Chapter 7: Thromboembolic Disease Complicating Pregnancy

Thromboembolic disease is a major contributor to both perinatal and maternal morbidity and mortality worldwide, accounting for 14.9% of maternal deaths in 2006, according to the World Health Organization (WHO).¹ In developed countries, thromboembolism has risen above hemorrhage and hypertension as the leading cause of maternal mortality.² Venous thromboembolic diseases (VTE)—such as deep venous thrombosis (DVT), pulmonary embolism (PE), septic pelvic thrombophlebitis (SPT), and ovarian vein thrombosis (OVT)—complicate 0.76 to 1.72 per 1000 pregnancies.³ The cornerstones of VTE management lie in prevention, accurate diagnosis, and prompt treatment. This chapter will review the etiology, diagnosis, treatment, and prevention of VTE.

A detailed discussion of the clotting system, the anticoagulant system, and the fibrinolytic system is beyond the scope of this manual and can be found elsewhere in more comprehensive textbooks. A practical and user-friendly version of the complex regulatory pathways of hemostasis and fibrinolysis is presented in Fig. 7-1.

Pregnancy

As a result of physiologic changes in pregnancy, VTE occurs at a rate that is 4-fold higher compared to the nonpregnant state.⁴ The postpartum period is even more thrombogenic, with VTE twice as likely as a given 6-week period during pregnancy. That VTE does not occur more often is remarkable, given the paradoxical challenges presented to the hemostatic system during pregnancy.

During early placentation, syncytiotrophoblasts penetrate maternal uterine vessels to establish the primordial uteroplacental circulation. Subsequently, endovascular extravillous cytotrophoblasts invade decidual and superficial myometrial spiral arteries, orchestrating a morphologic conversion of these vessels to achieve high-volume, low-resistance blood flow into the intervillous space. Fetal survival requires that these processes occur in the absence of either significant decidual hemorrhage (ie, abruption) or intervillous thrombosis. To ensure maternal survival, decidual hemorrhage must be avoided throughout pregnancy.

The most profound hemostatic challenge is faced by mothers during the third stage of labor. Following separation of the placenta from the uterine wall after delivery of the infant, hemostasis must be rapidly achieved in 140 remodeled spiral arteries to avoid potentially catastrophic hemorrhage. While local factors such as high decidual tissue factor (aka thromboplastin) expression contribute to this placental site hemostasis, dramatic changes in the mother’s expression of clotting and anticlotting factors are also required to meet this hemostatic challenge.

In addition to an innate hypercoagulability, venous stasis and vascular trauma complete Virchow classic triad⁵ (Fig. 7-2). Venous stasis is present as a result of mechanical impedance of the lower extremity vasculature by the gravid uterus, and estrogen-mediated vascular dilation.⁶ Endothelial damage is often present during the puerperium, especially with operative delivery, hypertensive disease, tobacco use, and infections.

Risk Factors

In a review of International Classification of Disease-9 (ICD-9) codes from over 9 million pregnancy admissions and over 73,000 postpartum admissions in the United States National Inpatient Sample (NIS), a list of medical and obstetric risk factors for VTE was identified. See Tables 7-1 and 7-2 for a listing of common risk factors in the development of VTE.

Thrombophilia

Patients with underlying hypercoagulable states are at even higher risk for VTE and other obstetric adverse outcomes. These thrombophilic states can be divided into inheritable mutations and acquired disorders.

Inheritable Thrombophilia

The most common significant inherited thrombophilias include heterozygosity for the factor V Leiden (FVL) mutation heterozygosity, and prothrombin G20210A (PGM) gene mutations. Rarer causes of inherited thrombophilias include antithrombin (AT) deficiency, protein S deficiency, and protein C deficiency. See Table 7-3 for a summary of these thrombophilias, their respective inheritance patterns, and risks of thromboses.

Acquired Thrombophilia

The most common acquired thrombophilia is antiphospholipid antibody syndrome (APAS). Approximately 2% of APAS patients will experience a VTE in pregnancy, accounting for approximately 14% of VTE events in pregnancy. Diagnosis of APAS requires one clinical criterion and one laboratory criterion, as defined at the international consensus conference in 2006.⁸ (See Table 7-4).

APAS is a thrombogenic disorder that arises from autoimmune targeting of proteins binding to exteriorized anionic phospholipids on endothelial cell membranes, such as cardiolipin and phosphatidylserine. In more than half of APAS patients, the responsible antibodies arise as a result of underlying disorders such as systemic lupus erythematosus (SLE). Diseases such as SLE induce endothelial compromise, which expose the anionic phospholipids that bind to specialized proteins, creating neoantigens recognized by the immune system. The antiphospholipid antibodies increase the thrombogenic potential by inhibiting anionic phospholipid-binding endogenous anticoagulants (such as β2-glycoprotein-I, annexin V, antithrombin, thrombomodulin, proteins C and S) and inducing procoagulants (such as tissue factor, plasminogen activator inhibitor-1, von Willebrand factor, and activation of complement).

The type and concentration of antiphospholipid antibody predict its pathogenicity. Low-positive anticardiolipin IgG and IgM are seldom associated with medical complications. Medium or high titers of anticardiolipin and presence of lupus anticoagulant are associated with 4-fold higher rates of thrombosis.

