Both these techniques are unstudied in pregnancy.

Anticoagulation Medications in Pregnancy:

The following terminology is used to describe the prophylaxis regimens:

  1. Low-dose prophylaxis - a fixed dose of anticoagulant given 1-2 times per day without use of routine monitoring to verify a therapeutic prolongation of the activated partial thromboplastin time (APTT).
  2. Adjusted-dose prophylaxis - anticoagulant administrated for prophylaxis to achieve traditional therapeutic effects, given 2-3 times per day with frequent laboratory testing to verify adequate APTT prolongation of at least 1.5 to 2.5.

Heparin

There is considerable clinical experience with heparin use in pregnancy. The major concerns with heparin use during pregnancy are not fetal but maternal and include heparin-induced osteoporosis and heparin-induced thrombocytopenia (HIT). There are two types of heparin-induced thrombocytopenia: benign, reversible non-immune form and severe type is immune form of HIT. Benign form occurs in patients within the first few days of therapy and typically resolves in 5 days. This condition does not require cessation of heparin therapy. The less common but more severe type is the immune form of HIT, which occurs within 5-14 days of full-dose heparin therapy in as many as 3% of patients and may result in widespread thrombosis (5).

Low-Molecular-Weight Heparin (LMWH) may reduce three of the complications caused by standard heparin: bleeding, osteoporosis, and thrombocytopenia. It does not cross placenta and another advantage of LMWH is that dosing can be limited to once or twice daily. If laboratory monitoring is used, monitoring peak antifactor Xa levels every 4-6 weeks should be utilized particularly when twice daily dosing is given. The activated partial thromboplastin time (APTT) does not correlate well with the anticoagulant effect of LMWH.

Prophylactic Heparin Regimens in Pregnancy:
Source: The British Society for Hematology guidelines on the use and monitoring of heparin 1998

Unfractionated Heparin

  1. Low-dose prophylaxis:
    • 5,000 - 7,500 U every 12 hours during the first trimester; 7,500 - 10,000 U every 12 hours during the second trimester; 10,000 U every 12 hours during the third trimester unless the APTT is elevated. The APTT can be checked near term and the heparin dose reduced if prolonged.
    OR
    • 5,000 - 10,000 U every 12 hours throughout pregnancy
  2. Adjusted-dose prophylaxis:
    • >10,000 U twice a day to three times a day to achieve APTT of 1.5 - 2.5

Low-Molecular-Weight Heparin (LMWH):

  1. Low-dose prophylaxis:
    • Dalteparin, 5,000 U once or twice daily, or enoxaparin, 40 mg once or twice daily
  2. Adjusted-dose prophylaxis:
    • Dalteparin, 5,000 - 10,000 U every 12 hours, or enoxaparin, 30-80 mg every 12 hours

Heparin-induced Thrombocytopenia:

The problem of heparin-induced thrombocytopenia is especially relevant to obstetric practice because there has been a dramatic increase in the use of heparins during pregnancy. In the past, heparins were reserved for pregnant women with or at risk for thromboembolism. However, women are increasingly being treated in hopes of improving obstetric outcome in cases of antiphospholipid syndrome, heritable thrombophilias, unexplained pregnancy loss, prior preeclampsia, and prior fetal growth impairment. Efficacy has not been proven for the majority of these conditions.

Heparin-induced thrombocytopenia is a syndrome requiring both clinical and laboratory criteria to warrant a diagnosis (6). This includes heparin-induced thrombocytopenia antibody formation as well as an unexplained fall in platelet count (by more than 50%), skin lesions at the injection site, and systemic reactions after intravenous injection. The pertinent antibodies recognize two epitopes formed by heparin binding to platelet factor 4. Assays that assess antibodies that activate platelets (e.g., serotonin release assay) are more specific for heparin-induced thrombocytopenia than immunoassays for heparin-platelet factor 4 antibodies. It is imperative that clinicians screen for and diagnose heparin-induced thrombocytopenia. The condition may occur up to 3% of patients exposed to heparin. The risk is higher with fractionated compared with low molecular weight heparins and with surgical compared with medical patients. It is uncommon in pregnancy but still occurs. The condition is potentially morbid because of a (sometimes fatal) thrombotic risk of 30-75%. Heparin-induced thrombocytopenia typically occurs within 14 days of initiating therapy, and evidence-based recommendations are available regarding screening in specific populations, including pregnant women.

Warfarin

Warfarin derivatives cross the placenta and in most cases are relatively contraindicated in pregnancy; therefore, they are primarily used in postpartum or in patients with certain types of mechanical heart valves. Warfarin use should be restricted to the second or early third trimesters in selected patients whom prolonged high-dose heparin therapy is relatively contraindicated. A skeletal embryopathy resulting in stippled epiphyses and nasal and limb hypoplasia can occur when warfarin is given between 6 to 12 weeks of gestation. Midtrimester exposure may result in optic atrophy, microcephaly, and developmental delay. Bleeding can occur in the fetus at any time, resulting in a high fetal loss rate.