Screening for Thrombophilias in Pregnancy

The utility of screening for thrombophilia in pregnancy remains highly debated. The American College of Obstetricians and Gynecologists currently recommend screening in cases where results will affect management decisions such as duration and dosage of treatment.⁹ Screening may be considered in the following clinical settings:

• A personal history of VTE that was associated with a nonrecurrent risk factor (eg, fractures, surgery, prolonged immobilization)

• A first-degree relative (eg, parent or sibling) with known high-risk thrombophilia or VTE before age 50 years in the absence of other risk factors

Routine screening for inheritable thrombophilias is not recommended in other situations, such as a history of adverse pregnancy outcomes, fetal loss, preeclampsia, fetal growth restriction, and placental abruption. However, screening for acquired thrombophilias, such as antiphospholipid antibodies, may be appropriate in patients with such a history.

Diagnosis

Most cases of VTE in pregnancy occur in the lower extremities, with predisposition (~90%) for the left lower extremity, secondary to the anatomic compression of the left iliac vein by the right iliac, and ovarian arteries.^10,11 The clinical diagnosis of DVT is complicated by nonspecific symptoms that overlap with physiologic changes in pregnancy, such as lower extremity edema. In one report, clinical suspicion for DVT was confirmed in only 10% of pregnant patients, compared to approximately 25% in the nonpregnant population.¹² Accurate prompt diagnosis is essential to decreasing maternal and fetal morbidity, and may require a combination of various modalities.

Clinical Signs and Symptoms

• Acute onset of symptoms

• Unilateral extremity erythema, pain, warmth, edema

• May have reflex arterial spasm, with cool, pale extremity and decreased pulses (“phlegmasia alba dolens”)

• Lower abdominal pain

• Homan sign

• A risk assessment model combining physical findings with risk factors has been developed by Wells and associates for use in nonpregnant populations, allowing a determination of pretest probabilities¹³ (Table 7-5).

Laboratory Studies

• d-dimer: d-dimer is the breakdown product of cross-linked fibrin and elevations may be detected by enzyme-linked immunosorbent assay (ELISA) in acute thrombotic events outside of pregnancy. In normal pregnancy, however, physiologic elevations of d-dimer are found in a gestational-age dependent fashion, with 84% of women in the first trimester with a normal d-dimer, 33% in the second trimester, and 1% in the third trimester.¹⁴ d-dimer levels further peak at the time of delivery and early puerperium. Obstetric complications such as placental abruption, preeclampsia, and sepsis can also elevate d-dimer levels. Therefore, although d-dimer plays an important role in the exclusion of VTE in nonpregnant populations, its use in pregnancy is still highly debated.

Imaging

• Compression Doppler ultrasonography: The primary diagnostic tool for DVT is compression ultrasonography. Compression color Doppler ultrasound is both highly sensitive (92%) and specific (98%) for popliteal and femoral vein thrombosis, but slightly less effective for evaluating calf vein thrombosis with a sensitivity of only 50% to 70% and specificity of 60%.¹⁵ Isolated iliac vein thrombosis can sometimes be diagnosed by placing patients in the left lateral decubitus position and assessing Doppler flow variations with respirations. If these sonographic findings are abnormal, venous thrombosis can be diagnosed and treatment started. Conversely, if the sonographic findings are normal and the patient has no other risk factors (eg, history of VTE, thrombophilia, or clinical progression), the study can be repeated in a week and if negative, no treatment is required. However, contrast venography or venous magnetic resonance imaging (MRI) should be performed if the sonographic findings are normal but there is a high index of suspicion.

• Ascending contrast venography: Contrast venography was previously considered the gold standard for diagnosing DVT in pregnancy, with a negative predictive value of 98%. However, given its invasive nature and high rate of complication, contrast venography has fallen out of favor. Contrast agents are injected into lower extremity veins and the venous system of the leg and pelvis are evaluated radiographically. When used with an abdominal lead shield, it exposes the fetus to very low levels of radiation (0.0005 Gy), well below that associated with childhood cancers and teratogenicity. Chemical phlebitis and thrombosis occur in 3% of cases.

• Impedance plethysmography: Impedance plethysmography is a noninvasive measurement of differentials in electrical resistance in the extremity, a reflection of blood volume changes induced by inflation and deflation of a pneumatic thigh cuff. Although sensitivity is high for obstructions at proximal veins, sensitivity is only 50% in smaller calf vessels.¹⁶ False positives are also high secondary to the mechanical obstruction from the gravid uterus.

• Magnetic resonance imaging (MRI): MRI is useful for detecting thigh and pelvic vein thrombosis. Although the safety of MRI in pregnant women is yet to be proven, no adverse effects have been noted. The use of IV gadolinium in pregnancy remains under debate. At high and repeated doses of intravenous gadolinium, teratogenicity in animals has been observed.¹⁷ Gadolinium-induced nephrogenic systemic fibrosis has been observed in adult populations. This concern carries over the placenta to the fetal circulation, where persistent concentration of gadolinium in the amniotic fluid may be present. Currently, gadolinium is classified as a category C drug by the US Food and Drug Administration and can be used if benefits of diagnosis of PE outweigh the risks.¹⁸

In summary, compression Doppler ultrasound is recommended as the initial test in pregnant women with suspected DVT. If this study proves positive for a DVT, treatment should be initiated. With equivocal test results, venous MRIs (for pelvic thromboses) are performed as detailed in Fig. 7-3.

General DVT Management Principles

• Heparin anticoagulation (see separate section for details)

• Therapeutic anticoagulation should be for 12 to 20 weeks.

• Prophylactic anticoagulation should be initiated after initial treatment, for 6 to 12 weeks and until the patient reaches 6 weeks postpartum.

• For complicated DVTs, including those involving the iliofemoral vessels, prophylaxis is recommended for 4 to 6 months.

• Conversion to oral warfarin may be considered in the postpartum period, if the patient is compliant with drug level monitoring.

• Leg elevation.

• Warm moist heat packs to decrease swelling and provide symptomatic relief.

• Avoidance of sequential compression stocking devices in the presence of a DVT.

Pulmonary embolism (PE) complicates approximately 1 in 2500 pregnancies. A thrombotic obstruction in the pulmonary vascular tree results in obstruction to pulmonary arterial blood flow, vasoconstriction of small arterial vessels, and progressive loss of alveolar surfactant. In pregnancy, thromboemboli most commonly originate in the iliac vessels.

Diagnosis

Clinical Signs and Symptoms

• Acute onset of symptoms

• Dyspnea, tachypnea, pleuritic chest pain, hemoptysis

• Tachycardia

• Cyanosis

• Syncope

• Pleural friction rub

• Fixed S2

Laboratory Studies

• d-dimer (see DVT).

• Arterial blood gases (ABG): In nonpregnant patients with PE, ABG may reveal hypoxemia, hypocapnia, and respiratory alkalosis. Although patients with PE may display hypoxia, 17% of patients will have a normal Pao₂. A decreased Pao₂ is also not overly specific, since the supine position may lower Pao₂ by as much as 15 mm Hg in the third trimester. In addition, respiratory alkalosis is a very common feature that is present in both normal pregnancy and PE.

Imaging

• Compression Doppler ultrasonography: Normal venous ultrasound does not necessarily rule out pulmonary emboli. Fewer than 30% of unselected patients with PE have sonographic or radiographic signs of a DVT at the time of presentation. Conversely, since the treatment of DVT and PE both involve anticoagulation, therapy can be initiated for positive Doppler ultrasound of the extremity alone.

• Electrocardiogram: An ECG may reveal right bundle branch block, right axis shift, Q wave in leads III and aVF, S wave in leads I and aVL >1.5 mm, T-wave inversions in leads III and aVF, or new onset of atrial fibrillation. However, these cardiac findings are insensitive predictors since they require large pulmonary artery occlusions.

• Echocardiogram: Echocardiographic findings include right ventricular dilation and hypokinesis, tricuspid regurgitation, and pulmonary artery dilation. Only 30% to 40% of patients with PE have echocardiogram findings on transthoracic echocardiogram (TTE).¹⁹ Transesophageal echocardiogram (TEE) allows for direct imaging of the main pulmonary artery, significant portion of the right pulmonary artery, and proximal portion of the left pulmonary artery, allowing for an improved sensitivity of 58% to 97% and specificity of 88% to 100%.²⁰

• Chest x-ray (CXR): Findings of PE on CXR include pulmonary parenchymal abnormality, atelectasis, pleural effusion, cardiomegaly, ipsilateral hemidiaphragm, pulmonary artery enlargement, and wedge-shaped perfusion defects. However, these findings are neither sensitive nor specific, and are seen in both healthy patients and those with PE. A quarter of patients with PE exhibit normal CXR.²¹ CXR exposes the fetus to less than 0.001 rad of radiation, well below the 5-rad cutoff for adverse effects of spontaneous abortion, teratogenicitiy, and perinatal morbidity.

• Ventilation/perfusion scan (V/Q scan): The initial evaluation of a suspected PE should be a V/Q scan. However, the scan must be interpreted in the context of clinical probability. Only negative and low probability scans in the setting of a low clinical risk, and high probability scans in the setting of high clinical risks are considered diagnostic. Nondiagnostic scans (ie, intermediate probability) or low probability scans in high-risk patients (eg, thrombophilia, suggestive ECG, or echocardiogram) should be followed up with a color Doppler compression ultrasound study of the lower extremities. Fetal radiation exposure from a V/Q scan is less than 0.012 rad from the ⁹⁹technetium perfusion scan and 0.019 rad from the ¹³³Xenon ventilation scan. Although the amount of total exposure is less than 0.031 rad, radiation exposure can be further limited by triaging with the perfusion study first. Since a normal perfusion study requires no further testing, radiation exposure may be reduced by more than half.

• Pulmonary angiography (PA): PA once was considered the gold standard for diagnosis of PE outside of pregnancy, and is often obtained in high-risk patients with negative compression ultrasound. A negative PA excludes clinically relevant PE. However, radiation exposure is greater than that from spiral computed tomographic pulmonary angiography (CT-PA), and its sensitivity may actually be lower for subsegmental emboli.²² Fetal radiation exposure from PA is 0.05 rad from the brachial route, and 0.22 to 0.33 rad from the femoral route.

• Spiral computed tomographic pulmonary angiography (CT-PA): The reported sensitivities of CT-PA compared with PA vary widely (64%-93%). While CT-PA is relatively sensitive and specific for diagnosing central pulmonary artery thrombi, it is insensitive for diagnosing subsegmental clots. Therefore, CT-PA appears to have a role as a rule-in test for large central emboli, but cannot exclude smaller peripheral lesions. Like compression ultrasonography, an equivocal V/Q scan in a high-risk patient with a positive CT-PA should require therapy, but a negative CT-PA in a high-risk setting should prompt pulmonary angiography or MRI angiography. Advantages of CT-PA over V/Q scanning include relative decrease in fetal radiation, easier technique, and straightforward interpretation. CT-PA, with appropriate abdominal shielding and employing minimal fluoroscopy, exposes the fetus to 0.013 rad for the entire examination, compared to the 0.031 rad for V/Q scan. Conversely, however, CT-PA exposes maternal breast tissue to increased levels of irradiation, compared to a V/Q scan.