Who are the candidates for thrombo-prophylaxis in pregnancy?
Thrombo-prophylaxis is defined as administration of anticoagulants because of an increased risk of venous thromboembolism (VTE) during pregnancy rather than treatment of an acute event. Often this can be accomplished using relatively low dose, which have a minimal effect on laboratory measures of coagulation. There are certain high-risk conditions that require dosage adjustments to achieve higher therapeutic levels of anticoagulation (adjusted-dose heparin prophylaxis). Patients with the following conditions are at highest risk and should have adjusted-dose heparin prophylaxis:

  • Artificial heart valves
  • Antithrombin-III deficiency with or without a history of thrombosis
  • Antiphospholipid syndrome
  • History of rheumatic heart disease with current atrial fibrillation
  • Homozygous factor V Leiden mutation, homozygous prothrombin G20210A mutation
  • Patients receiving chronic anticoagulation for recurrent thromboembolism

How should heparin be administered to women with acute thrombosis or embolism during pregnancy?
Acute thromboembolism associated with pregnancy requires an intravenous heparin bolus of 5,000 U (80 IU/kg) followed by continuous infusion of at least 30,000 IU for 24 hours titrated to achieve full anticoagulation. Intravenous anticoagulation should be maintained for at least 5-7 days. The patient can then be changed to sub-cutaneous adjusted-dose heparin therapy. APTT at least 1.5-2.5 times control throughout the dosing interval, similar to patients who are not pregnant. Therapeutic heparinization with subcutaneous dosing every 8-12 hours should be continued for at least 3 months after the acute event. After 3 months of therapeutic heparinization experts differ as to what should be done for the remainder of the pregnancy. Some recommend using a lower dose of subcutaneous heparin; others suggest continuing therapeutic anticoagulation for the remainder of the pregnancy (6).

Intrapartum and Postpartum Management:

Patients requiring therapeutic adjusted-dose heparin during pregnancy, including those with recent thromboembolism, and patients with mechanical heart valves may be switched to intravenous heparin at the time of labor and delivery to take advantage of its short half-life (1 hours). Patients can then be switched to warfarin postpartum. Heparin and warfarin therapy should be overlapped for the first 5-7 days postpartum until an international normalization ratio (INR) of approximately 2.0-3.0 has been achieved.

Patients receiving prophylactic anticoagulation with heparin should be instructed to withhold their injections at the onset of labor. Patients requiring adjusted-dose, prophylactic anticoagulation for high-risk conditions can resume their heparin injections 4-8 hours after an uncomplicated delivery, and warfarin can be administered the following morning. Postpartum dosing for women on low-dose prophylactic heparin varies widely, although all concur that the postpartum period is one of high risk. There are no definitive studies to guide one's approach in such situations.

Can Regional Anesthesia be administered to patients receiving anticoagulants?
Spinal and epidural anesthesia in patients receiving anticoagulant is controversial. The safety of epidural anesthesia with twice-daily dosing of LMWH is of concern and should be withheld until 24 hours after the last injection. Epidural anesthesia appears to be safe in women taking unfractionated low-dose heparin if the APTT is normal. Sometimes epidural or spinal hematomas can cause neurologic injury, including long-term or permanent paralysis (7).

Prevention of Deep Vein Thrombosis and Pulmonary Embolism:

Venous thromboemblism most commonly occurs in the form of deep vein thrombosis or pulmonary embolism. Alternatives for thromboprophylaxis for moderate-risk patients include the following: graduated compression stocking placed before initiation of surgery or during pregnancy and continued until the patient is fully ambulatory or at least 3 months postpartum; pneumatic compression devices placed before the initiation of surgery and continued until the patient is fully ambulatory; unfractionated heparin (5,000 units) administered subcutaneously 2 hours before surgery and every 12 hours after surgery until discharge. Low molecular weight heparin (dalteparin 2,500 antifactor-Xa units, or enoxaparin 40 mg) administered subcutaneously, 12 hours before surgery and once a day postoperatively until discharge. Alternatives for prophylaxis for highest-risk patients include the following: combination prophylaxis (such as the combination of pneumatic compression and either low-dose unfractionated heparin or low molecular weight heparin); consideration of continuing low molecular weight heparin prophylaxis as an outpatient for up to 28 days postoperatively. If administration of low molecular weight heparin 12 hours before surgery is impractical, initial dosing should commence 6-12 hours postoperatively. Low-risk patients who are undergoing surgery do not require specific prophylaxis other than early ambulation (8).