In summary, V/Q scan after a normal CXR should be considered the first-line test, with or without compression Doppler ultrasonography of the lower extremities. Confirmation in the nondiagnostic population should be performed with spiral CT-PA. Figures 7-4 and 7-5 summarize 2 recommended algorithms for diagnosis of PE.²³ Table 7-6 summarizes the radiation exposure of each recommended imaging modality.

Prediction of DVT

• Recently, the “LEFt” clinical prediction rule was derived and internally validated among 194 pregnant women investigated for a suspected DVT. This rule combines 3 variables: symptoms in the left leg (L), calf circumference difference of 2 cm or over (E for edema), and a first trimester presentation (Ft). They found no DVT among the 46% women with none of the LEFt criteria but in 16.2% women with at least one LEFt criterion.²⁴ A subsequent study of 157 pregnant women showed that a negative LEFt rule accurately identifies pregnant women in whom the proportion of confirmed DVT appears to be very low. However, the authors recommend that the rule should not be used as stand-alone test for excluding DVT during pregnancy, but rather might be implemented in a diagnostic strategy in association with d-dimer measurement and compression ultrasonography.²⁵

General PE Management Principles

• Heparin anticoagulation (see separate section for details)

• Therapeutic anticoagulation should be initial treatment for 12 to 20 weeks.

• For patients with PE, prophylactic anticoagulation is recommended for 4 to 6 months.

• Maintain maternal Pao₂ above 70 mm Hg or O₂ saturation of greater than 94%.

There are 2 types of pelvic thromboses: septic pelvic thrombophlebitis (SPT) and ovarian vein thrombosis (OVT). The 2 entities may share the same pathogenesis, clinical manifestations, and often the same patient. Incidence of pelvic thromboses is approximately 1 in 3000 deliveries (1 in 9000 vaginal deliveries and 1 in 800 cesarean deliveries). Risk factors include cesarean delivery, pelvic surgery, infection, and underlying malignancy.^{26,27, 28}

Septic Pelvic Thrombophlebitis

SPT is an uncommon complication of pelvic infection. It is more common after cesarean than vaginal delivery but has also been reported after gynecologic procedures. Thrombus formation in the pelvic veins appears to result from inflammatory cytokine induction of tissue factor expression in the endothelium of pelvic vessels.

Clinical Signs and Symptoms

• Nonspecific symptoms

• Spiking fevers, despite adequate antibiotic coverage

• May have multiple infected emboli

• Usually present within a few days after delivery or surgery

• Often present without abdominal tenderness

Laboratory Testing

• Complete blood count: Leukocytosis of more than 12,000/μL occurs in 70% to 100% of patients with SPT.²⁹

• Blood culture: Blood cultures should be obtained in the evaluation of postpartum fever, particularly with persistent spiking fevers. Negative blood culture would point to the diagnosis of SPT, while positive blood cultures may enable targeted alterations in antibiotic regimen.

Imaging

MRI or CT may aid in the diagnosis of SPT. CT imaging may reveal enlargement of affected vein, with mural enhancement, and low-density vessel lumen. MRI reveals hyperintensity in thrombosed vessels compared to those with normal flow. However, as a surgical specimen revealing thrombosis in the pelvic vasculature is the only gold standard in confirmation of SPT diagnoses, the utility of imaging modalities remains unproven.

General Management Principles

Traditional management was a course of therapeutic anticoagulation. Clinical response was considered both therapeutic and diagnostic with defervescence expected in 48 to 72 hours and the recommended duration of treatment ranging from 7 to 10 days to a full 6 weeks of anticoagulation. However, a recent study has called into question the role of anticoagulation in SPT. In a small study of 14 patients with CT documented SPT, 8 received continued antibiotic therapy alone (ampicillin, gentamicin, and clindamycin) and 6 received a combination of heparin and antibiotic therapy. No difference was noted in the duration of fever between the 2 groups.³⁰

Ovarian Vein Thrombosis

OVT typically presents with acute pain 2 to 3 days postpartum (with or without fever). It occasionally can be mistaken for appendicitis in a postpartum patient. Moreover, OVT can occur in the absence of infection and has been described in antepartum patients. The incidence of OVT is 1 in 4000 deliveries. Thrombosis can be diagnosed with CT or MRI and is most commonly noted in the right ovarian vein. Treatment for OVT is the same as outlined for SPT.

Pregnancy-related cerebrovascular accidents are rare, but confer significant maternal morbidity and mortality, including an 8% to 15% risk of death. An epidemiologic study from the United States, a diagnosis of stroke was made in 34.2 per 100,000 deliveries. Two percent of these events were attributable to cerebral venous thromboses (CVT).³¹ Seventy-five percent of cases are postpartum, although patients with underlying thrombophilia may present earlier in pregnancy.³² Risk factors for CVT in pregnancy include cesarean delivery, dehydration, traumatic delivery, anemia, elevated homocystenemia, thrombophilias, poor nutrition, lower socioeconomic status, and low cerebrospinal fluid (CSF) pressure due to dural puncture from a neuraxial anesthetic.³² Superior sagittal sinus is most commonly involved.³³

Clinical Signs and Symptoms

• Headache: The most common symptom of CVT is a progressive, severe, diffuse, unrelenting headache, although 10% may present with acute “thunderclap" headaches.³³

• Dizziness, nausea, lethargy.

• Seizures may occur in 40% of patients.

• Papilledema.

• Focal neurologic symptoms: These symptoms may vary depending on the location of the affected vein, presence of collateral circulation, and effects on intracranial pressure.

  • Superior sagittal sinus thrombosis may lead to headache, increased intracranial pressure, papilledema, motor deficits, scalp edema, and dilated scalp veins.

  • For lateral sinus thromboses, symptoms related to an underlying condition (middle ear infection) may be noted, including constitutional symptoms, fever, and ear discharge. In addition, Hemianopia, contralateral weakness, and aphasia may sometimes be seen owing to cortical involvement.

  • Thromboses of the deep cerebral venous system (internal cerebral vein, vein of Galen, and straight sinus) may lead to thalamic or basal ganglial infarction with rapid neurologic deterioration. These lesions may result in bilateral brain involvement.

• Coma.

Laboratory Testing

• American Heart Association (AHA) and American Stroke Association (ASA) recommend routine blood studies consisting of a complete blood count, chemistry panel, prothrombin time, and activated partial thromboplastin time for patients with suspected CVT.³³

• Lumbar puncture (LP): LP is not routinely indicated unless there is a clinical suspicion of meningitis. If an LP is performed, an elevated opening pressure is a frequent finding in 80% of patients with CVT.

• d-dimer: As is the case with its use in DVT and PE, the specificity of d-dimer is poor. A normal d-dimer level may be considered to help identify patients with low probability of CVT.

Imaging

Magnetic resonance imaging is the gold standard imaging modality in diagnosis of CVT. Noncontrast CT scans are often negative, but 30% of cases might show a clot or signs of infarction. Head CT may be useful in ruling out other etiologies for neurologic symptoms.³²

General Management Principles

The AHA/ASA proposed algorithm for management of CVT is shown in Fig. 7-6.

Prompt treatment with anticoagulation should be initiated upon diagnosis of DVT or PE. In some cases, particularly in setting of high suspicion of acute PE, without contraindication to anticoagulation, empiric treatment may be initiated prior to completion of diagnostic evaluation. Five categories of treatment are available to the nonpregnant population: heparins, warfarin, surgery, IVC filter, and thrombolytic therapy. However, secondary to teratogenicity and increased risks of bleeding, a unique understanding of the risks of benefits of each therapy in pregnancy is necessary in the management of obstetric VTE.

Heparins

The current armamentarium of heparin and its derivatives includes unfractionated heparin (UFH), biologic low-molecular-weight heparin (LMWH), and synthetic pentasaccharide inhibitors of factor Xa. All forms of heparin are administered via an injectable route, either subcutaneous or intravenous.

General Concepts

• Actions of heparin

  • Enhances antithrombin (AT) activity

  • Increases factor Xa inhibitor activity

  • Inhibits platelet aggregation

• Benefits of heparin

  • Levels may be monitored and adjusted during pregnancy

  • No teratogenicity

  • Does not cross placenta or enter breast milk

  • Rapidly reversible

• Disadvantages of heparin

  • Requires injection.

  • Not as effective in prophylaxis of patients with mechanical heart valves.

  • Required therapeutic doses display interpatient variability due to variable levels of heparin-binding proteins such as vitronectin, fibronectin, von Willebrand factor, platelet factor 4, and histidine-rich glycoprotein during pregnancy.

• Goals for drug monitoring levels

  • Antifactor Xa activity

    • Therapeutic levels: 0.6 to 1.2 U/mL

    • Prophylactic levels: 0.1 to 0.2 U/mL

    • Activated partial thromboplastin time (aPTT): Therapeutic levels between 1.5 and 2.5 times control values

    • Heparin levels (protamine assay) between 0.2 and 0.4 U/mL for therapy

Unfractionated Heparins

• Route of administration: Subcutaneous or intravenous

• Dosing

  • Intravenous UFH for therapeutic treatment: Initial treatment is with intravenous bolus of UFH at 80 U/kg, followed by continuous infusion of 18 U/kg/h. Titration is performed every 6 hours until therapeutic aPTT, heparin, or antifactor Xa level is achieved. A common weight-based algorithm is listed in Table 7-7.³⁴

  • Subcutaneous UFH for therapeutic treatment: Conversion from intravenous to subcutaneous UFH may be undertaken when any of these 3 criteria are met: (1) clinical improvement is noted; (2) completion of 5 days of IV treatment after uncomplicated VTE; or (3) completion of 7 to 10 days of IV treatment after large thrombosis or massive PE. Dosing for subcutaneous UFH is 10,000 to 15,000 units every 8 to 12 hours. Steady state is achieved in subcutaneous UFH after 4 doses (or 48 hours) in 99% of patients.³⁵

  • Subcutaneous UFH for prophylactic treatment: Prophylactic treatment with UFH should be dosed at 5000 units subcutaneously twice daily. Given decreases in plasma levels with advanced gestation, empiric increases may be employed, with 7500 units twice daily in the second trimester or 10,000 units twice daily in the third trimester.