New Anticoagulants and Pregnancy:

For decades, the mainstays of anticoagulant therapy have been heparins and vitamin K antagonists. Although these drugs are quite effective, they have serious limitations. Vitamin K derivatives require close monitoring of anticoagulant levels and are rarely used during pregnancy owing to concerns of untoward fetal effects. Heparins do not directly harm the fetus but must be parenterally administered and may cause rare but serious side effects. These limitations have prompted a search for alternative anticoagulant drugs that are safe, convenient, efficacious, and inexpensive. The most promising therapeutic agents currently available include direct inhibitors of thrombin and factor Xa. Lepirudin is a recombinant hirudin that acts as a direct thrombin inhibitor. Other anticoagulants have been used successfully during pregnancy in women with heparin-induced thrombocytopenia or heparin allergy. Danaparoid, a combination of heparin, dermatan, and chondroitin sulfates, has been used in such patients, and the drug does not appear to cross the placenta. Although some patients have cross-reactivity of heparin-induced thrombocytopenia antibodies with danaparoid, the drug rarely causes worsening of thrombocytopenia. Danaparoid is not currently available in the United States. Another attractive option for these women is fondaparinux, a synthetic pentasaccharide that stimulates the heparin-binding site to antithrombin III, specifically inhibiting factor Xa. Fondaparinux is considered a class B medication and has been successfully used during pregnancy. The drug has relatively long half-life, which allows for once-daily dosing but poses a challenge during labor and delivery. Although it does not cross the placenta in animal models, small amounts have been detected in cord blood in human pregnancy (9). Several other drugs, including the thrombin inhibitors desirudin, bivalirudin, argatroban, and ximelagatran, anti-Xa agents including idraparinux and several other drugs in phase II testing, may prove to be useful alternatives to heparins. A major problem with new anticoagulants (and medications in general) is that few drugs are ever tested in pregnant women (or U.S. Food and Drug Administration-approved in pregnancy) because of fear of untoward fetal affects and associated liability.

The U.S. Food and Drug Administration has approved hirudin for the treatment of heparin-induced thrombocytopenia and thrombosis syndrome. In recent studies, recombinant hirudin as a potent and specific thrombin inhibitor has been demonstrated to be a safe and effective alternative for this indication (10). One of the main advantages of lepirudin is the absence of cross-reactivity with heparin antibodies. Lepirudin also has half-life (0.8 to 2 hours) and does not require a plasma cofactor to exert its antithrombotic action. Included in the disadvantages of lepirudin use is the need for strict laboratory monitoring and the risk of bleeding. Intravenous lepirudin use at therapeutic doses in late gestation as an alternative to heparin has been accomplished with minimal maternal and fetal morbidity. This alternative anticoagulant is well suited for treatment during the last trimester, when a short half-life and suspension of therapy during labor and delivery are important factors.

Summary

Pregnant patients with a history of isolated venous thrombosis directly related to a transient, highly thrombogenic event in which an underlying thrombophilia has been excluded may be offered heparin prophylaxis or no prophylaxis during the antepartum period. However, they should be counseled that their risk of thromboembolism is likely to be higher than the normal population. Prophylactic warfarin should be offered for 6 weeks postpartum. Pregnant patients with a history of idiopathic thrombosis, thrombosis related to pregnancy or oral contraceptive use, or a history of thrombosis accompanied by an underlying thrombophilia other than homozygous for both the factor V Leiden mutation, heterozygous for both the factor V Leiden and the prothrombin G20210A mutation or AT-III deficiency should be offered antepartum and postpartum low-dose heparin prophylaxis.

References:

  1. Cushman M, Tsai AW, White RH et al. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of Thromboembolism etiology. Am J Med 2004;117:19-25. (Level I)
  2. Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves. Arch Intern Med 2000;160:191-196. (Level III)
  3. ACOG Practice Bulletin. Thromboembolism in Pregnancy. Number 19, August 2000
  4. Rosendaal FR. Venous thrombosis: the role of genes, environment, and behavior. Hematology Am Soc Hematol Educ Program 2005;1-12. (Level III)
  5. Holzheimer RG. Prophylaxis of thrombosis with low-molecular-weight heparin (LMWH). Eu J Med Res 2004;9:150-170. (Level III)
  6. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombotic Therapy. Chest 2005;127:416-421
  7. Food and Drug Administration (US). Subject: Reports of epidural or spinal hematomas with the concurrent use of low molecular weight heparin and spinal/epidural anesthesia or spinal puncture. FDA Public Health Advisory. Rockville (MD): FDA; available as: http://www.fda.gov/medwatch/safety/1997/antico.htm Retrieved September 4, 2008. (Level III)
  8. ACOG Practice Bulletin. Prevention of Deep vein thrombosis and pulmonary embolism. Number 84; August 2007
  9. Silver RM. New anticoagulants and pregnancy. Obstet Gynecol 2008;112:419-420
  10. Chapman ML, Martinez-Borges AR, Mertz HL. Lepirudin for treatment of acute thrombosis during pregnancy. Obstet Gynecol 2008;112:432-433

Published: 6 August 2009

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