• Monitoring

  • aPTT: Therapeutic levels of aPTT is laboratory-specific, and should be confirmed with your laboratory. The general goal is aPTT of 1.5 to 2 times control (or heparin level of at least 0.2 U/mL) 6 hours after injection. It is important to realize that aPTT is not reliable in patients with lupus anticoagulant.

  • Antifactor Xa: This test is used as an alternative in lupus anticoagulant patients. Goal for therapeutic treatment is 0.6 to 1.2 U/mL, while prophylactic is 0.1 to 0.2 U/mL.

• Timing of anticoagulation, relative to delivery

  • For prophylactic doses, optimal timing of delivery is 4 hours after dosing.

  • For therapeutic doses, aPTT should be checked preoperatively.

  • Anticoagulation can be restarted safely 6 hours after vaginal delivery and 8 to 12 hours after cesarean delivery.

• Reversing UFH activity

  • Protamine sulfate reverses the action of heparin by binding to the heparin molecules. Dosage is protamine 1 mg intravenously for every 100 units of residual heparin. Administration should be slower than 20 mg/min, with no more than 50 mg over 10 minutes.

Low-Molecular-Weight Heparins

• Route of administration: Subcutaneous only

• Dosing

  • Enoxaparin (Lovenox)

    • Therapeutic: 1 mg/kg subcutaneously every 12 hours

    • Prophylactic: 40 mg subcutaneously daily, or 30 mg subcutaneously every 12 hours

  • Dalteparin sodium (Fragmin)

    • Therapeutic: 100 U/kg subcutaneously every 12 hours or 200 U/kg subcutaneously every 24 hours

    • Prophylactic: 5000 units subcutaneously daily

  • Tinzaparin (Innohep): 175 IU/kg subcutaneously daily

• Monitoring

  • Antifactor Xa levels should be titrated to 0.6 to 1.2 U/mL for therapy. Optimal timing for checking levels is 4 hours after the fourth administration of an adjusted dose. Adjustments should be an increase or decrease of 10% to 25% of previous dose.

  • Conversion from LMWH to UFH at approximately 36 weeks of gestation is recommended to avoid increased risk of bleeding and complications from regional anesthesia.

• Timing of medication, relative to delivery

  • For prophylactic doses, optimal timing of delivery is

    12 hours after dosing.

  • For therapeutic doses, optimal timing of delivery is

    18 to 24 hours after dosing.

  • Anticoagulation can be restarted safely 6 hours after vaginal delivery and 8 to 12 hours after cesarean delivery.

• Reversing LMWH activity

  • Unlike UFH, protamine sulfate does not completely reverses the activity of LMWH. However, its use may be recommended to decrease amount of bleeding. Dosage is calculated at 1 mg per 100 anti-Xa units of LMWH.

Synthetic Low-Molecular-Weight Heparins

Synthetic heparin pentasaccharides, such as fondaparinux or idraparinux, bind to AT with high affinity. Its use in pregnancy has been uncommon because safety profiling has, thus far, been inadequate. Indications for synthetic LMWH heparin use include patients with heparin-induced thrombocytopenia (HIT), secondary to the lack of interaction with platelet factor 4 in these synthetic forms. Initial in vitro studies reveal absence of placental transfer at recommended doses; however, small amounts of fondaparinux have been detected in umbilical cord blood following multiple doses in pregnancy.³⁶ Fondaparinux is labeled as class B in pregnancy.

• Route of administration: Subcutaneous only

• Dosing

  • Fondaparinux

  • Therapeutic: 5 to 10 mg subcutaneously per day, based on body weight, with an average of approximately 0.1 mg/kg

  • <50 kg: 5 mg/d

  • 50 to 100 kg: 7.5 mg/d

  • >100 kg: 10 mg/d

  • Prophylactic: 2.5 mg subcutaneously per day

  • Idraparinux (weekly fondaparinux)

  • Not recommended in pregnancy, secondary to its long-acting nature

• Monitoring: Monitoring can be performed with antifactor Xa levels, as noted above.

• Reversing: No antidote is known.

Heparins and Neuraxial Analgesia

The following recommendations are from the American Society of Regional Anesthesia and Pain Medicine 2010 consensus guidelines on neuraxial anesthesia and anticoagulation.³⁷

• UFH and neuraxial analgesia

  • IV UFH should be discontinued with the onset of labor.

  • Subcutaneous UFH should be stopped 24 hours prior to planned induction of labor or cesarean delivery, or with the onset of spontaneous labor.

  • Timing of neuraxial analgesia placement

    • Neuraxial anesthesia can be administered when the aPTT returns to normal.

    • If anticoagulation with IV heparin is needed in patients with recent epidural catheterization, heparin should not be given for at least 1 hour after the epidural catheter has been inserted or removed.

  • Timing of neuraxial analgesia removal

    • Remove the epidural catheter 2 to 4 hours after the last heparin dose, after confirmation of the patient’s normal coagulation status.

• LMWH and neuraxial analgesia

  • Timing of neuraxial analgesia placement

    • Prophylactic (low-dose) LMWH: Neuraxial block should not be performed until at least 12 hours after the last dose of prophylactic (low-dose) LMWH, secondary to concerns regarding spinal hematoma formation.

    • Therapeutic (high-dose) LMWH: Neuraxial block should not be performed until at least 24 hours after the last dose of therapeutic (high-dose) LMWH.

  • Timing of neuraxial analgesia removal

    • Once-daily LMWH regimen: An epidural catheter may be maintained, but the catheter should not be removed for at least 10 to 12 hours after the last LMWH dose.

    • Twice-daily LMWH regimen: For patients receiving a twice-daily LMWH regimen, an epidural catheter should be removed prior to initiation of LMWH thromboprophylaxis. If an epidural is to be maintained with the twice-daily regimen, the catheter may be left indwelling overnight and removed the following day, with the first dose of LMWH administered 2 hours after catheter withdrawal.

  • Timing of anticoagulation after delivery and neuraxial analgesia

    • Once-daily LMWH regimen: Administer the first dose at least 6 to 8 hours postoperatively.

    • Twice-daily LMWH regimen: Administer the first dose no earlier than 24 hours postoperatively, and only in the presence of adequate surgical hemostasis.

    • Following removal of an indwelling epidural catheter postoperatively, in setting of either single or twice-daily LMWH, initiate LMWH after at least 2 hours have elapsed.

Complications/Side Effects

• Hemorrhage: Risks increase with concomitant aspirin use, recent surgery, thrombocytopenia, and liver disease.

• Heparin-induced thrombocytopenia: HIT occurs in 3% of patients, and has 2 forms. The early-onset, transient form occurs secondary to heparin-induced platelet aggregation. A delayed-onset, immune-mediated form occurs approximately 2 weeks after initiation of therapy, secondary to formation of IgG. Diagnosis can be confirmed with a heparin-platelet factor 4 antibody test (ELISA) for HIT.

• Cessation is mandatory for the immune-mediated form, but is less frequently seen with LMWH compared to unfractionated forms. We recommend checking a platelet count 1 week after initiation of therapy, or sooner if there is a higher index of suspicion for HIT.

• Osteoporosis: This rare side effect is more common when doses of UFH are greater than 15,000 U/d for more than 6 months. We recommend supplementation with 1500 mg of calcium each day. Bone densitometry can be considered postpartum for patients on long-term anticoagulation, with subsequent referral to medical or reproductive endocrinology specialist.

Direct Thrombin Inhibitor

Direct thrombin inhibitors may offer advantages over heparin because they do not bind plasma proteins, do not rely on levels of AT, resist neutralization by platelet factor 4, and inhibit both fibrin-bound and circulating thrombin.³⁸ This class of hirudin-like medications can be used in patients who experience HIT or local adverse reaction from UFH or LMWH. The following are the types of commercially available direct thrombin inhibitors in the United States:

• Lepirudin is a bivalent recombinant form of hirudin that is approved for treatment of acute thrombosis with HIT. This medication is pregnancy category B, however, literature is limited to case reports of successful use in pregnancy.³⁹

• Bivalirudin is bivalent synthetic polypeptide analog of hirudin, and is also pregnancy category B.

• Argatroban is a univalent synthetic direct thrombin inhibitor with a very short half-life, and is also pregnancy category B.

Direct Factor Xa Inhibitor

Direct factor Xa inhibitors are a new class of anticoagulants and include the oral rivaroxaban (Xarelto), and investigational apixaban and otamixaban. This class of anticoagulants is FDA-approved for prevention of VTE in patients who have undergone orthopedic surgery. No trials or case reports have been reported to date in pregnancy.

Warfarin

• Actions of warfarin

  • Inhibition of the action of vitamin K, which is a cofactor in the synthesis of the final molecular forms of factors VII, IX, X, and prothrombin.

  • Readily crosses placenta.

  • Does not concentrate in breast milk.

• Disadvantages of warfarin

  • Exposure between 7 to 12 weeks of gestation is linked to a 33% risk of embryopathy. Stigmata includes nasal hypoplasia, stippled epiphysis, and central nervous system abnormalities including agenesis of the corpus callosum, Dandy-Walker malformation, midline cerebellar atrophy, and ventral midline dysplasia with optic atrophy.

  • Risk of placental and fetal hemorrhage throughout pregnancy.

  • Risk of warfarin-induced paradoxical thromboembolism, secondary to rapid inhibitory effect of warfarin on the anticoagulant protein C, compared to the other clotting factors.

• Indications in obstetrics

  • Mechanical heart valve: Use of UFH or LMWH in patients with older-generation prosthetic heart valves has shown an increase in thrombogenic complications, including fatal valve thrombosis. The risk of fatal maternal valve thrombosis may outweigh the risks of warfarin to the fetus between 12 and 36 weeks of gestation.

  • Postpartum period.

• Route of administration: Oral only

• Dosing

  • Initial dosing: 5 to 10 mg for 2 days, with subsequent titration.

  • UFH or LMWH should always be maintained during the initial 4 days of warfarin therapy and until a therapeutic international normalized ratio (INR) is achieved.

• Monitoring

  • INR: This test is the ratio of the patient’s prothrombin time (PT) over the mean population PT adjusted for the effects of the local laboratory’s thromboplastin. Warfarin dose should be adjusted to the patient’s INR, with goal for 2 to 3. Warfarin has a peak effect at 36 to 72 hours after initiation of therapy, with a half-life of 36 to 42 hours.

• Reversal of warfarin action

  • Vitamin K or fresh frozen plasma can be used to reverse the effects of warfarin, with normalization of the PT within 6 hours of an oral or subcutaneous 5-mg dose of vitamin K.

Inferior Vena Cava Filter

Percutaneous placement of an inferior vena cava (IVC) filter provides a mechanical obstacle to the deportment of clots present in the distal IVC, thereby preventing passage of emboli that have showered from lower extremity VTE. Multiple filter compositions and shapes are available today. Retrievable IVC filters may prove ideal for pregnant patients requiring this therapy.

• Indications for use

  • Contraindications to anticoagulation

    • Recent surgery

    • Hemorrhagic stroke

    • Active bleeding

  • Adverse reactions to or ineffectiveness of prior anticoagulation

    • Recurrent PE despite adequate anticoagulation

    • Prior serious hemorrhagic complication

    • Allergic reactions

    • Massive PE with significant compromise of pulmonary vascular tree, with high risk of fatality if recurrent PE occurs

Surgery and Thrombolytic Therapy

Surgical embolectomy should be reserved for life-threatening settings. Massive PE with hemodynamic instability should be the only indication for thrombolytic therapy (ie, tissue-type plasminogen activator [tPA], urokinase, and streptokinase) in pregnancy, given the high risk that these agents will induce abruption. However, no controlled studies exist examining the efficacy and safety of thrombolytic therapy in pregnancy. In a review of 172 pregnant patients treated with thrombolytic therapy, the maternal mortality rate was 1.2%, the fetal loss rate was 6%, and maternal complications from hemorrhage occurred in 8%.⁴⁰

Recurrence Risk

Among pregnant patients who have had a previous VTE during pregnancy, recurrence risks of 2.4% to 10% have been reported.⁴¹ In a review of hospital discharge data from 1085 women with pregnancy-associated VTE and 7625 women with unprovoked VTE, recurrence risk was 5.8% and 10.4%, respectively.⁴²

Indications for Prophylaxis

Figure 7-7 outlines a proposed summary algorithm for thrombophilia work-up and anticoagulation therapy.

• In the following patients populations, if not already receiving therapeutic anticoagulation, antepartum DVT prophylaxis should be considered:

  • Thrombophilias

  • High-risk (FVL homozygosity, PGM homozygosity, AT deficiency, compound heterozygous FVL/PGM) thrombophilia

  • Low-risk thrombophilia (FVL heterozygosity, PGM heterozygosity, protein C deficiency, protein S deficiency) with personal or family (first-degree relative with VTE at <50 years of age) history of VTE

  • Antiphospholipid antibody syndrome (would require prophylactic aspirin treatment, along with therapeutic anticoagulation if a history of VTE is present)

• Prior VTE that occurred in the setting of the following

  • Recurring condition, or

  • During pregnancy, or

  • During oral contraceptive pill use

• Postpartum DVT prophylaxis should be considered in the following

  • All patients receiving antepartum prophylactic anticoagulation, unless the indication is only for prevention of recurrent fetal loss in the setting of a low-risk thrombophilia

  • Low-risk thrombophilia without history of prior VTE, if patient requires a cesarean delivery or has other risk factors for VTE (eg, obesity, prolonged immobilization)

  • Prior VTE with nonrecurring condition

  • Obesity (BMI ≥30 kg/m²)

Mechanical Preventative Measures

• Left-lateral decubitus positioning during the third trimester displaces the gravid uterus and allows for improved venous return from lower extremities.

• Pneumatic compression stockings: Pneumatic compression stockings improve blood flow, decrease stasis, increase blood flow in the femoral vessels by 240%, and increase fibrinolysis. In a meta-analysis of moderate-risk surgery, they were shown to decrease the incidence of DVT by 60%. Since pneumatic compression stockings have no hemorrhagic risk, and have been shown to be an effective means of DVT prophylaxis in gynecologic oncology surgery, they should be an ideal device for prophylaxis in high-risk pregnant patients (eg, thrombophilic patients at prolonged bed rest or who are undergoing a cesarean delivery).

• Graduated elastic compression stockings: Graduated elastic compression stockings have been shown to increase femoral vein flow velocity in late pregnancy but their role in decreasing VTE in pregnancy is yet to be defined.

Pharmacologic Preventative Measures

Please see the previous section on heparins for prophylactic dosing and drug monitoring.

• Long-term impact on quality of life

• Postthrombotic syndrome (PTS) is a sequelae of acute DVT in which the affected limb may develop edema, pain, skin discoloration, and ulcers.⁴³ A large cross-sectional case-control study revealed that general long-term quality of life and subjective well-being 3 to 16 years after a pregnancy-related VTE without PTS were not significantly different from a reference population, but that women who developed PTS after DVT seemed to have poorer quality of life and impaired general health.⁴⁴

Summary

• Clinical signs and symptoms of DVT and PE are frequently unreliable, and diagnostic imaging should be employed. For DVT, compression Doppler ultrasonography is standard. For PE, a combination of V/Q scanning, spiral CT, or lower extremity compression Doppler ultrasonography can be utilized, depending on clinical suspicion.

• Treatment with heparin and LMWH is standard during the antepartum period, should be prompt, and should continue for a total of 12 to 20 weeks of therapeutic anticoagulation.

• Prophylaxis during the antepartum and postpartum periods should be considered in patients without VTE who are at risk for developing VTE.

• Screening for inheritable and acquired thrombophilias may be performed in patients with a personal history of VTE that was associated with a nonrecurrent risk factor, or a first-degree relative with known high-risk thrombophilia or VTE before age 50 years in the absence of other risk factors. Routine screening for inheritable thrombophilias is not recommended in other situations, such as a history of adverse pregnancy outcomes. Screening for antiphospholipid antibodies may be appropriate in patients with an obstetric history.